Conditions: Renal Cell Cancer
Keywords: Cancer, renal cell cancer, kidney disease, kidney neoplasms, axitinib
Allocation: NA | Intervention model: 
Enrollment: 55
Healthy volunteers: no

Brief summary:
This is a Phase 1b, open-label, multi-center, multiple-dose trial designed to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of avelumab (MSB0010718C) in combination with axitinib (AG-013736). Once the MTD of avelumab administered in combination with axitinib is estimated (dose finding portion), the dose expansion phase will be opened to further characterize the combination in term of safety profile, anti tumor activity, pharmacokinetics, pharmacodynamics and biomarker modulation.

Detailed description:

Arms:
arm 1: To test the maximum tolerated dose of avelumab (MSB0010718C) in combination with axitinib (AG-013736)

Interventions: intervention 1: Avelumab (MSB0010718C) intervention 2: Axitinib (AG-013736)
Intervention descriptions: intervention 1: Avelumab with two dose levels: 10 mg/kg IV and 5 mg/kg IV every two weeks to find the maximum tolerated dose in combination with axitinib and continue treatment in a dose expansion. intervention 2: Axitinib with two dose levels: 5 mg and 3 mg oral BID to find the maximum tolerated dose in combination with avelumab and continue treatment in a dose expansion.

Protocol document:
Prot_001.pdf: 
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CLINICAL PROTOCOL
RENAL CELL CARCINONA −JAVELIN RENAL 100
A PHASE 1B, OPEN-LABEL, DOSE-FINDING STUDY TO EVALUATE SAFETY, 
PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB 
(MSB0010718C) IN COMBINATION WITH AXITINIB (AG-013736) IN PATIENTS 
WITH PREVIOUSLY UNTREATED ADVANCED RENAL CELL CANCER
Compounds:
MSB0010718C, AG-013736
Compound Names:
Avelumab, Axitinib
US IND Numbers:
European Clinical Trials Database 
(EudraCT) Number :
2015-001137-25
Protocol Number:
B9991002
Phase:
1b
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Document History
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL SUMMARY
Background and Rationale:
Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes about 3% of 
all malignant tumors in adults.1 RCC is often first detected at an advanced stage, with 
25-30% of patients having metastatic disease at diagnosis.  Until 2005, interferon-alpha 
(IFN-α) and high-dose interleukin (IL)-2 therapies were the standards of care for patients 
with advanced RCC (aRCC), albeit with modest efficacy. Since then, development and 
approval of multiple vascular endothelial growth factor (VEGF) pathway and mammalian 
target of rapamycin (mTOR) inhibitors have significantly improved the outcomes of aRCC 
patients.  These agents include the VEGF receptor (VEGFR) tyrosine kinase inhibitors 
(TKIs) sunitinib, pazopanib, axitinib and sorafenib; the mTOR inhibitors temsirolimus and 
everolimus; and the anti-VEGF monoclonal antibody bevacizumab.  However, durable and 
complete responses in aRCC patients are uncommon; the majority of patients will eventually 
develop resistance, exhibit disease progression while on therapy, and succumb to death due 
to metastatic disease.  Response rates for previously treated aRCC patients are in the 
15-25% range, and median survival after diagnosis is under 1 year.1
There is a strong rationale for considering immunotherapy in aRCC patients.  Cytokine-based 
immunotherapy, especially high-dose IL-2, exhibited durable responses in some aRCC 
patients.  There are anecdotal reports of spontaneous remissions in aRCC patients with 
evidence of antigen-specific lymphocyte infiltration in tumor tissues.16 These reports have 
generated considerable interest in immunotherapeutic approaches in the treatment of aRCC 
patients, especially with advent of immune checkpoint inhibitors such as anti-programmed 
cell death protein-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) monoclonal 
antibodies in recent years.  Upregulation of PD-1 receptor on tumor-infiltrating lymphocytes 
(TILs), and its ligand PD-L1 on tumors, are associated with more aggressive disease and 
poor prognosis.17,18
Monoclonal antibodies (mAb) that block the PD-1/PD-L1 interaction are novel 
immunotherapeutic approaches for aRCC, which have shown single-agent efficacy in 
patients whose disease has progressed following VEGF pathway inhibitor therapy.19,20
Nivolumab, a high-affinity, fully human anti-PD-1 mAb has shown durable tumor responses 
with objective response rate (ORR) of about 20% and median progression-free survival 
(PFS) of about 16 weeks in heavily pretreated aRCC patients.21,22 When nivolumab was 
combined with a VEGF TKI (sunitinib or pazopanib), it demonstrated more pronounced 
anti-tumor response.  Amin et al reported the data from combinations of sunitinib or 
pazopanib with nivolumab at the American Society of Clinical Oncology (ASCO) 
2014 annual meeting.23 The pazopanib plus nivolumab arm was discontinued due to safety 
issues; however, sunitinib (50 mg, 4 weeks on/2 weeks off) was successfully combined with 
nivolumab 5 mg/kg every 3 weeks (Q3W), and dose expansion was subsequently completed 
in previously untreated aRCC patients.  ORR was 52% (17/33) for nivolumab in combination 
with sunitinib, and 45% (9/20) for nivolumab in combination with pazopanib.  Median 
duration of response (DR) was 37.1 weeks (95% confidence interval [CI]: 18.1-80.0+), and 
median PFS was 48.9 weeks (95% CI: 41.6-66.0) with sunitinib plus nivolumab.  
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MPDL3280A, another human mAb that targets PD-L1, has shown ORR of 13% and stable 
disease (SD) ≥24 weeks in 32% of patients with previously treated RCC when administered 
as a single agent.  Results from the combination of bevacizumab 15 mg/kg Q3W with 
MPDL3280A (20 mg/kg) were presented by McDermott et al at the European Society for 
Medical Oncology (ESMO) 2014 annual meeting.24 Data were limited, but in previously 
untreated aRCC patients, there were 4 of 10 (40%) patients who had partial responses (PRs).  
Five additional patients had a best response of SD, and almost all (9 out of 10) responding 
patients were still on treatment at the time of analysis.  These data, although preliminary, 
demonstrate the benefit of combining an anti-PD-1 or PD-L1 antibody with an anti-VEGF 
pathway agent in aRCC patients.
The combination of nivolumab with ipilimumab, a fully human monoclonal antibody to 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), showed acceptable safety and 
encouraging antitumor activity in patients with metastatic RCC.  Patients were randomized to 
receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg (Arm N3 + I1) or nivolumab 
1 mg/kg + ipilimumab 3 mg/kg (Arm N1 + I3) intravenously (IV) Q3W for 4 doses, then 
nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity.  Confirmed 
objective response (OR) was observed in 9/21 patients in Arm N3 + I1 and in 11/23 patients 
in Arm N1 + I3.  The median PFS was 36.6 weeks and 38.3 weeks in Arm N3 + I1 and in 
Arm N1 + I3, respectively.25
Avelumab (MSB0010718C) is a fully human mAb of the immunoglobulin (Ig) G1 isotype 
that specifically targets and blocks PD-L1.26 Avelumab is the proposed International 
Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody MSB0010718C. 
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial cancer, and 
Hodgkin’s Lymphoma, as a single agent or in combination with chemotherapy, tyrosine 
kinase inhibitors, or other immune-modulating agents. 
As of 05 November 2015, more than 1400 patients have been treated with avelumab.  The 
largest trial is study EMR100070-001, a Phase 1, open-label, multiple ascending-dose 
clinical study aimed to investigate the safety, tolerability, pharmacokinetics (PK), biological 
activity, and clinical activity of avelumab in patients with metastatic or locally advanced 
solid tumors.  Study EMR100070-001 consists of 2 parts, a dose-escalation phase and a 
dose-expansion phase, the latter performed in selected tumor indications.  Avelumab is 
administered intravenously (IV) at the assigned dose level as a 1-hour infusion once every 
2 weeks (Q2W). 
In the Phase 1 study EMR 100070-001, 53 patients have been treated with avelumab doses of 
1.0, 3.0, 10.0, and 20.0 mg/kg administered IV every 2 weeks (Q2W) in the dose escalation 
phase.  In the subsequent dose expansion phase, 1300 patients in the pooled malignancies 
with different tumor types have been treated at a dose of 10 mg/kg Q2W. 
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Preliminary Safety Data of Avelumab as Monotherapy in aRCC
In the aRCC cohort of the Phase 1 study EMR 100070-001, 18 patients with aRCC in the 
second-line and beyond treatment setting received avelumab IV Q2W at the dose of 
10 mg/kg (see Section 1.2.2.1).9 Current data indicate that the safety profile of the aRCC 
cohort is consistent with that of the overall population of study EMR 100070-001.  Since 
December 2015, an additional cohort of approximately 30 patients with aRCC in the first-line 
treatment setting has started enrollment within the EMR 100070-001 study.
Axitinib is an oral, potent and selective inhibitor of VEGFRs 1, 2, and 3 approved 
multinationally for the treatment of aRCC after failure of one prior systemic therapy (actual 
indication varies according to region/country).10 The antitumor activity of single-agent 
axitinib 5 mg twice daily (BID) in previously untreated patients with clear cell aRCC was 
assessed against sorafenib in a randomized, open-label, Phase 3 trial.  Although the study did 
not demonstrate a statistically significant difference in PFS, axitinib was associated with a 
longer median PFS (mPFS) time (mPFS of 10.1 months [95% CI: 7.2,12.1] with axitinib vs. 
6.5 months [95% CI: 4.7, 8.3] with sorafenib, stratified hazard ratio (HR) 0.77 [95% CI: 
0.56, 1.05]).13 The mPFS observed with axitinib in this study was similar to those 
demonstrated earlier in Phase 3 clinical trials of other approved VEGFR TKIs in the first-line 
treatment of aRCC patients.  Toxicities in this clinical trial were generally tolerable and 
manageable, and similar to those observed in clinical trials with axitinib in pre-treated aRCC 
patients.13
The most common adverse events (>20% of patients) reported among 1445 cancer patients 
receiving single-agent axitinib (regardless of causality) included diarrhea, hypertension, 
decreased appetite, nausea, weight decreased, dysphonia, palmar plantar erythrodysaesthesia 
syndrome, hypothyroidism, and proteinuria.  The most frequent Grade ≥3 adverse events 
were hypertension, fatigue, and diarrhea.11 The risk of hepatotoxicity was low in patients 
with aRCC with axitinib, with an overall rate of Grade 3/4 alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) increased <0.6% for each.27 The incidence of 
hematological toxicity was also low for axitinib in this patient population (eg, 
Grade 3/4 platelet count decreased and neutrophil count decreased 0.3% for each).27
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Based on the observations above, it is proposed that the addition of the PD-L1 inhibitor 
avelumab to the VEGF pathway inhibitor axitinib may provide additional clinical benefit 
compared to treatment with an anti-VEGFR TKI alone without unacceptable toxicity in 
previously untreated aRCC patients leveraging their complementary mechanisms of action.  
The combination of avelumab with axitinib has not been previously studied in patients; 
therefore, there are currently no safety data from this combination.  There are no expected 
overlapping toxicities between avelumab and axitinib, except for fatigue, nausea/diarrhea, 
and hypothyroidism, which are usually low-grade events easily manageable following the 
adverse event management guidelines implemented in the study protocol.  Additional safety 
concerns are not expected from combining avelumab with axitinib given their distinct 
mechanisms of action and toxicity profiles.
Overall, the observed benefit-risk profile supports the further investigation of avelumab in 
combination with axitinib in the patient population chosen for this study.
This clinical study, therefore, is designed to determine the recommended doses as well as the 
preliminary safety, pharmacokinetics (PK), and efficacy of this combination regimen needed 
to support a subsequent randomized clinical trial of avelumab in combination with axitinib 
versus VEGFR TKI in the first-line aRCC treatment setting.
Study Objectives:
Primary Objective
•
To assess the safety and tolerability of avelumab in combination with axitinib in 
patients with previously untreated advanced RCC in order to estimate the Maximum 
Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).
Secondary Objectives
•
To evaluate the overall safety profile of avelumab in combination with axitinib in 
patients with previously untreated advanced RCC.
•
To assess the preliminary anti-tumor activity of avelumab in combination with 
axitinib in patients with previously untreated advanced RCC.
•
To evaluate the overall survival (OS) of avelumab in combination with axitinib in 
patients with previously untreated advanced RCC.
•
To characterize the PK of avelumab and axitinib when administered in combination, 
and to assess the effect of avelumab on the PK of axitinib.
•
To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may 
aid in the identification of a patient subpopulation most likely to benefit from 
treatment with avelumab in combination with axitinib.
•
To assess the immunogenicity of avelumab when combined with axitinib.
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•
 
 
•
 
 
Study Endpoints:
Primary Endpoint
•
DLTs within the first 4 weeks (2 cycles) of treatment with avelumab in combination 
with axitinib.
Secondary Endpoints
•
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 (Appendix 4).
•
Vital signs (blood pressure, pulse rate).
•
Objective Response (OR) and Disease Control (DC) as assessed by Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Appendix 2).
•
Time-to-event endpoints: Duration of Response (DR), Progression-Free Survival 
(PFS), and Time to Tumor Response (TTR).
•
Overall Surival (OS).
•
PK parameters including Cmax, Tmax, AUCtau, and t1/2 as appropriate for axitinib; Ctrough
and Cmax for avelumab.
•
Tumor tissue biomarker status (ie, positive or negative based on, for example, 
PD-L1 expression and/or quantitation of tumor-infiltrating CD8+ T lymphocytes as 
assessed by immunohistochemistry [IHC]).
•
Anti-drug antibodies (ADAs; neutralizing antibodies [Nabs]) of avelumab when 
combined with axitinib.
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•
 
 
 
 
•
 
 
Study Design:
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, PK and pharmacodynamic 
study of avelumab in combination with axitinib in adult patients with previously untreated 
aRCC.  This clinical study will be composed of a Dose Finding Phase and a Dose Expansion 
Phase. 
The Dose Finding Phase will estimate the MTD and RP2D in patients with aRCC with clear 
cell histology who did not receive prior systemic therapy for advanced disease, using the 
modified toxicity probability interval (mTPI) method.29 Dose finding will follow an mTPI 
design, with up to 3 potential dose levels (DL) to be tested:
•
(DL1) avelumab 10 mg/kg Q2W + axitinib 5 mg BID.
•
(DL-1A) avelumab 5 mg/kg Q2W + axitinib 5 mg BID.
•
(DL-1B) avelumab 10 mg/kg Q2W + axitinib 3 mg BID.
DL-1A and DL-1B will be explored concurrently in a randomized fashion only if the MTD is 
exceeded in DL1. 
To understand the extent of any effects of avelumab on axitinib PK, a 7-day lead-in period 
with single-agent axitinib will be included prior to Cycle 1 in all patients in the Dose Finding 
Phase of the study.  Since avelumab has a half-life of 3-5 days, it would not be feasible to run 
a lead-in with avelumab alone to study the PK of avelumab alone.  Therefore, the effect of 
axitinib on avelumab will be evaluated by comparing avelumab trough concentrations at 
steady state in the presence of axitinib with those reported for avelumab alone in prior 
studies. 
The Dose Finding Phase will lead to the identification of an Expansion Test Dose for 
avelumab in combination with axitinib in patients with aRCC who did not receive prior 
systemic therapy for their advanced disease.  The Expansion Test Dose will either be the 
MTD (ie, the highest dose of avelumab and axitinib associated with the occurrence of DLTs 
in <33% of patients) or the RP2D, ie, the highest tested dose that is declared safe and 
tolerable by the investigators and sponsor.  Once the Expansion Test Dose is identified, the 
Dose Expansion Phase will be opened, and avelumab in combination with axitinib will be 
evaluated in up to 20-40 patients with previously untreated aRCC.
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Based on the emerging PK data, and after completion of the dose-finding part of the study 
based on the mTPI method, it may be necessary to enroll up to approximately 8 additional 
patients to further assess the effect of avelumab on the PK of axitinib.  These additional 
patients will undergo the same evaluations and procedures as those described in the Schedule 
of Activities table for the Dose Finding Phase of the study and will be treated concurrently 
with the initiation of the Dose Expansion Phase of the study.  With the exception of the 
mTPI-related assessments leading to determination of MTD, any other assessments or 
procedures described for the Dose Finding Phase will also apply to these additional patients.
Throughout the course of the study, patient safety will be closely monitored by the sponsor's 
study team.  The number of patients to be enrolled in the Dose Finding Phase will depend on 
the observed safety profile, and the number of tested dose levels. 
All patients will be followed for survival until death, end of the study, or patient withdrawal 
of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.  
Patients who do not return to the site should be contacted by telephone every 3 months as an 
alternative.
Study Treatment:
Axitinib will be given orally (PO) twice daily (BID), with or without food, on a continuous 
dosing schedule.  Avelumab will be given as a 1-hour IV infusion Q2W.  All patients will 
continue treatment with study drugs 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 6.4). 
Patients will be monitored closely for toxicity, and in the event of significant toxicity, dosing 
of one or both drugs may be modified.  Specifically, avelumab doses may be omitted or 
permanently discontinued, and axitinib doses may be delayed, reduced or permanently 
discontinued, as per Section 5.3.5.  Based on the known safety profile of axitinib, blood 
pressure as well as thyroid function will be monitored throughout the treatment period.  
Axitinib treatment may be adjusted by dosing interruption with or without dose reduction 
(Section 5.3.5.3).  Avelumab treatment modification for drug-related toxicities, including 
immune-related adverse events (irAEs) and infusion-related adverse events (AEs) is 
described in Section 5.3.5.
In the Dose Finding Phase, intrapatient axitinib dose escalation is not permitted, except for 
patients treated at DL-1B.  In these patients, after the completion of the primary DLT 
observation period, intrapatient axitinib dose escalation may occur according to the criteria 
described in Section 5.3.5.1.  In the Dose Expansion Phase, intrapatient axitinib dose 
escalation may occur if the intrapatient escalation criteria are met (see Section 5.3.5.1).
Patients who stop one of the two study drugs (avelumab or axitinib) for reasons other than 
confirmed disease progression may continue on single-agent treatment with the other drug 
until disease progression (RECIST v.1.1), patient refusal, patient lost to follow up, 
unacceptable toxicity, or the study is prematurely terminated by the sponsor, whichever 
comes first.  Patients who are still deriving clinical benefit following continued treatment for 
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more than 2 years will be provided an option for continued study treatment (eg, a rollover 
study).
Patients who stop avelumab after initial clinical benefit while on treatment and then 
experience radiologic disease progression thereafter will be eligible for re-treatment with 
avelumab at the discretion of the investigator and after discussion with the sponsor’s medical 
monitor if 1) no cancer treatment was administered other than axitinib since the last dose of 
avelumab, 2) the patient does not meet the safety withdrawal criteria, and 3) the trial is still 
open.  Patients will resume avelumab therapy at the same dose and schedule applied at the 
time of discontinuation. 
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:
Dose finding will follow the mTPI method,29 using doses of avelumab and axitinib.
The escalation/de-escalation rules will follow the mTPI method. Briefly, the mTPI method 
relies upon a statistical probability algorithm, calculated using all patients treated in prior and 
current cohorts at the same dose level) to determine when future cohorts should involve dose 
escalation, no change in dose, or dose de-escalation.
Rules for dose-finding, using the mTPI method, include the following:
•
The target enrollment cohort size is 3 patients.  However, patients may be enrolled in 
cohort sizes of 3-4 depending on the number of potential patients identified at 
participating sites.  The patients treated at each dose level may initiate dosing 
simultaneously.  If the first 2 patients experience a DLT prior to enrollment of the 
third one, the dose level will be deemed intolerable and the dose level will be 
de-escalated.
•
The next cohort may be enrolled when all patients at the current dose cohort have 
been evaluated for 4 weeks (ie, the first 2 treatment cycles), or experience a DLT, 
whichever comes first.
•
If a patient withdraws from study treatment before receiving at least 75% of the 
planned first 2 cycles of axitinib or 2 infusions of avelumab for reasons other than 
study drug-related toxicity, another patient will be enrolled to replace that patient at 
the current dose level.
•
The dose-finding component of the trial is completed when 6 DLT-evaluable patients 
have been treated at the highest dose associated with DLT rate <0.33.  It is estimated 
that approximately 15 DLT-evaluable patients will need to be enrolled to reach 
6 DLT-evaluable patients at the estimated MTD.
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•
The RP2D will be confirmed in the Dose Expansion Phase, taking into account the 
MTD determination from the Dose Finding Phase, and other factors related to safety, 
efficacy, PK, and pharmacodynamics (PD) involving all available data from test 
cohorts. 
Sample Size Determination
The sample size planned for the dose finding phase arises from logistic feasibility and is not 
entirely driven by statistical considerations.  Due to the dynamic nature of the dose allocation 
procedure and unknown safety profile of the combination, the sample size of the interval 
design cannot be determined in advance.  It is expected that approximately 15 DLT-evaluable 
patients will be required for the dose finding phase. 
Up to approximately 40 patients will be included in the dose expansion phase of the study for 
each MTD dose level cohort expanded.  A sample size of 40 patients will provide at least 
90% probability to observe at least 1 AE if the true incidence of the AE in the population is 
≥6%. 
Dose-Finding Criteria
Dose finding will follow the mTPI design, using doses of avelumab and axitinib as shown 
below. 
Dose Levels in the Dose Finding Phase
Dose Level
Avelumab
Axitinib
1 (Starting Dose Level)
10 mg/kg IV Q2W
5 mg oral BID
-1A
5 mg/kg IV Q2W
5 mg oral BID
-1B
10 mg/kg IV Q2W
3 mg oral BID
BID: twice daily; Q2W: every 2 weeks
Alternative doses, schedule(s), and PK time points may be reconsidered during the study 
based on the emerging safety and PK data.
Based on the emerging PK data and after the completion of the dose-finding part of the study 
based on mTPI method, it may be necessary to enroll up to approximately 8 additional 
patients to further assess the effect of avelumab on the PK of axitinib.  These additional 
patients will undergo the same evaluations and procedures as those described in the Schedule 
of Activities for the Dose Finding Phase of the study and will be treated concurrently with 
the initiation of the Dose Expansion Phase. 
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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 in the 
Schedule of Activities table in order to conduct evaluations or assessments required to 
protect the well-being of the patient.
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SCHEDULE OF ACTIVITIES for SCREENING and STUDY TREATMENT Periods
Patients participating in Dose Finding Phase and up to 8 additional patients enrolled for further PK assessment
Visit Identifiers1
Screening
Lead-In
PK Period
(Single-Agent Axitinib)2
Study Treatment
(1 cycle = 14 days)
Cycle 1
Cycle 2
Cycles ≥3 
(until 
amend. #4 
approval)
Cycles ≥3
(after 
amend. #4 
approval)
≤28 Days Prior 
to Enrollment
Day 1
Day 7
Day 1
Day 8
(±1 day)
Day 1
(±3 days)
Day 8
(±1 day)
Day 1
(±3 days)
Day 1
(±3 days)
Clinical Assessments
Informed Consent3
X
Medical/Oncological History4
X
Baseline Signs/Symptoms5
X
Physical Examination6
X
X
X
X
X
X 
X (Q6W)
Contraception Check7
X
X
X
X
X 
X (Q6W)
ECOG Performance Status
X
X
X
X
X
X
X 
X (Q6W)
Vital Signs8
X
X
X
X
X
X
X
X
X
(Q6W)
Home Blood Pressure Monitoring9
X
Laboratory Studies
Hematology10
X
(X)
X
X
X
X
X
X
(Q6W)
Blood Chemistry10
X11
(X)11
X11
X11
X11
X11
X11
X11
(Q6W)
Coagulation10
X
(X)
X
X
X
X
X
If clinically 
indicated
Thyroid Function Tests12
X
(X)
Cycles 4,7, 13, then 
Q12W
ACTH13
X
X (Cycle 6, then Q12W)
HBV, HCV Tests
X
If clinically indicated
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Visit Identifiers1
Screening
Lead-In
PK Period
(Single-Agent Axitinib)2
Study Treatment
(1 cycle = 14 days)
Cycle 1
Cycle 2
Cycles ≥3 
(until 
amend. #4 
approval)
Cycles ≥3
(after 
amend. #4 
approval)
≤28 Days Prior 
to Enrollment
Day 1
Day 7
Day 1
Day 8
(±1 day)
Day 1
(±3 days)
Day 8
(±1 day)
Day 1
(±3 days)
Day 1
(±3 days)
Serum/Urine Pregnancy Test14
X
X
X
X
X
Urinalysis15
X
X
X (Cycle 3, 
then every 
odd cycle)
X (Q12W)
12-Lead ECG16
X
X
X
X (Cycle 4)
Disease Assessments
Tumor Assessments (including 
scans)17
X
Q6W after Cycle 1 Day 1 up to 1 year after the first dose;
Q12W thereafter
Other Clinical Assessments
Follow-up for Axitinib Dosing 
Compliance18
X18
(D5 ±3 days)
X18
(D5 ±3 days)
X18
(D5 ±3 days)
Adverse Events19
X
Concomitant 
Medications/Treatments20
X
(X)
X
X
X
X
X
X 
X 
Enrollment by Study Treatment21
Avelumab22
X21
X21
X21
Axitinib22
X
Other Samplings
Pharmacokinetics23
X
X
X
X
X (Cycles 3, 4, 6, 8, then 
Q12W, until cycle 50)
Mandatory Archival FFPE Tumor 
Tissue25
X
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Visit Identifiers1
Screening
Lead-In
PK Period
(Single-Agent Axitinib)2
Study Treatment
(1 cycle = 14 days)
Cycle 1
Cycle 2
Cycles ≥3 
(until 
amend. #4 
approval)
Cycles ≥3
(after 
amend. #4 
approval)
≤28 Days Prior 
to Enrollment
Day 1
Day 7
Day 1
Day 8
(±1 day)
Day 1
(±3 days)
Day 8
(±1 day)
Day 1
(±3 days)
Day 1
(±3 days)
Mandatory Recent or De Novo 
FFPE Tumor Tissue Block26
X
Anti-Avelumab Antibodies and 
Neutralizing Antibodies27
X
X
X (Cycles, 3, 4, 6, 8,
then Q12W, until cycle 
50)
ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed and 
paraffin-embedded; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetics; Q6W = every 6 weeks; Q12W = every 12 weeks.
Footnotes for Schedule of Activities for SCREENING and STUDY TREATMENT Periods
Patients participating in Dose Finding Phase and up to 8 additional patients enrolled for further pharmacokinetic (PK) assessment
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.
Lead-In PK Period: All patients in the Dose Finding Phase and up to approximately 8 additional patients enrolled for further PK assessment.
3.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure.
4.
Medical/Oncological History: To include information on prior systemic adjuvant or neoadjuvant therapy regimens, surgery, and radiation therapy.
5.
Baseline Signs/Symptoms: To be recorded predose on Lead-in Day 1.  Patients will be asked about any signs and symptoms experienced within the 
14 days prior to study enrollment.
6.
Physical Examination: Includes an examination of major body systems and weight (height included at Screening only).
7.
Contraception Check: Male patients with female partner of childbearing potential and female patients who are of childbearing potential will need to affirm 
that they meet the criteria for correct use of 1 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient 
the need to use 1 highly effective contraception method consistently and correctly and document such conversation in the patient’s chart.  In addition, the 
investigator or his or her designee will instruct the patient to call immediately if the selected contraception method is discontinued, or if pregnancy is known 
or suspected in the patient or the patient’s partner. 
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8.
Vital Signs: Vital signs to include: blood pressure, pulse rate.  Blood pressure and pulse rate should be taken with the patient in the seated position after the 
patient has been sitting quietly for at least 5 minutes.  Two blood pressure and pulse rate readings will be taken at least 1 hour apart at each clinic visit. 
After amendment #4 approval, required every 6 weeks.
9.
Home Blood Pressure Monitoring: All patients will receive home blood pressure monitoring devices and blood pressure will be monitored at home.  
While on axitinib (as a single agent during the Lead-in PK period and in up to 8 patients enrolled for further PK assessment, or when combined with 
avelumab), patients will monitor their blood pressure at least twice daily (before taking each dose of axitinib), and blood pressure should be recorded in a 
patient diary.  Patients should be instructed to contact the site immediately for guidance if their systolic blood pressure rises above 150 mm Hg, diastolic 
blood pressure rises above 100 mm Hg, or if they develop symptoms perceived to be related to elevated blood pressure (eg, headache, visual disturbances), 
although a different blood pressure threshold for contacting the site may be used according to the investigator’s clinical judgment (see Section 5.3.5.2). 
10. Hematology, Blood Chemistry, and Coagulation: Required tests are listed in Table 8.  May also be performed when clinically indicated.
11. Blood Chemistry: Full chemistry panel (required tests are listed in Table 8) is required as follows: at Screening, Day 1 of Lead-in PK Period (if not 
performed in prior 3 days), Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 7 Day 1, then every 6 weeks thereafter.  Core chemistry panel (required 
tests are listed in Table 8) is required as follows: on Cycle 1 Day 8, Cycle 2 Day 8, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 8 Day 1, then every 
2 weeks thereafter.  If full and core chemistry panels are scheduled at the same visit, only the full chemistry panel will be performed. After amendment #4 
approval, required every 6 weeks. Required tests are listed in Table 8.-
12. Thyroid Function Tests: free T4 and TSH will be performed at Screening, Lead-in Day 1 (only if not performed in prior 3 days), Cycle 4 Day 1, Cycle 
7 Day 1, and Cycle 13 Day 1, and then Q12W thereafter.  Additional tests should be performed when clinically indicated.  Hypothyroidism should be 
treated per standard medical practice to maintain euthyroid state.  See Table 8.
13. ACTH: ACTH tests will be performed at Screening, Cycle 6 Day 1, then Q12W thereafter.  Additional tests should be performed when clinically indicated.
See Table 8.
14. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed at up to three occasions prior to starting combination study treatment: once at the start of screening, once at Lead-in Day 1 immediately before 
axitinib administration, and at the Cycle 1 Day 1 visit immediately before the administration of avelumab in combination with axitinib.  Additional 
pregnancy tests (serum or urine) will also be routinely repeated at every treatment cycle during the active treatment period and additionally whenever one 
menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by 
Institutional Review Board (IRB)/Ethics Committees (ECs) or if required by local regulations (see Section 7.1.1). 
15. Urinalysis: Required at Screening, at Cycle 1 Day 1 and then at Day 1 of every odd cycle and at the End of Treatment.  After amendment #4 approval, 
required every 12 weeks. If protein ≥2+ by semiquantitative method (eg, urine dipstick), protein will have to be quantified by 24-hour urine collection. To 
be performed as clinically indicated at other time points.  See Table 8. 
16. 12-Lead Electrocardiogram (ECG): See Section 7.1.5 for details.  ECG measurements will be obtained at Screening, Lead-in Day 7, Cycle 1 Day 1, and 
Cycle 4 Day 1.  Clinically significant abnormal findings in baseline ECGs will be recorded as medical history.  At each time point, 3 consecutive 12-lead 
ECGs (triplicates) will be performed approximately 2 minutes apart to determine mean QTc (average of triplicates).  Triplicate ECGs at Lead-in Day 7 and 
Cycle 4 Day 1 will be collected pre-dose and at 2 hours post-axitinib dosing.  Triplicate ECGs at Cycle 1 Day 1 will be prior to avelumab infusion and 
within 30 minutes post end of -infusion.  When coinciding with blood samples draws for PK, ECG assessment should be performed prior to blood sample 
collection, such that the blood sample is collected at the nominal time.  If patient experiences a cardiac or neurologic adverse event (AE; eg, syncope, 
dizziness, seizures, or stroke), triplicate ECGs should be obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be 
re-evaluated by a qualified person at the institution for confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be performed as 
clinically indicated.  
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17. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen, and pelvis computed
tomography (CT) or magnetic resonance imaging (MRI) scans; brain CT or MRI scans (required at baseline and when suspected brain metastasis) and bone 
scans or 18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET, required at baseline then every 12 weeks only if bone metastases are present 
at baseline).  Otherwise, bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of complete response for 
patients who have bone metastases.  See Section 7.6.  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.  Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, at 6 weeks after the first dose of therapy (ie, 
Cycle 1 Day 1), then every 6 weeks up to 1 year from the first dose of therapy and every 12 weeks thereafter until confirmed disease progression regardless 
of initiation of subsequent anti-cancer therapy.  Assessments will be performed according to calendar days, regardless of treatment delays or interruptions.  
Further imaging assessments may be performed at any time if clinically indicated (eg, suspected progressive disease [PD], symptomatic deterioration, etc.).  
Complete response (CR) and partial response (PR) must be confirmed with repeat imaging performed at least 4 weeks after initial documentation of 
response.  If radiologic imaging shows PD, then tumor assessment should be repeated after at least 4 weeks to confirm PD unless clinical deterioration 
occurs.  Assessment of response will be made using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
 
.  See Section 7.6 for additional information.
18. Follow-up for Axitinib Dosing Compliance: Follow-up by telephone will be done to confirm patient understanding and compliance with dosing 
instructions on Cycle 1 Day 5.  Axitinib dosing compliance will also be assessed following any dose modification.  If needed, patients will be retrained.
19. Adverse Events: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for 
Advers Events (CTCAE) version 4.03. After amendment #4 approval, patients receiving axitinib single agent will visit the site every 6 weeks.  Between site 
visits, AEs collection will be performed every 2 weeks by telephone call (eg, nurse) in a standardized form, unless the patient is visiting the site for other 
reasons.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving study treatment, through and including 90 calendar days after the last dose of study treatment.  SAEs occuring to a patient after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to the study drug are to be reported to the sponsor. 
AEs (serious and non serious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of study treatment 
through and including 90 calendar days after the last dose of study treatment.  If a patient begins a new anticancer therapy, the AE reporting period for 
nonserious AEs ends at the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last dose of study 
drug, irrespective of any intervening treatment.
20. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 90 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions). After amendment #4 approval, patients receiving axitinib single agent will visit the site every 6 weeks.  Between site visits, concomitant 
medication collection will be performed every 2 weeks by telephone call (eg, nurse) in a standardized form, unless the patient is visiting the site for other 
reasons.
21. Enrollment: Patient number and dose level allocation will be operated by the sponsor (see Section 5.1).  Required information: site and patient identifiers 
and demographic information.  Study treatment should begin within 3 days after enrollment.  
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22. Study Treatment: Axitinib will be given orally (PO) twice daily (BID) on a continuous schedule.  Avelumab will be given as a 1-hour intravenous (IV) 
infusion every 2 weeks (see Section 5).  Patients who develop disease progression on study treatment but who are otherwise continuing to derive clinical 
benefit from study treatment will be eligible to continue with single agent axitinib, avelumab, or avelumab combined with axitinib, provided that the 
treating physician has determined that the benefit/risk for doing so is favorable. 
23. Pharmacokinetics: Samples will be collected at the time points indicated in the Schedule for Pharmacokinetic Sample Collection Table.  Pharmacokinetic 
samples for avelumab will be collected from all patients in the study.  Pharmacokinetic samples for axitinib will be collected from all patients in the Dose 
Finding Phase and up to approximately 8 additional patients to further evaluate the effect of avelumab on the PK of axitinib.  Details are outlined in Section 
7.2.  
25. Mandatory Archival FFPE Tumor Tissue:  An archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from primary diagnosis specimen 
must be provided for all patients enrolled in the study and submitted to the Central Laboratory prior to enrollment. 
 
 
  Cytology samples 
(eg FFPE cell pellet from Fine Needle Aspiration biopsy) are not acceptable.  See Section 6.1.1 and Section 7.4.1.
26. Mandatory Recent FFPE Tumor Tissue Block: A baseline de novo tumor biopsy (biopsied tumor lesion should not be a RECIST target lesion) must be 
obtained for all patients enrolled in the study.  
 
 
  For baseline de novo biopsy, tumor tissue from 
cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted.  The de novo biopsy(ies) 
should be formalin-fixed and paraffin-embedded as per routine (see Study Manual), and the resulting FFPE tissue block(s) should be submitted to the 
Central Laboratory.  
 See 
Section 6.1.1 and Section 7.4.1.
27. 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, 2, 3, 4, 6 and 8.  Subsequently, testing should be performed approximately every 12 weeks until cycle 50.
All samples should be drawn within 2 hours before start of avelumab infusion.  Also see the Schedule for Pharmacokinetic Sample Collection Table.  
Additional samples for anti-avelumab antibodies (and simultaneous PK draws for measurement of avelumab) will be collected at the Day 30 Follow-up visit 
after the end of avelumab treatment.  All the samples that are positive for ADA may also undergo characterization for Nab.  See Section 7.3.
(X) = only if activity not performed in prior 3 days.
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SCHEDULE OF ACTIVITIES for END OF TREATMENT and SHORT-/LONG-TERM FOLLOW-UP Periods
Patients participating in Dose Finding Phase and up to 8 additional patients enrolled for further PK assessment
Visit Identifiers1
End of 
Treatment/Withdrawal2
Post-Treatment Follow-Up
Short-Term Follow-Up
(Day 30, Day 60, Day 90 [±3 days])3
Long-Term Follow-Up
(±14 days)
Clinical Assessments
Physical Examination4
X
X
Contraception Check5
X
X (only at Fu Day 30)
ECOG Performance Status
X
X
X
Vital Signs6
X
X
Laboratory Studies
Hematology7
X
X
Blood Chemistry7
X
X
Coagulation7
If clinically indicated
Thyroid Function Tests8
X
X
ACTH9
X
X
HBV, HCV Tests
If clinically indicated
Serum/Urine Pregnancy Test10
X
X
Urinalysis11
X
12-Lead ECG12
X
Disease Assessments
Tumor Assessments (including scans)13
Q6W after Cycle 1 Day 1 up to 1 year after the first dose;
Q12W thereafter 
Survival14
X
X
Other Clinical Assessments
Adverse Events15
X
Concomitant Medications/Treatments16
X
X
New Anticancer Therapy
X
X
X
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Visit Identifiers1
End of 
Treatment/Withdrawal2
Post-Treatment Follow-Up
Short-Term Follow-Up
(Day 30, Day 60, Day 90 [±3 days])3
Long-Term Follow-Up
(±14 days)
Other Samplings
Pharmacokinetics17
See SoA for PK
De Novo FFPE Tumor Tissue Block19
X
Anti-Avelumab Antibodies and Neutralizing 
Antibodies20
See SoA for PK
ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed and 
paraffin-embedded; Fu= follow-up; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetics; Q12W = every 12 weeks.
Footnotes for Schedule of Activities for END OF TREATMENT and SHORT-/LONG-TERM FOLLOW-UP Periods
Patients participating in Dose Finding Phase and up to 8 additional patients enrolled for further PK assessment
1.
Visit Identifiers:  Acceptable time windows for performing each assessment are described in the column headers.  
2.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if 
performed within the prior 6 weeks.
3.
Short- and Long-Term Follow-up: All patients will be followed for safety every 30 days (±3 days) through 90 days after the last dose of investigational 
product or until the time of initiation of new anticancer treatment. 
Beyond the 90 days until the end of the study, all patients will be followed every 3 months (±14 days) for survival, Eastern Cooperative Oncology Group 
(ECOG) Performance Status (PS), and new systemic anticancer treatment within the long-term follow-up.  
4.
Physical Examination: Includes an examination of major body systems and weight (height included at Screening only).
5.
Contraception Check: Male patients with female partner of childbearing potential and female patients who are of childbearing potential will need to affirm 
that they meet the criteria for correct use of1 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient 
the need to use 1 highly effective contraception method consistently and correctly and document such conversation in the patient’s chart.  In addition, the 
investigator or his or her designee will instruct the patient to call immediately if the selected contraception method is discontinued, or if pregnancy is known 
or suspected in the patient or the patient’s partner. 
6.
Vital Signs: Vital signs to include: blood pressure, pulse rate. Blood pressure and pulse rate should be taken with the patient in the seated position after the 
patient has been sitting quietly for at least 5 minutes.  Two blood pressure and pulse rate readings will be taken at least 1 hour apart at each clinic visit. 
7.
Hematology, Blood Chemistry (Full Chemistry), and Coagulation: Required tests are listed in Table 8.  May also be performed when clinically 
indicated. 
8.
Thyroid Function Tests: free T4 and TSH will be performed at End of Treatment/Withdrawal and at the 30, 60, and 90 days Follow-up visits.  Additional 
tests should be performed when clinically indicated.  Hypothyroidism should be treated per standard medical practice to maintain euthyroid state.  See 
Table 8.
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9.
ACTH: ACTH tests will be performed at End of Treatment/Withdrawal and at the 30, 60, and 90 days Follow-up visits.  Additional tests should be 
performed when clinically indicated.  See Table 8.
10. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a pregnancy test (serum or urine) will be performed at the End of 
Treatment/Withdrawal visit and at the 30, 60, and 90 days Follow-up visits, and additionally whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by Institutional Review Board (IRB)/(Ethics Committees 
(ECs) or if required by local regulations (see Section 7.1.1). 
11. Urinalysis: Required only at End of Treatment. To be performed as clinically indicated at other time points.  See Table 8. 
12. 12-Lead Electrocardiogram (ECG): See Section 7.1.5 for details.  ECG measurements will be obtained at End of Treatment/Withdrawal.  Three 
consecutive 12-lead ECGs (triplicates) will be performed approximately 2 minutes apart to determine mean QTc (average of triplicates).  When coinciding 
with blood samples draws for PK, ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the 
nominal time.  If patient experiences a cardiac or neurologic adverse event (AE; eg, syncope, dizziness, seizures, or stroke), triplicate ECGs should be 
obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for 
confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
13. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen, and pelvis computed 
tomography (CT) or magnetic resonance imaging (MRI) scans; brain CT or MRI scans (required at baseline and when suspected brain metastasis) and bone 
scans or 18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET, required at baseline then every 12 weeks only if bone metastases are present 
at baseline).  Otherwise, bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of complete response for 
patients who have bone metastases.  See Section 7.6.  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.  Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, at 6 weeks after the first dose of therapy (ie, 
Cycle 1 Day 1), then every 6 weeks up to 1 year from the first dose of therapy and every 12 weeks thereafter until confirmed disease progression regardless 
of initiation of subsequent anti-cancer therapy.  Assessments will be performed according to calendar days, regardless of treatment delays or interruptions.  
Further imaging assessments may be performed at any time if clinically indicated (eg, suspected progressive disease [PD], symptomatic deterioration, etc.).  
Complete response (CR) and partial response (PR) must be confirmed with repeat imaging performed at least 4 weeks after initial documentation of 
response.  If radiologic imaging shows PD, then tumor assessment should be repeated after at least 4 weeks to confirm PD, unless clinical deterioration 
occurs.  Assessment of response will be made using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
 
).  See Section 7.6 for additional information.
14. Survival: All patients will be followed for survival and subsequent anticancer therapies every 3 months (±14 days) until death, end of the study or patient 
withdrawal of consent, whichever comes first.  For patients refusing to go back to the site a telephone contact is acceptable.
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15. Adverse Events: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria 
for Advers Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins 
from the time that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving study treatment, through and including 90 calendar days after the last administration of the study treatment.  SAEs 
occuring to a patient after the active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, 
all SAEs that the investigator believes have at least a reasonable possibility of being related to the study drug are to be reported to the sponsor. 
AEs (serious and non serious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of study treatment 
through and including 90 calendar days after the last of study treatment.  If a patient begins a new anticancer therapy, the AE reporting period for 
nonserious AEs ends at the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last dose of 
study drug, irrespective of any intervening treatment.
16. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and 
up to 90 days after the last dose of study treatment. All concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions). 
17. Pharmacokinetics: Samples will be collected at the time points indicated in the Schedule for Pharmacokinetic Sample Collection Table.  Pharmacokinetic 
samples for avelumab will be collected from all patients in the study.  Pharmacokinetic samples for axitinib will be collected from all patients in the Dose 
Finding Phase and up to approximately 8 additional patients to further evaluate the effect of avelumab on the PK of axitinib.  Details are outlined in 
Section 7.2.  
19. De Novo FFPE Tumor Tissue Block: A de novo (ie, fresh biopsy) tumor sample should be collected at the time of discontinuation of either drugs and at 
the End of Treatment/Withdrawal, unless clinically contraindicated.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell 
pellet material), is not adequate and should not be submitted.  The de novo biopsy(ies) should be formalin-fixed and paraffin-embedded as per routine (see 
Study Manual), 
 (see Section 6.1.1 for details) should be submitted to the 
Central Laboratory.  See Section 6.1.1 and Section 7.4.1.
20. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): One blood sample (3.5 mL) for anti-avelumab 
antibodies (and simultaneous PK draws for measurement of avelumab) will be collected at the Day 30 Follow-up visit after the end of avelumab treatment.  
All the samples that are positive for ADA may also undergo characterization for Nab.  Also see the Schedule for Pharmacokinetic Sample Collection
Table. See Section 7.3.
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SCHEDULE OF ACTIVITIES for SCREENING and STUDY TREATMENT Periods 
Patients participating in Dose Expansion Phase
Visit Identifiers1
Screening
Study Treatment
(1 cycle = 14 days)
Cycle 1
Cycles ≥2
(until 
amend. #4 
approval)
Cycles ≥2
(after 
amend. #4 
approval)
≤28 Days Prior to Enrollment 
or Randomization
Day 1
Day 8
(±1 day)
Day 1
(±3 days)
Day 1
(±3 days)
Clinical Assessments
Informed Consent2
X
Medical/Oncological History3
X
Baseline Signs/Symptoms4
X
Physical Examination5
X
X
X
X
X (Q6W)
Contraception Check6
X
X
X
X (Q6W)
ECOG Performance Status
X
X
X
X
X (Q6W)
Vital Signs7
X
X
X
X
X (Q6W)
Home Blood Pressure Monitoring8
X
Laboratory Studies
Hematology9
X
X
X
X
X (Q6W)
Blood Chemistry9
X
X10
X10
X10
X10 (Q6W)
Coagulation9
X
X
X
X
If clinically 
indicated
Thyroid Function Tests11
X
X (Cycles 4, 7, 13 then 
Q12W)  
ACTH12
X
X (Cycle 6, then Q12W`) 
HBV, HCV Tests
X
If clinically indicated
Serum/Urine Pregnancy Test13
X
X
X
Urinalysis14
X
X
X (Cycle 
3 then every 
odd cycle)
X (Q12W)
12-Lead ECG15
X
X
X (Cycle 4)
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Visit Identifiers1
Screening
Study Treatment
(1 cycle = 14 days)
Cycle 1
Cycles ≥2
(until 
amend. #4 
approval)
Cycles ≥2
(after 
amend. #4 
approval)
≤28 Days Prior to Enrollment 
or Randomization
Day 1
Day 8
(±1 day)
Day 1
(±3 days)
Day 1
(±3 days)
Disease Assessments
Tumor Assessments (including scans)16
X
Q6W after Cycle 1 Day 1 up to 1 year 
after thet first dose; Q12W thereafter
Other Clinical Assessments
Follow-up for Axitinib Dosing Compliance17
X (D5 ± 3 days)
X17(D5 ± 3 days)
Adverse Events18
X
Concomitant Medications/Treatments19
X
X
X
X
X 
Enrollment by Study Treatment20
Avelumab21
X21
X21
Axitinib21
X
Other Samplings
Pharmacokinetics22
X
X
X (Cycles 2, 3, 4, 6, 8, 
then Q12W until cycle 50)
Mandatory Archival FFPE Tumor Tissue24
X
Mandatory Recent De Novo FFPE Tumor Block25
X
Anti-Avelumab Antibodies and Neutralizing 
Antibodies26
X
X (Cycles 2, 3, 4, 6, 8, 
then Q12W until cycle 50) 
ACTH=adrenocorticotropic hormone; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FFPE=formalin-fixed and paraffin-embedded; 
HBV=hepatitis B virus; HCV=hepatitis C virus; PK=pharmacokinetics; Q6W= every 6 weeks; Q12W=every 12 weeks.
Footnotes for Schedule of Activities for SCREENING and STUDY TREATMENT Periods 
Patients participating in Dose Expansion Phase
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.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure.
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3.
Medical/Oncological History: To include information on prior systemic adjuvant or neoadjuvant therapy regimens, surgery, and radiation therapy.
4.
Baseline Signs/Symptoms: To be recorded predose for all patients on Cycle 1 Day 1.  Patients will be asked about any signs and symptoms experienced 
within the 14 days prior to study enrollment.
5.
Physical Examination: Includes an examination of major body systems and weight (height included at Screening only).
6.
Contraception Check: Male patients with female partner of childbearing potential and female patients who are of childbearing potential will need to affirm 
that they meet the criteria for correct use of 1 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient 
the need to use 1 highly effective contraception method consistently and correctly and document such conversation in the patient’s chart.  In addition, the 
investigator or his or her designee will instruct the patient to call immediately if the selected contraception method is discontinued, or if pregnancy is known 
or suspected in the patient or the patient’s partner. 
7.
Vital Signs: Vital signs to include: blood pressure, pulse rate. Blood pressure and pulse rate should be taken with the patient in the seated position after the 
patient has been sitting quietly for at least 5 minutes.  Two blood pressure and pulse rate readings will be taken at least 1 hour apart at each clinic visit. 
After amendment #4 approval, required every 6 weeks.
8.
Home Blood Pressure Monitoring: All patients will receive home blood pressure monitoring devices and blood pressure will be monitored at home.  
Patients will monitor their blood pressure at least twice daily (before taking each dose of axitinib) and blood pressure should be recorded in a patient diary.  
Patients should be instructed to contact the site immediately for guidance if their systolic blood pressure rises above 150 mm Hg, diastolic blood pressure 
rises above 100 mm Hg, or if they develop symptoms perceived to be related to elevated blood pressure (eg, headache, visual disturbances), although a 
different blood pressure threshold for contacting the site may be used according to the investigator’s clinical judgment (see Section 5.3.5.2). 
9.
Hematology, Blood Chemistry, and Coagulation: Required tests are listed in Table 8.  May also be performed when clinically indicated. 
10. Blood Chemistry: Full chemistry panel (required tests are listed in Table 8) is required as follows: at Screening, Cycle 1 Day 1, Cycle 2 Day 1, 
Cycle 4 Day 1, Cycle 7 Day 1, then every 6 weeks thereafter.  Core chemistry panel (required tests are listed in Table 8) is required as follows: Cycle 1 Day 
8, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 8 Day 1, then every 2 weeks thereafter.  If full and core chemistry panels are scheduled at the same 
visit, only the full chemistry panel will be performed. After amendment #4 approval required every 6 weeks. Required tests are listed in Table 8.  
11. Thyroid Function Tests: Free T4 and TSH will be performed at Screening, Cycle 4 Day 1, Cycle 7 Day 1, and Cycle 13, Day 1, and then Q12W thereafter.  
Additional tests should be performed when clinically indicated.  Hypothyroidism should be treated per standard medical practice to maintain euthyroid state. 
See Table 8.
12. ACTH: ACTH tests will be performed at Screening, Cycle 6 Day 1, then Q12W thereafter.  Additional tests should be performed when clinically indicated.
See Table 8.
13. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed at two occasions prior to starting combination study treatment: once at the start of screening and at the Cycle 1 Day 1 visit immediately before 
the administration of avelumab in combination with axitinib.  Additional pregnancy tests (serum or urine) will also be routinely repeated at every treatment 
cycle during the active treatment period, and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
Additional pregnancy tests may also be undertaken if requested by Institutional Review Boards (IRB)/Ethics Committees (ECs) or if required by local 
regulations (see Section 7.1.1). 
14. Urinalysis: Required at Screening, at Cycle 1 Day 1 and then at Day 1 of every odd cycle and at the End of Treatment. After amendment #4 approval 
required every 12 weeks. If protein ≥2+ by semiquantitative method (eg, urine dipstick), protein will have to be quantified by 24-hour urine collection. To 
be performed as clinically indicated at other time points.  See Table 8. 
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15. 12-Lead Electrocardiogram (ECG): See Section 7.1.5 for details.  All ECG measurements will be obtained at Screening, Cycle 1 Day 1, and 
Cycle 4 Day 1.  Clinically significant abnormal findings in baseline ECGs will be recorded as medical history.  At each time point, 3 consecutive 12-lead 
ECGs (triplicates) will be performed approximately 2 minutes apart to determine mean QTc (average of triplicates).  Triplicate ECGs at Cycle 4 Day 1 will 
be collected pre-dose and at 2 hours post-axitinib dosing.  Triplicate ECGs at Cycle 1 Day 1 will be prior to avelumab infusion and within 30 minutes post 
end of infusion.  When coinciding with blood samples draws for PK, ECG assessment should be performed prior to blood sample collection, such that the 
blood sample is collected at the nominal time.  If patient experiences a cardiac or neurologic adverse event (AE; eg, syncope, dizziness, seizures, or stroke), 
triplicate ECGs should be obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person 
at the institution for confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
16. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen, and pelvis computed
tomography (CT) or magnetic resonance imaging (MRI) scans; brain CT or MRI scans (required at baseline and when suspected brain metastasis) and bone 
scans or 18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET, required at baseline then every 12 weeks only if bone metastases are present 
at baseline).  Otherwise, bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of complete response for 
patients who have bone metastases.  See Section 7.6.  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.  Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, at 6 weeks after the first dose of therapy (ie, 
Cycle 1 Day 1), then every 6 weeks up to 1 year from the first dose of therapy and every 12 weeks thereafter until confirmed disease progression regardless 
of initiation of subsequent anti-cancer therapy.  Assessments will be performed according to calendar days, regardless of treatment delays or interruptions.  
Further imaging assessments may be performed at any time if clinically indicated (eg, suspected progressive disease [PD], symptomatic deterioration, etc.).  
Complete response (CR) and partial response (PR) must be confirmed with repeat imaging performed at least 4 weeks after initial documentation of 
response.  If radiologic imaging shows PD, then tumor assessment should be repeated after at least 4 weeks to confirm PD, unless clinical deterioration 
occurs.  Assessment of response will be made using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
 
).  See Section 7.6 for additional information.
17. Follow-up for Axitinib Dosing Compliance: Follow-up by telephone will be done to confirm patient understanding and compliance with dosing 
instructions on Cycle 1 Day 5.  Axitinib dosing compliance will also be assessed following any dose modification.  If needed, patients will be retrained.
18. Adverse Events: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. After amendment #4 approval, patients receiving axitinib single agent will visit the site every 6 weeks.  Between 
site visits, AEs collection will be performed every 2 weeks by telephone call (eg, nurse) in a standardized form, unless the patient is visiting the site for 
other reasons. For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving study treatment, through and including 90 calendar days after the last administration of study treatment.  SAEs occuring to a patient after the 
active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to the study drug are to be reported to the sponsor. 
AEs (serious and non serious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of study treatment
through and including 90 calendar days after the last of study treatment.  If a patient begins a new anticancer therapy, the AE reporting period for nonserious 
AEs ends at the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last dose of study drug, 
irrespective of any intervening treatment.
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19. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 90 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions). After amendment #4 approval, patients receiving axitinib single agent will visit the site every 6 weeks.  Between site visits, concomitant 
medication collection will be performed every 2 weeks by telephone call (eg, nurse) in a standardized form, unless the patient is visiting the site for other 
reasons. 
20. Enrollment: Patient number and dose level allocation will be operated by the sponsor (see Section 5.1).  Required information: site and patient identifiers 
and demographic information.  Study treatment (avelumab in combination with axitinib) should begin within 3 days of registration/randomization.  
21. Study Treatment: Axitinib will be given orally (PO) twice daily (BID) on a continuous schedule.  Avelumab will be given as a 1-hour intravenous (IV) 
infusion every 2 weeks (see Section 5).  Patients who develop disease progression on study treatment but who are otherwise continuing to derive clinical 
benefit from study treatment will be eligible to continue with single agent axitinib, avelumab, or avelumab combined with axitinib, provided that the 
treating physician has determined that the benefit/risk for doing so is favorable. 
22. Pharmacokinetics: Samples will be collected at the time points indicated in the Schedule for Pharmacokinetic Sample Collection Table.  Pharmacokinetic 
samples for avelumab will be collected from all patients in the study.  Details are outlined in Section 7.2.  
24. Mandatory Archival FFPE Tumor Tissue: An archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from primary diagnosis specimen 
must be provided for all patients enrolled in the study and submitted to the Central Laboratory prior to enrollment. 
 
 
  Cytology samples 
(eg, FFPE cell pellet from Fine Needle Aspiration biopsy) are not acceptable.  See Section 6.1.1 and Section 7.4.1.
25. Mandatory Recent De Novo FFPE Tumor Tissue Block: A baseline de novo tumor biopsy (biopsied tumor lesion should not be a RECIST target lesion) 
must be obtained for all patients enrolled in the study. 
 
 
 The de novo biopsy should 
be formalin-fixed and paraffin-embedded as per routine (see Study Manual), and the resulting FFPE tissue block(s) should be submitted to the Central 
Laboratory.
  See 
Section 6.1.1 and Section 7.4.1.
26. 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, 2, 3, 4, 6, and 8.  Subsequently, testing should be performed approximately every 12 weeks until cycle 50.  
All samples should be drawn within 2 hours before start of avelumab infusion.  Also see the Schedule for Pharmacokinetic Sample Collection Table.  All 
the samples that are positive for ADA may also undergo characterization for Nab.  See Section 7.3.
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SCHEDULE OF ACTIVITIES for END OF TREATMENT and SHORT-/LONG-TERM FOLLOW-UP Periods
Patients participating in Dose Expansion Phase
Visit Identifiers1
End of 
Treatment
/Withdrawal2
Post-Treatment Follow-Up
Short-Term Follow-Up 
(Day 30, Day 60, Day 90 [[±3 days])3
Long-Term Follow-Up
(±14 days)3
Clinical Assessments
Physical Examination4
X
X
Contraception Check5
X
X (only at Fu Day 30)
ECOG Performance Status
X
X
X
Vital Signs6
X
X
Laboratory Studies
Hematology7
X
X
Blood Chemistry7
X
X
Coagulation7
if clinically indicated
Thyroid Function Tests8
X
X
ACTH9
X
X
HBV, HCV testing
if clinically indicated
Serum/Urine Pregnancy Test10
X
X
Urinalysis11
X
12-Lead ECG12
X
Disease Assessments
Tumor Assessments (including scans)13
Q6W after Cycle 1 Day 1 up to 1 year 
after the first dose; Q12W thereafter
Survival14
X
X
Other Clinical Assessments
Adverse Events15
X
Concomitant Medications/Treatments16
X
X
New Anticancer Therapy
X
X
X
Other Samplings
Pharmacokinetics17
See SoA for PK
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Visit Identifiers1
End of 
Treatment
/Withdrawal2
Post-Treatment Follow-Up
Short-Term Follow-Up 
(Day 30, Day 60, Day 90 [[±3 days])3
Long-Term Follow-Up
(±14 days)3
De Novo FFPE Tumor Block19
X
Anti-Avelumab Antibodies and Neutralizing 
Antibodies20
See SoA for PK
ACTH=adrenocorticotropic hormone; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FFPE=formalin-fixed and paraffin-embedded; 
Fu= follow-up; HBV=hepatitis B virus; HCV=hepatitis C virus; PK=pharmacokinetics; Q12W=every 12 weeks.
Footnotes for Schedule of Activities for END OF TREATMENT and SHORT-/LONG-TERM FOLLOW-UP Periods
Patients participating in Dose Expansion Phase
1.
Visit Identifiers: Acceptable time windows for performing each assessment are described in the column headers.  
2.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if 
performed within the prior 6 weeks.
3.
Short- and Long-Term Follow-up: All patients will be followed for safety every 30 days (±3 days) through 90 days after the last dose of investigational 
product or until the time of initiation of new anticancer treatment. 
Beyond the 90 days until the end of the study, all patients will be followed every 3 months (±14 days) for survival, Eastern Cooperative Oncology Group 
(ECOG) Performance Status (PS), and new systemic anticancer treatment within the long-term follow-up. 
4.
Physical Examination: Includes an examination of major body systems and weight (height included at Screening only).
5.
Contraception Check: Male patients with female partner of childbearing potential and female patients who are of childbearing potential will need to affirm 
that they meet the criteria for correct use of 1 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient 
the need to use 1 highly effective contraception method consistently and correctly and document such conversation in the patient’s chart.  In addition, the 
investigator or his or her designee will instruct the patient to call immediately if the selected contraception method is discontinued, or if pregnancy is known 
or suspected in the patient or the patient’s partner. 
6.
Vital Signs: Vital signs to include: blood pressure, pulse rate.  Blood pressure and pulse rate should be taken with the patient in the seated position after the 
patient has been sitting quietly for at least 5 minutes.  Two blood pressure and pulse rate readings will be taken at least 1 hour apart at each clinic visit. 
7.
Hematology, Blood Chemistry (Full Chemistry), and Coagulation: Required tests are listed in Table 8.  May also be performed when clinically 
indicated. 
8.
Thyroid Function Tests: Free T4 and TSH will be performed at End of Treatment/Withdrawal and at the 30, 60, and 90 day Follow-up visits.  Additional 
tests should be performed when clinically indicated.  Hypothyroidism should be treated per standard medical practice to maintain euthyroid state.  See 
Table 8.
9.
ACTH: ACTH tests will be performed at End of Treatment/Withdrawal and at the 30, 60, and 90 day Follow-up visits. Additional tests should be 
performed when clinically indicated.  See Table 8.
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10. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a pregnancy test (serum or urine) will be repeated at the End of 
Treatment/Withdrawal visit and at the 30, 60, and 90 day Follow-up visits, and additionally whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by Institutional Review Board (IRB)/Ethics Committees 
(ECs) or if required by local regulations (see Section 7.1.1).  
11. Urinalysis: Required only at End of Treatment.  To be performed as clinically indicated at other time points. See Table 8. 
12. 12-Lead Electrocardiogram (ECG): See Section 7.1.5 for details.  ECG measurements will be obtained at End of Treatment/Withdrawal.  At each time 
point, 3 consecutive 12-lead ECGs (triplicates) will be performed approximately 2 minutes apart to determine mean QTc (average of triplicates).  When 
coinciding with blood samples draws for PK, ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected 
at the nominal time.  If patient experiences a cardiac or neurologic adverse event (AE; eg, syncope, dizziness, seizures, or stroke), triplicate ECGs should be 
obtained at time of the event.  If the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for 
confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be performed as clinically indicated.  
13. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen, and pelvis computed 
tomography (CT) or magnetic resonance imaging (MRI) scans; brain CT or MRI scans (required at baseline and when suspected brain metastasis) and bone 
scans or 18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET, required at baseline then every 12 weeks only if bone metastases are present 
at baseline).  Otherwise, bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of complete response for 
patients who have bone metastases.  See Section 7.6.  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.  Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, at 6 weeks after the first dose of therapy (ie, 
Cycle 1 Day 1), then every 6 weeks up to 1 year from the first dose of therapy and every 12 weeks thereafter until confirmed disease progression regardless 
of initiation of subsequent anti-cancer therapy.  Assessments will be performed according to calendar days, regardless of treatment delays or interruptions.  
Further imaging assessments may be performed at any time if clinically indicated (eg, suspected progressive disease [PD], symptomatic deterioration, etc.).  
Complete response (CR) and partial response (PR) must be confirmed with repeat imaging performed at least 4 weeks after initial documentation of 
response.  If radiologic imaging shows PD, then tumor assessment should be repeated after at least 4 weeks to confirm PD, unless clinical deterioration 
occurs.  Assessment of response will be made using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
 
).  See Section 7.6 for additional information.
14. Survival: All patients will be followed for survival and subsequent anticancer therapies every 3 months (±14 days) until death, end of the study or patient 
withdrawal of consent, whichever comes first.  For patients refusing to go back to the site a telephone contact is acceptable.
15. Adverse Events: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for 
Advers Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving study treatment, through and including 90 calendar days after the last dose of study treatment.  SAEs occuring to a 
patient after the active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that 
the investigator believes have at least a reasonable possibility of being related to the study drug are to be reported to the sponsor. 
AEs (serious and non serious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of study treatment 
through and including 90 calendar days after the last dose of study treatment.  If a patient begins a new anticancer therapy, the AE reporting period for 
nonserious AEs ends at the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last dose of study 
drug, irrespective of any intervening treatment.
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16. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 90 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions). 
17. Pharmacokinetics: Samples will be collected at the time points indicated in the Schedule for Pharmacokinetic Sample Collection Table.  Pharmacokinetic 
samples for avelumab will be collected from all patients in the study.  Details are outlined in Section 7.2.  
19. De Novo FFPE Tumor Tissue Block: A de novo (ie,, fresh biopsy) tumor sample should be collected at the time of discontinuation of either drugs and at 
the End of Treatment/Withdrawal, unless clinically contraindicated.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell 
pellet material), is not adequate and should not be submitted.  The de novo biopsy(ies) should be formalin-fixed and paraffin-embedded as per routine (see 
Study Manual), and the resulting FFPE tissue block(s) or slides if blocks cannot be provided (see Section 6.1.1 for details) should be submitted to the 
Central Laboratory.  See Section 6.1.1 and Section 7.4.1.
20. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab):  One blood sample (3.5 mL) for anti-avelumab 
antibodies (and simultaneous PK draws for measurement of avelumab) will be collected at the Day 30 Follow-up visit after the end of avelumab treatment.  
All the samples that are positive for ADA may also undergo characterization for Nab.  Also see the Schedule for Pharmacokinetic Sample Collection Table.  
See Section 7.3.
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SCHEDULE FOR PHARMACOKINETIC SAMPLE COLLECTION
Pharmacokinetic samples are to be obtained on the same day as all other scheduled assessments outlined in the Schedule of Activities
table. 
Protocol Activity
Axitinib
Avelumab in Combination with Axitinib
Cycle 1
Cycles 2 and 3
Cycle 4
Cycle 6
Cycle 
8 and 
Every 
12 weeks 
Thereater 
until cycle 
50 
Day 30 
Follow-
Up
Lead-in Day 7
Day 1
Day 8
(±1 day)
Day 1
(±3 days)
Day 1
(±3 days)
Day 1
(±3 days)
Day 1
(±3 days)
Hours post dose
0f
1
2
3
4
6
8
0f
1
168
0f
0f
1
2
3
4
6
8
0f
0f
PK for axitiniba
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PK for avelumabb
x
xd
xe
X
x
xd
x
x
x
ADAsc
x
X
x
x
x
x
PK=pharmacokinetics; ADAs=anti-drug antibodies
Note that PK samples for avelumab and anti-avelumab-antibodies (ADA) will be collected from all patients in the study.  Axitinib PK samples will be collected from all patients in 
the Dose Finding Phase and up to approximately 8 additional patients enrolled to assess the effect of avelumab on the PK of axitinib. 
a.
One sample (3 mL) collected at each time point for axitinib.
b.
One sample (3.5 mL) collected at each time point for avelumab.  An additional PK samples will be collected at the Day 30 Follow-up visit after the end of avelumab 
treatment.
c.
One sample (3.5 mL) collected at each time point for anti-avelumab antibodies.  An additional anti-avelumab antibody samples will be collected at the Day 30 Follow-up visit 
after the end of avelumab treatment.
d.
Sample may be collected within 30 minutes after end of avelumab infusion.
e.
Sample may be collected at any time between Cycle 1 Day 7 and Cycle 1 Day 9 for avelumab; the exact time/day of collection is to be recorded on the case report form 
(CRF).
f.
Pre-dose sample.  
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................47
LIST OF FIGURES .................................................................................................................47
APPENDICES .........................................................................................................................47
1. INTRODUCTION ...............................................................................................................49
1.1. Mechanism of Action/Indication.............................................................................49
1.2. Background and Rationale ......................................................................................49
1.2.1. Renal Cell Cancer.......................................................................................49
1.2.2. Pharmaceutical and Therapeutic Background ............................................50
1.2.2.1. Avelumab (MSB0010718C) .....................................................50
1.2.2.2. Axitinib (INLYTA®, AG-013736)............................................52
1.2.3. Rationale for Studying Avelumab in Combination with Axitinib in 
Patients with Advanced Renal Cell Carcinoma...............................................54
1.2.4. Rationale for Avelumab and Axitinib Starting Doses................................57
1.2.4.1. Axitinib Starting Dose and Regimen ........................................57
1.2.4.2. Avelumab Starting Dose and Regimen .....................................57
1.3. Summary of Benefit Risk Assessment....................................................................57
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................58
2.1. Objectives................................................................................................................58
2.2. Endpoints.................................................................................................................59
3. STUDY DESIGN.................................................................................................................60
3.1. Study Overview.......................................................................................................60
3.1.1. Dose Finding Phase ....................................................................................64
3.1.1.1. Starting Doses for Avelumab and Axitinib (Dose Level 1)......64
3.1.1.2. Dose-Finding Criteria................................................................64
3.1.2. Dose-Limiting Toxicity Definition.............................................................67
3.2. Maximum Tolerated Dose Definition .....................................................................69
3.3. Dose Expansion Phase Test Dose Definition..........................................................69
3.3.1. Dose Expansion Phase................................................................................69
3.4. Recommended Phase 2 Dose Definition.................................................................69
4. PATIENT SELECTION......................................................................................................69
4.1. Inclusion Criteria.....................................................................................................69
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4.2. Exclusion Criteria....................................................................................................71
4.3. Life Style Guidelines...............................................................................................74
4.3.1. Contraception..............................................................................................74
4.3.1.1. Male Participant Contraception.................................................74
4.3.1.2. Female Participant Reproductive Status ...................................75
4.3.1.3. Woman of Childbearing Potential (WOCBP)...........................75
4.3.1.4. Contraception Methods .............................................................76
4.4. Sponsor Qualified Medical Personnel.....................................................................77
5. STUDY TREATMENTS.....................................................................................................77
5.1. Allocation to Treatment ..........................................................................................78
5.2. Patient Compliance .................................................................................................78
5.3. Investigational Product Supplies.............................................................................79
5.3.1. Dosage Form(s) and Packaging..................................................................79
5.3.1.1. Axitinib......................................................................................79
5.3.1.2. Avelumab ..................................................................................79
5.3.2. Preparation and Dispensing........................................................................79
5.3.2.1. Avelumab ..................................................................................79
5.3.2.2. Axitinib......................................................................................80
5.3.3. Administration............................................................................................80
5.3.3.1. Avelumab ..................................................................................81
5.3.3.2. Axitinib......................................................................................81
5.3.3.3. Treatment after Initial Evidence of Radiologic Disease 
Progression ........................................................................................82
5.3.4. Food Requirements.....................................................................................83
5.3.5. Recommended Dose Modifications............................................................83
5.3.5.1. Intrapatient Axitinib Dose Escalation and Dose Reduction......83
5.3.5.2. Management of Axitinib-Related Hypertension .......................84
5.3.5.3. Axitinib Dose Modifications and Avelumab Infusion 
Omissions for Treatment-Related Toxicity.......................................85
5.3.5.4. Special Precautions for Avelumab Administration...................91
5.3.5.5. Management of Avelumab Infusion-Related Reactions ...........91
5.3.5.6. Management of Avelumab-Related Severe 
Hypersensitivity Reactions and Flu-Like Symptoms........................92
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5.3.5.7. Management of Avelumab-Related Tumor Lysis 
Syndrome...........................................................................................93
5.3.5.8. Management of Avelumab Immune-Related Adverse 
Events ................................................................................................95
5.4. Investigational Product Storage ............................................................................101
5.5. Investigational Product Accountability.................................................................102
5.6. Destruction of Investigational Product Supplies...................................................102
5.7. Concomitant Treatments(s)...................................................................................102
5.7.1. Inhibitors and Inducers of CYP Enzymes ................................................103
5.7.2. Hematopoietic Growth Factors.................................................................104
5.7.3. Concomitant Surgery................................................................................104
5.7.4. Concomitant Radiotherapy.......................................................................104
5.7.5. Other Prohibited Concomitant Medications and Therapies......................104
5.8. Rescue Medications and Supportive Care.............................................................105
5.8.1. Supportive Care Guidelines......................................................................105
6. STUDY PROCEDURES ...................................................................................................106
6.1. Screening...............................................................................................................106
6.1.1. Tumor Biospecimens................................................................................106
6.2. Study Period ..........................................................................................................107
6.3. End of Treatment/Withdrawal and Follow-up Visits............................................107
6.4. End of Study..........................................................................................................107
6.5. Patient Withdrawal................................................................................................107
7. ASSESSMENTS................................................................................................................109
7.1. Safety Assessment.................................................................................................109
7.1.1. Pregnancy Testing ....................................................................................109
7.1.2. Adverse Events.........................................................................................109
7.1.3. Laboratory Safety Assessments................................................................110
7.1.4. Vital Signs and Physical Examination......................................................112
7.1.5. (12-Lead) Electrocardiogram Measurements ...........................................112
7.2. Pharmacokinetics Assessments.............................................................................113
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis .........................113
7.2.2. Collection of Axitinib Pharmacokinetic Samples.....................................114
7.2.3. Collection of Avelumab Pharmacokinetic Samples .................................114
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7.3. Immunogenicity Assessment.................................................................................114
7.4. Translational and Pharmacodynamic Assessments...............................................115
7.4.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies ...............115
7.6. Tumor Assessments...............................................................................................118
8. ADVERSE EVENT REPORTING....................................................................................118
8.1. Adverse Events......................................................................................................118
8.2. Reporting Period ...................................................................................................119
8.3. Definition of an Adverse Event.............................................................................119
8.3.1. Avelumab Adverse Events of Special Interest .........................................120
8.4. Medication Errors..................................................................................................120
8.5. Abnormal Test Findings........................................................................................121
8.6. Serious Adverse Events.........................................................................................122
8.6.1. Protocol-Specified Serious Adverse Events.............................................122
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................122
8.7. Hospitalization ......................................................................................................124
8.8. Severity Assessment..............................................................................................125
8.9. Causality Assessment............................................................................................125
8.10. Exposure During Pregnancy................................................................................126
8.11. Occupational Exposure .......................................................................................127
8.12. Withdrawal Due to Adverse Events (see Also the Section on Patient 
Withdrawal).............................................................................................................127
8.13. Eliciting Adverse Event Information ..................................................................127
8.14. Reporting Requirements......................................................................................127
8.14.1. Serious Adverse Event Reporting Requirements ...................................128
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................128
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............128
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................128
9.1. Analysis Sets .........................................................................................................129
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9.2. Statistical Methods and Properties ........................................................................130
9.2.1. Statistical Methods for Dose Escalation/De-Escalation: mTPI................130
9.3. Sample Size Determination...................................................................................131
9.4. Efficacy Analysis ..................................................................................................131
9.4.1. Analysis of Efficacy Endpoints ................................................................131
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................133
9.5.1. Analysis of Pharmacokinetics...................................................................133
9.5.1.1. Pharmacokinetic Analysis of Avelumab and Axitinib............133
9.5.1.2. Effect of Avelumab on Axitinib Pharmacokinetics ................133
9.5.1.3. Immunogenecity Assessment..................................................133
9.5.1.4. Population Pharmacokinetic Analysis.....................................133
9.5.1.5. Analysis of Biomarker Endpoints ...........................................134
9.6. Safety Analysis......................................................................................................134
9.6.1. Analysis of the Primary Safety Endpoint .................................................134
9.6.2. Analysis of Secondary Safety Endpoints..................................................134
9.6.2.1. Adverse Events........................................................................134
9.6.2.2. Laboratory Test Abnormalities ...............................................135
9.6.2.3. Electrocardiograms..................................................................135
9.6.3. Concomitant Medications/Follow-up Systemic Therapy.........................135
9.7. Data Safety Monitoring Committee ......................................................................136
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................136
11. DATA HANDLING AND RECORD KEEPING ...........................................................137
11.1. Case Report Forms/Electronic Data Record .......................................................137
11.2. Record Retention.................................................................................................137
12. ETHICS............................................................................................................................138
12.1. Institutional Review Board/Ethics Committee....................................................138
12.2. Ethical Conduct of the Study ..............................................................................138
12.3. Patient Information and Consent.........................................................................138
12.4. Patient Recruitment.............................................................................................139
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................139
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13. DEFINITION OF END OF TRIAL.................................................................................140
13.1. End of Trial in a Member State...........................................................................140
13.2. End of Trial in all other Participating Countries.................................................140
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................140
15. PUBLICATION OF STUDY RESULTS........................................................................140
15.1. Communication of Results by Pfizer ..................................................................140
15.2. Publications by Investigators ..............................................................................141
16. REFERENCES ................................................................................................................143
LIST OF TABLES
Table 1.
Dose Levels in the Dose Finding Phase ...............................................................64
Table 2.
Possible Dose Finding Sequences ........................................................................65
Table 3.
Detailed Dose Escalation/De Escalation Scheme.................................................66
Table 4.
Axitinib Dose Levels ............................................................................................84
Table 5.
Axitinib Dose Modifications and Avelumab Infusion Omissions for 
Investigational Product-Related Toxicity.............................................................86
Table 6.
Treatment Modification for Symptoms of Avelumab Infusion -Related 
Reactions...............................................................................................................92
Table 7.
Management of Avelumab Immune Related Adverse Events..............................95
Table 8.
Required Laboratory Tests .................................................................................111
Table 9.
Objective Response Status at Each Evaluation ..................................................152
Table 10.
Overall Response Derived from Changes in Target, Non- Target and New 
Lesions................................................................................................................154
LIST OF FIGURES
Figure 1.
Assessment and Initial Management of Tumor Lysis Syndrome.........................94
APPENDICES
Appendix 1. ECOG Performance Status................................................................................147
Appendix 2. Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 Guidelines.....................................................................................................148
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Appendix 4. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................155
Appendix 5. Abbreviations and Definitions of Term ............................................................156
Appendix 6. Treatment Recommendations for Symptoms of Avelumab 
Infusion-Related Reactions.................................................................................160
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Previously untreated advanced renal cell carcinoma (aRCC). 
The mechanisms of action of avelumab and axitinib are described in Sections 1.2.2.1 and 
1.2.2.2, respectively. 
1.2. Background and Rationale
1.2.1. Renal Cell Cancer
Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes about 3% of 
all malignant tumors in adults.1 RCC is often first detected at an advanced stage, with 
25-30% of patients having metastatic disease at diagnosis.
RCC arises from the renal epithelium, and 5 major subtypes are currently recognized.  
Approximately 70-80% of these are clear cell RCC tumors, while other less common cell 
types include papillary (Types I and II), chromophobe, collecting duct, and unclassified 
RCC.2 Four RCC predisposing genes have been identified – MET protooncogene, von 
Hippel-Lindau tumor suppressor gene (VHL), fumarate hydratase tumor suppressor gene 
(FH), and Birt-Hogg-Dubé tumor suppressor gene (BHD).
Patients with von Hippel-Lindau disease have a >70% risk of developing clear cell RCC.  
This hereditary form of RCC is caused by germline mutations in the VHL tumor suppressor 
gene on chromosome 3p.  More than 90% of sporadic clear cell RCC involves somatic VHL
gene mutations or methylation.  VHL gene mutations lead to loss of function of the VHL 
protein, accumulation of hypoxia-inducible transcription factors (eg, HIF-1alpha and 
HIF-2 alpha) which translocate to the nucleus and increase transcription of angiogenesis 
factors (such as vascular endothelial growth factor [VEGF] and platelet-derived growth 
factor [PDGF]) which induce tumorigenesis.  Clear cell RCC is a highly vascular tumor with 
high expression of VEGF, VEGF receptor (VEGFR), and PDGF receptor (PDGFR).3
About one-third of patients with clear cell RCC present with Stage IV disease.  Systemic 
therapy is given to patients with advanced disease (relapsed or Stage IV) that is not amenable 
to complete resection.  However, it is recommended that these patients undergo a 
cytoreductive nephrectomy where possible, prior to beginning systemic therapy, as per 
treatment guidelines.4
There are 7 molecularly targeted agents approved in the United States (US) as systemic 
therapy for advanced RCC that is predominantly clear cell.  First line systemic therapy is 
usually one of the VEGFR tyrosine kinase inhibitors (TKIs) (sunitinib, pazopanib, or 
sorafenib), the monoclonal anti-VEGF antibody bevacizumab (given in combination with 
interferon [IFN]-α) or the mammalian target of rapamycin (mTOR) inhibitor, temsirolimus.  
These drugs are used sequentially as single agents in subsequent lines of therapy for 
advanced clear cell RCC.4-7
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1.2.2. Pharmaceutical and Therapeutic Background 
1.2.2.1. Avelumab (MSB0010718C)
The first investigational product in the present clinical trial is avelumab (MSB0010718C), a 
fully human monoclonal antibody (mAb) of the immunoglobulin (Ig) G1 isotype.  
Avelumab is the proposed International Nonproprietary Name (INN) for the 
anti-PD-L1 monoclonal antibody MSB0010718C. 
Avelumab selectively binds to programmed death-ligand 1 (PD-L1) and competitively blocks 
its interaction with programmed death protein-1 (PD-1).  Compared with 
anti-PD-1 antibodies that target T-cells, avelumab targets tumor cells, and therefore, is 
expected to have fewer side effects, including a lower risk of autoimmune-related safety 
issues, as blockade of PD-L1 leaves the programmed death-ligand 2 (PD-L2)/PD-1 pathway 
intact to promote peripheral self-tolerance.8 For complete details of the in vitro and 
nonclinical studies, refer to the avelumab investigator’s brochure.9
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial cancer, and 
Hodgkin’s Lymphoma, as a single agent or in combination with chemotherapy, tyrosine 
kinase inhibitors, or other immune-modulating agents. 
As of 05 November 2015, more than 1400 patients have been treated with avelumab.  The 
largest trial is study EMR100070-001, a Phase 1, open-label, multiple ascending-dose 
clinical study aimed to investigate the safety, tolerability, pharmacokinetics (PK), biological 
activity, and clinical activity of avelumab in patients with metastatic or locally advanced 
solid tumors.  Study EMR100070 001 consists of 2 parts, a dose-escalation phase and a 
dose-expansion phase, the latter performed in selected tumor indications.  Avelumab is 
administered intravenously (IV) at the assigned dose level as a 1-hour infusion once every 
2 weeks (Q2W). 
As of 05 November 2015, a total of 53 patients were treated in the dose-escalation phase of 
Trial EMR10070-001, with 4, 13, 15, and 21 patients being treated with avelumab of 1, 3, 10, 
and 20 mg/kg, respectively.  None of the patients treated with doses up to 10 mg/kg 
experienced a dose-limiting toxicity (DLT), and the 10 mg/kg dose of avelumab was thus 
considered a safe and well-tolerated dose for further investigation in the dose-expansion 
cohorts.  One DLT (a Grade 3 immune-related adverse event characterized by increased 
creatine kinase, myositis, and myocarditis) was observed in 1 patient at the 20 mg/kg dose 
level.
As of 05 November 2015, 1300 patients have been enrolled in the tumor type specific 
expansion cohorts of study EMR 100070-001 and treated with the recommended dose of 
10 mg/kg avelumab Q2W.  A summary of the safety data for the pooled expansion cohort is 
provided here. 
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Complete information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab investigator’s brochure.  The reference safety 
information (RSI) can be found in tabular format in Section 6.2 of the avelumab IB 
(Investigator Brochure).9
1.2.2.2. Axitinib (INLYTA®, AG-013736)
The other investigational product 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 (aRCC) after failure of one prior systemic
therapy (actual indication varies according to region/country).10
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 juxtamembrane domain containing human 
VEGFR 2 recombinant protein.11 In additional kinase assays, axitinib showed potent and 
ATP-competitive inhibition of the VEGFRs 1, 2, and 3 and PDGFR-β, but not other closely 
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related family kinases.  Receptor binding studies and cell-based assays confirmed that 
axitinib is a potent and selective inhibitor of VEGFRs 1, 2, and 3.  Axitinib was shown to 
have antiangiogenic activity in a number of models including spontaneous pancreatic 
islet-cell tumors of RIP-TAG-2 transgenic mice model and demonstrated antitumor efficacy 
including marked cytoreductive antitumor activity in multiple tumor models implanted in 
athymic mice. 
The safety and efficacy of axitinib were evaluated in a randomized, open-label, multicenter 
Phase 3 study.  Patients with aRCC (99% clear cell) whose disease had progressed on or after 
treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, 
or cytokine-containing regimens were randomized to receive axitinib (N=361) or sorafenib 
(N=362).  There was a statistically significant advantage for axitinib over sorafenib for the 
primary progression-free survival (PFS) endpoint, 6.7 months (95% confidence interval 
[CI]: 6.3, 8.6) vs 4.7 months (95% CI: 4.6, 5.6), respectively (hazard ratio 0.665; 95% 
CI 0.544-0.812; one sided p <0.0001).  There was no statistically significant difference 
between the treatment arms in the secondary overall survival (OS) endpoint, 20.1 months 
(95% CI: 16.7, 23.4) vs 19.2 months (95% CI: 17.5, 22.3) for axitinib and sorafenib (hazard 
ratio 0.969, 95% CI 0.800-1.174; one sided p=0.3744), respectively.  The objective response 
rate (ORR) was 19.4% (95% CI: 15.4, 23.9) for axitinib and 9.4% (95% CI: 6.6, 12.9) for 
sorafenib.  The most common (≥20%) adverse reactions observed in this study following 
treatment with axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, 
dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, 
vomiting, asthenia, and constipation.12
In another randomized, open-label, Phase 3 trial, treatment-naïve clear cell RCC patients 
were randomized (2:1) to receive axitinib (N=192) or sorafenib (N=96).  There was no 
significant difference in median PFS between patients treated with axitinib or sorafenib, 
10.1 months (95% CI: 7.2, 12.1) vs 6.5 months (95% CI: 4.7, 8.3) as assessed by Independent 
Review Committee, respectively, with stratified hazard ratio 0.77 (95% CI: 0.56, 1.05; one 
sided p=0.038).  The axitinib ORR assessed by an Independent Radiology Review 
Committee was 32%, risk ratio 2.21, (95% CI: 1.31, 3.75, stratified one-sided p=0.0006).  
Adverse events more common (≥10%) with axitinib versus sorafenib were diarrhoea, 
hypertension, weight decrease, decreased appetite, dysphonia, hypothyroidism, and upper 
abdominal pain; those more common with sorafenib versus axitinib included palmar-plantar 
erythrodysesthesia (hand-foot) syndrome and rash, alopecia and erythema.13 Toxicities in 
this clinical trial were generally tolerable and manageable and similar to those observed in 
clinical trials of axitinib in pre-treated aRCC patients.13
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.11
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Following oral administration, axitinib is rapidly absorbed (median Tmax 2.5-4.1 hours).  The 
plasma half life of axitinib ranges from 2.5 to 6.1 hours and steady-state is expected within 
2 to 3 days of dosing.  Dosing of axitinib at 5 mg twice daily resulted in approximately 
1.4-fold accumulation compared to administration of a single dose.  At steady state, axitinib 
exhibits approximately linear PK within the 1-mg to 20-mg dose range.  The mean absolute 
bioavailability of axitinib after an oral 5 mg dose is 58%.  Axitinib may 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 
axitinib investigator’s brochure.  The RSI can be found in tabular format in Section 7.8 of the 
axitinib IB.11
1.2.3. Rationale for Studying Avelumab in Combination with Axitinib in Patients with 
Advanced Renal Cell Carcinoma
Tumor angiogenesis is a complex dynamic process necessary for the continued growth of 
solid tumors.  VEGF is one of the most important angiogenic factors secreted by the tumor 
and other cells.  Its production is enhanced by several stimuli, including hypoxia.  VEGF and 
VEGFRs are critical components of the processes leading to the branching, extension, and 
survival of endothelial cells which form new blood vessels during angiogenesis, and which is 
an absolute necessity for tumor growth beyond microscopic size.  Inhibitors of angiogenesis
are now widely used in the treatment of cancer, and most of these agents inhibit the VEGF 
pathway.  VEGF pathway inhibitors include the VEGFR TKIs axitinib, sunitinib, pazopanib, 
and sorafenib, and the monoclonal anti-VEGF antibody bevacizumab.  VEGF pathway 
inhibitors have been approved in a number of indications, including the treatment of 
aRCC.14,15
Until 2005, IFN-α and high-dose interleukin (IL)-2 therapies were the standards of care for 
patients with aRCC, albeit with modest efficacy.  Since then, development and approval of 
multiple VEGF pathway and mTOR inhibitors have significantly improved the outcomes of 
aRCC patients.  These agents include the VEGFR TKIs sunitinib, pazopanib, axitinib and 
sorafenib; the mTOR inhibitors temsirolimus and everolimus; and the anti-VEGF 
monoclonal antibody bevacizumab.  However, durable and complete responses in aRCC 
patients are uncommon; the majority of patients will eventually develop resistance, exhibit 
disease progression while on therapy, and succumb to death due to metastatic disease.  
Response rates for previously treated aRCC patients are in the 15-25% range, and median 
survival after diagnosis is under 1 year.1
There is a strong rationale for considering immunotherapy in aRCC patients.  Cytokine-based 
immunotherapy, especially high-dose IL-2, exhibited durable responses in some aRCC 
patients.  There are anecdotal reports of spontaneous remissions in aRCC patients with 
evidence of antigen-specific lymphocyte infiltration in tumor tissues.16 These reports have 
generated considerable interest in immunotherapeutic approaches in the treatment of aRCC 
patients, especially with advent of immune checkpoint inhibitors such as anti-PD-1 and 
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anti-PD-L1 antibodies in recent years.  Upregulation of PD-1 receptor on tumor-infiltrating 
lymphocytes (TILs), and its ligand PD-L1 on tumors, are associated with more aggressive 
disease and poor prognosis.17,18
Monoclonal antibodies (mAb) that block the PD-1/PD-L1 interaction are novel 
immunotherapeutic approaches for aRCC, which have shown single-agent efficacy in 
patients whose disease has progressed following VEGF pathway inhibitor therapy.19,20
Nivolumab, a high-affinity, fully human anti-PD-1 mAb has shown durable tumor response 
with ORR of about 20% and median PFS of about 16 weeks in heavily pretreated aRCC 
patients.21,22 When nivolumab was combined with a VEGF TKI (sunitinib or pazopanib), it 
demonstrated more pronounced anti-tumor response.  Amin et al reported the data from 
combinations of sunitinib or pazopanib with nivolumab at the American Society of Clinical 
Oncology (ASCO) 2014 annual meeting.23 The pazopanib plus nivolumab arm was 
discontinued due to early safety issues; however, sunitinib (50 mg, 4 weeks on/2 weeks off) 
was successfully combined with nivolumab 5 mg/kg every 3 weeks (Q3W), and dose 
expansion was subsequently completed in previously untreated aRCC patients.  ORR was 
52% (17/33) for nivolumab in combination with sunitinib, and 45% (9/20) for nivolumab in 
combination with pazopanib.  Median duration of response (DR) was 37.1 weeks (95% CI: 
18.1-80.0+), and median PFS was 48.9 weeks (95% CI: 41.6-66.0) with sunitinib plus 
nivolumab.  MPDL3280A, another human mAb that targets PD-L1, has shown ORR of 13% 
and stable disease (SD) ≥24 weeks in 32% of patients with previously treated RCC when 
administered as a single agent.  Results from the combination of bevacizumab 15 mg/kg 
Q3W with MPDL3280A (20 mg/kg) were presented by McDermott et al at the European 
Society for Medical Oncology (ESMO) 2014 annual meeting.24 Data were limited, but in 
previously untreated aRCC patients, there were 4 of 10 (40%) patients who had partial 
responses (PRs).  Five additional patients had a best response of SD, and almost all (9 out of 
10) responding patients were still on treatment at the time of analysis.  These data, although 
preliminary, demonstrate the benefit of combining an anti-PD-1 or PD-L1 antibody with an 
anti-VEGF pathway agent in aRCC patients.
The combination of nivolumab with ipilimumab, a fully human monoclonal antibody to 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), showed acceptable safety and 
encouraging antitumor activity in patients with metastatic RCC.  Patients were randomized to 
receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg (Arm N3 + I1) or nivolumab 1 mg/kg 
+ ipilimumab 3 mg/kg (Arm N1 + I3) IV Q3W for 4 doses, then nivolumab 3 mg/kg IV Q2W 
until disease progression or unacceptable toxicity.  Confirmed objective response (OR) was 
observed in 9/21 patients in arm N3 + I1 and in 11/23 patients in Arm N1 + I3.  The median 
PFS was 36.6 weeks and 38.3 weeks in Arm N3 + I1 and in Arm N1 + I3, respectively.25
Antitumor activity of single-agent axitinib 5 mg BID in previously untreated patients with 
clear cell aRCC was assessed against sorafenib in a randomized, open-label, Phase 3 trial.  
Although the study did not demonstrate a statistically significant difference in PFS between 
patients treated with axitinib or sorafenib, axitinib was associated with a longer median PFS 
time (mPFS of 10.1 months [95% CI: 7.2,12.1] with axitinib vs. 6.5 months [95% CI: 4.7, 
8.3] with sorafenib, stratified hazard ratio 0.77 [95% CI: 0.56, 1.05]).  The mPFS observed 
with axitinib in this study was similar to those demonstrated earlier in Phase 3 clinical trials 
of other approved VEGFR TKIs in the first-line treatment of aRCC patients.13 Toxicities in 
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this clinical trial were generally tolerable and manageable, and similar to those observed in 
clinical trials with axitinib in pre-treated aRCC patients.12
Avelumab (MSB0010718C) is a fully human monoclonal antibody (mAb) of the 
IgG1 isotype that specifically targets and blocks PD-L1 (see Section 1.2.2.1).26 Avelumab is 
the proposed International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal 
antibody MSB0010718C. 
As to the safety profile of avelumab see Section 1.2.2.1.
Currently, the 10 mg/kg dose is the recommended Phase 2 dose for avelumab in single-agent 
studies.  In the dose escalation study of avelumab, the 10 mg/kg dose was found to be 
well-tolerated and did not result in any DLT.  In addition, all patients treated at this dose had 
a median trough concentration >1 μg/mL, the necessary concentration for >95% TO.  
Therefore, the lower 5 mg/kg dose is expected to be well-tolerated and based upon 
pharmacokinetic modeling and the dose-linear PK characteristics of avelumab, median 
trough concentrations should achieve 95% TO in all patients. 
The risk of hepatotoxicity is low in aRCC patients on axitinib, with an overall rate of 
Grade 3/4 ALT or AST increased <0.6% for each.27 The incidence of hematological toxicity 
was also low for axitinib in this patient population (eg, Grade 3/4 platelet count decreased 
and neutrophil count decreased 0.3% for each).27
Preliminary Safety Data of Avelumab as Monotherapy in aRCC.
In the aRCC cohort of the Phase 1 study EMR 100070-001, 18 patients with aRCC in the 
second-line and beyond treatment setting received avelumab IV Q2W at the dose of 
10 mg/kg (see Section 1.2.2.1).9 Current data indicate that the safety profile of the aRCC 
cohort is consistent with that of the overall population of study EMR 100070-001.  Since 
December 2015, an additional cohort of approximately 30 patients with aRCC in the first-line 
treatment setting has started enrollment within the EMR 100070-001 study.
Safety Considerations for Avelumab in Combination with Axitinib
The combination of avelumab with axitinib has not been previously studied in patients; 
therefore, there are currently no safety data from this combination.  There are no expected 
overlapping toxicities between avelumab and axitinib, except for fatigue, nausea/diarrhea, 
and hypothyroidism, which are usually low-grade events easily manageable following the 
adverse event management guidelines implemented in the study protocol.  Additional safety 
concerns are not expected from combining avelumab with axitinib given their distinct 
mechanisms of action and toxicity profiles.
Overall, the observed benefit-risk profile supports the further investigation of avelumab in 
combination with axitinib in the patient population chosen for this study.
It is proposed that the addition of the PD-L1 inhibitor, avelumab, to the VEGF pathway 
inhibitor, axitinib, may provide additional clinical benefit compared to treatment with an 
anti-VEGFR TKI alone without unacceptable toxicity in untreated aRCC patients leveraging 
their complementary mechanisms of action.  This study, therefore, is designed to determine 
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the recommended doses and provide the safety, PK, and preliminary efficacy of this 
combination regimen needed to support a subsequent randomized clinical trial of avelumab 
in combination with axitinib versus VEGFR TKI in the first-line aRCC treatment setting.
1.2.4. Rationale for Avelumab and Axitinib Starting Doses
1.2.4.1. Axitinib Starting Dose and Regimen
In this clinical trial, the axitinib starting dose will be 5 mg administered orally (PO) twice 
daily (BID) with or without food.  This dose has proven to be safe and efficacious in aRCC 
and has been approved by regulatory authorities worldwide.
1.2.4.2. Avelumab Starting Dose and Regimen
In this clinical trial, the avelumab starting dose will be 10 mg/kg administered as 1-hour 
intravenous (IV) infusion every 2 weeks (Q2W).  This dose is the recommended dose 
administered to a total of 480 patients in the ongoing dose-expansion phase of study EMR 
100070-001 (see Section 1.2.2.1 for details). 
1.3. Summary of Benefit Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
Based on the nonclinical and Phase 1 clinical data available to date, the conduct of the trial 
with the proposed avelumab dose and regimen is considered justifiable. 
As noted above (Section 1.2.3), blocking the PD-1/PD-L1 pathway by agents binding either 
PD-1 or PD-L1 (anti-PD-1 mAb or anti-PD-L1 mAb) is a novel immunotherapeutic approach 
for aRCC, and anti-PD-1 and anti-PD-L1 agents have shown single-agent efficacy in patients 
whose disease has progressed following VEGF pathway inhibitor therapy.  Furthermore, 
anti-PD-1/PD-L1 antibodies have shown to produce objective response rates of 13% to 52% 
as single agents or in combination with a VEGF pathway inhibitor in patients with 
aRCC.19,20,23 Recent studies suggested that TKI administration induces PD-L1 expression 
which might lead to immune tolerance and acquired resistance to VEGF targeted agents such 
as axitinib.  Therefore, the addition of axitinib, which is a standard therapy for patients with 
RCC, might be synergistic with avelumab in treating patients with aRCC.
For single-agent avelumab, based on the nonclinical and Phase 1 trial EMR 
100070-001 clinical data available to date, the conduct of the trial with the proposed 
avelumab dosing regimen is considered justifiable.  The clinical safety data available to date, 
with single-agent avelumab in patients with advanced solid tumors, suggest an acceptable 
safety profile of the compound.  Most of the observed events were either in line with those 
expected in patients with advanced solid tumors or with similar class effects of monoclonal 
antibodies blocking the PD-1/PD-L1 axis.  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.
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Axitinib is approved multinationally for the treatment of aRCC after failure of one prior 
systemic therapy.  Furthermore, axitinib has been studied as first-line aRCC treatment in a 
Phase 3 clinical trial, and in this treatment setting, the safety profile is comparable to the one 
observed in the second-line treatment setting.12,13 Overall, the adverse events reported for 
axitinib in clinical studies is considered generally tolerable and manageable, and are well 
characterized (see Section 1.2.2.2). 
The combination of avelumab with axitinib has not been previously studied in patients; 
therefore, there are currently no safety data for the combination.  There are no expected 
overlapping toxicities between avelumab and axitinib, except for fatigue, nausea/diarrhea, 
and hypothyroidism, which are usually low-grade events easily manageable with 
symptomatic or steroid therapies and following the adverse event management guidelines 
implemented in the study protocol.  Additional safety concerns are not expected from 
combining avelumab with axitinib given their distinct mechanisms of action and toxicity 
profiles.
These results, together with the acceptable safety profile of avelumab as currently 
demonstrated by the ongoing Phase 1 trial EMR100070-001, support the hypothesis that 
avelumab in combination with axitinib may represent an important therapeutic approach in 
patients with aRCC.  Thus, the projected benefit/risk of avelumab given in combination with 
axitinib is favorable for investigation in this advanced cancer patient population.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective
•
To assess the safety and tolerability of avelumab in combination with axitinib in 
patients with previously untreated advanced RCC in order to estimate the Maximum 
Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).
Secondary Objectives
•
To evaluate the overall safety profile of avelumab in combination with axitinib in 
patients with previously untreated advanced RCC.
•
To assess the preliminary anti-tumor activity of avelumab in combination with 
axitinib in patients with previously untreated advanced RCC. 
•
To evaluate the OS of avelumab in combination with axitinib in patients with 
previously untreated advanced RCC.
•
To characterize the PK of avelumab and axitinib when administered in combination, 
and to assess the effect of avelumab on the PK of axitinib.
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•
To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may 
aid in the identification of a patient subpopulation most likely to benefit from 
treatment with avelumab in combination with axitinib.
•
To assess the immunogenicity of avelumab when combined with axitinib.
•
 
•
 
 
2.2. Endpoints
Primary Endpoint
•
DLTs within the first 4 weeks (2 cycles) of treatment with avelumab in combination 
with axitinib. 
Secondary Endpoints
•
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 (Appendix 4).
•
Vital signs (blood pressure, pulse rate).
•
Objective Response (OR) and Disease Control (DC) as assessed by Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Appendix 2). 
•
Time-to-event endpoints: Duration of Response (DR), Progression-Free Survival 
(PFS), and Time to Tumor Response (TTR). 
•
Overall Survival (OS).
•
PK parameters including Cmax, Tmax, AUCtau, and t1/2 as appropriate for axitinib; Ctrough
and Cmax for avelumab.
•
Tumor tissue biomarker status (ie, positive or negative based on, for example, 
PD-L1 expression and/or quantitation of tumor-infiltrating CD8+ T lymphocytes as 
assessed by immunohistochemistry [IHC]).
•
Anti-drug antibodies (ADAs; neutralizing antibodies [Nabs]) of avelumab when 
combined with axitinib.
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•
 
 
•
 
 
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, PK and pharmacodynamic 
study of avelumab in combination with axitinib in adult patients with previously untreated 
aRCC.  This clinical study will be composed of a Dose Finding Phase and a Dose Expansion 
Phase. 
The Dose Finding Phase will estimate the MTD and RP2D in patients with aRCC with clear 
cell histology who did not receive prior systemic therapy for advanced disease, using the 
modified toxicity probability interval (mTPI) method.29 Dose finding will follow an mTPI 
design, with up to 3 potential dose levels (DL) to be tested:
•
(DL1) avelumab 10 mg/kg Q2W + axitinib 5 mg BID.
•
(DL-1A) avelumab 5 mg/kg Q2W + axitinib 5 mg BID.
•
(DL-1B) avelumab 10 mg/kg Q2W + axitinib 3 mg BID. 
DL-1A and DL-1B will be explored concurrently in a randomized fashion only if the MTD is 
exceeded in DL1. 
To understand the extent of any effects of avelumab on axitinib PK, a 7-day lead-in period 
with single-agent axitinib will be included prior to Cycle 1 in all patients in the Dose Finding 
Phase of the study.  Since avelumab has a half-life of 3-5 days, it would not be feasible to run 
a lead-in with avelumab alone to study the PK of avelumab alone.  Therefore, the effect of 
axitinib on avelumab will be evaluated by comparing avelumab trough concentrations at 
steady state in the presence of axitinib with those reported for avelumab alone in prior 
studies. 
The Dose Finding Phase will lead to the identification of an Expansion Test Dose for 
avelumab in combination with axitinib in patients with aRCC who did not receive prior 
systemic therapy for their advanced disease.  The Expansion Test Dose will either be the 
MTD (ie, the highest dose of avelumab and axitinib associated with the occurrence of DLTs 
in <33% of patients) or the RP2D, ie, the highest tested dose that is declared safe and 
tolerable by the investigators and sponsor.  Once the Expansion Test Dose is identified, the 
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Dose Expansion Phase will be opened, and avelumab in combination with axitinib will be 
evaluated in up to approximately 40 patients with previously untreated aRCC. 
Based on the emerging PK data and after the completion of the dose-finding part of the study 
based on mTPI method, it may be necessary to enroll up to approximately 8 additional 
patients to further assess the effect of avelumab on the PK of axitinib.  These additional 
patients will undergo the same evaluations and procedures as those described in the 
Schedule of Activities table for the Dose Finding Phase of the study and will be treated 
concurrently with the initiation of the Dose Expansion Phase of the study.  With the 
exception of the mTPI-related assessments leading to determination of MTD, any other 
assessments or procedures described for the Dose Finding Phase will also apply to these 
additional patients. 
Throughout the course of the study, patient safety will be closely monitored by the sponsor’s 
study team. The number of patients to be enrolled in the Dose Finding Phase will depend on 
the observed safety profile, and the number of tested dose levels.
All patients will be followed for survival until death, end of the study, or patient withdrawal 
of consent, whichever comes first, regardless of initiation of new anti-cancer therapy.  
Patients who do not return to the site should be contacted by telephone every 3 months as an 
alternative.
Study Treatment: 
Axitinib will be given orally (PO) twice daily (BID), with or without food, on a continuous 
dosing schedule.  Avelumab will be given as a 1-hour IV infusion Q2W.  All patients will 
continue treatment with study drugs 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 6.4). 
Patients will be monitored closely for toxicity, and in the event of significant toxicity, dosing 
of one or both drugs may be modified.  Specifically, avelumab doses may be omitted or 
permanently discontinued, and axitinib doses may be delayed, reduced, or permanently 
discontinued, as per Section 5.3.5.  Based on the known safety profile of axitinib, blood 
pressure as well as thyroid function will be monitored throughout the treatment period.  
Axitinib treatment may be adjusted by dosing interruption with or without dose reduction 
(Section 5.3.5.3).  Avelumab treatment modification for drug-related toxicities, including 
immune-related adverse events (irAEs) and infusion-related AEs is described in 
Section 5.3.5.
In the Dose Finding Phase, intrapatient axitinib dose escalation is not permitted, except for 
patients treated at DL-1B.  In these patients, after the completion of the primary DLT 
observation period, intrapatient axitinib dose escalation may occur according to the criteria 
described in Section 5.3.5.1.  In the Dose Expansion Phase, intrapatient axitinib dose 
escalation may occur if the intrapatient escalation criteria are met (see Section 5.3.5.1).
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Patients who stop one of the two study drugs (avelumab or axitinib) for reasons other than 
confirmed disease progression may continue on single-agent treatment with the other drug 
until disease progression (RECIST v.1.1), patient refusal, patient lost to follow up, 
unacceptable toxicity, or the study is prematurely terminated by the sponsor, whichever 
comes first.  Patients who are still deriving clinical benefit following continued treatment for 
more than 2 years will be provided an option for continued study treatment (eg, a rollover 
study). 
Patients who stop avelumab after initial clinical benefit while on treatment and then 
experience radiologic disease progression thereafter will be eligible for re-treatment with 
avelumab at the discretion of the investigator and after discussion with the sponsor’s medical 
monitor if 1) no cancer treatment was administered other than axitinib since the last dose of 
avelumab, 2) the patient does not meet the safety withdrawal criteria, and 3) the trial is still 
open.  Patients will resume avelumab therapy at the same dose and schedule applied at the 
time of discontinuation. 
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.
Tumor Assessment: Anti-tumor activity will be assessed by radiological tumor assessments 
and will be based on RECIST v1.1 (Appendix 2) for secondary endpoints 
 
Increasing clinical experience indicates that traditional response criteria may not be sufficient 
to fully characterize activity in this new era of targeted therapies and/or biologics.  This is 
particularly true for immunotherapeutic agents such as anti-CTLA-4 and 
anti-PD-1/anti-PD-L1 antibodies which exert their antitumor activity by augmenting 
activation and proliferation of T cells, thus leading to tumor infiltration by T cells and tumor 
regression rather than direct cytotoxic effects.30,31 Clinical observations of patients with 
advanced melanoma treated with ipilimumab, for example, suggested that conventional 
response assessment criteria such as RECIST and World Health Organization (WHO) criteria 
are not sufficient to fully characterize patterns of tumor response to immunotherapy because 
tumors treated with immunotherapeutic agents may show additional response patterns that 
are not described in these conventional criteria.32 Furthermore, the conventional tumor 
assessment criteria (RECIST and WHO criteria) have been reported as not capturing the 
existence of a subset of patients who have an OS similar to those who have experienced 
complete response (CR) or PR but were flagged as progressive disease (PD) by WHO 
criteria.32 On these grounds, a tumor assessment system has been developed that 
incorporates these delayed or flare-type responses into RECIST v1.1
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Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, 6 weeks after the first dose of therapy (Cycle 1 Day 1), every 6 weeks up to 1 year 
after the first dose of therapy, and then every 12 weeks therafter until documented disease 
progression regardless of initiation of subsequent anticancer therapy.  In addition, 
radiological tumor assessments will also be conducted whenever disease progression is 
suspected (eg, symptomatic deterioration).  CR and PR must be confirmed with repeat 
imaging performed at least 4 weeks after initial documentation of response.  If radiologic 
imaging shows PD, tumor assessment should be repeated after at least 4 weeks to confirm 
PD, unless clinical deterioration occurs.  Details are provided in Section 5.3.3.3.
Brain Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) scans are 
required at baseline and when there is a suspected brain metastasis.  Bone scan (bone 
scintigraphy) or 18fluorodeoxyglucose-positron emission tomography/CT (18FDG-PET/CT) 
are required at baseline, then every 12 weeks only if bone metastases are present at baseline.  
Otherwise, bone imaging is required only if new bone mestastases are suspected.  Bone 
imaging is also required at the time of confirmation of CR for patients who have bone 
metastases.
Safety Assessments: Safety will be monitored at regular intervals throughout the study by 
means of laboratory tests and clinical visits as reported in the Schedule of Activities.
Pharmacokinetic/Immunogenicity Assessments: PK/immunogenicity sampling will be 
collected as described in the Schedule of Activities and in the Schedule for Pharmacokinetic 
Sample Collection.  To understand the PK effects of avelumab on axitinib, a 7-day lead-in 
period with single-agent axitinib will be included prior to Cycle 1 in all patients in the Dose 
Finding Phase of the study.  Based on the emerging PK profile of avelumab, and after the 
dose-finding per mTPI method is complete, it may be necessary to enroll up to approximately 
8 additional patients to further assess the effect of avelumab on the PK of axitinib.  Since 
avelumab has a half-life of 3-5 days, it would not be feasible to run a lead-in to study the PK 
of avelumab alone.  Therefore, the effect of axitinib on avelumab will be evaluated by 
comparing avelumab trough concentrations at steady state in the presence of axitinib with 
those reported for avelumab alone in prior studies. 
The proposed doses, schedule(s), and PK time points may be reconsidered and modified 
during the study based on emerging safety and PK data.
Biomarker Assessments: A key objective of the biomarker analyses that will be performed in 
this study is to investigate biomarkers that are potentially predictive of treatment benefit with 
the combination of avelumab and axitinib.  In addition, biomarker studies of tumor and blood 
biospecimens will be carried out to help further understand the mechanism of action of the 
avelumab in combination with axitinib, as well as potential mechanisms of resistance. 
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1.
 
 
 
 
 
 
 
 
 
 
2.
 
 
  
 
 
 
 
 
 
 
 
 
3.1.1. Dose Finding Phase
3.1.1.1. Starting Doses for Avelumab and Axitinib (Dose Level 1)
The starting doses (Dose Level 1) are avelumab 10 mg/kg IV Q2W and axitinib 5 mg BID in 
2-week cycles. 
3.1.1.2. Dose-Finding Criteria 
Dose finding will follow the mTPI method,29 using doses of avelumab and axitinib as shown 
in Table 1.
Table 1.
Dose Levels in the Dose Finding Phase
Dose Level
Avelumab
Axitinib
1 (Starting Dose Level)
10 mg/kg IV Q2W
5 mg oral BID
-1A
5 mg/kg IV Q2W
5 mg oral BID
-1B
10 mg/kg IV Q2W
3 mg oral BID
BID: twice daily; Q2W: every 2 weeks
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Dose de-escalation to DL-1A and DL-1B
Possible dose-finding scenarios based on the starting dose level (1) tolerability are illustrated 
in Table 2.  DL-1A and DL-1B will be explored only if the design recommends de-escalation 
at DL1. 
In this dosing algorithm, there are up to 3 potential dose levels (DL): (DL1) avelumab 
10 mg/kg Q2W + axitinib 5 mg BID, (DL-1A) avelumab 5 mg/kg Q2W + axitinib 5 mg BID, 
and (DL-1B) avelumab 10 mg/kg Q2W + axitinib 3 mg BID. 
Alternative doses, schedule(s), and PK time points may be reconsidered during the study 
based on the emerging safety and PK data.
There are several potential dose-finding sequences for avelumab in combination with 
axitinib.  The specific sequence to be followed depends upon the number of patients enrolled 
in the study and the number of DLTs observed at each specific dose combination.  The 
sequences are mutually exclusive, meaning only one of the sequences will be followed 
throughout the course of the study.  Possible sequences are listed below in Table 2. 
Table 2.
Possible Dose Finding Sequences
Possible Sequences Starting with Dose Level 1
a)
DL1
b)
DL1 →DL-1A and DL-1B
c)
DL1 →DL-1A and DL-1B →DL1
DL: dose level
Dosing will begin at DL1 and possibly be de-escalated to DL-1A and DL-1B according to 
Table 1 and Table 2.
Dose escalation from DL-1 back to DL1 will be allowed as long as DL1 has not been 
determined to have exceeded the MTD and the rule indicates escalation for both DL-1A and 
DL-1B.  The escalation/de-escalation rules will follow the mTPI method.29
Briefly, the mTPI method relies upon a statistical probability algorithm, calculated using all 
patients treated in prior and current cohorts at the same dose level to determine where future 
cohorts should involve dose escalation, no change in dose, or dose de-escalation.  The 
detailed dose-finding rules based on the mTPI are illustrated in Table 3.
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Table 3.
Detailed Dose Escalation/De Escalation Scheme
Number of patients treated at current dose
1
2
3
4
5
6
Number of Toxicities
0
E
E
E
E
E
E
1
D
S
S
S
S
E
2
DU
D
S
S
S
3
DU
DU
D
D
4
DU
DU
DU
5
DU
DU
6
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
U = The current dose is unacceptably toxic
Note: for the initial dose level (ie, “DL1”) evaluated, the doses are maintained (“S”), while DL-1A or DL-1B 
may be escalated (“E”). 
As an example, if the total number of patients treated at DL1 is 3, the following dosing rules 
are applied:
•
0 - 1 DLTs →remain at the same dose (DL1);
•
2 DLTs →de-escalate to DL-1 and allow for possible escalation back to DL1;
•
3 DLTs →de-escalate to DL-1 and consider DL1 as intolerable.
If the dose is de-escalated to DL-1A and DL-1B and the total number of patients then treated 
at DL-1A and DL-1B is 3, the following dosing rules are applied within each dose level:
•
0 DLTs (in DL-1A and DL-1B) →escalate back to DL1;
•
1 DLT (in either DL-1A or DL-1B) →remain at the same DL (DL-1);
•
2-3 DLTs (in either DL-1A or DL-1B)→de-escalation not possible and depending on 
the distribution of the DLTs one or both doses at DL-1 will be considered intolerable.
Rules for dose-finding, using the mTPI method, include the following:
•
The target enrollment cohort size is 3 patients.  However, patients may be enrolled in 
cohort sizes of 3-4 depending on the number of potential patients identified at 
participating sites.  The patients treated at each dose level may initiate dosing 
simultaneously.  If the first 2 patients experience a DLT prior to enrollment of the 
third one, the dose level will be deemed intolerable and the dose level will be 
de-escalated.
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•
The next cohort may be enrolled when all patients at the current dose cohort have 
been evaluated for 4 weeks (ie, the first 2 treatment cycles), or experience a DLT, 
whichever comes first.
•
If a patient withdraws from study treatment before receiving at least 75% of the 
planned first 2 cycles of axitinib or 2 infusions of avelumab for reasons other than 
study drug-related toxicity, another patient will be enrolled to replace that patient at 
the current dose level.
•
The dose-finding component of the trial is completed when 6 DLT-evaluable patients 
have been treated at the highest dose associated with DLT rate <0.33.  It is estimated 
that approximately 15 DLT-evaluable patients will need to be enrolled to reach 
6 DLT-evaluable patients at the estimated MTD.
•
The RP2D will be confirmed in the Dose Expansion Phase, taking into account the 
MTD determination from the Dose Finding Phase, and other factors related to safety, 
efficacy, PK, and PD involving all available data from test cohorts.
3.1.2. Dose-Limiting Toxicity Definition
Severity of adverse events will be graded according to CTCAE version 
4.03 (see Appendix 4).  For the purpose of dose finding, any of the following adverse events 
occurring during the primary DLT observation period (4 weeks, from the time of first 
administration of avelumab [Cycle 1 Day 1] until the planned administration of the third dose 
of avelumab [Cycle 3 Day 1]) that are attributable to one, the other, or both agents in 
combination will be classified as DLTs:
•
Hematologic:
•
Grade 4 anemia; 
•
Grade 4 neutropenia lasting >7 days;
•
Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with 
a single temperature of >38.3 degrees C (>101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour; 
•
Grade ≥3 neutropenic infection;
•
Grade ≥3 thrombocytopenia with bleeding;
•
Grade 4 thrombocytopenia.
•
Non-Hematologic (including Non-Laboratory):
•
Any Grade ≥3 toxicity, except for any of the following:
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•
Transient (≤6 hours) Grade 3 flu-like symptoms or fever, which is controlled 
with medical management;
•
Transient (≤24 hours) Grade 3 fatigue, local reactions, or headache that 
resolves to Grade ≤1;
•
Grade 3-4 nausea and vomiting controlled by optimal medical therapy within 
72 hours;
•
Grade 3 hypertension controlled by medical therapy;
•
Grade 3 diarrhea or Grade 3 skin toxicity that resolves to Grade ≤1 in less 
than 7 days after medical management (eg, immunosuppressant treatment) has
been initiated;
•
Any Grade ≥3 amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis;
•
Tumor flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor.
•
Grade 3-4 liver function test elevation (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST]) concurrent with Grade 2 elevation of total bilirubin.
•
Non-hematologic Grade ≥3 laboratory abnormality if medical intervention is 
required to treat the patient, or if the abnormality leads to hospitalization. 
•
Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the investigator, do not have any clinical correlate, and 
resolve to Grade ≤1 within 7 days with adequate medical management are not
to be considered DLTs.
•
Inability to complete at least 75% of the first 2 cycles doses of axitinib (starting from 
Cycle 1 Day 1 after completion of the Lead-in PK period) or 2 infusions ofavelumab 
within the DLT observation period due to investigational product-related toxicity.
In absence of associated clinical abnormalities, abnormal laboratory tests should be repeated 
to confirm relevance.  While the rules for adjudicating DLTs in the context of dose 
finding/dose expansion phases are specified above, an AE not listed above, or an AE meeting 
the DLT criteria above but occurring outside of the DLT observation period may be defined 
as a DLT after consultation between sponsor and investigator, based on the emerging safety
profile.
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3.2. Maximum Tolerated Dose Definition
The MTD estimate is the highest dose level tested of avelumab and axitinib associated with 
the occurrence of DLTs within the first 2 cycles of treatment in <33% of DLT-evaluable 
patients.
3.3. Dose Expansion Phase Test Dose Definition
The Expansion Phase Test Dose will be the MTD identified in the Dose Finding Phase.  
Further experience in the Dose Expansion Phase cohort may result in the need to explore a 
lower Dose Expansion Phase Test Dose.
3.3.1. Dose Expansion Phase 
The Dose Expansion Phase Test Dose identified in the Dose Finding Phase will be expanded 
up to an additional 40 patients with the purpose of confirming the safety, efficacy, PK, and 
PD of that dose.
In case both DL-1A and DL-1B regimens are identified as Dose Expansion Phase Test 
Doses, both of them will be expanded up to an additional 40 patients randomly enrolled in 
each arm.
3.4. Recommended Phase 2 Dose Definition
The RP2D is the dose of avelumab and axitinib in combination chosen for further studies 
based on Phase 1 study results.  If the MTD proves to be clinically feasible for long-term 
administration in a reasonable number of patients, then this dose usually becomes the RP2D.  
Further experience with the MTD may result in a RP2D dose lower than the MTD.  Attention 
will be given to the percentage of patients that discontinue treatment due to treatment-related 
AEs, especially (both early and late occurring) immune-related (dose-limiting) toxicities.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol. 
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Diagnosis:
•
Histologically or cytologically confirmed advanced RCC with clear cell 
component;
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•
Primary tumor resected;
•
A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo
tumor biopsy obtained during screening will be required (biopsied tumor lesion 
should not be a RECIST target lesion).  Alternatively, a recently obtained archival 
FFPE tumor tissue block (not cut slides) from a primary or metastatic tumor 
resection or biopsy can be provided if the following criteria are met: 1) the biopsy 
or resection was performed within 1 year of enrollment AND 2) the patient has 
not received any intervening systemic anti-cancer treatment from the time the
tissue was obtained and enrollment.  If an FFPE tissue block cannot be provided 
as per documented regulations 15 unstained slides (10 minimum) will be 
acceptable (see Section 6.1.1). 
•
Availability of an archival FFPE tumor tissue block from primary diagnosis 
specimen (if available and not provided per above).  If an FFPE tissue block 
cannot be provided, as per documented regulations, 15 unstained slides 
(10 minimum) will be acceptable (see Section 6.1.1); 
•
At least one measureable lesion as defined by RECIST version 1.1 that has not 
been previously irradiated.
2. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative, as allowed by local 
guidance/practice) has been informed of all pertinent aspects of the study.
3. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures.
4. Age ≥18 years. (≥20 years in Japan).
5. Estimated life expectancy of at least 3 months.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see 
Appendix 1.
7. No evidence of pre-existing uncontrolled hypertension as documented by 2 baseline 
blood pressure (BP) readings taken at least 1 hour apart.  The baseline systolic BP 
readings must be ≤140 mm Hg, and the baseline diastolic BP readings must be 
≤90 mm Hg.  Use of antihypertensive medications to control BP is allowed. 
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 (may have been transfused).
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9. Adequate renal function, including:
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. Adequate liver function, including:
a.
Total serum bilirubin ≤1.5 x upper limit of normal (ULN); 
b. AST and ALT ≤2.5 x ULN. 
11. Serum pregnancy test (for females of childbearing potential) negative at screening.
12. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective methods of contraception 
throughout the study and for at least 90 days after the last dose of assigned treatment. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Any of the following prior cancer therapies:
•
Prior systemic therapy directed at advanced RCC;
•
Prior adjuvant or neoadjuvant therapy for RCC if disease progression or relapse 
has occurred during or within 12 months after the last dose of treatment;
•
Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab), or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways;
•
Prior therapy with axitinib as well as any prior therapies with other VEGF 
pathway inhibitors. 
2. Participation in other therapeutic studies within 4 weeks prior to enrollment in the 
current study.
3. Patients with known symptomatic brain metastases requiring steroids.  Patients with 
previously diagnosed brain metastases are eligible if they have completed their 
treatment and have recovered from the acute effects of radiation therapy or surgery 
prior to enrollment, have discontinued corticosteroid treatment for these metastases 
for at least 4 weeks, and are neurologically stable.
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4. Major surgery ≤4 weeks or major radiation therapy ≤2 weeks prior to enrollment.  
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been 
completed at least 48 hours prior to enrollment. 
5. Persisting toxicity related to prior therapy NCI CTCAE v4.03 Grade >1; however, 
sensory neuropathy Grade ≤2 is acceptable.
6. Current or prior use of immunosuppressive medication within 7 days prior to 
enrollment, except the following:
•
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection);
•
Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent;
•
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication). 
7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any 
history of anaphylaxis.
8. Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations.
9. Diagnosis of any other malignancy within 5 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on 
surveillance with no plans for treatment intervention (eg, surgery, radiation or 
castration).
10. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agents.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible. 
11. Gastrointestinal abnormalities including:
•
Inability to take oral medication;
•
Requirement for intravenous alimentation;
•
Prior surgical procedures affecting absorption including total gastric resection;
•
Treatment for active peptic ulcer disease in the past 6 months;
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•
Active gastrointestinal bleeding, unrelated to cancer, as evidenced by clinically 
significant hematemesis, hematochezia or melena in the past 3 months without 
evidence of resolution documented by endoscopy or colonoscopy;
•
Malabsorption syndromes.
12. Active infection requiring systemic therapy.
13. Diagnosis of prior immunodeficiency or organ transplant requiring 
immunosuppressive therapy, or known human immunodeficiency virus (HIV) or 
acquired immunodeficiency syndrome (AIDS)-related illness.
14. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or
chronic infection. 
15. Vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines (for example, inactivated 
influenza vaccines).
16. Requirement of anticoagulant therapy with oral vitamin K antagonists.  Low-dose 
anticoagulants for maintenance of patency of central venous access device or 
prevention of deep venous thrombosis is allowed.  Therapeutic use of low molecular 
weight heparin is allowed.
17. Evidence of inadequate wound healing.
18. Grade ≥3 hemorrhage within 4 weeks of patient enrollment. 
19. Any of the following within the previous 6 months: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack deep 
vein thrombosis, or symptomatic pulmonary embolism.
20. Current use or anticipated need for treatment with drugs or foods that are known 
strong CYP3A4/5 inhibitors, including their administration within 10 days prior to 
patient enrollment (eg, grapefruit juice or grapefruit/grapefruit-related citrus fruits 
[eg, Seville oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazole, 
posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, 
mibefradil, and conivaptan).  The topical use of these medications (if applicable), 
such as 2% ketoconazole cream, is allowed.
21. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, 
including their administration with 10 days prior to patient 
enrollment(eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, 
rifapentin, clevidipine, St John’s wort).
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22. Patients who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study. 
23. Pregnant female patients, breastfeeding female patients.
24. Other severe acute or chronic medical conditions including colitis, inflammatory 
bowel disease, uncontrolled asthma, and pneumonitis or psychiatric condition, 
including recent (within the past year) or active suicidal ideation or behavior, or 
laboratory abnormality that may increase the risk associated with study participation 
or investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study.
4.3. Life Style Guidelines 
4.3.1. Contraception
In this study, patients will receive avelumab (for which the teratogenic risk is currently 
unknown) in combination with axitinib, which has been associated with teratogenic risk.
The investigator or his or her designee, in consultation with the patient, will confirm that the 
patient has selected an appropriate method of contraception for the individual patient or her 
partner from the permitted list of contraception methods (see Section 4.3.1.4) and will 
confirm that the patient has been instructed in its consistent and correct use.  At time points 
indicated in the Schedule of Activities (SoA), the investigator or designee will inform the 
patient of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the patient’s chart 
(participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  
Patients must agree to use at least 1 of the selected methods of contraception throughout the 
study and continue to do so for at least 30 days after the last dose of study treatment. 
In addition, the investigator or designee will instruct the patient to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
participant or partner.
4.3.1.1. Male Participant Contraception
Male patients with female partner of childbearing potential must agree to use a male condom 
during the intervention period and for at least 30 days after the last dose of study treatment.
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4.3.1.2. Female Participant Reproductive Status
A female patient is eligible to participate if she is not pregnant or breastfeeding and at least 
1 of the following conditions applies:
•
Is not a Women of Childbearing Potential (WOCBP) (see definitions in Section 
4.3.1.3).
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below 
during the intervention period and for at least 30 days after the last dose of study 
treatment.  The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
4.3.1.3. Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:
•
Documented hysterectomy;
•
Documented bilateral salpingectomy;
•
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview.  The method of documentation should be recorded in the participant’s medical 
record for the study.
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2. Postmenopausal female:
•
A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 
•
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 
•
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
4.3.1.4. Contraception Methods
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.
•
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:
•
oral;
•
intravaginal;
•
transdermal;
•
injectable.
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2. Progestogen-only hormone contraception associated with inhibition of ovulation:
•
oral;
•
injectable.
3. Sexual abstinence:
•
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
If exposure during pregnancy will occur, please refer to Section 8.10 Exposure During 
Pregnancy.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Investigator site file.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patients participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems, however it should be used 
only in the event that the established communication pathways between the investigational
site and the study team are not available.  It is therefore intended to augment, but not replace 
the established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).  For the purpose of this study the 
investigational products are avelumab (MSB0010718C) and axitinib (AG-013736).
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5.1. Allocation to Treatment
Dose level allocation will be performed by the sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments.  In case DL-1A 
and DL-1B both are investigated, 6 patients will be randomly assigned to either dose levels 
(1:1 treatment allocation, 3 patients per dose level). 
The site staff will fax or e-mail a complete Registration Form to the designated sponsor study 
team member(s) requesting approval for patient enrollment.
After review of patient’s eligibility and concomitant medications, the sponsor will approve 
patient’s enrollment, if appropriate, and assign a patient identification number (8 digits, of 
which 4 belong to the site identifier number), which will be used on all Case Report Form 
(CRF) pages and other trial-related documentation or correspondence referencing that 
patient.  Demographic information will also be required.
The sponsor will fax or e-mail the approved Registration Form reporting the patient 
identification number to the site.  See also Schedule of Activities table.
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:
•
Confirmation of the patient’s enrollment.
•
Specification of the dose level for that patient.
•
Permission to proceed with dosing the patient.
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.  Study treatment (either 
single-agent axitinib for patients in Lead in or avelumab in combination with axitinib for all 
other patients) should begin within 3 days after enrollment or randomization.  See Schedule 
of Activities table.
5.2. Patient Compliance
A patient diary will be provided to the patients to aid in axitinib compliance.  The diary will 
be maintained by the patient to include missed or changed axitinib doses.
Patients will be required to return all bottles of axitinib at each clinic visit.  The number of 
axitinib tablets remaining will be documented and recorded at each clinic visit.  The patient 
diary may also be used to support this part of the axitinib accountability process.
The site is to follow up (for example, via a telephone call) with each patient at 
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.
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5.3. Investigational Product Supplies
Avelumab (MSB0010718C) and axitinib (AG-013736) will be supplied for the study by 
Pfizer Global Clinical Supply, Worldwide Research and Development.  Drug supplies will be 
shipped to the study sites with a Drug Shipment and Proof of Receipt form.  This form will 
be completed, filed, and the shipment confirmed as directed on the bottom of the Drug 
Shipment and Proof of Receipt form.  The investigator shall take responsibility for and shall 
take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution, and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations.
5.3.1. Dosage Form(s) and Packaging
5.3.1.1. Axitinib
Axitinib will be supplied as 1 mg and 5 mg film-coated tablets for oral administration in 
light-resistant high-density polyethylene (HDPE) bottles with desiccant.
5.3.1.2. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20.0 mg/mL solution and will be supplied by the sponsor in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene 
flip-off seal.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines.  Avelumab will be packed in 
boxes each containing one vial.  The information on the study treatment will be in 
accordance with approved submission documents. 
Avelumab will be shipped in transport cool containers (2°C to 8°C) that are monitored with 
temperature monitoring devices.
5.3.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.
5.3.2.1. Avelumab
Avelumab will be dosed at the investigational site.
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard cleanup procedures for biologic products.
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For application in this trial, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection).  Detailed information on infusion bags and medical devices to be 
used for the preparation of the dilutions and subsequent administration will be provided in 
the Dosage and Administration Instruction (DAI) contained in the Investigational Product 
Manual (IP Manual). 
Avelumab must not be used for any purpose other than the trial.  The administration of trial 
investigational product to patients who have not been enrolled into the trial is not covered by 
the trial insurance.
Any unused portion of the solution should be discarded in biohazard waste disposal with 
final disposal by accepted local and national standards of incineration.
See the DAI for instructions in the IP Manual 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.
5.3.2.2. Axitinib
Axitinib will be dispensed in opaque plastic bottles to protect the compounds from light.  
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 
Interactive Response Technology (IRT) system. 
Axitinib will be dispensed every 6 weeks 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.
Axitinib 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.
5.3.3. Administration
All investigational products will be administered on an outpatient basis.
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5.3.3.1. Avelumab
The DAI within the IP Manual contains specific instructions for avelumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Avelumab will be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as described in the Schedule of Activities table.  Avelumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle.
Avelumab will be administered as a 1-hour IV infusion once every 2-weeks.  In order to 
mitigate infusion-related reactions, a premedication with an antihistamine and with 
paracetamol (acetaminophen) approximately 30 to 60 minutes prior to each dose of avelumab 
is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol 
[acetaminophen] IV or oral equivalent).  This may be modified based on local treatment 
standards and guidelines, as appropriate.  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 CRFs.  Possible modifications of the infusion rate for the 
management of infusion-related reactions are described in Section 5.3.5.5. 
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kg).  All patients should be weighed within 3 days prior to 
dosing for every cycle.  If the patient experienced either a weight loss or gain 
>10% compared to the weight used to calculate the prior dose, the amount of study drug 
required for preparation and administration for the current cycle must be recalculated using 
this most recent weight obtained. For weight changes ≤10% compared to the weight used to 
calculate the prior dose, the decision on whether to recalculate the avelumab dose will be 
made in accordance with local practices. Avelumab dose reduction for toxicity management 
is not permitted, however next cycle administration may be omitted due to persisting toxicity 
as described in Table 5 and Section 5.3.5.
5.3.3.2. Axitinib
Axitinib will be administered orally BID at approximately the same time in the morning and 
evening on a continuous dosing schedule, ie, without a break in dosing in the absence of 
drug-related toxicity (see Section 5.3.5).  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 anytime after taking a dose, they 
must not “make it up” with an extra dose, but instead resume subsequent doses as prescribed.  
Any missed dose may be taken late, 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.  
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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.
If a patient inadvertently takes 1 extra dose during a day, the patient should not take the next 
dose.
5.3.3.3. Treatment after Initial Evidence of Radiologic Disease Progression 
Immunotherapeutic agents such as avelumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiologic imaging shows disease progression, tumor assessment should be repeated 
≥4 weeks later in order to confirm the observation, unless clinical deterioration occurs.  
Assigned study treatment may be continued at the investigator’s discretion while awaiting 
radiologic confirmation of disease progression. 
Patients may receive study treatment 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.
If repeat imaging no longer shows PD but rather CR, PR or SD compared to the initial scan, 
treatment may be continued/resumed.  In determining whether or not the tumor burden has 
increased or decreased, investigators should consider all target as well as non target lesions. 
If the repeat imaging confirms PD, patients should be discontinued from study treatment.  
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 single agent avelumab, 
axitinib, or avelumab combined with axitinib.  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. 
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Patients who stop avelumab after initial clinical benefit while on treatment and then 
experience radiologic disease progression thereafter will be eligible for re-treatment with 
avelumab at the discretion of the investigator and after discussion with the sponsor’s medical 
monitor if 1) no cancer treatment was administered other than axitinib since the last dose of 
avelumab, 2) the patient does not meet the safety withdrawal criteria, and 3) the trial is still 
open.  Patients will resume avelumab therapy at the same dose and schedule applied at the 
time of discontinuation.
5.3.4. Food Requirements
Both investigational products may be administered without regard for 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]).
5.3.5. Recommended Dose Modifications
Every effort should be made to administer investigational product on the planned dose and 
schedule.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify investigators at the first occurrence 
of any adverse symptom.  In addition to dose modifications, investigators are encouraged to 
employ best supportive care according to local institutional clinical practices and according 
to the guidance for selected adverse events provided below.
For axitinib dose modifications may occur in 2 ways:
•
Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle;
•
In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
For avelumab, no dose modifications are permitted in this study, but next infusion may be 
omitted based on persisting toxicity, as outlined in Table 5. 
Dose modifications and infusion omissions may occur independently for the two drugs used 
in this study and will be reported in the CRF.
Available axitinib dose levels for intrapatient dose modification are listed in Table 4.
5.3.5.1. Intrapatient Axitinib Dose Escalation and Dose Reduction 
In the Dose Finding Phase, intrapatient axitinib dose escalation is not permitted for patients 
treated at DL-1A.
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Intrapatient axitinib dose escalation is permitted for patients treated in the Dose Finding 
Phase at DL-1B (avelumab 10 mg/kg Q2W + axitinib 3 mg BID).  In these patients, after the 
completion of the primary DLT observation period (4 weeks), intrapatient axitinib dose 
escalation to 5 mg BID may occur according to the criteria reported below. 
In the Dose Expansion Phase, intrapatient axitinib dose escalation up to 10 mg BID may 
occur according to the criteria reported below. 
Criteria for Intrapatient Dose Escalation: Patients who tolerate the current axitinib dose 
without Grade >2 drug-related adverse events for 2 consecutive weeks (in the Dose 
Expansion Phase) or 4 consecutive weeks (in the Dose Finding Phase, only DL-1B), and who 
do not experience BP >150/90 mm Hg or concurrent administration of antihypertensive 
medication, have the option to have their axitinib dose increased (by one dose level at a time 
[Table 4]).  Patients treated in the Dose Finding Phase at DL-1B have the option to have their 
axitinib dose increased to a maximum dose of 5 mg BID.  Particular attention should be 
provided to a patient’s overall safety profile prior to implementing intrapatient axitinib dose 
escalation.
Table 4.
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, up to 2 dose levels (one dose level 
reduction at a time) will be allowed depending on the type and severity of toxicity 
encountered.  Management of patients requiring more than 2 dose reductions should be 
discussed with the sponsor’s medical monitor.
Patients who have undergone dose reduction may also undergo dose re-escalation back to the 
previous dose level at the discretion of the Investigator in the absence of 
Grade ≥2 non- hematologic treatment-related toxicity for at least 28 days.
5.3.5.2. Management of Axitinib-Related Hypertension
Patients will be issued BP cuffs (provided by the sponsor) for home monitoring and 
instructed to measure their BP twice daily, prior to taking each axitinib dose.  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 
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(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 axitinib, and patients should be 
monitored for hypertension.  To treat an increase in BP, standard antihypertensives may be 
used (for example, thiazide or thiazide-like diuretics, angiotensin II receptor blockers, 
angiotensin converting-enzyme inhibitors, and dihydropyridine [DHP] calcium channel 
blockers.33,34
5.3.5.3. 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 5.  These guidelines might be further modified at the 
discretion of the sponsor based on the emerging safety profile of the combination.  The 
investigator should discuss with the sponsor’s medical monitor any dose modification and or 
treatment discontinuation in case of persistent toxicity that would lead to dose modification
or treatment discontinuation per toxicity management guidelines.  Consult with the sponsor’s 
medical monitor before discontinuing the patient. 
Consider consulting with the sponsor’s medical monitor for Grades 1 and 2 drug-related 
toxicities (Table 5), and always consult with the sponsor’s medical monitor for Grades 3 and 
4 drug-related toxicities (Table 5).
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Table 5.
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
Hematologic 
Abnormalities
Grade 1
•
Continue at the same dose level.
•
Continue as per schedule.
Grade 2
•
Continue at the same dose level.
•
Continue as per schedule.
Grade 3
•
Continue at the same dose level.
•
Withhold avelumab
•
Re-initiate avelumab once toxicity is Grade 
≤1 or baseline.
•
Permanently discontinue avelumab if 
toxicities does not resolve to Grade ≤1 or 
baseline within 12 weeks (consult with the 
sponsor’s 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 
(consult with the sponsor’s medical 
monitor before permanently discontinuing 
the treatment).
•
Exceptions are:
Laboratory values that do not 
have any clinical correlate.
Proteinuria
Dipstick negative or 
shows 1+ (Grade 1)
•
Continue at the same dose level.
•
Continue as per schedule.
If dipstick shows >1+, perform 24 hour urine collection.  Dosing may continue 
while waiting for test results.
<2 g proteinuria/ 
24 hour
•
Continue at the same dose level.
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Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
≥2 g proteinuria/ 
24 hours
•
Withhold until proteinuria is <2 g/24 hours.
•
Repeat 24-hour urine collection for 
proteinuria and creatinine clearance (interval 
at investigator discretion) until proteinuria is 
<2 g/24 hours. 
•
Then, resume at the same dose level or reduce 
by 1 dose level as per investigator judgment.
Hypertension
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure ≤150 mm Hg 
(one or both readings) 
And
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
≤100 mm Hg (one or 
both readings)
•
Continue at the same dose level
•
See Section 5.3.5.2 for 
monitoring/management of axitinib-related 
hypertension.
•
Continue as per schedule
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >150 mm Hg
OR
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
>100 mm Hg
•
If not on maximal antihypertensive treatment, 
institute new or additional antihypertensive 
medication and continue at the same dose 
level. 
•
If on maximal antihypertensive treatment, 
reduce by 1 dose level.
•
See Section 5.3.5.2 for 
monitoring/management of axitinib-related 
hypertension.
•
Continue as per schedule.
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Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >160 mm Hg 
OR
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
>105 mm Hg
•
Withhold until BP is less than 150/100 mm 
Hg 1 and adjust antihypertensive medication.
•
Then, reduce by 1 dose level and resume 
treatment. 
•
1 If axitinib dosing is temporarily 
discontinued, patients receiving 
antihypertensive medications should monitor 
closely for hypotension.  The plasma half-life 
of axitinib is 2-4 hours and BP usually 
decreases within 1-2 days following dose 
interruption.
•
See Section 5.3.5.2 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 5.3.5.2 for 
monitoring/management of axitinib-related 
hypertension.
•
Continue as per schedule.
Infusion-related 
Reaction 
Grade 1-4
•
Continue at the same dose level.
•
See Section 5.3.5.5 and Table 6
Hypersensitivity 
reactions
Grade 3-4
•
Continue at the same dose level.
•
See Section 5.3.5.6 and Table 6
Tumor lysis syndrome
Grade 1-4
•
See Other Non-Hematologic
Toxicities and/or Laboratory Abnormalities.
•
See Section 5.3.5.7 and Figure 1
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Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
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 5.3.5.8 and Table 7
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 (consult 
with medical monitor before 
permanently discontinuing the 
treatment).
Exceptions are:
•
Laboratory values that do not 
have any clinical correlate (eg, 
amylase or lipase abnormality that 
is not associated with symptoms 
or clinical manifestations of 
pancreatitis).
•
Nausea and vomiting controlled 
by medical therapy.
•
Tumor flare phenomenon defined 
as local pain, irritation, or rash 
localized at sites of known or 
suspected tumor.
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Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
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 (consult with the 
sponsor’s medical monitor before 
permanently discontinuing the 
treatment).
Exceptions are:
•
Laboratory values that do not 
have any clinical correlate.
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5.3.5.4. Special Precautions for Avelumab Administration
In order to mitigate avelumab infusion-related reactions, a premedication with an 
antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to 
each dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 
500-650 mg paracetamol [acetaminophen] IV or oral equivalent).  This may be modified 
based on local treatment standards and guidelines, as appropriate. 
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications 
(IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access.
Infusion of avelumab will be stopped in case of Grade ≥2 infusion-related, allergic, or 
anaphylactic reactions.  If an allergic reaction occurs, the patient must be treated according to 
the best available medical practice.  Guidelines for the emergency treatment of anaphylactic 
reactions are available at www.resus.org.uk/pages/reaction.pdf (Working Group of the 
Resuscitation Council [United Kingdom], www.erc.edu (European Resuscitation Council 
[European Union]), www.heart.org (American Heart Association [United States]), and 
www.american cpr.com (American Cardio-Pulmonary Resuscitation [CPR] Training™ 
[United States]).  Patients should be instructed to report any delayed reactions to the 
investigator immediately. 
Treatment recommendations for the management of infusion-related reactions, severe 
hypersensitivity reactions, tumor lysis syndrome, and immune-related adverse events (irAEs) 
are outlined in Section 5.3.5.5, 5.3.5.6, 5.3.5.7, 5.3.5.8, respectively.
Investigators should also monitor patients closely for potential irAEs, which may become 
manifest at any time after the first dose of avelumab treatment. Such events may more often 
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 5.3.5.8.
5.3.5.5. Management of Avelumab Infusion-Related Reactions 
Since avelumab is administered IV, infusion-related reactions may occur (with symptoms 
such as fever, chills, rigors, diaphoresis, and headache).  Treatment of the infusion-related 
reaction and modifications of avelumab infusion are mainly dependent upon severity, as 
indicated in Table 6. 
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Table 6.
Treatment Modification for Symptoms of Avelumab Infusion -Related 
Reactions
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.
The total infusion time for avelumab should not 
exceed 120 minutes.
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hours.
Stop avelumab infusion.
Resume infusion at 50% of previous rate as soon as 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any recurrence or worsening.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop the avelumab infusion immediately and 
disconnect bag infusion tubing from the patient.
Avelumab treatment must be permanently 
discontinued.
IV=intravenous, NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events, 
NSAIDs=non-steroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% due to an infusion-related 
reaction, it must remain so for all subsequent infusions.  The total infusion time for avelumab 
should not exceed 120 minutes.
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 6 (including reducing the infusion 
rate by 50%), the investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed for that cycle.  At the next cycle, the investigator may consider the 
addition of H2-blocker antihistamines (eg, famotidine or ranitidine), meperidine, or 
ibuprofen to the mandatory premedication.  Prophylactic steroids are NOT permitted.
5.3.5.6. Management of Avelumab-Related Severe Hypersensitivity Reactions and 
Flu-Like Symptoms 
As with all monoclonal antibody therapies, avelumab can induce flu-like symptoms and 
hypersensitivity reactions, including impaired airway, decreased oxygen saturation (<92%), 
confusion, lethargy, hypotension, pale/clammy skin, and cyanosis.
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment if required.  Patient should be placed on 
monitor immediately and epinephrine injection and dexamethasone infusion should be 
available for immediate access.
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For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable non-steroidal 
anti-inflammatory drug (NSAID) dose (eg, ibuprofen 600 mg, naproxen sodium 500 mg) 
may be administered at investigator discretion 2 hours before and 8 hours after the start of 
each dose of avelumab IV infusion.  Alternative treatments for fever (eg, paracetamol or 
ibuprofen) and rigors (eg, meperidine) may be given to patients at the discretion of the 
investigator.
Additional treatment recommendations for symptoms of avelumab infusion-related reactions 
are provided in Appendix 6 and may be modified based on local treatment standards and 
guidelines, as appropriate.
5.3.5.7. Management of Avelumab-Related Tumor Lysis Syndrome
Avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), so there is a
potential risk of tumor lysis syndrome (TLS).  Should this occur, patients should be treated as 
per local guidelines and the management algorithm (Figure 1) published by Howard et al.35
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Figure 1.
Assessment and Initial Management of Tumor Lysis Syndrome 
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinolor ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia
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5.3.5.8. Management of Avelumab Immune-Related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of 
irAEs is mainly dependent upon severity (NCI CTCAE grade v. 4.03):
•
Grade 1 to 2: treat symptomatically or with moderate-dose steroids, more frequent 
monitoring;
•
Grade 1 to 2 (persistent): manage similar to Grade 3 to 4 AE;
•
Grade 3 to 4: treat with high-dose corticosteroids.
Treatment of irAEs should follow guidelines set forth in Table 7. 
Some potential irAEs described with anti-PD-L1 drugs such as avelumab may overlap with 
axitinib toxicities (eg, diarrhea, elevated liver function tests).  Any adverse event suspected to 
be immune-related should be managed according to the guidance for management of irAEs 
in this section.
For potential overlapping Grade 2 irAEs, hold both drugs used in the combination (avelumab 
and axitinib) and follow the specific management recommendations described in Table 7.  
When the event resolves to Grade ≤1, restart therapy with axitinib.  If the Grade ≥2 event 
does not recur, restart avelumab at the beginning of the next treatment cycle.  If the 
Grade ≥2 event does not resolve to Grade ≤1 after holding avelumab for 2 treatment cycles 
(up to 28 days) or if the Grade ≥2 event recurs after re-introduction of avelumab, 
permanently discontinue avelumab therapy.
For potential overlapping Grade ≥3 irAEs, hold axitinib and follow the specific guidance in 
Table 7 for avelumab.  When the event resolves to Grade ≤1, restart therapy with axitinib at 
reduced dose level.  Avelumab should be permanently discontinued.
Table 7.
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 patient to report worsening 
immediately.
If worsens:
Treat as Grade 2, 3 or 4.
Grade 2
Diarrhea: 4 to 6 stools per day 
over baseline; IV fluids indicated 
<24 hours; not interfering with 
ADL
Colitis: abdominal pain; blood in 
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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stool 
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over baseline; incontinence; 
IV fluids ≥24 hrs; interfering 
with ADL
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs
Grade 4: life-threatening, 
perforation
Withhold avelumab 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 5mg/kg (if no 
contraindication).
Note: infliximab should not be used 
in cases of perforation or sepsis.
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
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).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Intial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding avelumab 
therapy.
Monitor for symptoms every
2 to 3 days.
Re-assess at least every 3 weeks
If worsens:
Treat as Grade 2 or Grade 3 to 4.
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Consider Pulmonary and
Infectious Disease consults.
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.
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.
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 
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Add prophylactic antibiotics
for opportunistic infections.
Consult gastroenterologist/
Hepatologist.
Consider obtaining MRI/CT
scan of liver and liver biopsy
if clinically warranted.
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.
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.
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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).
*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.
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):
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
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- 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.
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.
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.
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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. 
5.4. Investigational Product Storage 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
label.
•
Axitinib must be stored at controlled room temperature (between 15-30°C) or as 
specified on the label.
•
Avelumab must be stored in the refrigerator (between 2-8°C) or as specified on the 
label. 
Storage conditions stated in the SRSD (ie, investigator’s brochure) will be superseded by the 
storage conditons stated on the label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be documented.  The operation of the temperature monitoring device 
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and storage unit (for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions. 
Site staff will instruct patients on the proper storage requirements for take-home 
investigational products.
5.5. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product-supplies.  All bottles of study drug must be 
returned to the investigator by the patient at every visit and at the end of the trial, Pfizer will 
provide instructions as to disposition of any unused investigational product. 
5.6. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatments(s)
Medications or vaccinations specifically prohibited in the Exclusion Criteria (Section 4.2) are 
also not allowed during the active treatment period, except for administration of the 
inactivated influenza vaccine.
If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy or 
medication/vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the patient’s primary physician.  However, the 
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decision to continue the patient on study therapy or medication/vaccination schedule requires 
the mutual agreement of the investigator, the sponsor, and the patient. 
Concomitant treatment considered necessary for the patient’s well being may be given at the 
discretion of the treating physician.
All concomitant treatments, blood products, as well as non-drug interventions received by 
patients from screening until the end of study visit will be recorded on the CRF. 
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatment and up to 90 days after the last dose of 
study treatment.  All concomitant medications should be recorded in the CRF including 
supportive care drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat 
adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
Concurrent anticancer therapy with agents other than avelumab and axitinib is not allowed.  
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
Recommended medications to treat infusion-related reactions, hypersensitivity reactions, 
flu-like symptoms, tumor lysis syndrome and immune-related events are reported in 
Sections 5.3.5.5, 5.3.5.6, 5.3.5.7, and 5.3.5.8, respectively. 
5.7.1. Inhibitors and Inducers of CYP Enzymes
In vitro studies with human liver microsomes and recombinant CYP enzymes indicate that 
axitinib metabolism is primarily mediated by the CYP3A4/5, and to a lesser extent by 
CYP1A2, CYP2C19, and UGT1A1. 
The concomitant use of strong CYP3A4/5 inhibitors (eg, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, 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, consider dose reduction if axitinib must be used with a 
CYP3A4/5 inhibitor. 
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 dose escalation if axitinib must be used with a 
CYP3A4/5 inducer.
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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.
5.7.2. Hematopoietic Growth Factors
Granulocyte colony-stimulating factor may be used in agreement with American Society of 
Clinical Oncology (ASCO) guidelines.46
Patients who enter the study on stable doses of erythropoietin or darbepoietin may continue 
this treatment, and patients may start either drug during the study at the discretion of the 
treating physician if clinically indicated.
5.7.3. Concomitant Surgery 
No formal studies of the effect of axitinib on wound healing have been conducted; however, 
caution is advised based on the mechanism of action.  If a major surgery or an interventional 
procedure (eg, endoscopy) is required, treatment with axitinib must be interrupted at least 
24 hours before the procedure, and the patient BP should be monitored closely for 
hypotension.  Patients may resume axitinib 7 days after minor surgery and 2-3 weeks after 
major surgery, assuming the wound has completely healed and there are no wound healing 
complications (eg, delayed healing, wound infection or fistula).
In case of surgical procedure avelumab treatment should be delayed.  Reinitiation should be 
discussed with the sponsor.
5.7.4. Concomitant Radiotherapy
Local radiotherapy (limited field) of isolated lesions with palliative intent is acceptable and 
allowed throughout the study (ie, starting from the screening through end of treatment) if 
considered medically necessary by the treating physician.  All attempts should be made to 
rule out disease progression in the event of increased localized pain.  If palliative 
radiotherapy is needed to control pain, the site(s) of disease causing pain should be present at 
baseline; otherwise, painful lesion(s) requiring radiotherapy will be considered as a sign of 
disease progression.  The Medical Monitor should be consulted prior to starting radiotherapy 
and prior to restarting study treatment after the end of radiotherapy.
5.7.5. Other Prohibited Concomitant Medications and Therapies 
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 
•
Immunotherapy, immunosuppressive drugs (ie, chemotherapy or systemic 
corticosteroids except for short-term treatment of allergic reactions or for the 
treatment of irAEs).  Short-term administration of systemic steroids (eg, for allergic 
reactions or the management of irAEs) is allowed.  Topical and inhalation steroids are 
allowed.
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•
Any vaccine therapies for the prevention of infectious disease within 4 weeks after 
the start of study treatment, except administration of the inactive influenza vaccine. 
•
Bisphosphonate or denosumab treatment is not allowed unless it has been initiated 
more than 14 days prior to receiving the first administration of avelumab.
•
Anti-cancer systemic chemotherapy or biological therapy or investigational agents 
other than avelumab and axitinib. 
•
Other experimental pharmaceutical products.
•
Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin).
Clarifications about Steroid Use: Data indicate that corticosteroids have an adverse effect 
on T cell function and that they inhibit and damage lymphocytes.36,37 Furthermore, as with 
all immunotherapies intended to augment cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit of the 
proposed study treatment.  However, studies with anti-CTLA-4 compounds indicate that 
short-term use of steroids may be employed without compromising clinical outcomes.38
Therefore, the use of steroids during this trial is restricted as follows:
•
Therapeutic use: for the treatment of infusion-related reactions and short-term 
treatment of irAEs, steroids are permitted according to the modalities indicated in 
Table 7.
•
Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
≤10 mg prednisone daily is acceptable.
•
Prophylactic use, eg, for the prevention of acute infusion-related reactions: is 
prohibited, except prior to CT or MRI scan.
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.8. Rescue Medications and Supportive Care 
5.8.1. Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
•
Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
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•
Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 
•
Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in Table 7.
•
Anti-inflammatory or narcotic analgesics may be offered as needed.  
Acetaminophen/paracetamol to a maximum total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited.
•
Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed. 
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures, see Schedule of Activities table and Assessments section 
(Section 7). 
6.1.1. Tumor Biospecimens
Provision of tumor biospecimen will be required for enrollment onto the study as follows:
1. Recent tumor biospecimen: a mandatory FFPE tumor tissue block from a de novo
tumor biopsy must be obtained from all patients during screening.  The biopsied 
tumor lesion should not be a RECIST target lesion.  
 
 
 
 
 
2. Archival tumor biospecimen: a mandatory archival FFPE tumor tissue block from the 
primary diagnosis specimen must be provided from all patients prior to 
enrollment/randomization. 
 
 
 
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3. End of Treatment Tumor Biospecimen: A de novo tumor sample (ie, fresh biopsy) 
should also be collected at the time of discontinuation of either drugs and at the End 
of Treatment unless clinically contraindicated. 
  
 
 
 
 
 
 
 
For all tumor biospecimen, tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material), is not adequate and should not be submitted.  The 
de novo biopsy(ies) should be FFPE as per routine (see Study Manual), and the resulting 
FFPE tissue block(s) or slides should be submitted to the Central Laboratory.  Additional 
information on tumor biospecimen collection procedures is included in the Study Manual.
6.2. Study Period
For treatment period procedures, see Schedule of Activities table and Assessments section 
(Section 7). After amendment #4 approval, patients receiving axitinib single agent will visit 
the site every 6 weeks. Between site visits, AEs and concomitant medications collection will 
be performed every 2 weeks by telephone call (eg, nurse) in a standardized form, unless the 
patient is visiting the site for other reasons.
6.3. End of Treatment/Withdrawal and Follow-up Visits
For follow-up procedures, see Schedule of Activities table and Assessments section 
(Section 7). 
6.4. End of Study
The study will end after all treated patients have died, been lost to follow-up or have 
withdrawn consent to be followed for survival.
6.5. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol- required schedule of study 
visits or procedures at a given study site. 
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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 with single-agent avelumab or axitinib, or with avelumab in combination 
with axitinib , provided that the treating physician has determined that the benefit/risk 
for doing so is favorable (see Section 5.3.3.3);
•
Global deterioration of health status requiring discontinuation;
•
Unacceptable toxicity.  If the unacceptable toxicity is attributed to one of the two 
study treatments, the investigator (in discussion with the sponsor) may continue 
treatment with the other study treatment;
•
Pregnancy;
•
Significant protocol violation;
•
Lost to follow-up;
•
Patient refused further treatment (follow-up permitted by patient);
•
Study terminated by sponsor;
•
Death.
Reasons for withdrawal from study follow-up may include:
•
Study terminated by sponsor;
•
Lost to follow-up;
•
Refused further follow-up;
•
Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs.
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If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, then no further evaluations should be performed, and no additional data should 
be collected.  The sponsor will retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well being of the patient.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he or she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the Schedule of Activities table. 
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed on up to 3 occasions prior to starting combination study 
treatment - once at the start of screening (all patients), and once at Lead-in Day 1 (patients in 
Dose Finding Phase only and up to approximately 8 additional patients enrolled for further 
PK assessment) immediately before axitinib administration, and at the Cycle 1 Day 1 visit 
(all patients) immediately before the administration of avelumab in combination with 
axitinib.  Following a negative pregnancy test result at screening, appropriate contraception 
must be commenced and another negative pregnancy test result will then be required at the 
baseline visit before the patient may receive the investigational product.  Additional 
pregnancy tests (serum or urine) will also be routinely repeated at every cycle during the 
active treatment period, at the end of study treatment, and during short tem Fu period, and 
additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  In the case of a positive hCG test, the patient will be withdrawn from treatment 
but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by Institutional Review 
Board/Ethics Committees (IRB/ECs) or if required by local regulations.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by NCI 
CTCAE version 4.03), timing, seriousness, and relatedness.
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7.1.3. Laboratory Safety Assessments
Haematology, blood chemistry, and urinalysis will be collected at the time points described 
in the Schedule of Activities table and analyzed at local laboratories.  They may also be 
performed when clinically indicated.  The required laboratory tests are listed in Table 8.  
Clinically significant abnormal laboratory results shoud be repeated as soon as possible 
(preferably within 24-48 hours) and followed up as per standard clinical practice unless 
otherwise specified in this protocol.
If a full and core chemistry panel are scheduled at the same visit, then only the full chemistry 
panel will be performed.
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Table 8.
Required Laboratory Tests
Hematology
Chemistry Panel
(* denotes core chemistry 
test)
After amendment #4 
approval 
Chemistry Panel
(# denotes test to be 
performed only when 
clinically indicated)
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT*
ALT
Protein, 
glucose, 
blood.
Urine 
dipstick/other 
semiquantitati
ve method, 
for urine 
protein: if 
≥2+, collect 
24-hour
PT, INR
For female 
patients of 
childbearin
g potential, 
serum or 
urine 
Platelets
AST*
AST
PTT or aPTT
WBC
Alkaline Phosphatase*
Alkaline Phosphatase
Absolute 
Neutrophils
Sodium*
Sodium
Absolute 
Lymphocytes
Potassium*
Potassium
Absolute 
Monocytes
Magnesium*
Magnesium
Absolute 
Eosinophils
Chloride*
Chloride
Absolute 
Basophils
Total Calcium*
Total Calcium
Total Bilirubin* °
Total Bilirubin °
BUN or Urea*
BUN or Urea
Creatinine*
Creatinine
Glucose (non-fasted)*
Glucose (non-fasted)
Phosphorus or Phosphate*
Phosphorus or 
Phosphate
Albumin
Albumin#
Total Protein
Total Protein#
Uric Acid
Uric Acid#
Amylase
Amylase
Gamma glutamyl 
transferase (GGT)
Gamma glutamyl 
transferase (GGT)
Cholesterol
Cholesterol#
Creatine kinase
Creatine kinase
C-reactive protein (CRP) 
C-reactive protein 
(CRP) #
Lactate dehydrogenase 
(LDH)
-
Lipase
Lipase
Triglycerides
Triglycerides#
Other tests: HBV, HCV
Thyroid Function Tests: TSH,  free T4
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Other Tests: 
ACTH
° For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time 
(PT)/INR, alkaline phosphatase.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin 
time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, 
GGT=gamma-glutamyltransferase, HBV= hepatitis B Virus, HCV= hepatitis C Virus, INR=international 
normalized ratio, LDH=lactate dehydrogenase, TSH=thyroid-stimulating hormone, WBC=white blood cell.
7.1.4. Vital Signs and Physical Examination
Physical examinations will be performed according to institutional guidelines on study days 
as described in the Schedule of Activities table. 
The physical examination will include major body systems, weight (height will be measured 
at screening only), assessment of ECOG performance status. 
Vital signs (blood pressure, pulse rate) will be measured at the time points described in the 
Schedule of Activities table.  Blood pressure and pulse rate should be taken with the patient 
in the seated position after the patient has been sitting quietly for at least 5 minutes.  Two 
blood pressure and pulse rate readings will be taken at least 1 hour apart at each clinic visit 
(every 6 weeks after amendment #4 approval). 
In addition, all patients will be monitoring BP at home as described in Section 5.3.5.2.
7.1.5. (12-Lead) Electrocardiogram Measurements
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECG 
assessments. 
All patients require a triplicate ECG measurement at screening and on treatment.  
On-treatment ECGs will be performed on Lead-in Day 7 (patients in Dose-Finding Phase and 
and up to approximately 8 additional patients enrolled to assess the effect of avelumab on the 
PK of axitinib), Cycle 1 Day 1 (all patients), Cycle 4 Day 1 (all patients), and End of 
Treatment/Withdrawal.  At each time point, 3 consecutive 12-lead ECGs (triplicates) will be 
performed approximately 2 minutes apart to determine mean QTc (average of triplicates).  
Triplicate ECGs at Cycle 1 Day 1 will be prior to avelumab infusion and within 30 minutes 
post end of -infusion.  When coinciding with blood sample draws for PK, ECG assessment 
should be performed prior to blood sample collection such that the blood sample is collected 
at the nominal time. 
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Clinically significant findings seen on subsequent ECGs should be recorded as adverse 
events.  In case of QTc >500 msec (ie, CTCAE Grade >2), ECG must be reviewed by 
qualified personnel at the site as soon as the finding is made, including verifying that the 
machine reading is accurate and that the Fridericia correction formula is applied.  If the 
manual reading verifies a rate corrected QTc of >500 msec, a repeat ECG should be 
immediately performed at least two times approximately 2 to 4 minutes apart. 
An electronic reading of prolonged QTc must be confirmed by manual reading.  Prior to 
conclusion that an episode of prolongation of the QTc interval is due to study drug, thorough 
consideration should be given to potential precipitating factors (eg, change in patient clinical 
condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation 
by specialist.  If QTc interval reverts to less than 500 msec, and in the judgment of 
investigator and sponsor is determined to be due to a cause other than study drug, treatment 
may be continued with regular ECG monitoring.
If patient experiences a cardiac or neurologic AE (eg, syncope, dizziness, seizures, or stroke), 
then triplicate ECGs should be obtained at time of the event.  If the mean QTc is prolonged 
(>500 msec), then the ECGs should be re-evaluated by a qualified person at the institution for 
confirmation and repeated as clinically indicated.  Additional triplicate ECGs may be 
performed as clinically indicated.
7.2. Pharmacokinetics Assessments
Plasma/serum samples will be obtained from patients for PK analysis of avelumab and 
axitinib depending on the study phase (Dose Finding or Dose Expansion) that they belong to.  
Samples for avelumab PK will be collected from all patients in the study.  Axitinib PK 
samples will be collected from all patients in the Dose Finding Phase and, if needed, up to 
approximately 8 additional patients enrolled to assess the effect of avelumab on the PK of 
axitinib. 
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis 
Where noted in the Schedule of Activities table, blood samples will be collected at 
approximately the same time as other assessments wherever possible. 
The PK table indicates PK blood sampling time points for axitinib alone and avelumab in 
combination with axitinib.  For all PK blood sample collections, the actual time of avelumab 
and axitinib dosing, as well as actual times of PK collections, will be recorded in the source 
documents and CRF.  On the days of axitinib PK sample collection, patients should be 
instructed to hold morning axitinib dosing until the pre-dose sample has been drawn.  
Patients should have been taking axitinib uninterrupted for at least 3 days prior to each of the 
axitinib PK sample collection visits.  Patients who do not take the scheduled axitinib doses 
for 3 consecutive days prior, must reschedule PK sample collections to a future date.  If this 
occurs in the axitinib Lead-in period, it may delay Cycle 1 Day 1; if it occurs during 
treatment cycles, it may delay Cycle 4 Day 1 avelumab infusion.  For all PK collections, the 
actual time of avelumab and axitinib dosing, as well as actual times of PK collections will be 
recorded in the source documents and CRF. 
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Blood samples for axitinib PK and avelumab PK will be collected as outlined in the Schedule 
for Pharmacokinetic Sample Collections table.  PK sampling schedule may be modified 
based on emerging PK data. 
PK samples for avelumab will also be collected at the Day 30 Follow-up visit after the end of 
avelumab treatment. 
In addition to samples collected at the scheduled times, additional blood samples for axitinib 
and avelumab should be collected from patients experiencing unexpected and/or serious AEs 
and the date and time of blood sample collection and of the last dosing prior to PK collection 
documented in the CRF.
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60-minute sample) will be considered protocol compliant, and the exact time of the sample 
collection noted on the CRF.  If a scheduled blood sample collection cannot be completed for 
any reason, the missed sample collection may be rescheduled with agreement of the 
investigator and sponsor.
PK samples will be assayed for avelumab and axitinib using validated analytical methods.  
Additional details regarding the collection, processing, storage, and shipping of the blood 
samples will be provided in the study manual.  As part of the understanding of the PK of the 
study drug, samples may be used for potential qualitative and/or quantitative metabolite 
analyses and/or evaluation of the bioanalytical methods for avelumab and axitinib.  The 
results of such analyses may be included in the clinical report.
7.2.2. 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 tube to provide a minimum of 1 mL plasma for axitinib PK 
analysis.
7.2.3. Collection of Avelumab Pharmacokinetic Samples
A total of 3.5 mL of whole blood will be collected into a serum separator tube (SST) at the 
designated times to provide serum for avelumab PK analysis.
7.3. Immunogenicity Assessment
A total of 3.5 mL of whole blood will be collected into a SST at the designated times to 
provide serum for evaluation of avelumab immunogenicity.  Immunogenicity blood samples 
will be assayed for anti-avelumab antibodies using a validated analytical method.  All of the 
samples that are positive for ADA may also undergo characterization for neutralizing 
antibodies.  Additional details regarding the collection, processing, storage, and shipping of 
the blood samples will be provided in the Study Manual.
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7.4. Translational and Pharmacodynamic Assessments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers that may have predictive value in identifying those patients 
who may benefit from treatment with the combination of avelumab and axitinib.  In addition, 
analyses of sequentially obtained blood biomarkers will provide an opportunity to investigate 
pharmacodynamic effects.  Samples collected at the End of Treatment visit will also help 
understand potential mechanisms of resistance to the drug combination.
 
 
 
Tumor biopsies obtained at the time of discontinuation of either drugs and at the End of 
Treatment will be used to investigate acquired mechanisms of resistance.  Only core needle 
or excisional biopsies, or resection specimen are suitable.  Cytologic preparations, such as 
fine needle aspirate biopsies, are not acceptable.  Additional information on tissue collection 
procedures can be found in the Study Manual.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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•
 
 
 
 
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.6. Tumor Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen, and pelvis CT or MRI scans; it may also include brain CT or MRI scan at 
baseline and whenever brain metastases are suspected.  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.
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline, at 6 weeks after the first dose of therapy (Cycle 1 Day 1), then every 6 weeks up to 
1 year from the first dose of therapy, and then every 12 weeks thereafter until documented 
disease progression regardless of initiation of subsequent anticancer therapy.  In addition, 
radiological tumor assessments will also be conducted whenever disease progression is 
suspected (eg, symptomatic deterioration) and at the time of withdrawal from the treatment 
(if not done in the previous 6 weeks).  CR and PR must be confirmed with repeat imaging 
performed at least 4 weeks after initial documentation of response.  If radiological imaging 
shows PD, then tumor assessment should be repeated after at least 4 weeks to confirm PD, 
unless clinical deterioration occurs.  See Schedule of Activities table and Section 5.3.3.3 for 
treatment after initial evidence of disease progression.
Brain CT or MRI scans are required at baseline and when there is a suspected brain 
metastasis.  Bone scan (bone scintigraphy) or 18FDG-PET/CT is required at baseline then 
every 12 weeks only if bone metastases are present at baseline.  Otherwise, bone imaging is 
required only if new bone metastases are suspected.  Bone imaging is also required at the 
time of confirmation of complete response for patients who have bone metastases.  
Otherwise, bone imaging is required only if new bone metastases are suspected and at the 
time of confirmation of CR for patients who have bone metastases.
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions unless increase in size has been observed following completion of radiation 
therapy.
Assessment of response will be made using RECIST version 1.1 (Appendix 2) 
 
All patients’ files and radiologic images must be available for source verification and for 
potential peer review by a third party.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
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For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any non-serious adverse event 
that is determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 90 calendar days after the last 
administration of the study treatment. 
SAEs occurring to a patient after the active reporting period has ended should be reported to 
the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product are to be reported to the sponsor. 
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least one dose of study treatment through and including 90 calendar days after the 
last administration of study treatment.  If a patient begins a new anticancer therapy, the AE 
reporting period for nonserious AEs ends at the time the new treatment is started.  Death 
must be reported if it occurs during the SAE reporting period after the last dose of study 
treatment, irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 
•
Abnormal test findings;
•
Clinically significant symptoms and signs;
•
Changes in physical examination findings;
•
Hypersensitivity;
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•
Drug abuse;
•
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:
•
Drug overdose;
•
Drug withdrawal;
•
Drug misuse; 
•
Drug interactions;
•
Extravasation;
•
Exposure during pregnancy (EDP);
•
Exposure via breastfeeding;
•
Medication error;
•
Occupational exposure;
•
Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.3.1. Avelumab Adverse Events of Special Interest
Any AE that is suspected to be a potential irAE is considered an AE of special interest 
(AESI).  Specific guidance for the management of irAEs is provided in Section 5.3.5.8.  
AESIs are reported according to the general AE reporting rules specified in Section 8.1 and 
8.2.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the serious adverse event 
(SAE) form when appropriate.  In the event of medication dosing error, the sponsor should 
be notified immediately.
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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:
•
Medication errors involving patient exposure to the investigational product;
•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page. 
The guidance on reporting of medication errors also applies to the reporting of overdose.
For purposes of this study, an overdose is defined as an increase ≥5% than the planned 
avelumab dose for that particular administration. 
For axitinib, an overdose is defined as a dose greater than 10 mg BID. 
There is no specific treatment for overdose of avelumab or axitinib.  In the event of overdose, 
the patient should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated. 
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
•
Test result is associated with accompanying symptoms; and/or
•
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or
•
Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or
•
Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
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8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:
•
Results in death;
•
Is life-threatening (immediate risk of death);
•
Requires inpatient hospitalization or prolongation of existing hospitalization;
•
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
•
Results in congenital anomaly/birth defect;
•
Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE (version 4.03) Grade 5 (see 
the section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see section on Serious Adverse Event Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT concurrent with abnormal elevations in total bilirubin 
that meet the criteria outlined below in the absence of other causes of liver injury are 
considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and should 
always be considered important medical events. 
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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:
•
Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 × ULN concurrent with a 
total bilirubin value ≥2 × ULN with no evidence of hemolysis and an alkaline 
phosphatase value ≤2 × ULN or not available.
•
For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:
•
For patients with preexisting AST or ALT baseline values above the normal 
range, AST or ALT value ≥2 times the baseline values and ≥3 × ULN, or 
≥8 × ULN (whichever is smaller).
•
Concurrent with:
•
For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least 1 × ULN or if the 
value reaches ≥3 × ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin 
time (PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug, 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for Liver Function Test (LFT) abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs.
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8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute an 
hospitalization; however, the event leading to the emergency room visit should be assessed 
for medical importance.
Hospitalization does not include the following:
•
Rehabilitation facilities;
•
Hospice facilities;
•
Respite care (eg, caregiver relief);
•
Skilled nursing facilities;
•
Nursing homes;
•
Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 
•
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);
•
Social admission (eg, patient has no place to sleep);
•
Administrative admission (eg, for yearly physical examination);
•
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);
•
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);
•
Hospitalization for observation without a medical AE;
•
Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;
•
Admission exclusively for the administration of blood products.
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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the iponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product”, 
this should be clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
For combination treatments, causality assessment will be performed for each of the 
individual drugs included in the combination. 
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8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
•
A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant women (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 study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 
•
Spontaneous abortion includes miscarriage and missed abortion.
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•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (see Also the Section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient/parent(s)/legal guardian/legally acceptable representative.  In addition, each 
study patient/parent(s)/legal guardian/legally acceptable representative will be questioned 
about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
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8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy escalations must be submitted as soon as possible to Pfizer or 
its designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment.
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9.1. Analysis Sets 
The following patient sets will be assessed:
•
Full Analysis Set.
The full analysis set includes all patients who receive at least 1 dose of study drug 
(axitinib or avelumab) and all patients who are randomized independent of whether 
they received a dose of study drug.  Patients will be classified according to the 
treatment actually received or according to the treatment assigned at randomization if 
randomization occurs in this study. 
•
Safety Analysis Set.
The safety analysis set includes all enrolled patients who receive at least 1 dose of 
avelumab or axitinib.
•
Per Protocol Analysis Set (Dose Finding Phase; evaluable for DLT).
The per protocol analysis set includes all enrolled patients during the Dose Finding 
Phase who:
•
Receive at least 1 dose of avelumab and axitinib; and 
•
Either experience DLT during the first 2 cycles of combination axitinib + 
avelumab treatment, or complete the primary DLT observation period for the 
first 2 cycles of combination treatment (4 weeks). 
Patients who withdraw from study treatment before receiving at least 75% of the 
planned first 2 cycles of axitinib starting from Cycle 1 Day 1 after completion of the 
Lead-in PK period or 2 infusions of avelumab within the primary DLT observation 
period due to reasons other than investigational product-related adverse events are not 
evaluable for DLT.
•
PK Analysis Set.
The PK analysis set is defined as all enrolled patients who receive at least 1 dose of 
avelumab or axitinib and who have at least 1 concentration above the below limit of 
quantitation (BLQ) of either study drug. 
The PK parameter analysis set is defined as all enrolled patients who receive at least 
1 dose of avelumab or axitinib and who have at least 1 of the PK parameters of 
interest of either study drug. 
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•
Immunogenicity Analysis Set.
The immunogenicity analysis set is defined as all enrolled patients who receive at 
least 1 dose of avelumab or axitinib and who have at least 1 ADA sample collected.
•
Biomarker Analysis Set.
The biomarker analysis set is defined as all enrolled patients who have at least one 
screening biomarker assessment and who receive at least 1 dose of avelumab or 
axitinib.  Analysis sets will be defined separately for blood-based and tumor 
tissue-based biomarkers.
9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Dose Escalation/De-Escalation: mTPI
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation trials that improve accuracy, efficiency, and statistical validity. 
The modified toxicity probability interval (mTPI) design29 is an interval-type of design that
uses a Bayesian statistics framework and a beta/binomial hierarchical model to compute the 
posterior probability of 3 dosing intervals that reflect the relative difference in probability 
between the toxicity rate of each dose level to the target rate (pT = 0.33).  If the toxicity rate 
of the currently used dose level is far smaller than pT, the mTPI will recommend escalating 
the dose level; if it is close to pT, the mTPI will recommend continuing at the current dose; if 
it is far greater than pT, the mTPI will recommend de-escalating the dose level.  These rules 
are conceptually similar to those used by the 3+3 design, except the decisions of an mTPI 
design are based on posterior probabilities calculated under a coherent probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different trials with different toxicity parameters.  More 
importantly, all the dose-escalation decisions for a given trial can be pre-calculated under the 
mTPI design.  Thus, compared to other advanced model-based designs published in the 
literature, the mTPI design is logistically less complicated and easier to implement. 
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of Avelumab as a single-agent in Study EMR100070-001, e1 is selected as 
0.05, and e2 is selected as 0.03.  Therefore, the target dosing interval for the DLT rate is 
(0.25, 0.33).
The 3 dosing intervals are associated with 3 different dose-escalation decisions.  The 
under-dosing interval corresponds to a dose escalation (E), over-dosing corresponds to a dose 
de-escalation (D), and proper-dosing corresponds to remaining at the current dose (R).  
Given a dosing interval and a probability distribution, the UPM of that dosing interval is 
defined as the probability of a patient belonging to that dosing interval divided by the length 
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of the dosing interval.  The mTPI design calculates the UPMs for the 3 dosing intervals, and 
the one with the largest UPM informs the corresponding dose-finding decision, which is the 
dose level to be used for future patients.  For example, if the under-dosing interval has the 
largest UPM, the decision will be to escalate, and the next cohort of patients will be treated at 
the next higher dose level.  Ji and collaborators29 have demonstrated that the decision based 
on UPM is optimal in that it minimizes a posterior expected loss (ie, minimizes the chance of 
making a wrong dosing decision). 
The dose finding component of the trial (Phase 1) uses a modified version of the mTPI 
design that maximizes the number of evaluable patients treated at each dose level at 6.  Dose 
finding is completed when 6 evaluable patients have been treated at the highest dose with 
DLT rate <0.33.
9.3. Sample Size Determination
The sample size planned for the dose finding part arises from logistic feasibility and is not 
entirely driven by statistical considerations.  Due to the dynamic nature of the dose allocation 
procedure and unknown safety profile of the combination, the sample size of the interval 
design cannot be determined in advance.  It is expected that approximately 15 DLT-evaluable 
patients will be required for the dose finding phase.
Up to approximately 40 patients will be included in the dose expansion phase of the study for 
each MTD dose level cohort expanded.  A sample size of 40 patients will provide at least 
90% probability to observe at least 1 AE if the true incidence of the AE in the population is 
≥6%. 
Based on the emerging PK data and after the completion of the dose-finding part of study 
phase on mTPI method, it may be necessary to enroll up to approximately 8 additional 
patients to further assess the effect of avelumab on the PK of axitinib.  These additional 
patients will undergo the same evaluations and procedures as those described in the Schedule 
of Activities for the Dose Finding Phase of the study and will be treated concurrently with 
the initiation of the Dose Expansion Phase. 
9.4. Efficacy Analysis 
In this study, assessement of anti-tumor activity is a secondary objective.  Efficacy analyses 
will be presented in the form of statistical summaries and data listings for the Dose 
Expansion Phase.  For patients enrolled in the Dose Finding Phase, only data listings for best 
overall response (BOR) may be presented. 
This study may include randomization to study treatments (see Section 5.1).  Efficacy 
endpoints will be defined based on ‘start date’ which is the start date of study treatment for 
patients who are not randomized, or the date of randomization for patients who are 
randomized to DL-1A or DL-1B.
9.4.1. Analysis of Efficacy Endpoints
Efficacy data will be analyzed by treatment group based on the full analysis set for patients 
enrolled in the Dose Expansion Phase.
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Confirmed objective Response (OR) is defined as complete response (CR) or partial response 
(PR) according to RECIST v1.1 from the start date until disease progression or death due to 
any cause.  Both CR and PR must be confirmed by repeat tumor assessment performed no 
less than 4 weeks after the criteria for response are first met.  Patients who do not have an
on-treatment radiographic tumor assessment due to early disease progression, who receive 
anti-tumor treatments other than the study treatments prior to achieving CR or PR, or who 
die, experience disease progression, or drop out for any reason prior to achieving CR or PR 
will be counted as non-responders in the assessment of OR.  OR rate (ORR) is defined as the 
proportion of patients who have an OR. 
Disease Control (DC) is defined as OR (CR or PR) or stable disease (SD) per RECIST 
v1.1 from the start date until the first documentation of objective disease progression or death 
due to any cause.  DCR is defined as the proportion of patients with DC.
Time to Tumor Response (TTR) is defined as the time from start date to the first 
documentation of objective tumor response (CR or PR) that is subsequently confirmed.
Duration of Response (DR) is defined as the time from the first documentation of objective 
tumor response (CR or PR) that is subsequently confirmed to the first documentation of 
objective tumor progression or to death due to any cause, whichever occurs first. The 
censoring rules for DR are as defined below for PFS. 
Progression Free Survival (PFS) is defined as the time from the start date to the date of the 
first documentation of objective progression of disease (PD) or death due to any cause, 
whichever occurs first.  PFS data will be censored on the date of the last adequate tumor 
assessment for patients who do not have an event (PD or death), for patients who start new 
anti-cancer treatment prior to a PFS event, or for patients with a PFS event after ≥2 missing 
tumor assessments.  Patients who do not have a baseline tumor assessment or who do not 
have any post-baseline tumor assessments will be censored on the start date unless death 
occurred on or before the time of the first planned post-baseline tumor assessment in which 
case the death will be considered an event.
Overall survival (OS) is defined as the time from the start date to the date of death due to any 
cause.  Patients last known to be alive will be censored at the date of last contact.
ORR and DCR will be estimated and the corresponding exact 2-sided 95% confidence 
intervals will be reported.  TTR will be summarized using simple descriptive statistics 
(eg, median and range). DR, PFS, and OS will be analyzed using Kaplan-Meier methods.  In 
addition, progression date, death date, date of first response, and last tumor assessment date 
will be listed, together with BOR, TTR, DR, and PFS.
 
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9.5. Analysis of Pharmacokinetics and Pharmacodynamics
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Pharmacokinetic Analysis of Avelumab and Axitinib
Standard plasma PK parameters for axitinib will be estimated using non-compartmental 
analysis.  For axitinib, standard PK parameters will include Cmax, Tmax, AUCtau, t1/2, oral 
plasma clearance (CL/F), and apparent volume of distribution (Vz/F).  Dose normalized 
parameters (eg, CDN-Cmax, DN-AUC) will be reported as appropriate).  Descriptive statistics 
for the PK parameters for axitinib will be provided by dose, cycle and day of assessment in 
tabular form.
Axitinib plasma concentrations will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by 
dose, cycle, day and nominal time.  Individual patient and median profiles of the axitinib 
concentration-time data will be plotted by dose, cycle and day using nominal times.  Median 
axitinib profiles will be presented on both linear-linear and log-linear scales.
Ctrough and Cmax for avelumab will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by 
dose, cycle, and day.  The trough concentrations for avelumab will be plotted for each dose 
using a box-whisker plot by cycle and day in order to assess the attainment of steady-state.
9.5.1.2. Effect of Avelumab on Axitinib Pharmacokinetics 
The effect of repeated avelumab dosing on axitinib PK will be evaluated based on overall 
assessment of the geometric mean ratios for Cmax and AUCtau of axitinib on 
Cycle 4 Day 1 (avelumab in combination with axitinib) in relation to Lead-in Day 7 (axitinib 
alone).  The associated 90% confidence intervals will also be computed for the geometric 
mean ratios.
9.5.1.3. Immunogenecity Assessment
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized by dose.  For patients with positive ADA, the magnitude 
(titer), time of onset, and duration of ADA response will also be described, if data permit. 
Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials. 
9.5.1.4. Population Pharmacokinetic Analysis
Avelumab disposition will be evaluated using a population PK model for the drug and will be 
reported separately.
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9.5.1.5. Analysis of Biomarker Endpoints 
Biomarkers will be assessed separately for blood and tumor tissue biospecimens.  Summaries 
of baseline levels and, when on-treatment biomarker data is available, changes from baseline, 
will be reported.  Summary statistics may include the mean and standard deviation, median, 
and minimum/maximum levels of biomarker measures or frequency statistics, as appropriate.
Data from biomarker assays will be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach may examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
  
9.6. Safety Analysis
Summaries and analyses of the primary safety endpoint will be based on the per protocol 
analysis set.  All other summaries and analyses of safety parameters will include all patients 
in the safety analysis set.  Safety data will be summarized by treatment group for all treated 
patients using appropriate tabulations and descriptive statistics separately for each phase of 
the study.  Safety data collected during the lead-in PK period will be reported separately.  All 
safety data collected through 90 days after the last administration of study drug will be listed.
9.6.1. Analysis of the Primary Safety Endpoint
Dose-Limiting Toxicity (DLT) is the primary endpoint of the Dose Finding Phase of the 
study.  The incidence of DLTs observed in the Dose Finding Phase is used to estimate the 
MTD (if reached) as described in Section 3.1.1.2.  Adverse Events constituting DLTs will be 
listed per cohort.
9.6.2. Analysis of Secondary Safety Endpoints
9.6.2.1. Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html).  The 
frequency of patients experiencing treatment emergent adverse events corresponding to body 
systems and MedDRA preferred term will be reported.  Adverse events will be graded by 
worst NCI CTCAE v4.03 severity grade, and will be summarized by cycle and by relatedness 
to study treatment. 
Emphasis in the analysis will be placed on AEs classified as treatment emergent.  Adverse 
events leading to death or discontinuation of study treatment, events classified as NCI 
CTCAE v4.03 Grade ≥3, trial drug-related events, and serious adverse events will be 
considered with special attention. 
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Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study treatment, action taken, and 
clinical outcome. 
9.6.2.2. Laboratory Test Abnormalities
Laboratory test results will be graded according to the NCI CTCAE v4.03 severity grade.  
The frequency of patients with laboratory test abnormalities will be summarized according to 
the worst grade for each laboratory test. 
For laboratory tests without an NCI CTCAE grade definition, results will be categorized as 
normal (within normal ranges), abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory abnormalities. 
9.6.2.3. Electrocardiograms 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed QT, HR, RR, PR, QRS, QTc. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post-baseline corrected QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT.  Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment.  Patients 
experiencing clinically relevant morphological ECG changes will be summarized (including 
frequency and percentage).
9.6.3. Concomitant Medications/Follow-up Systemic Therapy 
All medications received during the treatment period will be considered as concomitant 
medications and will be coded by WHO medical dictionary.  Patients who received 
concomitant medications will be listed.  Follow-up systemic therapy for the primary 
diagnosis will be summarized by categories of follow-up therapy and will be listed for each 
patient as appropriate.
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9.7. Data Safety Monitoring Committee
An external 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. 
Periodic safety review procedures will include:
•
Surveillance for SAEs according to regulatory guidelines.
•
Discussions between the investigators and the sponsor of AEs, laboratory test 
abnormalities, vital signs, and ECG findings observed at each dose level in an 
ongoing manner at regular teleconferences and/or meetings to determine the safety 
profile, make risk/benefit assessments, and decide if further enrollment is appropriate.  
During the Dose Finding Phase in particular, monitoring and safety findings 
satisfying DLT criteria will be discussed in an ongoing manner. 
•
Safety findings that have immediate implications for the management of patients on 
study will be communicated to all investigators in the timeframe associated with 
unexpected and drug-related SAEs.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
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.
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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are complied for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients. The study 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent document(s) used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
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The investigator must ensure that each study patient, or his or her legally acceptable 
representative (as allowed by local guideline/practice), is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
Whenever consent is obtained from patient’s parent(s), legal guardian or legally acceptable 
representative, the patient’s assent (affirmative agreement) must subsequently be obtained 
when the patient has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a patient’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the patient’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study patient does not provide 
his or her own consent, the source documents must record why the patient did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the patient’s legally acceptable representative, the consent 
signer’s relationship to the study patient (eg, parent, spouse), and that the patient’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative before any 
study-specific activity is performed.  The investigator will retain the original of each patient's 
signed consent document.
12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in all other Participating Countries
End of Trial in all other participating countries is defined as Last Patient Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab alone or in combination with axitinib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 1 month.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
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Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicentre study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
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For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other
issues.
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Motzer RJ, Rini BI, McDermott DF., et al. Nivolumab for metastatic renal cell 
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Motzer R.J., Rini B.I., McDermott D.F., et al. Randomized, dose-ranging phase II trial 
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25 (suppl_4): iv280-iv304.
25.
Hammers H. J., Plimack E. R., Infante J.R. Phase I study of nivolumab in combination 
with ipilimumab in metastatic renal cell carcinoma (mRCC). ASCO 2014 Annual 
Meeting.
26.
Heery C.R., O'Sullivan Coyne G.H., Madan R.A., et al. Phase I open-label, multiple 
ascending dose trial of MSB0010718C, an anti-PD-L1 monoclonal antibody, in 
advanced solid malignancies. J Clin Oncol 32:5s, 2014 (suppl; abstr 3064).   
27.
Inlyta Summary of Product Chracteristics, Pfizer Inc. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002406/WC500132188.pdf.
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29.
Ji Y et al. A modified toxicity probability interval method for dose-finding trials. 
Clinical Trials 2010; 7:653 663.
30.
Hoos A, Egermont AM, Janetzki S, et al. Improved endpoints for cancer 
immunotherapy trials. J Natl Cancer Inst 2010; 102(18):1388-97.
31.
Hodi FS, Bulter M, Oble DA, Seiden MV, haluska FG, Kruse A, et al. Immnologic and 
clinical effects of antibody blockade of cytotoic T lymphocyte-associated antigen 4 in 
previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008; 105:3005-10.
32.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res 2009; 
15:7412.
33.
Larochelle P., Kollmannsberger C., Feldman R.D., et al. Hypertension management in 
patients with renal cell cancer treated with anti-angiogenic agents. Curr. Oncol 
2012;19:202-208.
34.
Rini B.I., Quinn D.I., Baum M., et al.  Hypertension among patients with renal cell 
carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS 
trial.  Targ Oncol DOI 10.1007/s11523-014.
35.
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011 May 
12;364(19):1844-54.
36.
Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T cell-mediated cytotoxicity by 
anti-inflammatory steroids. J Immunol. 1984; 132:266-71.  
37.
Khan MM, Immunosuppressive Agents. In: Immunopharmacology. New York: 
Springer; 2008.
38.
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events 
and kinetics of response with ipilimumab. J Clin Oncol. 2012 Jul 20; 30(21): 2691-7.
39.
Nishino M, Jagannathan JP, Krajewski KM, O'Regan K, Hatabu H, Shapiro G, Ramaiya 
NH. Personalized tumor response assessment in the era of molecular medicine: cancer-
specific and therapy-specific response criteria to complement pitfalls of RECIST. AJR 
Am J Roentgenol. 2012;198(4):737–745. doi: 10.2214/AJR.11.7483.
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45.
Eisenhauer, et al. New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
46.
Update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. J Clin Oncol Jul 2006 1:3187-3205.
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Appendix 1. ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair
5
Dead
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Appendix 2. Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 Guidelines
Adapted from E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.45
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions 
•
Lesions that can be accurately measured in at least one dimension.
•
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).
•
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
•
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
•
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-Measurable Disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.
•
Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 
•
Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
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. 
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Table 9.
Objective Response Status at Each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
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
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
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/recurrence (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 6 weeks. 
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•
 
 
 
•
 
 
 
 
 
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Appendix 4. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study Reference 
Binder for this protocol.  Alternatively, the NCI CTCAE may be reviewed online at the 
following NCI website:
http://ctep.cancer.gov/reporting/ctc.html.
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Appendix 5. Abbreviations and Definitions of Term
18FDG-PET
18fluorodeoxyglucose-positron emission tomography 
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse event
AESI
Adverse event of special interest
AHFS
American Hospital Formulary Service
AIDS 
Acquired immune deficiency syndrome
ALT 
Alanine aminotransferase
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
ASCO
American Society of Clinical Oncology
ATP
Adenosine triphosphate
aRCC
Advanced renal cell carcinoma
ASHP
American Society of Hospital Pharmacists
AST 
Aspartate aminotransferase
AUC
Area under the curve
BHD
Birt-Hogg-Dube
BID
Twice daily
BLQ
Below limit of quantification 
BOR
Best oveall response
BP
Blood pressure
BUN 
Blood urea nitrogen
CI
Confidence interval
CG
Cockcroft Gault
CL
Clearance
Cmax
Maximum plasma concentration 
Cmin
Minimum plasma concentration
COPD
Chronic obstructive pulmonary disease
CPR
Cardiopulmonary resuscitation
CR
Complete response
CRF
Case report form
CSA
Clinical Study Agreement
CT
Computerized Tomography
CTA
Clinical Trial Application
CTCAE 
Common Terminology Criteria for Adverse Events (US NCI)
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CYP1A2
Cytochrome P450 enzyme-1A2
CYP3A4/5
Cytochrome P450 enzyme-3A4/5
DAI
Dosage and Administration Instruction
DC
Disease control
DHP
Dihydropyridine
DL
Dose level
DL1
Dose Level 1
DL-1A
Dose Level -1A
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DL-1B
Dose Level -1B
DLT
Dose-limiting toxicity
DR
Duration of response
EC
Ethics Committee
ECG 
Electrocardiogram
ECOG
Easter Cooperative Oncology Group
EDTA
Ethylenediaminetetraacetic acid
EDP
Exposure during pregnancy
ESMO
European Society for Medical Oncology
EU
European Union
EudraCT
European Clinical Trials Database
FDG
Fluorodeoxyglucose
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin-embedded
FH
Fumarate hydratase
FSH
Follicle-stimulating hormone
GCP 
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HDPE
High density polyethylene
HIF
Hypoxia-inducible factor
HIV 
Human immunodeficiency virus
HR
Hazard ratio
HRT 
Hormone replacement therapy
ICH
International Committee on Harmonisation
ID
Identification
IFN
Interferon
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL
Interleukin
IND
Investigational New Drug
INN
International Nonproprietary Name
INR 
International normalized ratio
IRB 
Institutional Review Board
IRT
Interactive Response Technology
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IUD
Intrauterine device
IUS
Intrauterine hormone releasing system
IV
Intravenous
kg
Kilogram
LFT
Liver function test
mAb
Monoclonal antibody
MCC
Merkel Cell Carcinoma
MedDRA
Medical Dictionary for Regulatory Activities
mPFS
Median progression-free survival
MRI 
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
mTPI
Modified toxicity probability interval
mTOR
Mammalian target of rapamycin
Nab
Neutralizing antibodies
NCI 
National Cancer Institute
NSAID
Non-steroidal anti-inflammatory drug
OR
Objective response
ORR
Objective response rate
OS 
Overall survival
PD
Pharmacodynamic
PD
Progressive disease 
PD-1
Programmed death-1
PDGF 
Platelet-derived growth factor
PDGFR
Platelet-derived growth factor receptor
PD-L1
Programmed death-ligand 1
PD-L2
Programmed death-ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
PO
Per os (by mouth)
PR
Partial response
PS
Performance Status
PT
Prothrombin time
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QD
Every day
RCC
Renal cell cancer
RSI
Reference Safety Information 
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 Dose
SAE
Serious adverse event
SD
Stable disease
SD
Standard deviation
SOA
Schedule of activities
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SRSD
Single Reference Safety Document
SST
Serum separator tube
SUSAR
Suspected unexpected serious adverse reaction
t½
Plasma elimination half life
TEAE
Treatment-emergent adverse event
TIL
Tumor infiltrating lymphocytes 
TKI
Tyrosine kinase inhibitor
TLS
Tumor lysis syndrome
Tmax
Time to maximum plasma concentration
TO
Target occupancy
TSH
Thyroid-stimulating hormone
TTR
Time to tumor response
ULN 
Upper limit of normal
UPM
Unit probability mass
US
United States
VEGF 
Vascular endothelial growth factor
VEGFR 
Vascular endothelial growth factor receptor
VHL
von Hippel-Lindau 
WBC 
White blood cell
WHO
World Health Organization
WOCBP
Women of Childbearing Potential
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Appendix 6. Treatment Recommendations for Symptoms of Avelumab 
Infusion-Related Reactions
The following treatment recommendations for symptoms of avelumab infusion-related 
reactions may be modified based on local treatment standards and guidelines, as appropriate.
For Grade 1 Symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Decrease the avelumab infusion rate by 50% and monitor closely for any worsening 
(the total infusion time for avelumab should not exceed 120 minutes).
•
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).
•
Stop the avelumab infusion.
•
Treat based on emerging symptoms.  Treatment may include:
•
Normal saline IV;
•
H1 blockers, such as diphenhydramine 25 to 50 mg IV (or equivalent);
•
H2 blockers, such as ranitidine 50 mg IV (or equivalent);
•
NSAIDs, such as ibuprofen 600 mg (or equivalent);
•
Meperidine 12.5 to 50 mg IV;
•
Corticosteroids, such as hydrocortisone 100 to 500 mg IV (or equivalent);
•
Bronchodilators.
•
Remain at bedside, and monitor patient until resolution of symptoms.
•
Resume infusion at 50% of previous rate 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 bag 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.
•
Avelumab treatment must be permanently discontinued.
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SAP_000.pdf: 
Avelumab 
B9991002 (MSB0010718C, AG -013736) Statistical Analysis Plan
Page 1 
RENAL CELL CARCINOMA − JAVELIN RENAL 100
A PHASE 1B, OPEN-LABEL, DOSE-FINDING STUDY TO EVALUATE SAFETY, 
PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB 
(MSB0010718C) IN COMBINATION WITH AXITINIB (AG-013736) IN PATIENTS 
WITH PREVIOUSLY UNTREATED ADVANCED RENAL CELL CANCER 
STATISTICAL ANALYSIS PLAN – B9991002 
Compounds:
MSB0010718C, AG-013736
Compound Name:
Avelumab, Axitinib
Version:
3.0
Date:
20-Dec-2017


Avelumab 
B9991002 (MSB0010718C, AG -013736) Statistical Analysis Plan
Page 2 
TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................6 
APPENDICES ...........................................................................................................................6 
1. VERSION HISTORY ............................................................................................................7 
2. INTRODUCTION ...............................................................................................................11 
2.1. Study Objectives .....................................................................................................11 
2.2. Study Design ...........................................................................................................12 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................13 
3.1. Primary Endpoints ...................................................................................................13 
3.2. Secondary Endpoints ...............................................................................................14 
3.2.1. Safety endpoints ..........................................................................................14 
3.2.2. Efficacy endpoints ......................................................................................15 
3.2.3. Pharmacokinetic endpoints .........................................................................15 
3.2.4. Immunogenicity endpoints .........................................................................16 
3.2.5. Biomarker endpoints ...................................................................................16 
 
3.4. Baseline Variables ...................................................................................................17 
3.4.1. Study drug, study treatment and baseline definitions .................................17 
3.4.2. Baseline characteristics ...............................................................................19 
3.5. Safety Endpoints .....................................................................................................19 
3.5.1. Adverse events ............................................................................................19 
4. ANALYSIS SETS ...............................................................................................................19 
4.1. Full Analysis Set .....................................................................................................20 
4.2. Safety Analysis Set ..................................................................................................20 
4.3. Other Analysis Set ...................................................................................................20 
4.3.1. DLT-evaluable set ......................................................................................20 
4.3.2. PK analysis set ............................................................................................20 
4.3.3. Biomarker analysis set ................................................................................21 
4.3.4. Immunogenicity analysis set .......................................................................21 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................21 
5.1. Hypotheses and Decision Rules ..............................................................................21 
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5.1.1. Hypotheses and sample size determination ................................................21 
5.1.2. Decision rules .............................................................................................22 
5.2. General Methods .....................................................................................................23 
5.2.1. Data handling after the cut-off date ............................................................23 
5.2.2. Pooling of centers .......................................................................................23 
5.2.3. Presentation of continuous and qualitative variables ..................................24 
5.2.4. Definition of study day ...............................................................................24 
5.2.5. Definition of start of new anti-cancer drug therapy ....................................24 
5.2.6. Definition of start of new anti-cancer therapy ............................................24 
5.2.7. Definition of on-treatment period ...............................................................25 
5.2.8. Standard derivations and reporting conventions .........................................25 
5.2.9. Unscheduled visits ......................................................................................26 
5.2.10. Adequate baseline tumor assessment ........................................................26 
5.2.11. Adequate post-baseline tumor assessment................................................26 
5.3. Methods to Manage Missing Data ..........................................................................26 
5.3.1. Missing data ................................................................................................26 
5.3.1.1. Pharmacokinetic concentrations ................................................27 
5.3.1.2. Pharmacokinetic parameters .....................................................27 
5.3.2. Handling of incomplete dates .....................................................................27 
5.3.2.1. Disease history ..........................................................................27 
5.3.2.2. Adverse events ..........................................................................28 
5.3.2.3. Prior and concomitant medications ...........................................28 
5.3.2.4. Exposure ....................................................................................29 
5.3.3. Imputation rules for date of last contact and efficacy assessments ............29 
5.3.3.1. Date of last contact ....................................................................29 
5.3.3.2. Death date ..................................................................................30 
5.3.3.3. Tumor assessments ....................................................................30 
5.3.3.4. Date of start of new anti-cancer therapy ...................................31 
6. ANALYSES AND SUMMARIES ......................................................................................32 
6.1. Primary Endpoints ...................................................................................................33 
6.1.1. DLT in Dose-finding Phase ........................................................................33 
6.1.1.1. Primary analysis ........................................................................33 
6.2. Secondary Endpoint(s) ............................................................................................33 


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6.2.1. Safety endpoints ..........................................................................................33 
6.2.2. Efficacy endpoints ......................................................................................33 
6.2.2.1. Objective response and tumor shrinkage from baseline ............33 
6.2.2.2. Disease control ..........................................................................35 
6.2.2.3. Duration of response .................................................................35 
6.2.2.4. Time to response .......................................................................35 
6.2.2.5. Progression-free survival ...........................................................36 
6.2.2.6. Overall survival .........................................................................38 
6.2.3. Pharmacokinetic endpoints .........................................................................39 
6.2.3.1. Pharmacokinetic Analysis of Avelumab and Axitinib ..............39 
6.2.3.2. Effect of avelumab on axitinib pharmacokinetics .....................41 
6.2.4. Population pharmacokinetic endpoints .......................................................41 
6.2.5. Biomarker endpoints ...................................................................................41 
6.2.6. Immunogenicity Endpoints .........................................................................41 
6.2.6.1. Time to and Duration of ADA and nAb response .....................43 
6.2.6.2. ADA titer ...................................................................................44 
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity 
status ..................................................................................................44 
6.4. Subset Analyses .......................................................................................................49 
6.5. Baseline and Other Summaries and Analyses .........................................................49 
6.5.1. Baseline summaries ....................................................................................49 
6.5.1.1. Demographic characteristics .....................................................49 
6.5.1.2. Medical history ..........................................................................50 
6.5.1.3. Disease characteristics ...............................................................51 
6.5.1.4. Prior anti-cancer therapies .........................................................53 
6.5.2. Study conduct and patient disposition ........................................................53 
6.5.2.1. Patient disposition .....................................................................53 
6.5.2.2. Protocol deviations ....................................................................54 
6.5.3. Study treatment compliance and exposure .................................................54 
6.5.3.1. Exposure to avelumab ...............................................................55 
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6.5.3.2. Exposure to axitinib ..................................................................56 
6.5.3.3. Dose Reductions ........................................................................57 
6.5.3.4. Dose escalations ........................................................................57 
6.5.3.5. Dose interruptions .....................................................................57 
6.5.3.6. Dose Delays ...............................................................................58 
6.5.3.7. Infusion rate reductions .............................................................58 
6.5.3.8. Infusion interruptions ................................................................59 
6.5.4. Concomitant medications and non-drug treatments ...................................59 
6.5.5. Subsequent anti-cancer therapies ................................................................60 
6.6. Safety Summaries and Analyses .............................................................................60 
6.6.1. Adverse events ............................................................................................60 
6.6.1.1. All adverse events .....................................................................61 
6.6.1.2. Adverse events leading to dose reduction .................................62 
6.6.1.3. Adverse events leading to interruption of study treatment .......63 
6.6.1.4. Adverse events leading to discontinuation of study 
treatment ............................................................................................63 
6.6.2. Deaths .........................................................................................................64 
6.6.3. Serious adverse events ................................................................................64 
6.6.4. Other significant adverse events .................................................................65 
6.6.5. Laboratory data ...........................................................................................65 
6.6.5.1. Hematology and chemistry parameters .....................................65 
6.6.5.2. Other laboratory parameters ......................................................69 
6.6.6. Vital signs ...................................................................................................69 
6.6.7. Electrocardiogram .......................................................................................70 
6.6.8. Physical examination ..................................................................................71 
6.6.9. ECOG performance status ..........................................................................71 
7. INTERIM ANALYSES .......................................................................................................71 
7.1. Introduction .............................................................................................................72 
7.2. Interim Analyses and Summaries ............................................................................72 
8. REFERENCES ....................................................................................................................73 
9. APPENDICES .....................................................................................................................74 


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LIST OF TABLES 
Table 2. 
PK Parameters to be Determined for Avelumaba and Axitinib ............................15 
Table 3. 
Biomarker Definition and Determination .............................................................16 
Table 4. 
Outcome and event dates for PFS and DR analyses .............................................37 
Table 5. 
PFS Censoring Reasons and Hierarchy ................................................................38 
Table 6.    OS Censoring Reasons and Hierarchy ..................................................................39 
Table 7  
Patients Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ...................................................................................................................42 
Table 8  
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) ...................................................................................................................43 
Table 9. 
Outcome and event dates for irPFS and irDR analyses ........................................48 
Table 10. 
Case Definition for irAEs .....................................................................................74 
Table 11. 
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs ..............................................................76 
APPENDICES 
Appendix 1. Immune-Related Adverse Events ........................................................................74 
Appendix 2. Infusion Related Reactions .................................................................................76 
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1. VERSION HISTORY 
   
Version
Version Date
Summary of Changes
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2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991002.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment. 
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie,
pharmacokinetic (PK) data, and 
 tumor derived biomarker data). The primary 
analysis will include DLT data within the first 4 weeks (2 cycles) of treatment with avelumab 
in combination with axitinib and all data up to a cut-off date corresponding to 18 months (78 
weeks) after the last patient receives the first dose of study treatment. The final analysis of 
the data will be performed after last patient last visit (LPLV).  
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes. 
Throughout this document, ‘start date’ refers to date of randomization for randomized phase 
and first dose of study treatment for non-randomized phase. 
2.1. Study Objectives 
Primary Objectives 
x
To assess the safety and tolerability of avelumab in combination with axitinib in patients 
with previously untreated advanced RCC in order to estimate the Maximum Tolerated 
Dose (MTD) and select the Recommended Phase 2 Dose (RP2D).  
Secondary Objectives
x
To evaluate the overall safety profile of avelumab in combination with axitinib in patients 
with previously untreated advanced RCC. 
x
To assess the preliminary anti-tumor activity of avelumab in combination with axitinib in 
patients with previously untreated advanced RCC  
x
To evaluate the OS of avelumab in combination with axitinib in patients with previously 
untreated advanced RCC. 
x
To characterize the PK of avelumab and axitinib when administered in combination, and 
to assess the effect of avelumab on the PK of axitinib. 
x
To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may aid in 
the identification of a patient subpopulation most likely to benefit from treatment with 
avelumab in combination with axitinib. 
x
To assess the immunogenicity of avelumab when combined with axitinib.  
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x
x
2.2. Study Design 
This is a Phase 1b, open-label, multi-center, multiple-dose, safety, PK and pharmacodynamic 
study of avelumab in combination with axitinib in adult patients with previously untreated 
aRCC.  This clinical study will be composed of a Dose-finding Phase and a Dose-expansion 
Phase.  
The Dose-finding Phase will estimate the MTD and RP2D in patients with aRCC with clear 
cell histology who did not receive prior systemic therapy for advanced disease, using the 
modified toxicity probability interval (mTPI) method.  Dose finding will follow an mTPI 
design, with up to 3 potential dose levels (DL) to be tested: 
x
(DL1): avelumab 10 mg/kg Q2W + axitinib 5 mg BID 
x
(DL-1A): avelumab 5 mg/kg Q2W + axitinib 5 mg BID 
x
(DL-1B): avelumab 10 mg/kg Q2W + axitinib 3 mg BID  
DL-1A and DL-1B will be explored concurrently in a randomized fashion only if the MTD is 
exceeded in DL1.  
To understand the extent of any effects of avelumab on axitinib PK, a 7-day lead-in period 
with single-agent axitinib will be included prior to Cycle 1 in all patients in the Dose-finding 
Phase of the study.  Since avelumab has a half-life of 3-5 days, it would not be feasible to run 
a lead-in with avelumab alone to study the PK of avelumab alone.  Therefore, the effect of 
axitinib on avelumab will be evaluated by comparing avelumab trough concentrations at 
steady state in the presence of axitinib with those reported for avelumab alone in prior 
studies.  
The Dose-finding Phase will lead to the identification of an Expansion Test Dose for 
avelumab in combination with axitinib in patients with aRCC who did not receive prior 
systemic therapy for their advanced disease.  The Expansion Test Dose will either be the 
MTD (ie, the highest dose of avelumab and axitinib associated with the occurrence of DLTs 
in <33% of patients) or the RP2D, ie, the highest tested dose that is declared safe and 
tolerable by the investigators and sponsor.  Once the Expansion Test Dose is identified, the 
Dose-expansion Phase will be opened, and avelumab in combination with axitinib will be 
evaluated in up to approximately 40 patients with previously untreated aRCC.   
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Based on the emerging PK data and after the completion of the dose-finding phase of the 
study based on mTPI method, it may be necessary to enroll up to 8 additional patients to 
further assess the effect of avelumab on the PK of axitinib.  These additional patients will 
undergo the same evaluations and procedures as those described in the Schedule of Activities 
table for the Dose-finding Phase of the study and will be treated concurrently with the 
initiation of the Dose-expansion Phase of the study.  With the exception of the mTPI-related 
assessments leading to determination of MTD, any other assessments or procedures 
described for the Dose-finding Phase will also apply to these additional patients.   
The number of patients to be enrolled in the Dose-finding Phase will depend on the observed 
safety profile, and the number of tested dose levels.  Up to approximately 55 patients 
(including Dose-finding and Dose-expansion phases) are projected to be enrolled in the 
study. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
x
DLTs within the first 4 weeks (2 cycles) of treatment with avelumab in combination with 
axitinib. 
Severity of adverse events will be graded according to CTCAE version 4.03.  For the 
purpose of dose finding, any of the following adverse events occurring during the 
primary DLT observation period (4 weeks, from the time of first administration of 
avelumab [Cycle 1 Day 1] until the planned administration of the third dose of avelumab 
[Cycle 3 Day 1]) that are attributable to one, the other, or both agents in combination will 
be classified as DLTs: 
Hematologic: 
- 
Grade 4 anemia  
- 
Grade 4 neutropenia lasting >7 days; 
- 
Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 degrees C (>101 degrees F) or a sustained temperature of 
t38 degrees C (100.4 degrees F) for more than 1 hour;  
- 
Grade t3 neutropenic infection; 
- 
Grade t3 thrombocytopenia with bleeding; 
- 
Grade 4 thrombocytopenia. 
Non-Hematologic (including Non-Laboratory): 
- 
Any Grade t3 toxicity, except for any of the following: 

Transient (d6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management; 


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
Transient (d24 hours) Grade 3 fatigue, local reactions, or headache that resolves 
to Grade d1; 

Grade 3-4 nausea and vomiting controlled by optimal medical therapy within 
72 hours;

Grade 3 hypertension controlled by medical therapy; 

Grade 3 diarrhea or Grade 3 skin toxicity that resolves to  Grade d1 in less than 
7 days after medical management (eg, immunosuppressant treatment) has been 
initiated; 

Any Grade t3 amylase or lipase abnormality that is not associated with symptoms 
or clinical manifestations of pancreatitis; 

Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor. 
- 
Grade 3-4 liver function test elevation (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST]) concurrent with Grade 2 elevation of total bilirubin. 
- 
Non-hematologic Grade t3 laboratory abnormality if medical intervention is required 
to treat the patient, or if the abnormality leads to hospitalization.  

Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the investigator, do not have any clinical correlate, and 
resolve to Grade d1 within 7 days with adequate medical management are not to 
be considered DLTs. 
- 
Inability to complete at least 75% of the first 2 cycles doses of axitinib (starting from 
Cycle 1 Day 1 after completion of the Lead-in PK period) or 2 infusions of avelumab 
within the DLT observation period due to investigational product-related toxicity. 
In absence of associated clinical abnormalities, abnormal laboratory tests should be 
repeated to confirm relevance.  While the rules for adjudicating DLTs in the context of 
dose finding/dose expansion phases are specified above, an AE not listed above, or an AE 
meeting the DLT criteria above but occurring outside of the DLT observation period may 
be defined as a DLT after consultation between sponsor and investigator, based on the 
emerging safety profile. 
3.2. Secondary Endpoints 
3.2.1. Safety endpoints 
x
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; 
AEs will be graded by the investigator according to CTCAE version 4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) 
x
Vital signs (blood pressure, pulse rate). 


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3.2.2. Efficacy endpoints 
x
Objective Response (OR) and Disease Control (DC) as assessed by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1. 
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the ‘start date’ until the date of the first documentation 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. 
DC is defined as CR, PR, non-CR/non-PD or SD.  Both CR and PR must be confirmed 
by repeat assessments performed no less than 4 weeks after the criteria for response are 
first met. Criteria for SD and non-CR/non-PD must have been met at least 6 weeks after 
the ‘start date’. 
x
Time-to-event endpoints: Duration of Response (DR), Progression-Free Survival (PFS), 
and Time to Tumor Response (TTR); 
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 ‘start date’ to the first 
documentation of objective response (CR or PR) which is subsequently confirmed.  
PFS is defined as the time from the ‘start date’ to the date of the first documentation of 
PD or death due to any cause, whichever occurs first. 
x
Overall Survival (OS); 
OS is defined as the time from the ‘start date’ to the date of death due to any cause. 
3.2.3. Pharmacokinetic endpoints 
x
PK parameters including Cmax, Tmax, AUCτ, and t1/2 as appropriate for axitinib; Ctrough and 
Cmax for avelumab;
Table 2. 
PK Parameters to be Determined for Avelumaba and Axitinib
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time 
profile from time zero to the time of the 
last quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUC0-12
Area under the plasma concentration-time 
profile after single dose from time zero to 
12 hours
Linear/Log trapezoidal method
AUCss,W
Area under the plasma concentration-time 
profile after single dose from time zero to 
the next dose (at steady state)
Linear/Log trapezoidal method
Cmax
Maximum observed plasma concentration 
Observed directly from data


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Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t½
b
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear regression 
of the log-linear concentration-time curve.  
Only those data points judged to describe 
the terminal log-linear decline were used in 
the regression.
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
CL/Fb
Apparent clearance
Dose / AUCτ for steady state
Vz/Fb
Apparent volume of distribution
Dose / (AUCτ ·kel) for steady state
AUClast(dn)
Dose normalized AUClast
AUClast / Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
a Only Cmax and Ctrough
b If data permit
3.2.4. Immunogenicity endpoints 
x
Anti-Drug Antibody (ADA; Neutralizing antibodies (nAb)) of avelumab when combined 
with axitinib. 
3.2.5. Biomarker endpoints 
x
Tumor tissue biomarker status (ie, positive or negative based on, for example, PD L1 
expression and/or quantitation of tumor infiltrating CD8+ T lymphocytes as assessed by 
immunohistochemistry [IHC]). 
Table 3. 
Biomarker Definition and Determination 
Parameter
Definition
Method of Determination
PD-L1 expression
The number of PD-L1 positive cells and/or 
qualitative assessment of  PD-L1 staining on 
tumor and inflammatory cells in regions of 
interest that are defined by tumor cell 
morphology and the presence or absence of 
CD8+ and CD68+ cells
Pathologist, assisted by image 
analysis
Tumor infiltrating 
CD8+ lymphocytes
The number of CD8+ cells per unit area and 
the percent of counted cells that are scored as 
CD8+ 
Pathologist, assisted by image 
analysis
Tumor associated 
CD68+ macrophages
The number of CD68+ cells per unit area and
the percent of counted cells that are scored as 
CD68+
Pathologist, assisted by image 
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x
   
  
    
x
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: 
x
DL1 with lead-in: axitinib 5 mg oral BID followed by avelumab 10 mg/kg IV Q2W in 
combination with axitinib 5 mg oral BID, or 
x
DL-1A with lead-in: axitinib 5 mg oral BID followed by avelumab 5 mg/kg IV Q2W in 
combination with axitinib 5 mg oral BID, or 
x
DL-1B with lead-in: axitinib 3 mg oral BID followed by avelumab 10 mg/kg IV Q2W in 
combination with axitinib 3 mg oral BID, or 
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x
DL1: avelumab 10 mg/kg IV Q2W in combination with axitinib 5 mg oral BID, or 
x
DL-1A: avelumab 5 mg/kg IV Q2W in combination with axitinib 5 mg oral BID, or 
x
DL-1B: avelumab 10 mg/kg IV Q2W in combination with axitinib 3 mg oral BID. 
Start and end dates of study treatment:  
The date/time of first dose of study treatment is the earliest date/time of the first non-zero 
dose date/time for the study drugs in the combination. 
The date/time of last dose of study treatment 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 in randomized phase 
The last measurement prior to randomization will serve as the baseline measurement for 
efficacy analyses. If such a value is missing, the last measurement prior to the first dose of 
study treatment will be used as the baseline measurement except for analyses of tumor data 
where the baseline assessment would be considered as missing.  
Definition of baseline for immunogenicity analyses 
The last available assessment prior to the start of treatment with avelumab is defined as 
‘baseline’ result or ‘baseline’ assessment.  If an assessment is planned to be performed prior 
to the first dose of avelumab in the protocol and the assessment is performed on the same day 
as the first dose of avelumab, it will be assumed that it was performed prior to avelumab 
administration, if assessment time point is not collected or is missing. 
Definition of baseline for efficacy analyses in non-randomized phase and for safety analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety and efficacy (for non-randomized phase) analyses.  
If an assessment is planned to be performed prior to the first dose of study treatment in the 
protocol and the assessment is performed on the same day as the first dose of study 
treatment, it will be assumed that it was performed prior to study treatment administration, if 
assessment time point is not collected or is missing. If assessment time points are collected, 
the observed time point will be used to determine pre-dose on study day 1 for baseline 
calculation. Unscheduled assessments will be used in the determination of baseline. 
However, if time is missing, an unscheduled assessment on study day 1 will be considered to 
have been obtained after study treatment administration. 
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection.  


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If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing.  Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point. 
3.4.2. Baseline characteristics 
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 
are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6.  
3.5. Safety Endpoints 
3.5.1. Adverse events 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period.  
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs) 
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendices 1 and 2, 
respectively. 
4. ANALYSIS SETS 
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures. 
Only patients who signed informed consent will be included in the analysis sets below. 


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4.1. Full Analysis Set 
For the randomized phase: The full analysis set (FAS) will include all randomized patients.  
Patients will be classified according to the study treatment assigned at randomization.  
For the non-randomized phase: 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 study treatment the patient will be classified 
according to the first study treatment received.  
4.2. Safety Analysis Set 
For the randomized phase: The safety analysis set will include all patients who receive at 
least one dose of study drug. Patients will be classified according to the study treatment 
assigned at randomization unless the incorrect treatment(s) was/were received throughout the 
dosing period in which case patients will be classified according to the first study treatment 
received.  
For the non-randomized phase: 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 the non-randomized phase of the 
study, the FAS and the safety analysis set are identical.
4.3. Other Analysis Set 
4.3.1. DLT-evaluable set 
The DLT-evaluable set includes all enrolled patients during the dose-finding phase who: 
x
receive at least 1 dose of avelumab and axitinib, and  
x
either experience DLT during the first 2 cycles of combination axitinib + avelumab 
treatment, or complete the primary DLT observation period for the first 2 cycles of 
combination treatment (4 weeks).   
Patients who withdraw from study treatment before receiving at least 75% of the planned 
first 2 cycles of axitinib starting from Cycle 1 Day 1 after completion of the Lead-in PK 
period or 2 infusions of avelumab within the primary DLT observation period due to reasons 
other than investigational product-related adverse events are not evaluable for DLT. 
This analysis set will be used only in the Dose-finding phase of the study for determination 
of MTD/RP2D.
4.3.2. PK analysis set 
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for avelumab or axitinib.  


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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. 
4.3.3. Biomarker analysis set  
The biomarker analysis set for biomarkers that are measured only at screening is a subset of 
the safety analysis set and will include patients who have at least one screening biomarker 
assessment.
The biomarker analysis set for biomarkers that are measured sequentially is a subset of the 
safety analysis set and will include patients who have at least one screening and one on-
treatment biomarker assessment for the same marker. 
Analysis sets will be defined separately for blood-based and tumor tissue-based biomarkers. 
4.3.4. Immunogenicity analysis set 
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample collected for avelumab. 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and sample size determination 
Dose-finding phase 
There is no formal hypothesis testing planned for this study. The objective of the dose-
finding phase is to determine MTD or RP2D. 
Due to the dynamic nature of the dose allocation procedure and unknown safety profile of the 
combination, the sample size using mTPI approach (see Section 5.1.2 for details) cannot be 
determined in advance. It is expected that approximately 15 DLT-evaluable patients will be 
required for the dose-finding phase based on the mTPI method. 
Based on the emerging PK data and after the completion of the dose-finding phase of study 
based on the mTPI method, it may be necessary to enroll up to 8 additional patients to further 
assess the effect of avelumab on the PK of axitinib. These additional patients will be treated 
concurrently with the initiation of the dose-expansion phase. 
Dose-expansion phase 
Up to approximately 40 patients will be included in the dose-expansion phase of the study for 
each MTD dose level cohort expanded.  A sample size of 40 patients will provide at least 90% 
probability to observe at least 1 AE if the true incidence of the AE in the population is ≥6%.  
It is expected that at most approximately 55 patients will be enrolled to achieve all study 
objectives. 


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5.1.2. Decision rules 
Dose-finding phase 
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation trials that improve accuracy, efficiency and statistical validity.  
The modified toxicity probability interval (mTPI) design  is an interval-type of design that 
uses a Bayesian statistics framework and a beta/binomial hierarchical model to compute the 
posterior probability of  3 dosing intervals that reflect the relative difference in probability 
between the toxicity rate of each dose level to the target rate (pT = 0.33).  If the toxicity rate 
of the currently used dose level is far smaller than pT, the mTPI will recommend escalating 
the dose level; if it is close to pT, the mTPI will recommend continuing at the current dose; if 
it is far greater than pT, the mTPI will recommend de-escalating the dose level.  These rules 
are conceptually similar to those used by the 3+3 design, except the decisions of an mTPI 
design are based on posterior probabilities calculated under a coherent probability model.  
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different trials with different toxicity parameters.  More 
importantly, all the dose-escalation decisions for a given trial can be pre-calculated under the 
mTPI design.  Thus, compared to other advanced model-based designs published in the 
literature, the mTPI design is logistically less complicated and easier to implement.   
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of avelumab as a single-agent in Study EMR100070-001, e1 is selected as 
0.05, and e2 is selected as 0.03.  Therefore, the target dosing interval for the DLT rate is 
(0.25, 0.33). 
The 3 dosing intervals are associated with 3 different dose-escalation decisions.  The 
under-dosing interval corresponds to a dose escalation (E), over-dosing corresponds to a dose 
de-escalation (D), and proper-dosing corresponds to remaining at the current dose (R).  
Given a dosing interval and a probability distribution, the unit probability mass (UPM) of 
that dosing interval is defined as the probability of a patient belonging to that dosing interval 
divided by the length of the dosing interval.  The mTPI design calculates the UPMs for the 3 
dosing intervals, and the one with the largest UPM informs the corresponding dose-finding 
decision, which is the dose level to be used for future patients.  For example, if the 
under-dosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level.  Ji and collaborators 1 have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (ie, minimizes the chance of making a wrong dosing decision).  
The dose finding phase of the trial uses a modified version of the mTPI design that 
maximizes the number of evaluable patients treated at each dose level at 6. Dose finding is 
completed when 6 DLT-evaluable patients have been treated at the highest dose with a DLT 
rate < 0.33. 


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Dose-expansion phase 
There are no decision rules associated with this phase. 
5.2. General Methods 
As described in Section 3.4, in this study ‘treatment group’ refers to one of the following:
x
DL1 with lead-in: axitinib 5 mg oral BID followed by avelumab 10 mg/kg IV Q2W in 
combination with axitinib 5 mg oral BID, or 
x
DL-1A with lead-in: axitinib 5 mg oral BID followed by avelumab 5 mg/kg IV Q2W in 
combination with axitinib 5 mg oral BID, or 
x
DL-1B with lead-in: axitinib 3 mg oral BID followed by avelumab 10 mg/kg IV Q2W in 
combination with axitinib 3 mg oral BID, or 
x
DL1: avelumab 10 mg/kg IV Q2W in combination with axitinib 5 mg oral BID, or 
x
DL-1A: avelumab 5 mg/kg IV Q2W in combination with axitinib 5 mg oral BID, or 
x
DL-1B: avelumab 10 mg/kg IV Q2W in combination with axitinib 3 mg oral BID. 
Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment group.  
DLTs will be summarized based on the DLT-evaluable set by treatment group including data 
from the dose-finding phase only. 
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 sets by treatment group. 
Biomarker data will be summarized based on the biomarker analysis sets by treatment group. 
Immunogenicity data will be summarized based on the immunogenicity analysis set by 
treatment group. 
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 


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to the high number of participating centers in contrast to the anticipated small number of 
patients randomized/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. 
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 6.2.2). 


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


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x
BMI (kg/m2) = weight (kg)/[height (m)]2
x
BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6. 
5.2.9. Unscheduled visits 
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits. 
5.2.10. Adequate baseline tumor assessment 
Adequate baseline is defined using the following criteria: 
x
All baseline assessments must be within 31 days prior to and including the ‘start date’. 
x
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 6.2.2.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date. 
5.3. Methods to Manage Missing Data 
5.3.1. Missing data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used. 
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged. 
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’. 


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5.3.1.1. Pharmacokinetic concentrations 
Concentrations Below the Limit of Quantification 
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures. 
Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true: 
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample); 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist. 
Summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data. 
5.3.1.2. Pharmacokinetic parameters 
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.  If a PK parameter 
cannot be derived from a patient’s concentration data, the parameter will be coded as NC (ie,
not calculated).  NC values will not be generated beyond the day that a patient discontinues. 
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing. 
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables and will not 
be included in the calculation of summary statistics or statistical analyses. 
5.3.2. Handling of incomplete dates 
5.3.2.1. Disease history 
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
x
If the day is missing, it will be imputed to the 15th day of the month.  


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


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treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014. 
x
In all other cases the missing medication day or missing medication month will be 
replaced by 1. 
x
Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
x
In all other cases the incomplete medication stop date will not be imputed.  
5.3.2.4. Exposure 
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows: 
x
If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date 
x
If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then
imputed last dose date is: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date)  
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date) 
= min (EOT date, death date), for all other cases. 
5.3.3. Imputation rules for date of last contact and efficacy assessments 
5.3.3.1. Date of last contact 
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following: 
x
All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments) 
x
Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation. 
x
AE start and end dates 
x
Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’)


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x
Study drug start and end dates 
x
Randomization date 
x
Withdrawal of consent date 
x
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up). 
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date. 
5.3.3.2. Death date 
Missing or partial death dates will be imputed based on the last contact date: 
x
If the date is missing it will be imputed as the day after the date of last contact  
x
If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following: 
-
Missing day:  
 
1st day of the month and year of death 
-
Missing day and month: 
January 1st of the year of death 
5.3.3.3. Tumor assessments 
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year. 
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment. 
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates (eg,
X-ray, CT-scan).   
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used.  
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment.  If both a previous and following assessments are not available, this 
assessment will not be used for any calculations. 


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5.3.3.4. Date of start of new anti-cancer therapy 
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment. 
x
The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is 
o
completely missing then it will be ignored in the imputations below 
o
partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy 
o
partially missing with only month and year  available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy 
x
For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below.  
x
If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is derived as follows: 
o
Start date of new anti-cancer therapy is completely missing 
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy] 
o
Only year (YYYY) for start of anti-cancer therapy is available 
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY;  
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = 01JANYYYY 
o
Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available 
IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  


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THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY ; 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]);
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = 01 MMM YYYY; 
ELSE IF 
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = 01 MMM YYYY. 
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.  
At the time of the SAP amendment 01 (SAP V2), the dose-finding phase had been completed 
and the only dose levels tested in the study will be DL1 and DL1 with lead-in.  Therefore, no 
randomization will be implemented in the study. 
Data will be summarized separately for DL1 and for DL1 with lead-in as well as for both 
treatment groups combined. 


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6.1. Primary Endpoints  
6.1.1. DLT in Dose-finding Phase 
6.1.1.1. Primary analysis 
The following analyses will be based on the DLT-evaluable set for patients in the dose-
finding phase only.  DLTs will be listed and summarized by treatment group. 
6.2. Secondary Endpoint(s) 
6.2.1. Safety endpoints 
Refer to Section 6.6. 
6.2.2. Efficacy endpoints 
The following analyses will be based on the FAS by treatment group.   Assessment of 
response by the Investigator will be made using RECIST v1.1.  
6.2.2.1. Objective response and tumor shrinkage from baseline
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the ‘start date’ until the first documentation of PD, 
according to the following rules. Only tumor assessments performed on or before the start 
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:
x
CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD 
x
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)  
x
SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the ‘start date’ and before first documentation of 
PD (and not qualifying for CR or PR). 
x
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 ‘start date’ and 
before first documentation of PD (and not qualifying for CR or PR). 
x
PD = first documentation of PD ≤ 12 weeks after the ‘start date’ (and not qualifying for 
CR, PR, SD or non-CR/non-PD).
x
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 


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documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
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 (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 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 BOR of NE will be summarized by reason for having 
NE status. The following reasons will be used: 
x
No baseline assessment 
x
No post-baseline assessments due to death 
x
No post-baseline assessments due to other reasons 
x
All post-baseline assessments have overall response NE 
x
New anti-cancer therapy started before first post-baseline assessment 
x
SD of insufficient duration (<6 weeks after the ‘start date’) 
x
PD too late (>12 weeks after the ‘start date’) 
Special and rare cases where BOR is NE due to SD of insufficient duration and late PD will 
be classified as ‘SD of insufficient duration’.
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: 
x
((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 the 
start of subsequent anti-cancer therapy, as: 


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x
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 diameter 
of all target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment. 
6.2.2.2. Disease control 
Disease Control (DC) is defined as BOR of CR, PR, non-CR/non-PD or SD.   DC rate (DCR) 
is the proportion of patients with DC.   
DCR will be summarized by frequency counts and percentages. 
6.2.2.3. Duration of response 
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are as described for PFS 
in Table 4.
 
DR (months) = [date of event or censoring– first date of OR +1]/30.4375 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with 2-sided 
95% CIs.  In particular, the DR rate at 3, 6 and 12 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided. 
6.2.2.4. Time to response 
Time to response (TTR) is defined, for patients with OR, as the time from the ‘start date’ to
the first documentation of objective response (CR or PR) which is subsequently confirmed.  
 
TTR (in months) = [first date of OR – ‘start date’ +1]/30.4375 
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3). 


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6.2.2.5. Progression-free survival 
Progression-Free Survival (PFS) is defined as the time from the ‘start date’ to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.    
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.   Patients who do not have an adequate baseline tumor assessment or who do 
not have an adequate post-baseline tumor assessment will be censored on the ‘start date’
unless death occurred on or before the time of the second planned tumor assessment (ie, ≤ 12 
weeks after the ‘start date’) 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 6 weeks until PD regardless of initiation of subsequent 
anti-cancer therapy.  After 1 year from the ‘start date’, tumor assessments will be conducted 
less frequently, ie, at 12-week intervals.
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 4.   
 
PFS (months) = [date of event or censoring– ‘start date’ +1]/30.4375


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


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Table 5. 
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy before event.
Start of new anti-cancer therapy
3
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/ ‘start date’
Event after 2 or more missing 
assessments a
4
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Subject refused further follow-up] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments. 
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
Time of Follow-Up for PFS 
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment group. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment groups reversing the PFS censoring and event 
indicators. Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
group together with a summary of associated statistics including the median time of follow-
up for PFS with 2-sided 95% CIs.   In particular, the rate at 3, 6, 9, 12, 15, 18 and 24 months 
will be estimated with corresponding 2-sided 95% CIs. 
6.2.2.6. Overall survival 
Overall survival (OS) is defined as the time from the ‘start date’ to the date of death due to 
any cause. Patients last known to be alive will be censored at date of last contact. 
 
OS (months) = [date of death or censoring– ‘start date’ +1]/30.4375 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rate at 3, 6, 9, 12, 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 and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.  


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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 6 following the hierarchy shown. 
Table 6.  OS Censoring Reasons and Hierarchy 
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Subject refused further follow-up] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 16 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS 
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators.  Kaplan-Meier 
estimates (product-limit estimates) will be presented by treatment group together with a 
summary of associated statistics including the median time of follow-up for OS with 2-sided 
95% CIs.  In particular, the rate at 3, 6, 9, 12, 15, 18 and 24 months will be estimated with 
corresponding 2-sided 95% CIs. 
6.2.3. Pharmacokinetic endpoints 
6.2.3.1. Pharmacokinetic Analysis of Avelumab and Axitinib 
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
group.   
Ctrough and Cmax for avelumab and axitinib will be summarized descriptively (n, mean, SD, 
CV, median, minimum, maximum, geometric mean, its associated CV, and 95% CI) by
treatment group, cycle, and day. Other standard parameters for axitinib will be calculated 
including, but not limited to Tmax, AUClast, Tlast, t1/2, CL, and Vz, as data permit. Multiple 
Dose (MD) - Tss,max, AUCss,W, t1/2, Css,av, CL, and Vss, as data permit. 
Dose normalized parameters (eg, CDN- Cmax, CDN- Ctrough) will be reported as appropriate. 
The trough concentrations for avelumab and axitinib will be plotted for each dose using a 
box whisker plot by cycle and day in order to assess the attainment of steady state. 
Pharmacokinetic parameters for avelumab and axitinib will be taken from observed values or 
derived using non-compartmental methods from plasma concentration-time data as described 
in Section 3.2.3.


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Presentation of pharmacokinetic data will include: 
x
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of plasma 
concentrations for axitinib will be presented in tabular form by treatment group, dose 
level, cycle, day and nominal time. Additionally similar descriptive statistics will also be 
generated for dose-normalized axitinib pharmacokinetic parameters 
x
Linear-linear and log-linear plots of mean and median plasma concentrations by nominal 
time for axitinib will be presented for PK sampling days by cycle and study day. Similar 
plots will be presented for axitinib for each individual patient concentrations. Only 
patients who have matched pairs of PK collections available on both planned treatments 
(when administered alone and in combination with avelumab) will be included in the 
axitinib plasma concentration descriptive summary and median concentration profiles. 
Patients who have undergone intrapatient dose reduction or escalation will be excluded 
from the median plasma concentration-time plots. 
x
Pharmacokinetic parameters for axitinib will be listed and summarized by cycle and 
study day using descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, 
geometric mean and its associated %CV, and 95% CI). For Tmax, the range (min, max) 
will also be provided. Only patients who have a matched pair of estimated axitinib PK 
parameters available on both planned treatments (when administered alone and in 
combination) will be included in the axitinib PK parameter summary tables. PK 
parameters with zero values will be excluded from the calculation of geometric means 
and its associated %CV. If an intrapatient dose escalation or reduction occurs, dose-
dependent PK parameters (AUC and Cmax) for that patient may be dose-normalized 
when it is known that the drug exhibits linear PK within the dose range and other PK 
parameters will be reported as estimated; or may only be included in descriptive statistics 
and summary plots up to the time of the dose change. In addition, dose-normalized 
axitinib Cmax and AUC parameters will be summarized (as described above) using data 
pooled across cohorts in which different axitinib doses were administered. 
x
Box plots for AUCτ and Cmax for axitinib (during treatments when given alone and in
combination) 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 cohort 
has limited evaluable PK data (n<4), matchstick plots showing changes in AUC and 
Cmax for each drug (during treatments when given alone and in combination) 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 AUCτ parameters will be created using data pooled across cohorts in which 
different axitinib doses were administered. 
x
Ctrough and Cmax for avelumab will be plotted for each treatment group using a box-
whisker plot by cycle and day within cycle in order to assess the attainment of steady-
state. Individual data points, the geometric mean and the median of the parameter in each 
treatment will be overlaid on the box plots. 


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6.2.3.2. Effect of avelumab on axitinib pharmacokinetics 
The effect of repeated avelumab dosing on steady-state axitinib PK will be evaluated using 
Cmax and AUCτ of axitinib on Lead-in Day 7 and Cycle 4 Day 1 as the primary PK 
parameters. The ratio of geometric means of Cmax and AUCτ, (axitinib in presence of 
avelumab/axitinib alone) will be computed to assess the magnitude of the effect. 
The associated 90% CIs will also be computed for the geometric mean ratios. 
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 
Biomarkers will be summarized at all appropriate timepoints.  For soluble proteins this is 
screening, Lead-in PK D1, C1D1, C2D1, C3D1, C4D1, C6D1, EOT and follow-up at day 30.  
For Anti-avelumab Antibodies, this is C1D1, C2D1, C3D1, C4D1, C6D1, C8D1, then 
Q12W, and 30 days after end of avelumab treatment. For biomarkers from Archival FFPE 
Tumor Tissue Block, this is screening only.  For biomarkers from DeNovo Tumor Biopsy, 
this is screening and end of treatment. Appropriate summary statistics at each timepoint and 
ratio to screening (for continuous markers) will be provided separately for each dose 
escalation cohort, the dose expansion cohort, and dose expansion cohort plus the same dose 
escalation cohort. For continuous biomarkers, ratio to screening within each cohort will be 
tested using the Wilcoxon Signed-Rank Test when n ≥ 5 for a specific timepoint.  P-values 
will be compared to unadjusted and adjusted alpha; alpha will be adjusted using the 
Bonferroni adjustment (eg, 0.05/# tests).  The adjustment will be determined before data base 
lock.   
To assess whether biomarkers are related to outcome, screening (and ratio to screening for 
follow-up timepoints, if available) will be summarized versus OR status (0: no OR; 1: OR).  
For continuous variables, the value of the biomarker will also be displayed in a box plot vs 
OR status (0: no OR; 1: OR), for each visit. 
6.2.6. Immunogenicity Endpoints 
All analyses described below are performed for all treatment groups combined.
Blood samples for avelumab immunogenicity testing will be collected pre-dose on Cycle 1, 
2, 3, 4, 6 and 8. Subsequently, testing should be performed approximately every 12 weeks. 
All samples should be drawn within 2 hours before start of avelumab infusion.  Additional 
samples for anti-avelumab antibodies (and simultaneous PK draws for measurement of 
avelumab) will be collected at the Day 30 Follow-up visit after the end of avelumab 
treatment.  


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Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.  As of the 
finalization of this SAP, the nAb assay is not yet available, therefore the analyses of nAb data 
described in the following sections will only be conducted contingent upon assay and data 
availability at the time of reporting.  
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 7.   
Table 7  
Patients Characterized Based on Anti-Drug Antibody Results (ADA Status) 
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
ADA never-positive 
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint)
Number of patients with at least one 
valid ADA result at any time point
ADA ever-positive 
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint)
Number of patients with at least one 
valid ADA result at any time point
Baseline ADA 
positive
A positive ADA result at baseline
Number of patients with valid baseline 
ADA result
Treatment-boosted 
ADA
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result
Treatment-induced 
ADA
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive past-baseline 
ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Transient ADA 
response
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Persistent ADA 
response
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
ADA: anti-drug antibody, NR = not reportable. 
Patients will be characterized into different nAb categories based on the criteria in Table 8.
For nAb, treatment-boosted is not applicable since no titer result is available. 


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Table 8  
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
nAb never-positive 
No positive nAb results at any time point
Number of patients with at least one 
valid ADA result at any time point
nAb ever-positive 
At least one positive nAb result at any time 
point
Number of patients with at least one 
valid ADA result at any time point
Baseline nAb 
positive
A positive nAb result at baseline
Number of patients with valid baseline 
ADA result
Treatment-induced 
nAb
Patient is not nAb positive at baseline and  has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive past-
baseline ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
Transient nAb 
response
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive.
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR)
Persistent nAb 
response
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result. 
The number and percentage of patients in each ADA and nAb category will be summarized.  
6.2.6.1. Time to and Duration of ADA and nAb response  
The ADA and nAb analyses described below will include patients with treatment-induced 
ADA or nAb, respectively.   
Time (weeks) to ADA response is defined as: 
(Date of first positive ADA result – date of first dose of avelumab + 1)/7.  
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3). 
Duration (weeks) of ADA response is defined as: 
(Date of last positive ADA result – date of first positive ADA result + 1)/7.  
Duration of ADA response will be censored if:  
x
the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or 


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x
the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (day 30 follow-up visit) is after the cut-off date. 
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result.  
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley 
(1982) and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2011) (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided 
As data permit, the analyses described above will be repeated for patients with treatment-
induced nAb.  
6.2.6.2. ADA titer 
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated. The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory.  
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided. The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks. In this categorization, the censoring in duration of ADA response is ignored.  
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity status 
The following ADA and nAb status will be used for the analyses described below. 
ADA
x
ADA ever-positive versus ADA never-positive  
x
ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive 


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


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


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CCI
CCI
CCI


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CCI
CCI
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6.4. Subset Analyses 
Subset analyses will be performed for OR, DR and PFS per Investigator assessment, and OS 
based on the FAS for the subgroups defined below. 
x
MSKCC prognostic criteria at baseline (detailed in Section 6.5.1.3) 
-
Favorable (Reference) 
-
Intermediate or Poor 
x
Heng prognostic criteria at baseline (detailed in Section 6.5.1.3) 
-
Favorable (Reference) 
-
Intermediate  
-
Poor 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline summaries 
The following analyses will be based on the FAS overall and separately by treatment group. 
6.5.1.1. Demographic characteristics 
Demographic characteristics and physical measurements will be summarized by treatment 
group using the following information from the ‘Screening/Baseline Visit’ eCRF pages. 
x
Demographic characteristics  
-
Gender: Male, Female  
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Unknown 
-
Ethnic origin: Hispanic/Latino (Yes/No) 
-
Age (years): summary statistics  
-
Age categories :  

< 65 years, ≥ 65 years 

<65, 65-<75, 75-<85, ≥ 85
-
Pooled Geographical Region:  
CCI


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
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 

Australasia

Middle East 

Asia 

Africa 
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4
x
Physical measurements 
-
Height (cm) 
-
Weight (kg) 
-
Body Mass Index (BMI) (kg/m2) 
-
Body Surface Area (BSA) (m2) 
Center codes will be used for the determination of the patient’s geographic region. 
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), BSA (m2) and ECOG performance status.
6.5.1.2. Medical history 
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC. 


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Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order. 
6.5.1.3. Disease characteristics 
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Abuse’
and RECIST eCRF pages will be summarized overall and by treatment group. Summary 
statistics will be presented for the following. 
From the ‘Primary Diagnosis’ eCRF page: 
x
Body side 
x
Site of primary tumor 
x
Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page) 
x
Time since initial diagnosis to ‘start date’ (months), defined as (‘start date’ – date of 
initial diagnosis)/30.4375 
x
Time since diagnosis of local/regional recurrence of disease (months), defined as (‘start 
date’– date of diagnosis of local/regional recurrence of disease)/30.4375 
x
Time since diagnosis of recurrence/metastatic disease (months), defined as (‘start date’ –
date of diagnosis of recurrence/metastatic disease)/30.4375 
Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria (Motzer et al., 1999) 
are based on the detection of five risk factors:  
x
Karnofsky PS < 80% (since Karnofsky PS is not collected in the eCRF, the derivation of 
risk factors will use ECOG PS ≥2 (Oken et al., 1982)) 
x
high LDH (> 1.5 times the ULN)  
x
serum hemoglobin < LLN 
x
high corrected serum calcium (> 10 mg/dL) 
x
prior nephrectomy 
According to MSKCC prognostic criteria, patients will be assigned to one of the following 
risk groups: 
x
Favorable (0 risk factors) 
x
Intermediate (1 or 2 risk factors) 


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x
Poor (3 or more risk factors) 
Heng prognostic criteria (Heng et al., 2009) are based on the detection of six risk factors:  
x
Karnofsky PS < 80% (since Karnofsky PS is not collected in the eCRF, the derivation of 
risk factors will use ECOG PS ≥ 2 (Oken et al., 1982)) 
x
high corrected serum calcium (> 10 mg/dL) 
x
serum hemoglobin < LLN 
x
time from diagnosis to start of systemic treatment < 12 months 
x
absolute neutrophils count > ULN  
x
platelets count > ULN  
According to Heng prognostic criteria, patients will be assigned to one of the following risk 
groups: 
x
Favorable (0 risk factors) 
x
Intermediate (1 or 2 risk factors) 
x
Poor (3 or more risk factors) 
From the RECIST eCRF page: 
x
Measurable disease (lesions) at baseline (Yes, No) 
x
Involved tumor sites at baseline 
From the ‘Substance Use’ eCRF page: 
x
Smoking history 
-
Never smoker vs current vs former smoker  
-
Smoking exposure (pack-years): 0, <20, 20-<40, ≥40 and summary statistics
-
Years since quitting: never smoker, current smoker, <5, 5-<10, ≥10 and summary 
statistics 
Specifications for computation: 
x
Cigarette equivalents are calculated as follows: one cigar is regarded equivalent to 5 
cigarettes and 1 pipe is regarded equivalent to 3 cigarettes 


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x
Duration of nicotine consumption [years]: 
(end of nicotine consumption – start of nicotine consumption + 1) / 365.25 
x
Pack-years: 
-
calculate cigarette equivalents per day using the conversion factors given above 
-
convert to packs per day where 20 cigarettes are regarded as 1 pack 
-
pack-years = packs per day × duration of nicotine consumption [years] 
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ and ‘Substance Use’ eCRF pages) and derived variables as above.
6.5.1.4. Prior anti-cancer therapies 
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages. 
The number and percentage of patients with at least one prior anti-cancer surgery will be 
tabulated. 
Prior anti-cancer therapies will be included in the listings that follow with a flag to identify 
prior therapies. These will include the patient identification number, and all the relevant 
collected data-fields on the corresponding eCRF pages. 
x
Listing of anti-cancer drug therapies  
x
Listing of anti-cancer radiotherapy  
x
Listing of anti-cancer surgeries 
6.5.2. Study conduct and patient disposition 
The following analyses will be based on the FAS overall and separately by treatment group. 
6.5.2.1. Patient disposition 
The percentages below will be calculated based on the number of patients in the FAS. 
x
Total number of patients screened overall
x
Number of patients who discontinued from the study prior to treatment with study drug 
overall and by the main reason for discontinuation 
x
Number and percentage of patients in each of the analysis sets defined in Section 4 
x
Number and percentage of patients with study drug ongoing (separately for each study 
drug)


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x
Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug)
x
Number and percentage of patients who entered follow-up
x
Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation 
x
Number and percentage of patients who entered long-term follow-up
x
Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation
In addition the following will be summarized: 
x
Number and percentage of treated patients overall, by region (Europe, EEA (required by 
EudraCT), North America, Latin America, Middle East, Asia, Australasia Africa), by 
country within region 
x
Number and percentage of treated patients by center
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: 
x
Patients who are dosed on the study despite not satisfying the inclusion criteria;
x
Patients who develop withdrawal criteria whilst on the study but are not withdrawn;
x
Patients who receive the wrong treatment or an incorrect dose;
x
Patients who receive an excluded concomitant medication.
x
Deviations from GCP
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study treatment compliance and exposure 
The following analyses will be based on the safety analysis set by treatment group. 
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. 


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For Cycle X, actual cycle start date for each patient is 
x
the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the 
patient received study treatment on that visit (ie, any study drug with dose>0 at that visit)
x
the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (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,  
x
for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day;
x
for the last cycle, actual cycle end date = actual cycle start date + 14 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 will 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 derivations below are provided for the following: 
x
Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg or 5 mg/kg once 
every 2 weeks in 2-week cycles.
x
Axitinib administered BID PO at a dose of 5 mg or 3 mg.
Analysis of exposure will be based on the calculated actual dose levels 
x
Avelumab - total dose / weight  
x
Axitinib – total dose.
Exposure and compliance will be summarized by cycle (avelumab only) and overall 
(avelumab and axitinib) for each study drug in each treatment group. 
6.5.3.1. Exposure to avelumab  
The dose level for avelumab is calculated as actual dose administered/weight (mg/kg). The 
last available weight of the patient on or prior to the day of dosing will be used. 
Intended duration of treatment with avelumab (weeks) =
(end date–date of first dose of avelumab +1)/7, 


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where end date = start date of last cycle with non-zero dose of avelumab + 14 – 1
Duration of exposure to avelumab (weeks) =  
(last dose date of avelumab –first dose date of avelumab + 14)/7 
Cumulative dose in a cycle or overall is the sum of the actual dose levels of avelumab 
received in a cycle or overall, respectively. 
Actual Dose Intensity (DI)
x
By cycle actual DI (mg/kg/2-week cycle) = [cumulative dose in the cycle (mg/kg)]/[cycle 
duration (weeks)/2] 
x
Overall actual DI (mg/kg/2-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/2].  
Relative Dose Intensity (RDI)   
x
Intended DI (mg/kg/2-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 2 weeks in a cycle] = [d (mg/kg)] / [1(2-week cycle)]  = d (mg/kg/2-week 
cycle) 
x
By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [d (mg/kg/2-week cycle)]   
x
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [d (mg/kg/2-week cycle)] 
where d can be 5 or 10. 
6.5.3.2. Exposure to axitinib  
The dose level is calculated as actual dose administered (mg/day).   
The Intended duration of treatment with axitinib (weeks) =
(last dose date of axitinib – first dose date of axitinib + 1)/7 
Duration of exposure to axitinib (weeks) =  
(last dose date of axitinib – first dose date  of axitinib + 1)/7 
Cumulative dose is the sum of the actual doses of axitinib received in the study.   
Actual Dose Intensity (DI)
x
Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)] 


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Relative Dose Intensity (RDI) 
x
RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of study drug to last dose of axitinib]
x
= 100 × [overall cumulative dose] / [7×2×d×duration of exposure to axitinib (weeks)], 
where d = 3 or 5. 
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 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. 
The number and percentage of patients with at least one dose escalation as well as a 
breakdown of dose escalations (1, 2, ≥3) 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. What follows 
defines how dose interruptions will be counted in the case of multiple dose interruptions. 
x
If an interruption occurs consecutively for at least two days due to the same reason, then 
it will be counted only once (example: If the actual dose on days 1-3 is 10 mg and actual 
dose on days 4-5 is 0 mg and dose interruption on days 4-5 is due to AE, then the total 
number of dose interruptions is 1).
x
If an interruption occurs consecutively for at least two days due to different reasons, then 
it will be counted for each reason (example: If the actual dose on days 1-3 is 10 mg and 
actual dose on days 4-5 is 0 mg and dose interruption on day 4 is due to AE and dose 
interruption on day 5 is due to dosing error, then the total number of dose interruptions is 
2). 
x
If an interruption occurs for more than one day due to the same reason, but the days are 
not consecutive, ie there is at least one dosing day in between, then each dose interruption 
will be counted as a different occurrence (example: If the actual dose on days 1, 3 and 5, 
is 10 mg and actual dose on days 2 and 4 is 0 mg, and dose interruptions on day 2 and 4 
are both due to dosing error, the total number of dose interruptions is 2). 


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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.  
In Cycle 1,  
Dose Delay (days) = day of first dose of avelumab – 1.
In Cycle >1 
Dose Delay (days) = Date of first dose of avelumab in Cycle x – Date of first dose of 
avelumab in Cycle (x-1) – 14.
Dose Delays will be grouped into the following:  
x
No delay 
x
1-3 days delay 
x
4-6 days delay
x
7 or more days delay 
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16, 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.


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


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6.5.5. Subsequent anti-cancer therapies 
The following analyses will be based on the FAS by treatment group. 
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’,
‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages.  
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages. 
6.6. Safety Summaries and Analyses 
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of 
AEs and other safety parameters will be based on the safety analysis set 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 for the first time, or if the worsening of an event is during the 
on-treatment period as defined in Section 3.5.1.
All analyses described 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. 
x
Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (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).
x
Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).
x
Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction
of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
= Dose reduced).
x
Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).   IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.


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


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-
TEAEs leading to interruption of avelumab
-
TEAS 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 
x
TEAEs by SOC and PT and worst grade 
x
Related TEAEs by SOC and PT and worst grade
x
TEAEs related to avelumab by SOC and PT and worst grade 
x
TEAEs related to axitinib by SOC and PT and worst grade
x
TEAEs related to any study drug by SOC and PT and worst grade
x
TEAEs leading to death by SOC and PT 
x
Related TEAEs leading to death by SOC and PT 
x
TEAEs Excluding SAEs, with frequency ≥ 5% in any treatment group by SOC and PT
6.6.1.2. Adverse events leading to dose reduction 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment group: 
x
TEAEs leading to dose reduction of avelumab by SOC and PT
x
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 
x
IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.6). These IRRs will be considered as IRRs leading to 
interruption of infusion.
x
IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.6).
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: 
x
TEAEs leading to interruption of avelumab by SOC and PT 
x
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 interruption of each study drug by treatment group: 
x
TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT
x
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: 
x
TEAEs leading to discontinuation of avelumab by SOC and PT
x
Related TEAEs leading to discontinuation of avelumab by SOC and PT


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


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x
Related SAEs by SOC and PT
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period. 
6.6.4. Other significant adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group: 
x
irAEs leading to death, by Cluster and PT
x
irAEs, by Cluster and PT
x
irAEs, Grade ≥ 3, by Cluster and PT
x
irAEs leading to discontinuation of avelumab, by Cluster and PT 
x
irAEs leading to discontinuation of axitinib, by Cluster and PT 
x
irAEs leading to discontinuation of any study drug, by Cluster and PT
x
irAEs leading to discontinuation of all study drugs, by Cluster and PT
x
Serious irAEs, by Cluster and PT
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period.  
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group: 
x
IRRs leading to death, by PT
x
IRRs, by PT 
x
IRRs, Grade ≥ 3, by PT
x
IRRs leading to discontinuation of avelumab, by PT 
x
Serious IRRs, by PT 
x
Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later) 
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period. 
6.6.5. Laboratory data 
6.6.5.1. Hematology and chemistry parameters 
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03.  
Non-numerical qualifiers (with the exception of fasting flags) will not be taken into 


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consideration in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are 
only distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges).  
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9). End of Treatment visit laboratory results will be 
summarized separately. The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories (ie,
Low, Normal, High).  
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:  
x
Lymphocyte count decreased:   
-
derived absolute count does not meet Grade 2-4 criteria, and 
-
% value < % LLN value, and 
-
derived absolute count  ≥ 800/mm3
x
Neutrophil count decreased  
-
derived absolute count does not meet Grade 2-4 criteria, and 
-
% value < % LLN value, and 
-
derived absolute count  ≥ 1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows 


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Corrected Calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 – serum 
Albumin [g/L]).
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.    
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment group: 
x
ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
x
AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN
x
(ALT or AST) ≥ 3×ULN, (ALT or AST)  ≥ 5×ULN, (ALT or AST)  ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN 
x
TBILI ≥ 2×ULN 
x
Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN
x
Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN 
x
Concurrent (ALT or AST)  ≥ 3×ULN and TBILI ≥ 2×ULN  
x
Concurrent (ALT or AST)  ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN 
x
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or 
missing)
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, 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 
x
peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at
ALT=3×ULN and total bilirubin=2×ULN.
x
peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
AST=3×ULN and total bilirubin=2×ULN.
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided. 


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Parameters with NCI-CTC grades available:  
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie those
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).  
x
The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4),
laboratory abnormalities during the on-treatment period.
x
The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary.  
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie: 
x
Hematology:  
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased). 
x
Serum Chemistry: 
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase 
(CPK 
increased), 
Potassium 
(hypokalemia/ 
hyperkalemia), 
Sodium 
(hyponatremia/ 
hypernatremia), 
Magnesium 
(hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), 
Gamma Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased),
Phosphates (hypophosphatemia), Triglycerides (hypertriglyceridemia).
Parameters with NCI-CTC grades not available: 
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with:  
x
shifts from baseline normal to at least one result above normal during on-treatment period  
x
shifts from baseline normal to at least one result below normal during on-treatment 
period 
In this study, these apply to the following parameters:  
x
Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils 


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x
Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH), TSH,  Free T4 , ACTH, ANA (performed at baseline and 
if clinically indicated), ANCA (performed at baseline and if clinically indicated), RF 
(performed at baseline and  if clinically indicated), HBV and HCV (performed at baseline 
and if clinically indicated).
6.6.5.2. Other laboratory parameters 
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF.  
x Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT),  
international normalized ratio (INR),  and PTT.
x Urinalysis: all urinalysis parameters, including protein, glucose, blood and albumin
x Other parameters: hormone, and immunology parameters
x Pregnancy test 
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests.  
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing.  
For all tests not mentioned above but present in the clinical data, a listing of patients with at
least one result for the relevant test will be provided. 
6.6.6. Vital signs 
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle. Height will be measured at screening only. 
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing.  
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline. 


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


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ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category 
x
Pearson correlation between QT and HR, QTc (QTcB, QTcF and, if applicable, QTcP) 
and HR using individual (non-averaged) baseline assessments  
x
For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point  
x
Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:            
- 
QT/QTc increase from baseline >30 ms,  >60 ms 
- 
QT/QTc > 450 ms, > 480 ms, > 500 ms 
- 
HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm
- 
HR ≥ 120 bpm and increase from baseline ≥ 20 bpm
- 
PR ≥ 220 ms and increase from baseline ≥ 20 ms
- 
QRS ≥ 120 ms 
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters. 
6.6.8. Physical examination 
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system.
6.6.9. ECOG performance status 
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment group. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing. 
7. INTERIM ANALYSES 
Not applicable. 


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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 (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika; 26, 404-413. 
3.
Ji Y et al. A modified toxicity probability interval method for dose-finding trials. 
Clinical Trials 2010; 7:653 663 
4.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience   
5.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
6.
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-Alfa as a 
comparative treatment for clinical interferon-alfa as a comparative treatment for clinical 
cell carcinoma. Journal of Clinical Oncology. 20: 289-296, 2002. 
7.
Heng DYC, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether 
JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott 
DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK. Prognostic Factors for 
Overall Survival in Patients With Metastatic Renal Cell Carcinoma Treated With 
Vascular Endothelial Growth Factor–Targeted Agents: Results From a Large, 
Multicenter Study. Journal of Clinical Oncology. 27: 5794-5799, 2009. 
8.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982 Dec;5(6):649-55.


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9. APPENDICES 
Appendix 1. Immune-Related Adverse Events 
The MedDRA PTs and clusters for irAEs are defined in the Safety Review Plan (SRP) for 
avelumab. 
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 8.   
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step. 
Table 10. Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs if 
A) OR B) below are met then the AE is in for the 
next step
A) conmed ATC code is in (H02A, H02B, H02C, 
D07, A01AC, S01BA, S01BB, L04AA,  L04AB,  
L04AC,   L04AD,  L04AX) 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”


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5
A) No clear etiology (other than immune 
mediated etiology)
B) Histopathology / biopsy consistent with 
immune-mediated event
Event is in if 
[Answer to 5B1 and 5B2 is YES  (regardless 
of answer to 5A)]
OR
[Answer to 5B1 is YES AND answer to 5B2 
is NO AND answer to 5A is NO] 
OR
[Answer to 5B1 is NO AND answer to 5A is 
NO]
A) From the AE eCRF page
Is the AE clearly related to an etiology other than 
immune-mediated etiology?    Yes / No
If answer is Yes, check all that apply:
x Underlying malignancy / progressive disease.
x Other medical conditions. 
x Prior or concomitant medications / procedures.  
x Other.  Specify.
B) From the AE eCRF page
B1) Was there a pathology /histology evaluation 
performed to investigate the AE?  Y/N
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text)
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (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.  
x
All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of avelumab infusion (during or 
after infusion) and the event resolved with end date within 2 days after onset.  
x
All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, 
will be considered potential IRRs when onset is on the day of avelumab infusion 
(during or after the infusion) or the day after the avelumab 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 9 
and will be identified for IV drugs only.      
Table 11. 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
x
AE onset date = date of infusion of study drug AND
x
AE timing related to study drug (‘DURING’, ‘AFTER’) AND
x
AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND
x
AE  end date – AE onset date <=2 
3
PT is included in the ‘IRRs CORE’ list 
4A
x
AE onset date = date of infusion of study drug AND
x
AE timing related to study drug in (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion