Conditions: Carcinoma, Hepatocellular
Keywords: Cancer Hepatocellular carcinoma Liver disease Avelumab Axitinib
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
To evaluate the safety, efficacy and PK of avelumab in combination with axitinib as first line treatment in patients with advanced HCC

Detailed description:

Arms:
arm 1: Avelumab (MSB0010718C) in combination with axitinib (AG-013736)

Interventions: intervention 1: Avelumab (MSB0010718C) intervention 2: Axitinib (AG-013736)
Intervention descriptions: intervention 1: Patients will receive avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID. intervention 2: Patients will receive avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID.

Protocol document:
Prot_000.pdf: 
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AN OPEN LABEL, SINGLE ARM PHASE 1B STUDY OF AVELUMAB PLUS 
AXITINIB AS FIRST LINE TREATMENT IN PATIENTS WITH ADVANCED 
HEPATOCELLULAR CARCINOMA
Investigational Product Number:
MSB0010718C, AG-013736
Investigational Product Name:
Avelumab, Axitinib
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable (N/A)
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
B9991024
Phase:
1b


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
SCHEDULE OF ACTIVITIES..................................................................................................4
LIST OF TABLES
Table 1.
Axitinib Dose Levels ............................................................................................33
Table 2.
Axitinib Dose Modifications and Avelumab Infusion Omissions for 
Investigational Product-Related Toxicity.............................................................35
Table 3.
Treatment Modification for Symptoms of Infusion-Related Reactions 
Caused by Avelumab............................................................................................40
Table 4.
Management of Avelumab Immune-Related Adverse Events .............................42
Table 5.
Required Laboratory Tests ...................................................................................58
Table 6.
Objective Response Status at Each Evaluation ....................................................94
Table 7.
Objective Response Status at Each Evaluation for Patients with Non-Target 
Disease Only.........................................................................................................94
APPENDICES
Appendix 1. ECOG Performance Status..................................................................................88
Appendix 2. Child-Pugh Classification ...................................................................................89
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Guidelines.............................................................................................................90
Appendix 5. Treatment Recommendations for Symptoms of Avelumab 
Infusion-Related Reactions...................................................................................98
Appendix 6. Abbreviations....................................................................................................100
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Study Procedures and 
Assessments sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the Schedule of Activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Visit Identifiers1
Screening
Study Treatment
(1 cycle = 14 days)
End of 
Treatment
/Withdrawal3
Post-Treatment Follow-Up
28 Days 
Prior to 
Enrollment 
Cycle 1
Cycles 2
Short-Term4
Long-Term4
Day 12
Day 8
(1 day)
Day 1
(3 days)
Day 30, Day 60, Day 90
(3 days)
Every 3 months
(14 days)
Clinical Assessments
Informed Consent5
X
Medical/Oncological History6
X
Baseline Signs/Symptoms7
X
Physical Examination8
X
X
X
X
X
X
Contraception Check9
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Vital Signs10
X
X
X
X
X
X
Home Blood Pressure Monitoring11
X
Laboratory Studies
Hematology12
X
X
X
X
X
X
Blood Chemistry13
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
X
Thyroid Function Tests14
X
X (Cycles 4, 7, 13 then 
Q12W)  
X
X
ACTH15
X
X (Cycle 6, then Q12W`) 
X
X
AFP, PIVKA-II16
X
X (Q2W)
X
HBV, HCV Tests17
X
X (Cycle 3, then Q4W)
X
Serum/Urine Pregnancy Test18
X
X
X
X
X
Urinalysis19
X
X
X
X


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Visit Identifiers1
Screening
Study Treatment
(1 cycle = 14 days)
End of 
Treatment
/Withdrawal3
Post-Treatment Follow-Up
≤28 Days 
Prior to 
Enrollment 
Cycle 1
Cycles ≥2
Short-Term4
Long-Term4
Day 12
Day 8
(±1 day)
Day 1
(±3 days)
Day 30, Day 60, Day 90
(±3 days)
Every 3 months
(±14 days)
LVEF by MUGA Scan or 
Echocardiogram20
X
X (Q8W)
X
X (Day 30 only)
12-Lead ECG21
X
X
X (up to Cycle 4)
X
Disease Assessments
Tumor Assessments22
X
Q8W
X
Survival23
X
Other Clinical Assessments
Follow-up for Axitinib Dosing 
Compliance24
X (D5 ± 3 days)
Adverse Events25
X
X
X
Concomitant 
Medications/Treatments26
X
X
X
X
X
X
New Anticancer Therapy
X
X
X
Study Treatment27
Avelumab28
X
X
Axitinib28
X
Other Samplings
Pharmacokinetics for axitinib29
X
X (Cycles 2, 3)
Pharmacokinetics for avelumab30
X
X (Cycles 2, 3, 4, 6, 8, 
then every 4 cycles)
Mandatory Archival or de novo 
FFPE Tumor Tissue32
X
X
(optional)
Anti-Avelumab Antibodies and 
Neutralizing Antibodies33
X
X (Cycles 2, 3, 4, 6, 8, 
then every 4 cycles)
X
X (Day 30 only)
ACTH=adrenocorticotropic hormone; AFP=α-fetoprotein; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FFPE=formalin-fixed and 
paraffin-embedded; HBV=hepatitis B virus; HCV=hepatitis C virus; LVEF=left ventricular ejection fraction; MUGA=multigated acquisition; PIVKA-II= Protein 
induced by vitamin K absence or antagonist II; QXW=every X weeks.
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Footnotes for Schedule of Activities 
1.
Visit Identifiers: All assessments should be performed prior to the start of study treatment unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headers. 
2.
Visit window: -3 days visit window is allowed for all laboratory assessments on Cycle 1 Day 1 except for serum/urine pregnancy test.
3.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if 
performed within the prior 8 weeks.
4.
Short- and Long-Term Follow-up: All patients will be followed for safety every 30 days (±3 days) through 90 days after the last dose of investigational 
product or until the time of initiation of new anticancer treatment. Beyond the 90 days until the end of the study, all patients will be followed every 
3 months (±14 days) for survival, and new systemic anticancer treatment will also be recorded.
5.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure.
6.
Medical/Oncological History: To include information on prior systemic adjuvant or neoadjuvant therapy regimens, surgery, locoregional therapy and 
radiation therapy.
7.
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.
8.
Physical Examination: Includes an examination of major body systems and weight (height included at Screening only).
9.
Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they 
meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need 
to use 2 highly effective contraception methods consistently and correctly and document such conversation in the patient’s chart.  In addition, the 
investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if 
pregnancy is known or suspected in the patient or the patient’s partner.
10. Vital Signs: To include blood pressure and pulse rate. Blood pressure and pulse rate should be taken with the patient in the seated position after the patient 
has been sitting quietly for at least 5 minutes.  Two blood pressure and pulse rate readings will be taken at least 1 hour apart at each clinic visit.
11. 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 5.4.5.2). 
12. Hematology and Coagulation: Required tests are listed in Table 5.  May also be performed when clinically indicated. 
13. Blood Chemistry: Full chemistry panel (required tests are listed in Table 5) 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, End of Treatment and Short-Term Follow-up.  Core chemistry panel (required tests are listed 
in Table 5) 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.
14. 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, then Q12W thereafter and
End of Treatment and at each visit during Short-Term Follow-up.  Additional tests should be performed when clinically indicated.  .See Table 5.
15. ACTH: To be performed at Screening, Cycle 6 Day 1, then Q12W thereafter, at End of Treatment and at each visit during Short-Term Follow-up.  
Additional tests should be performed when clinically indicated. See Table 5.


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16. AFP, PIVKA-II: To be performed at Screening, Cycle 2 Day 1, then Q2W thereafter, and at End of Treatment.  Additional tests should be performed 
when clinically indicated. See Table 5
17. HBV, HCV Tests: The viral status in the patients with chronic infection by HBV or HCV will be monitored at Screening, Cycle 3 Day 1, then Q4W 
thereafter, End of Treatment and Short-Term Follow-up .
18. 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 (IRBs)/Ethics Committees (ECs) or if required by local 
regulations (see Section 7.1.1). 
19. Urinalysis: Required at Screening, at Cycle 1 Day 1 and then at Day 1 of every cycle and at the End of Treatment.  If protein ≥2+ by semiquantitative 
method (eg, urine dipstick), protein will have to be quantified by 24-hour urine collection or urine protein creatinine (UPC) ratio. To be performed as 
clinically indicated at other time points.  See Table 5. 
20. LVEF by MUGA Scan or Echocardiogram: For the evaluation of the LVEF, the technique used at screening will also be consistently used for the 
following assessments throughout the study..
21. 12-Lead Electrocardiogram (ECG): See Section 7.1.4 for details.  ECG measurements will be obtained at Screening, Cycle 1 Day 1, Day 1 of every cycle 
up to Cycle 4 and End of Treatment.  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) before avelumab 
infusion and at the 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. 
22. 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, and every 8 weeks from Cycle 1 Day 1
until confirmed disease progression. If a patient discontinues the study treatment due to a reason other than disease progression, tumor assessments should 
be conducted until confirmed disease progression or initiation of new anticancer treatment, whichever come first. 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) version 1.1
  See Section 7.6 for additional information.
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23. 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.
24. Follow-up for Axitinib Dosing Compliance: Follow-up by telephone will be done on Day 5 of the first cycle to confirm patient understanding and 
compliance with dosing instructions.  Axitinib dosing compliance will also be assessed following any dose modification.  If needed, patient will be 
retrained.
25. Adverse Events: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v. 4.03.  For adverse events (AEs), 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.  Serious adverse events (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. 
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at the time the new treatment is started.  Death must be 
reported if it occurs during the SAE reporting period after the last dose of study drug, irrespective of any intervening treatment.
26. 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).
27. Enrollment: Required information: site and patient identifiers and demographic information.  Study treatment (avelumab in combination with axitinib) 
should begin within 3 days of registration.  
28. 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 avelumab, axitinib, or avelumab combined with axitinib, provided that the 
treating physician has determined that the benefit/risk for doing so is favorable. 
29. Pharmacokinetics for axitinib: PK samples for axitinib (3 mL) will be collected at pre-dose and 2 hours post-dose on Day 1 of Cycle 1, Cycle 2 and 
Cycle 3.  Details are outlined in Section 7.1.5.
30. Pharmacokinetics for avelumab: Blood samples (3.5 mL) for avelumab PK will be collected in all patients: pre-dose and at the end of infusion 
(immediately before the end of avelumab infusion) on Day 1 of Cycle 1, 2, 3 and 4. After that, trough (pre-dose) samples will be collected at cycles 6 and 8 
and then every 4 cycles, ie., every 8 weeks thereafter. Pre-dose samples can be taken up to 2 hours prior to the start of avelumab infusion. Details are 
outlined in Section 7.1.5.
 
 
 
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32. Mandatory Archival or de novo FFPE Tumor Tissue: 
 
 The biopsy sample(s) should be 
formalin-fixed and paraffin-embedded and the resulting FFPE tissue block(s) should be submitted to the Central Laboratory. 
 
 or de novo tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material) is not adequate and should not be submitted.  See Section 6.1.1 and Section 7.4.1.
33. 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 Day 1 of Cycle 1, 2, 3, 4, 6, and 8 and then every 4 cycles, ie., every 8 weeks thereafter.  All samples should be 
drawn within 2 hours before start of avelumab infusion.  All the samples that are positive for ADA may also undergo characterization for nAb.  ADA 
sample at 30 day follow up is collected at 30 days after end of treatment of avelumab regardless of continuation of axitinib therapy.  See Section 7.3.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Treatment naïve advanced or metastatic hepatocellular carcinoma
1.2. Background and Rationale
1.2.1. Hepatocellular carcinoma
An estimated 782,500 new cases and 745,500 death of liver cancer occurred worldwide 
during 2012, with the second leading cause of cancer death. 1  The most common histologic 
type of primary liver cancer, hepatocellular carcinoma (HCC), arise from hepatocytes.  
Approximately 80%-85% of primary liver cancers are HCC.2  The majority of patients with 
HCC have underlying cirrhosis, most commonly associated with hepatitis B or C, but also 
attributable to other predisposing factors like aflatoxin B-contaminated food, excessive 
alcohol intake or hypermetabolic disorders (eg, obesity, diabetes, hyperlipidemia, etc.).  
Geographical differences in incidence reflect variations in the main causal factors.3  Whereas 
viral hepatitis appears to be more prevalent in Asia, several other factors, including mainly 
alcohol consumption and hypermetabolic disorders arise more frequently in Western 
countries.  HCC treatment is conventionally divided into curative versus palliative 
approaches and is guided by both the stage of disease and the degree of remaining liver 
function secondary to frequently underlying cirrhosis.  Curative treatments such as surgical 
resection or liver transplantation, percutaneous ethanol injection and radiofrequency ablation 
induce complete responses in a high proportion of patients, with a 5-year survival of about 
40%-50%.  However, fewer than 30% of patients are eligible for these procedures.  Most of 
the patients with HCC are suitable for palliative treatment only because of the extent of their 
tumor, poor hepatic function, or both.4  Patients with localized unresectable disease are 
usually treated with some form of local therapy, including chemotherapy targeted through the 
hepatic artery combined with embolization (TACE), percutaneous ethanol ablation, hepatic 
artery infusion of chemotherapy, radiofrequency ablation, and cryosurgery.3,5  There is no 
approved chemotherapy for systemic treatment of advanced HCC.  Doxorubicin is the most 
widely used agent in patients without significantly altered hepatic function, and is associated 
with a response rate of about 15%, but without improvement in 1-year survival rate (between 
30%-50% according to the natural history of the disease) and with a high-risk of increased 
toxicity in patients with altered hepatic function, and impaired performance status (PS).6,7,8
More aggressive combinations of chemotherapy have proven equally disappointing. For 
molecular target agent, only sorafenib is approved for systemic treatment of advanced HCC 
which has not been treated with prior systemic therapy, based on the results from 2 Phase 3 
studies in patients with advanced HCC: one is the study in Caucasian population and the 
other is the study in Asian population.9,10 However median overall survival (OS) and time to 
progression (TTP) with sorafenib are only ~1 year and ~4 months, respectively, with frequent 
dose reductions or discontinuations due to adverse events.11,12,13  Therefore, more effective 
and safe therapeutic options for patients with advanced HCC are needed.
1.2.2. Avelumab (MSB0010718C)
One of the investigational products in the present clinical trial is avelumab (MSB0010718C), 
a fully human monoclonal antibody (mAb) of the immunoglobulin (Ig) G1 isotype.  


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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.14  
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in Phase 1, 2 and 3 clinical protocols in a variety of cancers, including non-small cell 
lung cancer, gastric cancer, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, 
urothelial cancer, head and neck cancer, and Hodgkin’s and non-Hodgkin’s Lymphomas, as 
single agent or in combination with chemotherapy, tyrosine kinase inhibitors, radiotherapy, 
or other immune modulating agents.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2.3. Axitinib (INLYTA®, AG 013736)
One of the investigational products in the present clinical trial is axitinib (INLYTA®, AG 
013736), an oral, small molecule, TKI selective for VEGFRs 1, 2, and 3, approved 
multinationally for the treatment of advanced RCC after failure of one prior systemic therapy 
(actual indication varies according to region/country).
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Axitinib is an adenosine triphosphate (ATP) competitive inhibitor that binds to the 
unphosphorylated (non activated) “DFG out” conformation of the catalytic domain of a 
receptor tyrosine kinase.  In enzymatic assays, axitinib was found to be highly potent 
(Ki = 28 picomolar) against the kinase activity of juxta membrane (JM) domain containing 
human VEGFR 2 recombinant protein.  In additional kinase assays, axitinib showed potent 
and ATP competitive inhibition of the VEGFRs 1, 2, and 3 and PDGFR-, but not other 
closely related family kinases.  Receptor binding studies and cell based assays confirmed that 
axitinib is a potent and selective inhibitor of VEGFRs 1, 2, and 3.  Axitinib was shown to 
have antiangiogenic activity in a number of models including spontaneous pancreatic islet 
cell tumors of RIP TAG 2 transgenic mice model and demonstrated antitumor efficacy 
including marked cytoreductive antitumor activity in multiple tumor models implanted in 
athymic mice. 
Overall, the adverse events reported for axitinib in clinical studies were considered generally 
tolerable and manageable.  For single agent axitinib, the most common adverse events (>20% 
of patients) reported from 1445 cancer patients regardless of causality included diarrhea, 
hypertension, decrease appetite, nausea, weight decreased, dysphonia, palmar-plantar 
erythrodysaesthesia syndrome, hypothyroidism, and proteinuria.  Grade 3 events that 
occurred most frequently were hypertension, fatigue, and diarrhea.
The most common adverse events reported in patients with advanced HCC who received 
axitinib single agent in randomized Phase 2 study (n = 133) were diarrhea, hypertension, 
decreased appetite, fatigue, abdominal pain, palmar-plantar erythrodysaesthesia syndrome, 
weight decreased, nausea, dysphonia and hypothyroidism.15  Grade 3 events that occurred 
most frequently were hypertension, diarrhea and palmar-plantar erythrodysaesthesia 
syndrome. Overall safety profile in patients with advanced HCC was similar to known safety 
profile of axitinib single agent.
Following twice daily oral administration, axitinib is rapidly absorbed (median Tmax 2.5-4.1 
hours).  The plasma half life of axitinib ranges from 2.5 to 6.1 hours and steady state is 
expected within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice daily resulted in 
approximately 1.4 fold accumulation compared to administration of a single dose.  At steady 
state, axitinib exhibits approximately linear pharmacokinetics within the 1 mg to 20 mg dose 
range.  The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%. Axitinib 
can be administered with or without food.  Axitinib is metabolized primarily in the liver by 
CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.  The predominant 
sulfoxide and N-glucuronide metabolites in human plasma show approximately ≥400 fold 
less in vitro potency against VEGFR 2 compared to axitinib.
Complete information for axitinib may be found in the SRSD, which for this study is the 
axitinib IB.  The reference safety information (RSI) can be found in tabular format in Section 
7.8 of the axitinib IB.
1.2.4. Clinical Experience of Combination therapy of avelumab plus axitinib 
The combination of avelumab with axitinib is being tested in study B9991002, a Phase 1b 
open-label, dose-finding study aiming to evaluate the safety, pharmacokinetics (PK) and 


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pharmacodynamics of avelumab in combination with axitinib in patients with previously 
untreated advanced RCC.  This study also evaluated preliminary antitumor activity as 
secondary endpoint.  This study was designed to establish the dosing regimen of avelumab 
and axitinib to be used for any further study with this combination.  Study B9991002 is 
comprised of a dose-finding phase and a dose-expansion phase.  The initial doses to be tested 
(Dose Level 1, [DL1]) were avelumab 10 mg/kg IV Q2W in combination with axitinib 5 mg 
orally (PO) twice a day (BID) continuously, with 2 lower dose levels to be explored only if 
the maximum tolerated dose (MTD) was exceeded in DL1.
The dose-finding phase was completed on 12 February 2016.  The 6 patients enrolled in this 
phase of the study completed the 4-week DLT follow-up period as per protocol 
(corresponding to 2 cycles of 2 weeks each).  There was 1 DLT reported: Grade 3 
proteinuria, related to axitinib per investigator assessment, which resolved after reducing the 
dose of axitinib to 3 mg BID.  As of 12 February 2016, the AEs recorded in the dose-finding 
phase were mostly low grade and manageable, with no new unexpected safety signals for the 
combination when compared to the safety profile of each drug as monotherapy.  No patients 
discontinued the combination due to AEs. Based on these findings, the MTD/recommended 
Phase 2 dose (RP2D) for the combination is avelumab 10 mg/kg IV Q2W and axitinib 5 mg 
PO BID continuously.  Enrollment in the dose-expansion began on 15 February 2016, with a 
target enrollment of approximately 48 patients.  As of 15 August 2016, 46 patients were 
enrolled and started treatment in this part of the study, and 52 patients were treated overall (6 
patients in the dose-finding part and 46 patients in the dose-expansion part).
As of 15 August 2016, the B9991002 study clinical database included data from 47 treated 
patients (6 patients in the dose-finding part and 41 patients in the dose-expansion part).  
Overall, the reported TEAEs were mostly low grade and manageable.  The most frequent 
TEAEs (any cause, any grade, experienced by ≥10% patients) were dysphonia (17 patients, 
36.2%), fatigue (16 patients, 34.0%), hypertension (14 patients, 29.8%), diarrhea 
(13 patients, 27.7%), constipation (11 patients, 23.4%), nausea (9 patients, 19.1%), 
arthralgia, dyspnea, palmar-plantar erythrodysesthesia syndrome, rash (8 patients each, 
17.0%), decreased appetite, headache, hypothyroidism, infusion-related reaction (IRR), 
vomiting (7 patients each, 14.9%), ALT increased (6 patients, 12.8%), dizziness, lipase 
increased, mucosal inflammation and proteinuria (5 patients each, 10.6%).  Fifteen (15) 
patients (31.9%) experienced a Grade 3 TEAE of any cause, including hypertension (5 
patients, 10.6%), lipase increased, amylase increased and ALT increased (2 patients each, 
4.3%), AST increased, dehydration, fatigue, gamma-glutamyltransferase increased, 
hyponatremia, hypophosphatemia, IRR, spinal cord compression, mucosal inflammation, 
pain in extremity, palmar-plantar erythrodysesthesia syndrome, proteinuria, pulmonary 
embolism, rash, venous thrombosis and urticaria (1 patient each, 2.1%).  Three (3) patients 
(6.4%) experienced a Grade 4 TEAEs of any cause: lipase increased (2 patients, 4.3%) and 
blood creatine phosphokinase increased (1 patient, 2.1%).  One (1) case of Grade 5 TEAE 
myocarditis (see below for details) was recorded.  All Grades 3-5 TEAEs were assessed as 
related to study treatment by the investigator with the exception of 
gamma-glutamyltransferase increased, hyponatremia, spinal cord compression, and 
pulmonary embolism.


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With respect to the potential immune-related AEs, 7 patients (14.9%) developed Grade 1-2 
hypothyroidism, 3 patients (6.4%) Grade 1 hyperthyroidism, and 1 patient (2.1%) Grade 1 
autoimmune hypothyroidism.  In addition, diarrhea (27.7 %, all of Grade 1-2 severity), rash 
(17% all grades, 2.1% Grade 3), ALT increased (12.8% all grades, 4.3% Grade 3), and AST 
increased (8.5% all grades, 2.1% Grade 3) were reported.  Both hyperthyroidism and 
hypothyroidism are expected AEs for both avelumab and axitinib.  Rash, diarrhea and 
increased liver enzymes have also been reported with axitinib monotherapy.  Medical review 
of these cases to confirm their immune-related nature is ongoing.  In addition, there was one 
case of fatal myocarditis which was assessed as related to both avelumab and axitinib by the 
investigator and in which pathology confirmed an immune-mediated cause.
Seven (7) out of 47 treated patients included in the study database discontinued study 
treatment: 4 patients due to disease progression, 2 patients due to adverse event (fatal 
myocarditis and Grade 3 creatinine phosphokinase increased, 1 patient each), and 1 due to 
consent withdrawal.
As of 15 August 2016, 17 SAEs were notified to the sponsor.  Fourteen (14) out of the 
52 treated patients experienced a total of 23 treatment-emergent SAEs, regardless of 
causality.  A total of 12 treatment-related treatment-emergent SAE were reported for 
8 patients, including the following events: dehydration, IRR, venous thrombosis, 
transaminases increased, pyrexia, neutropenia, lipase increased, amylase increased, 
palpitation, dyspnea, ALT increased, and myocarditis.  The patient with myocarditis died 
suddenly at home after 19 days of treatment with the combination, and 5 days after the 
second dose of avelumab.  The patient had visited the site 5 days before his death and at that 
time had no signs or symptoms suggestive of cardiac toxicity, nor remarkable laboratory 
abnormalities.  An autopsy was performed and a myocarditis with heavy lymphocytic 
infiltration was identified as the cause of death.  Tests for viral myocarditis were negative.  
Myocarditis is an expected adverse drug reaction for avelumab.
In conclusion, as of 15 August 2016, the safety profile of the combination appears consistent 
with that of each study drug as monotherapy.  Safety continues to be closely monitored by 
the B9991002 study team and discussed in regular teleconferences between the study team 
and the investigators. 
In addition, as of 15 August 2016, 36 out of 47 patients in the clinical database were treated 
for at least 12 weeks prior to the analysis cut-off date and were included in the analysis of 
best overall response (BOR).  The BOR included 1 patient with confirmed CR (2.8%), 
15 patients with confirmed PR and 4 patients with unconfirmed PR (52.8%), 9 patients with 
SD (25.0%), 5 patients with PD (13.9%) and 2 patients not evaluable for response (5.6%; one 
patient died before the first oncologic assessment due to myocarditis, and another one who 
never started the combination treatment, discontinued axitinib treatment due to Grade 3 
creatinine phosphokinase increased).  The objective response rate (including confirmed and 
unconfirmed responses) is 55.6% (95% CI: 38.1-72.1).
Currently, this combination is tested in phase 3 (NCT02684006): A Study of Avelumab With 
Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101).


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1.2.5. Rationale for Studying Avelumab in Combination with Axitinib in Patients with 
Advanced Hepatocellular Carcinoma
HCC is a highly vascular tumor in which vascular recruitment and invasion greatly 
contribute to pathogenesis.  The vascular endothelial growth factor (VEGF) is thought to 
have an important role in HCC angiogenesis; its expression has been confirmed in this 
disease16 and has been associated with poor prognosis.17  The expression of VEGF receptors 
has also been investigated in HCC, and the results suggest that an angiogenesis mechanism 
operates via the VEGFR1 or VEGFR2 pathway.18,19,20,21  
Two oral multi-kinase inhibitors, sorafenib and regorafenib that block the activity of protein 
kinase involved angiogenesis showed survival benefit in Phase 3 studies.  Results from the 
Phase 3 trial (SHARP) testing single-agent sorafenib in patients with advanced HCC showed 
a significant improvement in OS compared to placebo from a median of 7.9 months to 10.7 
months (hazard ratio [HR] = 0.69 [95% CI: 0.55 - 0.87, p <0.001]).9  In addition, Phase 3 
trial that tested single-agent sorafenib in advanced HCC in Asian patients also showed a
significant improvement in OS from a median of 4.2 months to 6.5 months (HR = 0.68 [95% 
CI: 0.50 - 0.93, p = 0.014]).10 Based on the results from these Phase 3 trials, sorafenib has 
been used for 1st line treatment as a standard of care in patient with advanced HCC.  Phase 3 
study of regorafenib in patients with sorafenib resistant or refractory HCC showed a
significant improvement in OS compared to placebo (HR = 0.63 [95% CI: 0.50 - 0.79, 
p <0.0001]) with median OS of 10.6 months and 7.8 months, respectively.24  Recently, 
lenvatinib, VEGFR tyrosine kinase inhibitor, showed promising efficacy results in single arm 
Phase 2 study in patients with advanced HCC who did not have prior systemic therapy.  In 
this Phase 2 study, median OS was 18.7 months (95% CI: 12.7 - 25.1) and 17 of 46 patients 
showed PR per modified Response Evaluation Criteria in Solid Tumors (RECIST)25
(objective response rate [ORR]: 37%).26  
Although axitinib did not show statistically significant improvement in OS compared to 
placebo in Phase 2 study in patients with advanced HCC resistant, refractory or intolerant to 
sorafenib (HR = 0.907 [95% CI: 0.646 - 1.274], p = 0.287)15, subgroup analysis in the 
population excluding patients intolerant to sorafenib from the overall population showed 
clinically significant improvement in OS with median OS of 12.3 months in axitinib arm (N 
= 121) and 9.2 months in placebo arm (N = 51) (HR = 0.662 [95% CI: 0.458 - 0.956]) (Pfizer 
internal data).  In addition, Japanese and Korean population (excluding patients intolerant to 
sorafenib) also showed clinically significant results with median OS of 13.9 months in 
axitinib arm (N = 46) and 4.6 months in placebo arm (N = 17) (HR = 0.479 [95% CI: 0.250 -
0.918]) (Pfizer internal data).  The ORR was numerically higher in axitinib arm vs placebo 
arm (9.7 vs 2.9%; P=0.091) in the overall population.
CD8+ T-cell infiltration into tumor has been reported to correlate with low recurrence rate 
after resection of HCC,27 which suggests an immunotherapeutic approach is potentially 
effective for HCC.  PD-1 is one of CD28 superfamily member coinhibitory receptor of T-cell 
receptor, which binds to PD-L1 or PD-L2.  When PD-1 binds to PD-L1 or PD-L2, T-cell 
proliferation and cytokine release is inhibited.28  Using the cytokines from tumor-infiltrating
lymphocytes expressed into microenvironment, cancer cells express PD-L1 (and sometimes 
PD-L2) to evade immune surveillance.29   PD-1/PD-L1 expression in tumor was significantly


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correlated with HCC stage, local recurrence rate and poor prognosis.30  Recently, immune 
checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 antibodies have been investigated in 
various types of solid tumors in clinical trials and shows promising antitumor effects.  
Nivolumab, a high-affinity, fully human anti-PD-1 mAb, approved for treatment of 
melanoma, RCC and non-small cell lung cancer, has shown durable tumor response with 
ORR of 20% (95% CI 15 – 26) in 214 patients including 3 complete responses and median
OS has not yet been reached but 9-month OS rate of 74% (95% CI 67 – 79) in Phase 1/2 
study in patients with advanced HCC.31  
VEGF can also exert immunosuppressive effects in tumors by inhibiting maturation of 
dendritic cells, promoting immune suppressive cell infiltration and enhancing immune 
checkpoint molecule expression,28 which suggests potential synergy in anti-VEGF therapy in 
combination with immune checkpoint blockade.  The non-clinical and clinical findings 
described above support investigating axitinib in combination with avelumab in patients with 
advanced HCC.  In this study, the safety and tolerability of the combination of full dose of 
axitinib plus avelumab (which have showed tolerable safety profile in studies B9991002 and 
B9991003 in patients with advanced RCC) and the preliminary antitumor effect with the 
combination will be evaluated in patients with advanced HCC who have not had prior 
systemic therapy.
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
CCI
CCI


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s):
Primary Endpoint(s):
•
To evaluate the safety and tolerability of 
avelumab in combination with axitinib as 
first line treatment in patients with 
advanced HCC.
•
Adverse events (AEs) and laboratory 
abnormalities as graded by National 
Cancer Institute (NCI) Common 
Terminology Criteria for Adverse 
Events (CTCAE) v. 4.03.
Secondary Objective(s):
Secondary Endpoint(s):
•
To evaluate antitumor effect of 
avelumab in combination with axitinib 
as first line treatment in patients with 
advanced HCC per RECIST v.1.1.
•
To evaluate the OS of avelumab in 
combination with axitinib in patients 
with advanced HCC.
•
To evaluate the pharmacokinetics of 
avelumab and axitinib when 
administered in combination.
•
To evaluate candidate predictive 
biomarkers in pre-treatment tumor tissue 
that may aid in the identification of a 
patient subpopulation most likely to 
benefit from treatment with avelumab in 
combination with axitinib.
•
To assess the immunogenicity of 
avelumab when combined with axitinib.
•
Time to Progression (TTP), Progression 
Free Survival (PFS), Objective 
Response (OR), Disease Control (DC), 
Time to Tumor Response (TTR) and 
Duration of Response (DR), per 
RECIST v.1.1.
•
Overall Survival (OS).
•
PK parameters including trough and 
maximum concentrations (Ctrough, Cmax) 
of avelumab and axitinib.
•
Tumor tissue biomarker status (ie, 
positive or negative based on, for 
example, PD-L1 expression and/or 
quantitation of tumor-infiltrating CD8+ 
T lymphocytes as assessed by 
immunohistochemistry [IHC]).
•
Anti-drug antibodies (ADAs, 
neutralizing antibodies [nAbs]) for
avelumab when in combination with 
axitinib.
 
 
 
 
 
CCI


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3. STUDY DESIGN
This is an open-label, multi-center, single arm, Phase 1b study to evaluate the safety, efficacy
and PK of avelumab in combination with axitinib as first line treatment in patients with
advanced HCC.
Approximately 20 patients with advanced HCC who have not had prior systemic therapy will 
be enrolled in this study. The overall safety profile of these patients will be assessed after a 
minimum follow up of 3 months (ie. at least 3 months from last patient first dosing [LPFD]).  
Significant toxicities including irAEs which occur after 3 month follow up will also be 
included in the assessment.
Patients will receive avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID. If 
this dose level for the combination is not tolerable, a lower dose of the combination 
(avelumab 10 mg/kg IV Q2W plus axitinib 3 mg BID) may be evaluated with adding new 
cohort of patients.  A cohort of patients aimed to evaluate avelumab 800 mg flat dose Q2W 
in combination with axitinib 5 mg BID may be added after the tolerability of avelumab 
10 mg/kg Q2W in combination with axitinib 5 mg BID is confirmed.
Treatment with study drugs may continue until confirmed disease progression, patient 
refusal, patient lost to follow up, unacceptable toxicity, or the study is terminated by the 
sponsor, whichever comes first (see Section 6.3).
Patients who develop disease progression on study treatment but are otherwise continuing to 
derive clinical benefit from study treatment will be eligible to continue with avelumab 
combined with axitinib, single-agent avelumab, or single-agent axitinib provided that the 
treating physician has determined that the benefit/risk for doing so is favorable.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol.  
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.  
CCI


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4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Diagnosis of locally advanced or metastatic HCC, obtained by histology/cytology (on 
a prior tumor biopsy) or by imaging (acceptable imaging modalities include triphasic 
contrast-enhanced helical computerized tomography [CT], triphasic dynamic 
contrast-enhanced magnetic resonance imaging [MRI] and contrast-enhanced 
ultrasonography) with serum -fetoprotein (AFP) ≥400 ng/mL.
2. All patients must provide at least 1 archival tumor specimen. If archival tumor 
specimen is no longer available, de novo tumor biopsy will be required during 
screening. 
3. HCC not amenable to local therapy.
4. Measurable disease according to RECIST v. 1.1.
5. Child-Pugh Class A disease (see Appendix 2). Score for hepatic encephalopathy 
must be 1; ascites score must be ≤2.
6. Barcelona Clinic Liver Cancer (BCLC) stage B or C disease. Stage B disease must be 
unresectable, not amenable to local therapy or refractory to local therapy.
7. No evidence of uncontrolled hypertension as documented by 2 baseline blood 
pressure readings taken at least 1 hour apart.  The baseline systolic blood pressure 
readings must be 140 mm Hg, and the baseline diastolic blood pressure readings 
must be 90 mm Hg.  Patients whose hypertension is controlled by antihypertensive 
therapies are eligible.
8. Age 20 years.
9. ECOG performance status 0 or 1.
10. Estimated life expectancy of at least 3 months.
11. Required baseline laboratory data within the following parameters: 

Neutrophils ≥1,500/L;

Platelets ≥75,000/L;

Hemoglobin ≥9.0 g/dL;

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase 
(ALT) 5 × ULN;


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
Estimated creatinine clearance ≥50 mL/min as calculated using the Cockcroft 
Gault (CG) equation;

INR <1.7 or prothrombin time (PT) <4 seconds above ULN (ie, Child-Pugh Score 
is no greater than 1);

Serum albumin ≥2.8 g/dL (ie, Child-Pugh Score is no greater than 2);

Total bilirubin 3 mg/dL (ie, Child-Pugh Score is no greater than 2);

Urinary protein <2+ by urine dipstick.  If dipstick is ≥2+ then a 24 hour urine 
collection should be done and the patient may enter only if urinary protein is 
<2.0 g per 24 hours.
12. Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) as assessed 
by multigated acquisition (MUGA) scan or echocardiogram (ECHO).
13. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.
Female patients of nonchildbearing potential must meet at least 1 of the following 
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure. 
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.
14. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective methods of contraception 
(see Section 4.3.1) throughout the study and for at least 30 days after the last dose of 
assigned treatment.
15. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study. 
16. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.


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4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior systemic treatment for advanced HCC, including prior treatment with approved
or investigational drugs.

Prior immunotherapy with 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 sorafenib as well as any prior therapies with other VEGF 
pathway inhibitors.
2. Any prior locoregional therapy (such as hepatic arterial embolization, TACE, hepatic 
arterial infusion, radiofrequency ablation, percutaneous ethanol injection or 
cryoablation) within 4 weeks and radiotherapy or surgical procedure within 2 weeks 
(4 weeks for major surgery) of enrollment . Prior palliative radiotherapy to metastatic 
lesion(s) is permitted, provided it has been completed at least 48 hours prior to 
enrollment.
3. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade >1); however 
alopecia, sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a 
safety risk based on investigator's judgment are acceptable. 
4. 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 starting the study treatment, have discontinued corticosteroid treatment for 
these metastases for at least 4 weeks and are neurologically stable.
5. Presence of hepatic encephalopathy (ie, Child-Pugh score of 2 or 3) and/or clinically 
relevant ascites (ie, Child-Pugh score of 3).
6. Presence of main portal vein invasion by HCC (invasion to 1st or 2nd branch of 
portal vein is acceptable).
7. NCI CTCAE Grade ≥3 hemorrhage within 4 weeks of enrollment, or variceal 
hemorrhage of any grade within 12 months of enrollment.
8. Evidence of inadequate wound healing.
9. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days of enrollment.
10. Any of the following within the 12 months prior to enrollment: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 


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congestive heart failure, LVEF less than LLN, clinically significant pericardial 
effusion, cerebrovascular accident, transient ischemic attack.
11. Any of the following in the previous 6 months: deep vein thrombosis or symptomatic 
pulmonary embolism.
12. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2 or prolongation of the QTc 
interval to >500 msec.
13. Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus
extending to the heart.
14. History of or known active seizure disorder, spinal cord compression, or 
carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
15. Known prior severe hypersensitivity to investigational product or any component in 
its formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v. 4.03 Grade ≥3).
16. Current use of immunosuppressive medication at the time of enrollment, except the 
following: a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, 
intra-articular injection); b. Systemic corticosteroids at physiologic doses 10 mg/day 
of prednisone or equivalent; c. Steroids as premedication for hypersensitivity 
reactions (eg, CT scan premedication). 
17. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agents. Patients with type I diabetes mellitus, vitiligo, psoriasis, 
hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible.
18. Active infection requiring systemic therapy except for hepatitis C virus (HCV) and
hepatitis B virus (HBV) as follows:

Patients with chronic infection by HCV are eligible for study participation.

Patients with chronic infection by HBV are eligible for study participation only if 
they are on antiviral therapy and the infection is controlled by treatment prior to
enrollment.
19. Administration of a live vaccine within 28 days prior to enrollment.
20. Current use or anticipated need for treatment with botanical formulation having an 
approved indication for liver cancer treatment, such as “Kanglaite”
21. 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 starting the study treatment (eg, grapefruit juice or 


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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.
22. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, 
including their administration within 10 days prior to patient starting the study 
treatment (eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, 
rifapentin, clevidipine, and St John’s wort).
23. Requirement of anticoagulant therapy with oral vitamin K antagonists.  Low-dose 
anticoagulants for maintenance of patency of central venous access devise or 
prevention of deep venous thrombosis is allowed.  Therapeutic use of low molecular 
weight heparin is allowed.
24. 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 unless the ulcer is 
completely healed as confirmed by endoscopy prior to study treatment; 

Active gastrointestinal bleeding, unrelated to cancer, as evidenced by 
hematemesis, hematochezia or melena in the past 3 months without evidence of 
resolution documented by endoscopy or colonoscopy;

Malabsorption syndromes.
25. Prior organ transplantation including allogenic stem-cell transplantation
26. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome.
27. Diagnosis of any other malignancy within 3 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, low-grade (Gleason 6 or below) prostate cancer on 
surveillance with no plans for treatment intervention (eg, surgery, radiation, or 
castration), or pathologically diagnosed in situ gastric (T1 [M]; UL [-]), esophageal 
(TIS or T1a), or colorectal cancer (Stage 0 [M]) treated with curative resection.
28. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 


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patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
29. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
enrollment.
30. Concurrent colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis
31. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
32. Pregnant female patients; breastfeeding female patients.
4.3. Lifestyle Requirements
4.3.1. Contraception
In this study, fertile male patients and female patients who are of childbearing potential as 
applicable to the study will receive avelumab for which the teratogenic risk is currently 
unknown in combination with axitinib, which has been associated with demonstrated 
teratogenicity.  Patients who are, in the opinion of the investigator, sexually active and at risk 
for pregnancy with their partner(s) must agree to use 2 methods of highly effective 
contraception throughout the study and for at least 30 days after the last dose of 
investigational product.  The investigator or his or her designee, in consultation with the 
patient, will confirm that the patient has selected 2 appropriate methods of contraception for 
the individual patient and his/her partner(s) from the list of permitted contraception methods 
(see below) and will confirm that the patient has been instructed in their consistent and 
correct use.  At time points indicated in the Schedule of Activities, the investigator or 
designee will inform the patient of the need to use 2 highly effective methods of 
contraception consistently and correctly and document the conversation, and the patient’s 
affirmation, in the patient’s chart.  In addition, the investigator or designee will instruct the 
patient to call immediately if 1 or both of the selected contraception methods is discontinued 
or if pregnancy is known or suspected in the patient or partner.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.  


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2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational products are avelumab and axitinib. 
5.1. Allocation to Treatment
All patient will be assigned to starting dose of avelumab 10 mg/kg Q2W plus axitinib 5 mg 
BID after patients have given their written informed consent and have completed the 
necessary baseline assessments. The site staff will fax or e-mail a complete Registration 
Form to the designated sponsor study team member or designee.  The sponsor will assign a 


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patient identification number and supply this number to the site.  The patient identification 
number will be used on all study-related documentation at the site.
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 and; 

Permission to proceed with dosing the patient. 
5.2. Patient Compliance
For self-administration of axitinib at home, compliance will be captured and completed by 
the patient with recording every dosing to a patient diary.  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 after at least every other cycle.
All doses of avelumab will be administered by the appropriately designated study staff at the 
investigator site.
5.3. Investigational Product Supplies
Avelumab and axitinib will be supplied for the study by Pfizer Global Clinical Supply, 
Worldwide Research and Development.  Drug supplies will be shipped to the study sites with 
a Drug Shipment and Proof of Receipt form.  This form will be completed, filed, and the 
shipment confirmed as directed on the bottom of the Drug Shipment and Proof of Receipt 
form.  The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and usage 
of investigational product in accordance with the protocol and any applicable laws and 
regulations.
5.3.1. Dosage Form(s) and Packaging
5.3.1.1. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20.0 mg/mL solution and will be supplied by the sponsor in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene 
flip-off seal.
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.


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5.3.1.2. Axitinib
Axitinib will be supplied as 1 mg and 5 mg film-coated tablets for oral administration in 
light-resistant high-density polyethylene (HDPE) bottles with desiccant.
5.3.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
investigational agents.
5.3.2.1. Avelumab
Avelumab will be dosed at the investigational site.
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard cleanup procedures for biologic products.
For application in this trial, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection).  Detailed information on infusion bags and medical devices to be 
used for the preparation of the dilutions and subsequent administration will be provided in 
the Dosage and Administration Instruction contained in the Investigational Product Manual 
(IP Manual). 
Avelumab must not be used for any purpose other than the trial.  The administration of trial 
investigational product to patients who have not been enrolled into the trial is not covered by 
the trial insurance.
Any unused portion of the solution should be discarded in biohazard waste disposal with 
final disposal by accepted local and national standards of incineration.
See the Dosage and Administration Instruction in the IP Manual for instructions on how to 
prepare the investigational product for administration.  Investigational product should be 
prepared and dispensed by an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as allowed by 
local, state, and institutional guidance.
5.3.2.2. Axitinib
Axitinib is a hazardous drug (due to possible reproductive toxicity), and should be handled 
according to the recommended procedures described in the current edition of the American 
Society of Hospital Pharmacists (ASHP), Technical Assistance Bulletin on Handling 
Cytotoxic and Hazardous Drugs, American Hospital Formulary Service (AHFS) Drug 
Information (1999) and its references.  Procedures described in each institution’s pharmacy 
or hospital standard operating procedure manual should be followed when handling 
hazardous drugs.
Axitinib will be provided in quantities appropriate for the study visit schedule.  A qualified 
staff member will provide the study treatment via a unique container number using the
interactive response technology (IRT) system. 


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Axitinib will be dispensed on Day 1 of each cycle or as otherwise indicated.  Patients should 
be instructed to keep their study treatment in the bottles provided and not transfer it to any 
other container.  In the event of dose modification, a request should be made of the patient to 
return all previously dispensed study treatment to the clinic.
5.4. Administration
All investigational products will be administered on an outpatient basis.
5.4.1. Avelumab
The Drug Administration Instructions within the IP Manual contains specific instructions for 
avelumab dose calculation, reconstitution, preparation of the infusion fluid, and 
administration.
Avelumab will be administered on Days 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 dose. 
Avelumab will be administered as a 1-hour IV infusion once every 2 weeks.  
Sites should make every effort to target infusion timing to be as close to 1 hour as possible.  
The exact duration of infusion should be recorded in both source documents and Case Report 
Form (CRF).  
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 treatment must be recalculated 
using this most recent weight obtained.  
Avelumab dose reduction for toxicity management is not permitted, however next 
administration may be omitted due to persisting toxicity or treatment may be discontinued as 
described in Table 2 and Section 5.4.5.  Possible modifications of the infusion rate for the 
management of infusion-related reactions related to avelumab are described in
Section 5.4.5.5. 
5.4.2. Axitinib
Axitinib will be administered orally BID at approximately the same time in the morning and 
evening on a continuous dosing schedule, ie, without a break in dosing in the absence of 
drug-related toxicity (see Section 5.4.5).  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. 


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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.  
Patient must be instructed to record all doses (missed or vomited doses or extra doses) in a 
dosing diary supplied by the site.  If doses are missed or vomited or if an extra dose is taken, 
this must be indicated in the source documents and CRFs.
Patients experiencing toxicity may require treatment adjustment or discontinuation according 
to the guidelines specified in Table 1 and Table 2.
5.4.3. 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 


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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. 
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.
5.4.4. Food Requirements
All investigational products may be administered without regard to food but patients must 
avoid foods that are known strong CYP3A4/5 inhibitors (eg, grapefruit juice or 
grapefruit/grapefruit-related citrus fruits [eg, Seville oranges, pomelos]).
5.4.5. 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 avelumab, no dose modifications are permitted in this study, but next infusion may be 
omitted based on persisting toxicity, as outlined in Table 2.  Dose modifications of axitinib 
and infusion omissions of avelumab may occur independently for the two drugs and will be 
reported in the CRF.
Available axitinib dose level for intrapatient dose modification is listed in Table 1.
5.4.5.1. Intrapatient Axitinib Dose Escalation and Dose Reduction
Intrapatient axitinib dose escalation is permitted up to 10 mg BID and may occur according 
to the criteria described below. 
Patients who tolerate the current axitinib dose without Grade 2 axitinib-related adverse 
events for 2 consecutive weeks have the option to have their axitinib dose increased (one 
dose level increase at a time) as indicated in Table 1 (unless the patient’s blood pressure [BP]
is >150/90 mm Hg or the patient is receiving antihypertensive medication).  Particular 


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attention should be provided to a patient’s overall safety profile prior to implementing 
intrapatient axitinib dose escalation. 
Table 1.
Axitinib Dose Levels
Dose Level
Dose
+2
10 mg BID
+1
7 mg BID
Potential Starting Dose
5 mg BID
-1
3 mg BID
-2
2 mg BID
Patients will be monitored closely for toxicity, and axitinib treatment may be adjusted by 
dosing interruption with or without dose reduction as indicated in Table 2.  Dosing 
interruption and/or dose reduction by 1, and if needed, 2 dose levels (one dose level decrease 
at a time) as indicated in Table 1 will be allowed depending on the type and severity of 
toxicity encountered.  Management of patients requiring more than 2 dose reductions of 
axitinib (one dose level decrease at a time) should be discussed with the sponsor’s medical 
monitor.
Patients who have undergone dose reduction may also undergo dose re-escalation back to the 
previous dose level at the discretion of the Investigator in the absence of Grade 2 
non- hematologic treatment-related toxicity for at least 28 days.
5.4.5.2. Management of Axitinib-Related Hypertension
Patients will be issued BP cuffs (provided by the sponsor) for home monitoring and 
instructed to measure their BP at least once daily (before taking the morning dose of 
axitinib).  All BP measurements will be recorded in a diary and brought to the nurse or study 
coordinator at each clinic visit.  Patients should be instructed to contact the site immediately 
for guidance if their systolic blood pressure rises above 150 mm Hg, diastolic blood pressure 
rises above 100 mm Hg, or if they develop symptoms perceived to be related to elevated 
blood pressure (eg, headache, visual disturbances), although a different blood pressure 
threshold for contacting the site may be used according to the investigator’s clinical 
judgment.
Blood pressure should be well-controlled prior to initiating therapy and patients should be 
monitored for hypertension.32,33   To treat an increase in BP, standard antihypertensives may 
be used (eg, thiazide or thiazide-like diuretics, angiotensin II receptor blockers, angiotensin 
converting-enzyme inhibitors, and dihydropyridine (DHP) calcium channel blockers, 
etc.).32,33
Dose modification for axitinib in case of hypertension is described in Table 2.
5.4.5.3. 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 2.  The aforementioned guidelines might be further 


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modified at the discretion of the sponsor based on the emerging safety profile of the 
combination.  The investigator can consider consulting with the sponsor’s medical monitor in 
case of persistent toxicity that would lead to dose modification or treatment discontinuation 
per toxicity treatment guidelines. 


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Table 2.
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 or if the same Grade 3 toxicity recurs 
(consider consult with the medical monitor 
before permanently discontinuing the 
treatment).
Exceptions are:
Laboratory values that do not have any clinical 
correlate.
Grade 4

Withhold until recovery to Grade 2.

Then, reduce by 1 dose level and resume 
treatment.

For Grade 4 lymphopenia not associated with 
clinical events (eg, opportunistic infection) 
axitinib treatment may continue without 
interruption.

Permanently discontinue avelumab (consider 
consult with medical monitor before 
permanently discontinuing the treatment).
Exceptions are:
Laboratory values that do not have any clinical 
correlate.  
Proteinuria
Dipstick negative or 
shows 1+ (Grade 1)

Continue at the same dose level.

Continue as per schedule.
If dipstick shows >1+, perform 24 hour urine collection or urine protein 
creatinine (UPC) ratio. Dosing may continue while waiting for test results
<2 g proteinuria/ 
24 hour or UPC <2 

Continue at the same dose level.


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Table 2.
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
2 g proteinuria/ 
24 hours or UPC 2

Withhold until proteinuria is <2 g/24 hours or 
UPC <2.

Repeat 24-hour urine collection or UPC for 
proteinuria and creatinine clearance (interval at 
investigator discretion) until proteinuria is 
<2 g/24 hours or UPC <2.

Then, resume at the same dose level or reduce by 
1 dose level as per investigator judgment.
Hypertension
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure 150 mm Hg 
(one or both readings) 
And
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
100 mm Hg (one or 
both readings)

Continue at the same dose level.

See Section 5.4.5.2 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 5.4.5.2 for monitoring/management 
of axitinib-related hypertension.

Continue as per schedule.


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Table 2.
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >160 mm Hg 
OR
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
>105 mm Hg

Withhold until BP is less than 150/100 mm Hg
and adjust antihypertensive medication.

Then, reduce by 1 dose level and resume 
treatment. 

If axitinib dosing is temporarily discontinued, 
patients receiving antihypertensive medications 
should monitor closely for hypotension.  The 
plasma half-life of axitinib is 2-4 hours and BP 
usually decreases within 1-2 days following 
dosing interruption.

See Section 5.4.5.2 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 5.4.5.2 for monitoring/management 
of axitinib-related hypertension.

Continue as per schedule.


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Table 2.
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Axitinib
Avelumab
Dose Modification
Treatment Modification
Infusion-related 
Reaction 
Grade 1-4

Continue at the same dose level.

See Sections 5.4.5.5 and 5.4.5.6 and Table 3.
Immune-related AE 
(irAE)
Grade 1-4

Grade 1: continue at the same dose level.

Grade 2-4: hold treatment until recovery to Grade 
≤1 and restart axitinib at the same dose level for 
Grade 2 and at reduced dose level for Grade 3-4. 

See Section 5.4.5.7 and Table 4. 
Stevens-Johnson 
syndrome
Grade 3-4

Permanent discontinuation

Permanent discontinuation
Other Non-hematologic
Toxicities and 
Laboratory 
Abnormalities
Grade 1 

Continue at the same dose level.

Continue as per schedule 
Grade 2

Continue at the same dose level.

Continue as per schedule
Grade 3

Reduce by 1 dose level.

Grade 3 toxicities controlled with symptomatic 
medications, or Grade 3 asymptomatic 
biochemistry laboratory abnormalities: continue 
at the same dose or reduce by 1 dose level as per 
investigator judgment.

Withhold avelumab.

Re-initiate avelumab once toxicity is Grade 1 
or baseline. 

Permanently discontinue avelumab if toxicity 
does not resolve to Grade 1 or baseline value 
within 12 weeks or if the same Grade 3 toxicity 
recurs (consider consult with medical monitor 
before permanently discontinuing the 
treatment). 
Exceptions are:
Laboratory values that do not have any clinical 
correlate (eg, amylase or lipase abnormality 
that is not associated with symptoms or clinical 
manifestations of pancreatitis).
Grade 4

Hold treatment until recovery to Grade 2. 

Then, reduce by 1 dose level and resume 
treatment.

Grade 4 asymptomatic biochemistry laboratory 
abnormality: study treatment may continue 
without interruption. 

Permanently discontinue avelumab (consider 
consult with the medical monitor before 
permanently discontinuing the treatment). 
Exceptions are:
Laboratory values that do not have any clinical 
correlate.


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5.4.5.4. Special Precautions for Avelumab Administration
In order to mitigate avelumab infusion-related reactions, patients have to be premedicated 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab. Premedication 
should be administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity of prior infusion reactions. Premedication will include an antihistamine 
(for example, 25-50 mg diphenhydramine IV or oral equivalent), and paracetamol 
(acetaminophen) (eg. 500-650 mg paracetamol [acetaminophen] IV or oral equivalent). This 
regimen may be modified based on local treatment standards and guidelines, as appropriate, 
however, the prophylactic administration of systemic corticosteroids is not permitted.  
Following avelumab infusions, patients must be observed for 2 hours post-infusion for 
potential infusion-related reactions.  Patients should be instructed to report any delayed 
reactions to the investigator immediately.
Treatment recommendations for the management of infusion-related reactions and severe 
hypersensitivity reactions are outlined in Sections 5.4.5.5 and 5.4.5.6, respectively.
Investigators should also monitor patients closely for potential irAEs, which may become 
manifest at any time after the first dose of treatment.  Such events may consist of persistent 
rash, diarrhea and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, 
cardiomyopathy, or uveitis and other inflammatory eye conditions.  However potential irAEs 
can occur in any organ or tissue.  Treatment recommendations for the management of irAEs 
are outlined in Section 5.4.5.7.
5.4.5.5. Management of Avelumab Infusion-Related Reactions 
Since avelumab is administered IV, infusion-related reactions may occur. Symptoms of 
infusion-related reactions include but are not limited to fever, chills, flushing, hypotension, 
dyspnoea wheezing, back pain, abdominal pain, and urticaria. Management of infusion-
related reactions should follow the guidelines set forth in Table 3. 


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Table 3.
Treatment Modification for Symptoms of Infusion-Related Reactions 
Caused by Avelumab
NCI CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for 24 hours.
Temporarily discontinue avelumab infusion
Resume avelumab infusion at 50% of previous rate 
once infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any 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 infusion tubing from the patient.
Patients have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment.
IV=intravenous, NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% due to an infusion-related 
reaction, it must remain so for all subsequent infusions.  
5.4.5.6. Management of Avelumab-related Severe Hypersensitivity Reactions 
As with all monoclonal antibody therapies, there is a risk of severe hypersensitivity 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, epinephrine, allergy medications, bronchodilators, and oxygen should be available 
for immediate access.
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice.  
Additional treatment recommendations for symptoms of avelumab infusion-related reactions 
are provided in Appendix 5 and may be modified based on local treatment standards and 
guidelines, as appropriate. 
5.4.5.7. Management of Avelumab Immune-Related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of 
irAEs is mainly dependent upon severity as reported in Table 4:


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
Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring;

Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4);

Grade 3 to 4: treat with high dose corticosteroids.
For any irAE of any grade, the investigator may consider consulting with the sponsor’s 
medical monitor if deemed necessary.
Treatment of irAEs should follow guidelines set forth in Table 4. 
Some potential immune-related adverse events described with anti-PD-L1 monoclonal 
antibodies such as avelumab may overlap with some axitinib toxicities (eg, diarrhea, liver 
function tests increase).  Any adverse event suspected to be immune-related should be 
managed according to the guidance for management of immune-related adverse events in this 
Section 5.4.5.7.
For overlapping potential immune-related toxicities, follow the specific management 
recommendations described in Table 4.  


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Table 4.
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 (e.g. 
loperamide)
Close monitoring for worsening 
symptoms
Educate subject to report worsening 
immediately
If worsens:
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated <24 
hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤1: 
Resume avelumab therapy
If persists >5-7 days or recurs:
Treat as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over Baseline; incontinence; IV 
fluids ≥24 h; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention 
indicated, peritoneal signs
Grade 4: life-threatening, 
perforation
Withhold avelumab for 
Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3.
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade ≤1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids 
taper (for initial Grade 3). 
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis. 


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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)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding 
avelumab therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
Grade 2
Mild to moderate new symptoms 
Withhold avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily; 
consider hospitalization 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent   
Add prophylactic antibiotics 
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: 


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for opportunistic infections
Consider bronchoscopy, lung 
biopsy 
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 
× ULN and/or Total bilirubin > 
ULN to 1.5 × 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 × ULN 
and/or total bilirubin > 1.5 to ≤3 ×
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 × ULN and /or 
total bilirubin >3 × ULN 
Permanently discontinue 
avelumab therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consult gastroenterologist/ 
hepatologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted 
If returns to Grade ≤1: 
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily 
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants per local 
guidelines.


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Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 ×
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 ×
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 × 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 (e.g. 
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 (e.g. 
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 (i.e. 
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 
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤1 (with or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 


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


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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.
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
ACTH=adrenocorticotropic hormone, ADL=activities of daily living, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, BNP=B-type natriuretic peptide, CK-MB=creatine kinase MB, CT= 
computed tomography, FSH=follicle-stimulating hormone, GH=growth hormone, IGF-1=insulin-like growth 
factor 1, irAE=immune-related adverse event, IV=intravenous, LH=luteinizing hormone, MRI=magnetic 
resonance imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse 
Events, PRL=prolactin, T4=thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of normal.
5.5. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.


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Investigational products should be stored in their original containers and in accordance with 
the labels.  
See the IP manual for storage conditions of the product once reconstituted and/or diluted (for 
avelumab only).
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct patients on the proper storage requirements for take home 
investigational products. 
5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  All bottles of study drug must be 
returned to the investigator by the patient at every other cycle and at the end of the trial.


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5.7. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
Medications or vaccinations specifically prohibited in 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 
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, and 
immune-related events are reported in Section 5.4.5.5, Section 5.4.5.6, and Section 5.4.5.7, 
respectively. 
5.8.1. Inhibitors and Inducers of CYP Enzymes
In vitro studies with human liver microsomes and recombinant CYP enzymes indicate that 
axitinib metabolism is primarily mediated by the CYP3A4/5, and to a lesser extent by 
CYP1A2, CYP2C19, and UGT1A1. 
The concomitant use of strong CYP3A4/5 inhibitors (eg, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 


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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 a dose reduction if axitinib must be dosed 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 a dose increase if axitinib must be dosed with a 
CYP3A4/5 inducer.
If coadministration of the strong CYP3A4/5 inducer is discontinued, the axitinib dose should 
be de-escalated (after 10 days) to that used prior to initiation of the strong CYP3A4/5 
inducer.
A listing of CYP3A4 inhibitors and inducers will be provided to the sites and updated as 
needed.
5.8.2. Hematopoietic Growth Factors
Granulocyte colony stimulating factor may be used in agreement with American Society of 
Clinical Oncology (ASCO) guidelines.34
Patients who enter the study on stable doses of erythropoietin or darbepoietin may continue 
this treatment, and patients may start either drug during the study at the discretion of the 
treating physician if clinically indicated.
5.8.3. Concomitant Surgery 
No formal studies of the effect of axitinib on wound healing have been conducted; however, 
caution is advised based on the mechanism of action.  If a major surgery or an interventional 
procedure (eg, endoscopy) is required, treatment with axitinib must be interrupted at least 
24 hours before the procedure, and the patient BP should be monitored closely for 
hypotension.  Patients may resume axitinib 7 days after minor surgery and 2-3 weeks after 
major surgery, assuming the wound has completely healed and there are no wound healing 
complications (eg, delayed healing, wound infection or fistula).
In case of surgical procedure, avelumab treatment should be delayed.  Reinitiation should be 
discussed with the sponsor’s medical monitor.


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5.8.4. Concomitant Radiotherapy
Local radiotherapy (limited field) of isolated lesions with palliative intent is acceptable and 
allowed throughout the study (ie, starting from screening 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 also be 
present at baseline; otherwise, painful lesion(s) requiring radiotherapy will be considered as a 
sign of disease progression.  Investigators may consult the sponsor’s medical monitor prior to 
starting radiotherapy or prior to restarting study treatment after the end of radiotherapy.
5.8.5. Other Prohibited Concomitant Medications and Therapies 
Patients are prohibited from receiving the following therapies while receiving study 
treatment: 

Immunotherapy, immunosuppressive drugs (ie, chemotherapy or systemic 
corticosteroids except for short-term treatment of allergic reactions or for the 
treatment of irAEs).  Short-term administration of systemic steroids (eg, for allergic 
reactions or the management of irAEs) is allowed.  Topical and inhalation steroids are 
allowed.

Live vaccine within 28 days prior to study entry and during the study. 

Bisphosphonate or denosumab treatment is not allowed unless it has been initiated 
more than 14 days prior to receiving the first administration of study treatment.  The 
need to initiate while on study treatment or increase the dose of these therapies during 
the study for patients who started >14 days before study treatment start, will be 
considered as indicative of disease progression leading to the discontinuation of 
patient from the study treatment unless disease progression can be completely ruled 
out and the exact reason for the use of these therapies must clearly be documented.

Anti-cancer systemic chemotherapy or biological therapyor 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.35,36 Furthermore, as with 
all immunotherapies intended to augment cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit of the 
proposed study treatment.  However, studies with anti-CTLA4 compounds indicate that 
short-term use of steroids may be employed without compromising clinical outcomes.37  
Therefore, the use of steroids during this trial is restricted as follows:


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
Therapeutic use: for the treatment of infusion-related reactions treatment of irAEs, 
steroids are permitted according to the modalities indicated in Table 4.

Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
10 mg prednisone daily is acceptable.

Prophylactic use, eg, for the prevention of acute infusion-related reactions, is 
prohibited, except prior to CT or MRI.
5.9. Rescue Medications and Supportive Care 
5.9.1. Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.

Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in Table 4.

Anti-inflammatory or narcotic analgesics may be offered as needed.  
Acetaminophen/paracetamol to a maximum total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited.

Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed.
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures, see Schedule of Activities (SOA) and Assessments section 
(Section 7).


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6.1.1. Tumor Biospecimens
 
 
 The 
biopsy sample(s) should be formalin-fixed and paraffin-embedded and the resulting FFPE 
tissue block(s) should be submitted to the Central Laboratory.  Archived or de novo tumor 
tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet 
material) is not adequate and should not be submitted.  
 
 
6.2. Study Period
For study period procedures, see SOA and Assessments section (Section 7). 
 
 
6.2.1. Follow-up Visits
For Follow-up procedures, see SOA and Assessments section (Section 7).  In this study, all 
patients must be followed-up for 90 days after the last dose of study treatment.  After 
completion of Short-term follow-up, all patients will be followed every 3 months for survival 
(Long-term follow-up). Contact with the patient may be done via a phone call.
6.3. Patient Withdrawal 
Withdrawal of consent:
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information.  
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the patient is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: 
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the patient as noted above.  Lost 
CCI
CCI
CCI


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to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter.  All attempts should be documented in the patient’s medical records.  If it is 
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
Patients may withdraw from the study 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 (see Section 
8.1.3) or behavioral reasons, or the inability of the patient to comply with the protocol-
required schedule of study visits or procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to 
continue 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 5.4.3);

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:


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
Study terminated by sponsor;

Lost to follow-up; 

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety Assessment 
Safety assessments will include collection of AEs, Serious Adverse Events (SAEs), vital 
signs and physical examination, Electrocardiogram (ECG, 12-lead), LVEF by MUGA scan 
or Echocardiogram, laboratory assessments, including pregnancy tests, and verification of 
concomitant medications.
Safety will be monitored at regular intervals throughout the study as described in the SOA. 


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7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting 
administration of study treatment—once at the start of screening and once at the baseline 
visit, immediately before starting the study treatment(s).  Following a negative pregnancy test 
result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit before the patient may receive the 
study treatment(s).  Pregnancy tests will be repeated at every treatment cycle during the 
active treatment period, at the end of study treatment, and additionally whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy 
tests may also be undertaken if requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.  In the case of a positive confirmed 
pregnancy, the patient will be withdrawn from administration of investigational product but 
may remain in the study for survival follow-up.  
7.1.2. Laboratory Safety Assessments
Hematology, blood chemistry, and urinalysis will be collected at the time points described in 
the SOA and analysed at local laboratories.  They may also be performed when clinically 
indicated.  Clinically significant abnormal laboratory results should be repeated as soon as 
possible (preferably within 24-48 hours) and followed up as per standard clinical practice 
unless differently specified in the study protocol.
The required laboratory tests are listed in Table 5


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Table 5.
Required Laboratory Tests
Hematology
Chemistry Panel
(* denotes core chemistry 
test)
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT*
Protein, 
glucose, blood 
Urine dipstick/ 
other 
semiquantitativ
e method, for
urine protein: if 
2+, collect
24-hour or UPC
PT or INR
For female 
patients of 
childbearing 
potential, 
serum or 
urine 
Platelets
AST*
PTT or aPTT
WBC
Alkaline Phosphatase*
Absolute Neutrophils or %
Sodium*
Absolute Lymphocytes or %
Potassium*
Absolute Monocytes or %
Magnesium*
Absolute Eosinophils or %
Chloride*
Absolute Basophils or %
Total Calcium*
Total Bilirubin* °
BUN or Urea*
Creatinine*
Glucose (non-fasted)*
Phosphorus or Phosphate*
Albumin
Total Protein
Uric Acid
Amylase
Gamma glutamyl 
transferase (GGT)
Cholesterol
Creatine kinase
C-reactive protein (CRP) 
Lactate dehydrogenase
(LDH)
Lipase
Triglycerides
HBV, HCV tests**
Thyroid Function Tests:
TSH, free T4
Other Tests: 
ACTH, -fetoprotein 
(AFP), PIVKA-II
°For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, 
prothrombin time (PT or aPT)/INR, alkaline phosphatase.  
**HBV, HCV tests: The patients with chronic infection by HBV or HCV will be monitored viral status per 
standard practice of the study site.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPT=activated prothrombin time, 
aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, BNP=B-type natriuretic 
peptide, BUN=blood urea nitrogen, CK-MB=Creatine kinase-MB, CRP=C-reactive protein, 
GGT=gamma-glutamyltransferase, HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international 
normalized ratio, LDH=lactate dehydrogenase, PIVKA-II=protein induced by Vitamin K absence or 
antagonists-II, TSH=thyroid-stimulating hormone, UPC=urine protein creatinine, WBC=white blood cell 


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7.1.3. Physical Examinations and Vital Signs
Physical examinations will be performed according to institutional guidelines on study days 
as described in the SOA. 
The physical examination will include major body systems, weight, height (height will be 
measured at screening only), assessment of ECOG performance status.
Vital signs (blood pressure, pulse rate) will be measured on study days as described in the 
SOA.  Blood pressure and pulse rate should be taken with the patient in the seated position 
after the patient has been sitting quietly for at least 5 minutes.  Two blood pressure readings 
will be taken at least 1 hour apart at each clinic visit.  In addition, all patients will be 
monitoring BP at home as described in Section 5.4.5.2.
7.1.4. (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.  On-treatment ECGs will be 
performed as outlined in the SOA table.  At each time point, 3 consecutive 12-lead ECGs 
(triplicates) will be performed approximately 2 minutes apart to determine mean QTc 
(average of triplicates).  When coinciding with blood sample draws for PK, ECG 
assessment (as well as creatine kinase [CK] and troponin, if clinically indicated) should be 
performed prior to blood sample collection, such that the blood sample is collected at the 
nominal time. 
Clinically significant findings seen on subsequent ECGs should be recorded as AEs.  In case 
of QTc >500 msec (ie, CTCAE Grade >2), ECG must be reviewed by qualified personnel at 
the site as soon as the finding is made, including verifying that the machine reading is 
accurate and that the Fridericia correction formula is applied.  If the manual reading verifies a 
rate corrected QTc of >500 msec, repeat ECG should be immediately performed at least two 
times approximately 2 to 4 minutes apart. 
An electronic reading of prolonged QTc must be confirmed by manual reading.  Prior to 
conclusion that an episode of prolongation of the QTc interval is due to study drug, thorough 
consideration should be given to potential precipitating factors (eg, change in patient clinical 
condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation 
by specialist.  If QTc interval reverts to less than 500 msec, and in the judgment of 
investigator and sponsor is determined to be due to a cause other than study drug, treatment 
may be continued with regular ECG monitoring.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), triplicate ECGs should be obtained at time of the event.  If the mean QTc is 
prolonged (>500 msec), then ECGs should be re-evaluated by a qualified person at the 
institution for confirmation and repeated as clinically indicated.  Additional triplicate ECGs 


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may be performed as clinically indicated.  At that time, CK and troponin should be 
performed in association with clinically indicated ECG assessments.  
7.1.5. Left Ventricular Ejection Fraction by MUGA scan or Echocardiogram
For the evaluation of LVEF, both MUGA and Echocardiogram are acceptable. The same 
technique used at screening must be consistently used for the following assessments 
throughout the study.
7.2. Pharmacokinetics Assessments
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis
Blood samples for axitinib PK and avelumab PK will be collected as outlined in the SOA
table.  Where noted in the SOA table, PK blood samples will be collected at approximately 
the same time as other assessments wherever possible.
For all PK blood sample collections, the actual time of avelumab and axitinib dosing, as well 
as actual times of PK collections, will be recorded in the source documents and CRF.  On the 
days of axitinib PK sample collection, patients should be instructed to hold morning axitinib 
dosing until the pre-dose sample has been drawn.  On axitinib PK sampling days, the axitinib 
doses should be taken in the clinic under the supervision of the study site personnel.
In addition to PK blood samples collected at the scheduled times, additional PK blood 
samples for axitinib and avelumab should be collected from patients experiencing 
unexpected and/or serious AEs and the date and time of blood sample collection and of the 
last dosing prior to PK collection documented in the CRF.
All efforts will be made to obtain the PK blood samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60-minute sample) will be considered protocol compliant, and the exact time 
of the sample collection noted on the CRF.  If a scheduled PK blood sample collection 
cannot be completed for any reason, the missed sample collection may be rescheduled with 
agreement of the investigator and sponsor.
PK blood samples will be assayed for avelumab and axitinib using validated analytical 
methods.  Additional details regarding the collection, processing, storage, and shipping of the 
blood samples will be provided in the study manual.  As part of the understanding of the PK 
of the study drug, samples may be used for potential qualitative and/or quantitative 
metabolite analyses and/or evaluation of the bioanalytical methods for avelumab and axitinib.  
The results of such analyses may be included in the clinical report.
7.2.2. Collection of Axitinib Pharmacokinetic Samples
At each time point for axitinib, a 3 mL whole blood sample will be collected into an 
appropriately labeled K3 EDTA tube to provide a minimum of 1 mL plasma for axitinib PK 
analysis.


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7.2.3. Collection of Avelumab Pharmacokinetic Samples
A 3.5 mL 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 3.5 mL 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.  ADA 
sample at 30 day follow up is collected at 30 days after end of treatment of avelumab 
regardless of continuation of axitinib therapy. Additional details regarding the collection, 
processing, storage, and shipping of the blood samples will be provided in the Study Manual.
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 blood biomarkers obtained before, during and after treatment will provide an 
opportunity to investigate pharmacodynamic effects.  Samples collected at the End of 
Treatment/Withdrawal visit enable investigation of potential mechanisms of resistance to the 
drug combination.
 
 
 
 
Optional tumor biopsies obtained upon disease progression (End of Treatment) may be 
assessed relative to the mandatory pre-treatment biospecimens to examine tumoral and 
immunological changes which may occur over the course of therapy, including acquired 
mechanisms of resistance.  Only core needle, excisional biopsies, or resection specimens 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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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, and every 8 weeks thereafter until confirmed PD per RECIST v1.1. If a patient 
discontinues the study treatment due to a reason other than disease progression, tumor 
assessments should be conducted until confirmed disease progression or initiation of new 
anticancer treatment, whichever come first. 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 8 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 the 
SOA and Section 5.4.3 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 18-Fluorodeoxyglucose Positron Emission 
Tomography (18FDG-PET/CT) is required at baseline then every 12 weeks only if bone 
C
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metastases are present at baseline.  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 v. 1.1 (Appendix 3)
 
All patients’ radiologic images should be submitted for potential peer review by a third party.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) non-
serious adverse events (AEs); and (3) exposure to the investigational product under study 
during pregnancy or breastfeeding, and occupational exposure.  
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
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immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.


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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any study-
related procedure and/or receiving investigational product), through and including a 
minimum of 90 calendar days after the last administration of investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship on the CRF, and report such an 
assessment in accordance with the SAE reporting requirements, if applicable.  An 
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 


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investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);


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
Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
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
Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
o
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).


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o
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, CK, direct and indirect bilirubin, GGT, PT/INR, total bile acids, alkaline 
phosphatase and acetaminophen drug and/or protein adduct levels.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 


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product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.


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


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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
The full analysis set and the safety analysis set will be assessed.  These analysis sets are 
identical.  These analysis sets include all enrolled patients who receive at least 1 dose of 
study drug (avelumab or axitinib).  Analyses will be conducted by dose cohort if lower dose 
of the combination (avelumab 10 mg/kg IV Q2W plus axitinib 3 mg BID) will be evaluated
with adding cohort of patients.
9.1. Sample Size Determination
This study will enroll 20 patients to evaluate overall safety and tolerability with combination 
of avelumab plus axitinib.  A sample size of 20 patients will provide at least 88% probability 
to observe at least one AE if the true incidence of the AE in the population is 10% or more.
9.2. Efficacy Analysis
In this study, assessment of antitumor activity is a secondary objective.  Efficacy analyses 
will be presented in the form of statistical summaries and data listings. Efficacy endpoints 
will be defined based on ‘start date’ which is the start date of study treatment.
9.2.1. Analysis of Secondary Endpoints
Efficacy data will be analyzed based on the full analysis set. 
TTP is defined as the time from start date to the date of the first documentation of objective 
PD.  TTP data will be censored on the date the last adequate tumor assessment for patients 
without PD, for patients who start new anti-cancer treatment prior to PD, for patients who die 
without PD, or for patients with PD after ≥2 missing tumor assessments.  Patients who do not 


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have a baseline tumor assessment or who do not have any post-baseline tumor assessments 
will be censored on the start date.
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 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 second planned post-baseline 
tumor assessment in which case the death will be considered an event.
OR is defined as CR or PR according to RECIST v. 1.1 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. 
DC is defined as OR (CR or PR) or stable disease (SD) per RECIST v. 1.1 from the start date 
until the first documentation of objective disease progression or death due to any cause.  DC
rate (DCR) is defined as the proportion of patients with DC.
TTR is defined as the time from start date to the first documentation of objective tumor 
response (CR or PR) that is subsequently confirmed. DR and TTR will only be summarized 
among patients with confirmed 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 same as 
for the definition of PFS. 
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.
TTP, PFS, DR, and OS will be analyzed using Kaplan-Meier methods.  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).  In 
addition, start date, progression date, death date, date of first response, and last tumor 
assessment date will be listed, together with best overall response, TTP, PFS, TTR and DR.
 
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9.3. Analysis of Other Endpoints
9.3.1. Analysis of Secondary Endpoints
9.3.1.1. Pharmacokinetic Analysis of Avelumab and Axitinib
Axitinib Ctrough (concentration at pre dose of axitinib) and Cmax (concentration at 2-hour post 
dose) plasma concentrations will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by 
dose, cycle, and day.  The trough concentrations for axitinib will be plotted for each dose 
using a box-whisker plot by cycle and day in order to assess the attainment of steady state. 
Avelumab Ctrough (concentration at pre dose of avelumab) and Cmax (concentration at end of 
infusion) plasma concentrations will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by 
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.
All the concentration data will be listed but for summarization of Ctrough and Cmax, the 
concentrations deviated more than 20% from the planned time will not be included.
Avelumab disposition will be evaluated using a population PK model for the drug and the 
relationship between exposure and efficacy and safety endpoints will be explored, as 
necessary, based on emerging efficacy and safety data.  The data may be combined with the 
data in other aveluab protocol for the analysis. The results of these modeling analyses may be 
reported separately from the clinical study report.
9.3.1.2. Immunogenicity Assessment
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized.  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.
 
 
 
 
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9.4. Safety Analysis
Summaries and analyses of the safety endpoint will be based on the safety analysis set.
9.4.1. Analysis of Primary Safety Endpoints
9.4.1.1. 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 v. 4.03 whenever possible.  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 v. 4.03 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 v. 4.03 Grade≥3, trial drug-related events, and serious adverse events will be 
considered with special attention. 
Detailed information collected for each AE will include a description of the event, timing of 
onset, duration, whether the AE was serious, intensity, relationship to study treatment, action 
taken, and clinical outcome.
9.4.1.2. Laboratory Test Abnormalities
Laboratory test results will be graded according to the NCI CTCAE v. 4.03 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. 
9.4.2. Analysis of Other Safety Endpoints
Further details regarding other safety endpoints (definitions and analyses) will be provided in 
the SAP.
9.4.2.1. Electrocardiograms
ECG measurements will be used for the statistical analysis and all data presentations. 
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Interval measurements from repeated ECGs will be included in the outlier analysis 
(categorical analysis) as individual values obtained at unscheduled time points. QT intervals 
will be corrected for heart rate (QTc) using standard correction factors [ie, Fridericia’s 
(default correction), Bazett’s, and possibly a study specific factor, as appropriate]. 
Data will be summarized and listed for QT, heart rate (HR), and RR, PR, QRS, QTc intervals. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment. Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post baseline corrected QT interval.
Shift tables will be provided for baseline vs worst on treatment corrected QT. Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment. Patients 
experiencing clinically relevant morphological ECG changes will be summarized (including 
frequency and percentage).
9.4.2.2. Vital Signs
Vital signs including blood pressure and pulse rate will be summarized using descriptive 
statistics.  Any additional analyses of vital signs will be further detailed in the SAP.
9.5. Interim Analysis 
No formal interim analysis will be conducted for this study. However, as this is a single-arm 
open-label study, the sponsor may conduct reviews of the data during the course of the study 
for the purpose of safety and efficacy assessment, facilitating pharmacokinetics /
pharmacodynamics modeling, and/or to support clinical development.
9.6. Data Monitoring Committee 
This study will not use an external data monitoring committee.
Pfizer procedures for periodic safety review will be applied by an internal safety review team.  
Safety findings that have immediate implications for the management of patients on study 
will immediately be communicated to all investigators.  Periodic safety review procedures 
will include:
•
Monthly internal safety assessment including AEs, SAEs, Lab tests, vital signs, and 
ECG findings will be conducted.
•
Discussions between the investigators and the sponsor of AEs, laboratory test 
abnormalities, vital signs, and ECG findings observed in an ongoing manner at 
regular teleconferences and/or meetings to determine the safety profile and to make 
risk/benefit assessments. 
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 


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review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be patient to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician’s patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 


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In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Patients (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
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12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study patient, is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The investigator 
will retain the original of each patient's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as last patient last visit (LPLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 


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discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab in combination with axitinib at any time.
If a study is prematurely terminated, 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 (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.


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15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, patient to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.
16. REFERENCES
1.
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin
2015;65:87-108.
2.
Gelband H, Chen CJ, Chen W, et al. Liver Cancer. In: Gelband H, Jha P, 
Sankaranarayanan R, Horton S, eds. Cancer: Disease Control Priorities, Third Edition 


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(Volume 3). Washington (DC): The International Bank for Reconstruction and 
Development / The World Bank; 2015 Nov 1 Chapter 8.
3.
Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-17.
4.
Pawarode A, Voravud N, Sriuranpong V, et al. Natural history of untreated primary 
hepatocellular carcinoma. Am J Clin Oncol 1998;21:386-91.
5.
Bruix J, Llovet JM. Prognostic Prediction and Treatment Strategy in Hepatocellular 
Carcinoma. Hepatology 2002;35:519-24.
6.
Llovet JM, Bruix J. Systematic Review of Randomized Trials for Unresectable 
Hepatocellular Carcinoma: Chemoembolization Improves Survival. Hepatology
2003;37:429-42.
7.
Nowak AK, Chow PKH, Findlay M. Systematic Therapy for Advanced Hepatocellular 
Carcinoma: a Review. EJC 2004;40:1474-84.
8.
Schwartz JD, Beutler A. Therapy for Unresectable Hepatocellular Carcinoma: Review 
of the Randomized Clinical Trials-II: Systemic and Local non-Embolization-based 
Therapies in Unresectable and Advanced Hepatocellular Carcinoma. Anti-cancer Drugs
2004;15:439-52.
9.
Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular 
Carcinoma. N Engl J Med 2008;359:378-90.
10.
Cheng AL, Kang YK, Cheng ZD, et al. Efficacy and safety of sorafenib in patients in 
the Asia-Pacifi c region with advanced hepatocellular carcinoma: a phase III 
randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-33.
11.
Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for phase III failure 
and novel perspectives on trial design. Clin Cancer Res 2014;20:2072-9.
12.
Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced 
hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 
2013;31:4067-75.
13.
Ogasawara S, Kanai F, Obi S, et al. Safety and tolerance of sorafenib in Japanese 
patients with advanced hepatocellular carcinoma. Hepatol Int 2011;5:850-6.
14.
Latchman Y, Wood CR, Chernova T, et al. PD-L1 is a second ligand for PD-1 and 
inhibits T cell activation. Nat Immunol 2001;2:261-68.
15.
Kang YK, Yau T, Park JW, et al. Randomised phase II study of axitinib versus placebo 
plus best supportive care in second-line treatment of advanced hepatocellular 
carcinoma. Annals of Oncol 2015;26:2457-63.


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16.
Yamaguchi R, Hirohisa Y, Iemura A, et al. Expression of Vascular Endothelial Growth 
Factor in Human Hepatocellular Carcinoma. Hepatology 1998;28:68-77.
17.
Poon RTP, Ho JWY, Tong CSW, et al. Prognostic Significance of Serum Vascular 
Endothelial Growth Factor and Endostatin in Patients with Hepatocellular Carcinoma. 
BJS 2004;91:1354-60.
18.
Yamaguchi R, Yano H, Nakashima Y, et al. Expression and localization of vascular 
endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC 
tissues. Oncology Reports 2000;7:725-9.
19.
Zhao ZC, Zheng SS, Wan YL, et al. The molecular mechanism underlying angiogenesis 
in hepatocellular carcinoma: the imbalance activation of signaling pathways. 
Hepatobiliary & Pancreatic Diseases International 2003;2:529-36.
20.
Ng IO, Poon RT, Lee JM, et al. Microvessel density, vascular endothelia growth factor 
and its receptors Fl-1 ad Flk-1/KDR in hepatocellular carcinoma. Am J of Clin Pathol
2001;116:838-45.
21.
Shimamura T, Saito S, Morita K, et al. Detection of vascular endothelial growth factor 
and its receptor expression in human hepatocellular carcinom biopsy specimens. J of 
Gastroenter & Hepatol 2000;15:640-6.
22.
Schwartz JD, Schwartz M, Goldman J, et al. Bevacizumab in Hepatocellular Carcinoma 
(HCC) for Patients without Metastasis and without Invasion of the Portal Vein. Proc 
ASCO 2004;Abstr# 4088.
23.
Patt YZ, Hassan MM, Lozano RD, et al. Thalidomide in the Treatment of Patients with 
Hepatocelular Carcinoma. Cancer 2005;103:749-55.
24.
Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma 
who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, 
placebo-controlled, phase 3 trial. Lancet 2017;389:56-66.
25.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Semin Liver Dis 2010;30:52-60.
26.
Ikeda K, Kudo M, Kawazoe S, et al. Phase 2 study of lenvatinib in patients with 
advanced hepatocellular carcinoma. J Gastroenterol 2017;52(4):512-9.
27.
Wada Y, Nakashima O, Kutami R, et al. Clinicopathological study on hepatocellular 
carcinoma with lymphocytic infiltration. Hepatology 1998;27(2):407-14.
28.
Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint 
inhibitors in hepatocellular carcinoma. Immunotherapy. 2016;8:299-313.


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29.
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. 
Rev. Immunol 2008;8:467-77.
30.
Shi F, Shi M, Zeng Z, et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell 
apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int. J.
Cancer 2011;128;887-96.
31.
Melero I, Sangro B, Yau C, et al. Nivolumab dose escalation and expansion in patients 
with advanced hepatocellular carcinoma (HCC): The CheckMate 040 study. J Clin 
Oncol 35 2017:suppl 4S;abstract 226.
32.
Larochelle P, Kollmannsberger C, Feldman RD, et al. Hypertension management in 
patients with renal cell cancer treated with anti-angiogenic agents. Curr. Oncol 
2012;19:202-8.
33.
Rini BI, Quinn DI, 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.
34.
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth 
Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J 
Clin Oncol 2015;33:3199-212.
35.
Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T cell-mediated cytotoxicity by 
anti-inflammatory steroids. J Immunol 1984;132:266-71.
36.
Khan MM. Immunosuppressive Agents. In: Immunopharmacology. New York:
Springer; 2008.
37.
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.


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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. Child-Pugh Classification
Parameter
Point
1
2
3
Encephalopathy
None
Grade 1-2 
(Moderate)
Grade 3-4
(Severe)
Ascites
Absent
Mild
Moderate
Prothrombin time prolonged (sec.)  
or
INR
<4
<1.7
4-6
1.7-2.3
>6
>2.3
Bilirubin (mg/dL)
<2
2-3
>3
Albumin  (g/dL)
>3.5
2.8-3.5
<2.8
Note: Patients in grayed-out portion of the table not eligible in this study
Class A: 5-6 points 
Class B: 7-9 points
Class C: 10-15 points


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Appendix 3. Response Evaluation Criteria in Solid Tumors Version 1.1
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions  

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater  
when assessed by CT or MRI (slice thickness 5-8 mm)

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray  

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper  

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable Disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and <15 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.

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.


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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 post-baseline. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded. If 
the lesion is considered to have disappeared, 0 mm should be recorded; otherwise if a 
lesion is determined to be present but too small to measure, the lesion status will 
indicate “too small to measure and judged to be less than 10 mm” and 5 mm will be 
used in the calculation of the sum of the diameters.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target Disease 
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE (i.e., Not Evaluable), 
PRESENT/NOT INCREASED, INCREASED.  Multiple non-target lesions in one organ may 
be recorded as a single item on the case report form (e.g., ‘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 
should be discussed with the radiologist and the Sponsor to determine if substitution is 
possible.  If not, subsequent objective statuses are not evaluable.  


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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.  All target lesions must be assessed.  

Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions 
must be assessed.  Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir (smallest sum of diameters consider baseline and all 
assessments prior to the time point under evaluation), but enough that a previously 
documented 30% decrease no longer holds.  

Progressive Disease (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm.  

Not evaluable (NE): Progression has not been documented, and 
o
one or more target lesions have not been assessed or
o
assessment methods used were inconsistent with those used at baseline or
o
one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure) or
o
one or more target lesions were excised or irradiated and have not reappeared 
or increased.  
Non-target Disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels 
(if being followed). All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level (if 
being followed) above the normal limits. 

PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.  

Not evaluable (NE): Progression has not been determined and 
o
one or more non-target lesion sites have not been assessed or
o
assessment methods were inconsistent with those used at baseline or
o
one or more non-target lesions cannot be assessed (e.g., poorly visible or 
unclear images) or


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o
one or more non-target lesions were excised or irradiated and have not 
reappeared or increased. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document PD even after discontinuation of study 
treatment.  
Determination of Tumor Response by RECIST
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  New lesions will also be recorded separately.  Determination of tumor response 
at each assessment based on target, non-target and new lesions is summarized in the 
following table.


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Table 6.
Objective Response Status at Each Evaluation for Patients with 
Measurable Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD or not all evaluated
No
PR
PR
Non-PD* or not all evaluated
No
PR
SD
Non-PD* or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes**
PD
*Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 7.
Objective Response Status at Each Evaluation for Patients with Non-
Target Disease Only
Non-target Disease
New Lesions
Objective Status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Not all evaluated
No
NE
Unequivocal progression
Yes or No
PD
Any
Yes*
PD
* New lesions must be unequivocal
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment/randomization 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 start of the 
treatment/randomization at a minimum interval of 8 weeks.


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if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
CCI


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orsening of the underlying chronic liver disease and be unrelated to
cancer progression.
CCI


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CCI


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Appendix 5. Treatment Recommendations for Symptoms of Avelumab 
Infusion-Related Reactions
The following treatment recommendations for symptoms of avelumab infusion-related
reactions may be modified based on local treatment standards and guidelines, as appropriate.
For Grade 1 Symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)

Decrease the avelumab infusion rate by 50% and monitor closely for any worsening. 

Remain at bedside and monitor patient until recovery from symptoms.
For Grade 2 Symptoms: (Moderate reaction; Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (e.g, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated for 24 hours.)

Temporarily discontinue avelumab infusion.

Treat based on emerging symptoms.  Treatment may include:

Normal saline IV;

H1 blockers, such as diphenhydramine 25 to 50 mg IV (or equivalent);

H2 blockers, such as ranitidine 50 mg IV (or equivalent);

NSAIDs, such as ibuprofen 600 mg (or equivalent);

Meperidine 12.5 to 50 mg IV;

Corticosteroids, such as hydrocortisone 100 to 500 mg IV (or equivalent);

Bronchodilators.

Remain at bedside and monitor patient until resolution of symptoms.

Resume avelumab infusion at 50% of previous rate as soon as infusion related 
reaction has resolved or decreased to at least Grade 1 in severity, and monitor closely 
for any recurrence or worsening.
For Grade 3 or Grade 4 Symptoms: (Severe reaction; Grade 3: prolonged [e.g, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for clinical sequelae 
[e.g, renal impairment, pulmonary infiltrates]; Grade 4: life-threatening consequences; urgent 
intervention indicated).


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
Stop the avelumab infusion immediately and disconnect infusion tubing from the 
patient.

Begin an IV infusion of normal saline, and treat the patient with one or more of the 
following:

Airway maintenance;

Oxygen;

Bronchodilators;

Epinephrine 0.01 mg/kg of a 1:1,000 (1 mg/mL) solution IM, up to a maximum 
dose of 0.5 mg;

H1 blockers, such as diphenhydramine 25 to 50 mg IV (or equivalent);

H2 blockers, such as ranitidine 50 mg IV (or equivalent);

Corticosteroids, such as hydrocortisone 100 to 500 mg IV (or equivalent).

Remain at bedside and monitor patient until recovery from symptoms. 

Patients have to be withdrawn immediately from avelumab treatment and must not 
receive any further avelumab treatment.


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Appendix 6. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody
AE
adverse event
AFP
-fetoprotein
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BBS
Biospecimen Banking System
BID
twice daily
BOR
best overall response
BP
blood pressure
CI
confidence interval
CK
creatine kinase
CR
complete response
CRF
case report form
CSA
clinical study agreement
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DR
duration of response
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EU
European Union
EudraCT
European Clinical Trials Database
FDG-PET
fluorodeoxyglucose positron emission tomography
FFPE
formalin-fixed and paraffin-embedded
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
ICH
International Conference on Harmonisation


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Abbreviation
Term
ID
identification
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
irAE
immune-related adverse event
IRB
institutional review board
IRR
infusion-related reaction
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
LLN
lower limit of normal
LSLV
last subject last visit 
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition
N/A
not applicable
nAb
Neutralizing Antibody
NCI
National Cancer Institute
OR
objective response
ORR
objective response rate
OS
overall survival
PCD
primary completion date
PD
progressive disease
PFS
progression free survival
PI
principal investigator
PK
pharmacokinetic(s)
PR
partial response
PT
prothrombin time
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumor
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOA
schedule of activities
SRSD
single reference safety document
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Abbreviation
Term
TBili
total bilirubin
TTP
time to progression 
TTR
time to tumor response
ULN
upper limit of normal
US
United States
UPC
urine protein creatinine

SAP_001.pdf: 
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B9991024 (MSB0010718C, AG-013736) Statistical Analysis Plan
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AN OPEN LABEL, SINGLE ARM PHASE 1B STUDY OF AVELUMAB PLUS 
AXITINIB AS FIRST LINE TREATMENT IN PATIENTS WITH ADVANCED 
HEPATOCELLULAR CARCINOMA
STATISTICAL ANALYSIS PLAN – B9991024
Compounds:
MSB0010718C
AG-013736
Compound Name:
Avelumab, Axitinib
Version:
3.0
Date:
20-Feb-2019


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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................5
APPENDICES ...........................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives .......................................................................................................9
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoints...................................................................................................10
3.2. Secondary Endpoints...............................................................................................10
3.2.1. Efficacy Endpoints......................................................................................10
3.2.2. Pharmacokinetic Endpoints ........................................................................11
3.2.3. Immunogenicity Endpoints.........................................................................11
3.2.4. Biomarker Endpoints..................................................................................11
3.4. Baseline Variables...................................................................................................12
3.4.1. Study Drug, Study Treatment and Baseline Definitions ............................12
3.4.2. Baseline Characteristics..............................................................................13
3.5. Safety Endpoints .....................................................................................................13
3.5.1. Adverse Events...........................................................................................13
4. ANALYSIS SETS ...............................................................................................................14
4.1. Full Analysis Set .....................................................................................................14
4.2. Safety Analysis Set..................................................................................................14
4.3. Other Analysis Set...................................................................................................14
4.3.1. PK Analysis Set ..........................................................................................14
4.3.2. Biomarker Analysis Set..............................................................................14
4.3.3. Immunogenicity Analysis Set.....................................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................15
5.1. Hypotheses and Decision Rules ..............................................................................15
5.1.1. Hypotheses and Sample Size Determination..............................................15
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5.1.2. Decision Rules............................................................................................15
5.2. General Methods .....................................................................................................15
5.2.1. Data Handling after the Cut-off Date .........................................................15
5.2.2. Pooling of Centers ......................................................................................15
5.2.3. Presentation of Continuous and Qualitative Variables...............................16
5.2.4. Definition of Study Day..............................................................................16
5.2.5. Definition of Start of New Anti-cancer Drug Therapy...............................16
5.2.6. Definition of Start of New Anti-cancer Therapy........................................16
5.2.7. Definition of On-treatment Period..............................................................17
5.2.8. Standard Derivations and Reporting Conventions .....................................17
5.2.9. Unscheduled Visits.....................................................................................18
5.2.10. Adequate Baseline Tumor Assessment ....................................................18
5.2.11. Adequate Post-baseline Tumor Assessment.............................................18
5.3. Methods to Manage Missing Data ..........................................................................18
5.3.1. Missing Data...............................................................................................18
5.3.1.1. Pharmacokinetic Concentrations...............................................19
5.3.1.2. Pharmacokinetic Parameters .....................................................19
5.3.2. Handling of Incomplete Dates....................................................................19
5.3.2.1. Disease History .........................................................................19
5.3.2.2. Adverse Events..........................................................................20
5.3.2.3. Prior and Concomitant Medications..........................................20
5.3.2.4. Exposure....................................................................................21
5.3.3. Imputation Rules for Date of Last Contact and Efficacy Assessments......21
5.3.3.1. Date of Last Contact..................................................................21
5.3.3.2. Death Date.................................................................................22
5.3.3.3. Tumor Assessments...................................................................22
5.3.3.4. Date of Start of New Anti-cancer Therapy ...............................23
6. ANALYSES AND SUMMARIES ......................................................................................25
6.1. Primary Endpoints...................................................................................................25
6.1.1. Adverse Events and Laboratory Abnormalities..........................................25
6.1.1.1. Primary Analysis.......................................................................25
6.2. Secondary Endpoint(s) ............................................................................................25
6.2.1. Efficacy Endpoints......................................................................................25


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6.2.1.1. Objective Response...................................................................25
6.2.1.2. Tumor shrinkage from Baseline................................................27
6.2.1.3. Disease Control .........................................................................27
6.2.1.4. Duration of Response................................................................27
6.2.1.5. Time to Response......................................................................28
6.2.1.6. Time to Progression ..................................................................28
6.2.1.7. Progression-free Survival..........................................................30
6.2.1.8. Overall Survival ........................................................................32
6.2.2. Pharmacokinetic Endpoints ........................................................................33
6.2.3. Population Pharmacokinetic Endpoints......................................................34
6.2.4. Biomarker Endpoints..................................................................................34
6.2.5. Endpoints for Immunogenicity Data of Avelumab ....................................34
6.2.5.1. Time to and Duration of ADA and nAb Response ...................36
6.2.5.2. ADA Titer .................................................................................37
6.2.5.3. Analysis of PK, Safety and Efficacy by Immunogenicity 
Status .................................................................................................37
6.4. Subset Analyses.......................................................................................................39
6.5. Baseline and Other Summaries and Analyses.........................................................40
6.5.1. Baseline Summaries....................................................................................40
6.5.1.1. Demographic Characteristics ....................................................40
6.5.1.2. Medical History.........................................................................41
6.5.1.3. Disease Characteristics..............................................................41
6.5.1.4. Prior Anti-cancer Therapies ......................................................43
6.5.2. Study Conduct and Patient Disposition......................................................45
6.5.2.1. Patient Disposition ....................................................................45
6.5.2.2. Protocol Deviations...................................................................46
6.5.3. Study Treatment Compliance and Exposure ..............................................46
6.5.3.1. Exposure to Avelumab..............................................................47
6.5.3.2. Exposure to Axitinib .................................................................48
6.5.3.3. Dose Reductions........................................................................49
6.5.3.4. Dose Escalations .......................................................................49
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6.5.3.5. Dose Interruptions.....................................................................49
6.5.3.6. Dose Delays...............................................................................50
6.5.3.7. Infusion Rate Reductions ..........................................................51
6.5.3.8. Infusion Interruptions................................................................51
6.5.4. Concomitant Medications and Non-drug Treatments.................................51
6.5.5. Subsequent Anti-cancer Therapies .............................................................52
6.6. Safety Summaries and Analyses .............................................................................52
6.6.1. Adverse Events...........................................................................................52
6.6.1.1. All Adverse Events....................................................................53
6.6.1.2. Adverse Events Leading to Dose Reduction.............................55
6.6.1.3. Adverse Events Leading to Interruption of Study 
Treatment...........................................................................................55
6.6.1.4. Adverse Events Leading to Discontinuation of Study 
Treatment...........................................................................................56
6.6.2. Deaths .........................................................................................................56
6.6.3. Serious Adverse Events ..............................................................................57
6.6.4. Other Significant Adverse Events ..............................................................57
6.6.5. Laboratory Data..........................................................................................58
6.6.5.1. Hematology and Chemistry Parameters....................................58
6.6.5.2. Other Laboratory Parameters ....................................................61
6.6.6. Vital Signs ..................................................................................................62
6.6.7. Electrocardiogram.......................................................................................62
6.6.8. MUGA/ECHO............................................................................................64
6.6.9. Physical Examination .................................................................................65
6.6.10. ECOG Performance Status .......................................................................65
7. INTERIM ANALYSES.......................................................................................................65
8. REFERENCES ....................................................................................................................66
9. APPENDICES .....................................................................................................................67
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................7
Table 2.
PK Parameters to be Determined for Avelumab and axitinib ..................11
Table 3.
Biomarker Definition and Determination.................................................12


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Table 4.
TTP Outcome and Event Dates ................................................................28
Table 5.
TTP Censoring Reasons and Hierarchy....................................................29
Table 6.
Outcome and event dates for PFS and DR analyses.................................30
Table 7.
PFS Censoring Reasons and Hierarchy....................................................31
Table 8.
OS Censoring Reasons and Hierarchy......................................................32
Table 9 
Patients Characterized Based on Anti-Drug Antibody Results 
(ADA Status) ............................................................................................35
Table 10 
Patients Characterized Based on Neutralizing Antibody Results 
(nAb Status)..............................................................................................36
Table 11.
Case Definition for irAEs.........................................................................67
Table 12.
Case Definition for IRRs – IV Study Drugs Administered Alone Or 
In Combination With Non-IV Study Drugs..............................................69
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................67
Appendix 2. Infusion Related Reactions .................................................................................69


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1. VERSION HISTORY
 
  
Table 1.
Summary of Major Changes in SAP Amendments
Version
Version Date
Summary of Changes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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3
20-Feb-2019
 
 
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991024.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data 
(ie, pharmacokinetics/pharmacodynamics and tumor assessment results by the Blinded 
Independent Central Review (BICR)). The primary analysis will include all data up to a 
clinical cut-off date corresponding to 18 months (78 weeks) after the last patient is treated.  
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.
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2.1. Study Objectives
Primary Objectives
•
To evaluate the safety and tolerability of avelumab in combination with axitinib as 
first line treatment in patients with advanced hepatocellular carcinoma (HCC).
Secondary Objectives
•
To evaluate antitumor effect of avelumab in combination with axitinib as first line 
treatment in patients with advanced HCC per Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1; 
•
To evaluate the OS of avelumab in combination with axitinib in patients with 
advanced HCC;
•
To evaluate the pharmacokinetics of avelumab and axitinib when administered in 
combination;
•
To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may 
aid in the identification of a patient subpopulation most likely to benefit from 
treatment with avelumab in combination with axitinib;
•
To assess the immunogenicity of avelumab when combined with axitinib.
 
 
 
2.2. Study Design
This is an open-label, multi-center, single arm, Phase 1b study to evaluate the safety, efficacy
and pharmacokinetics (PK) of avelumab in combination with axitinib as first line treatment
in patients with advanced HCC.
Approximately 20 patients with advanced HCC who have not had prior systemic therapy will 
be enrolled in this study. The overall safety profile of these patients will be assessed after a 
minimum follow up of 3 months (ie, at least 3 months from last patient first dosing [LPFD]).  
Significant toxicities including immune-related adverse events (irAEs) which occur after 
3 month follow up will also be included in the assessment.
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Patients will receive avelumab 10 mg/kg every 2 weeks (Q2W) in combination with axitinib 
5 mg twice a day (BID). If this dose level for the combination is not tolerable, a lower dose 
of the combination (avelumab 10 mg/kg IV Q2W plus axitinib 3 mg BID) may be evaluated 
with adding new cohort of patients.  A cohort of patients aimed to evaluate avelumab 800 mg 
flat dose Q2W in combination with axitinib 5 mg BID may be added after the tolerability of 
avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID is confirmed.
Treatment with study drugs may continue until confirmed disease progression, patient 
refusal, patient lost to follow up, unacceptable toxicity, or the study is terminated by the 
sponsor, whichever comes first.
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.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
•
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.03.
AEs will be graded by the investigator according to the CTCAE v.4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).
Laboratory abnormalities as characterized by type, severity (as graded by 
NCI-CTCAE v.4.03) and timing.
3.2. Secondary Endpoints
3.2.1. Efficacy Endpoints
•
Time to Progression (TTP), Progression Free Survival (PFS), Objective Response 
(OR), Disease Control (DC), Time to Tumor Response (TTR) and Duration of 
Response (DR), per RECIST v.1.1;
TTP is defined as the time from the date of first dose of study treatment to the date of 
the first documentation of objective progression of disease (PD).
PFS is defined as the time from the date of first dose of study treatment to the date of 
the first documentation of PD or death due to any cause, whichever occurs first.
OR is defined as complete response (CR) or partial response (PR) according to 
RECIST v1.1 from the date of first dose of study treatment until the date of the first 
documentation of 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.


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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 8 weeks after date of first dose of study treatment.
TTR is defined, for patients with an OR, as the time from the date of first dose of 
study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
DR is defined, for patients with an 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.  
•
Overall Survival (OS).
OS is defined as the time from the date of first dose of study treatment to the date of 
death due to any cause.
3.2.2. Pharmacokinetic Endpoints
•
PK parameters including trough and maximum concentrations (Ctrough, Cmax) of
avelumab and axitinib.
These parameters will be calculated at Cycles 2, 3, 4, 6, 8, then every 4 cycles for
avelumab and at Cycles 2, 3 for axitinib.
Table 2.
PK Parameters to be Determined for Avelumab and axitinib
Parameter
Definition
Method of Determination
Cmax
Maximum observed concentration 
Observed directly from data
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
3.2.3. Immunogenicity Endpoints
•
Anti-drug antibodies (ADAs, neutralizing antibodies [nAbs]) for avelumab when in 
combination with axitinib.
These endpoints at Cycles 2, 3, 4, 6, 8, then every 4 cycles, end of 
treatment/withdrawal and 30 days after end of avelumab treatment regardless of 
continuation of axitinib therapy will be evaluated.
3.2.4. Biomarker Endpoints
•
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]).


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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+ 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
 
 
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 the following:
•
avelumab 10 mg/kg in combination with axitinib 5 mg.
If avelumab 10 mg/kg in combination with axitinib 5 mg is not tolerable, a lower dose of the 
combination may be added as another treatment group evaluated in a new cohort of patients.
Start and end dates of study treatment:
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination. 
The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination.
Definition of baseline: 
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety, biomarker and efficacy analyses.  If an assessment 
is planned to be performed prior to the first dose of study treatment in the protocol and the 
assessment is performed on the same day as the first dose of study treatment, it will be 
assumed that it was performed prior to study treatment administration, if assessment time 
point is not collected or is missing. If assessment time points are collected, the observed time 
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point will be used to determine pre-dose on study Day 1 for baseline calculation. 
Unscheduled assessments will be used in the determination of baseline. However, if time is 
missing, an unscheduled assessment on study Day 1 will be considered to have been obtained 
after study treatment administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study Day 1 (one during study and one in the End of 
Treatment (EOT)) visit. Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the 
average. QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
Replicate vital signs are collected in the study and the baseline for each vital sign parameter 
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.
3.4.2. Baseline Characteristics
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 
are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6. 
3.5. Safety Endpoints
3.5.1. Adverse Events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.


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Adverse Events of Special Interest (AESIs)
AESIs are irAE and infusion-related reactions (IRRs).  The criteria for classification of an 
AE as an irAE or IRR are described in Appendix 1 and Appendix 2, respectively.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
The full analysis set (FAS) will include all patients who receive at least one dose of study 
drug.  Patients will be classified according to the study treatment actually received.  If a 
patient receives more than one treatment the patient will be classified according to the first
study treatment received. 
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug.  
Patients will be classified according to the study treatment actually received.  If a patient 
receives more than one study treatment, the patient will be classified according to the first
study treatment received. In this non-randomized study, the FAS and the safety analysis set 
are identical. 
4.3. Other Analysis Set
4.3.1. PK Analysis 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. 
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least one of the PK parameters of interest for avelumab or axitinib.
4.3.2. Biomarker Analysis Set 
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 baseline and one on
treatment biomarker assessment for the same marker.
Analysis sets will be defined separately for blood-based and tumor tissue-based biomarkers.


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4.3.3. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample collected for avelumab.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and Sample Size Determination
There is no formal hypothesis testing planned for this study.
This study will enroll 20 patients to evaluate overall safety and tolerability with combination 
of avelumab plus axitinib.  A sample size of 20 patients will provide at least 88% probability 
to observe at least one AE if the true incidence of the AE in the population is 10% or more.
5.1.2. Decision Rules
Not applicable.
5.2. General Methods
As described in Section 3.4, in this study ‘treatment group’ refers to the following:
•
avelumab 10 mg/kg in combination with axitinib 5 mg.
If avelumab 10 mg/kg in combination with axitinib 5 mg is not tolerable, a lower dose of the 
combination may be added as another treatment group evaluated in a new cohort of patients.
Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment group.
Safety data, exposure data, concomitant medications and non-drug treatments will be 
summarized based on the safety analysis set by treatment group. 
PK data will be summarized based on the PK analysis set by treatment group.
Biomarker data will be summarized based on the biomarker analysis set by treatment group.
Immunogenicity data will be summarized based on the immunogenicity analysis set by 
treatment group.
5.2.1. Data Handling after the Cut-off Date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of Centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
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5.2.3. Presentation of Continuous and Qualitative Variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3). 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore, counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified.
5.2.4. Definition of Study Day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment 
(eg, baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. Definition of Start of New Anti-cancer Drug Therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of Start of New Anti-cancer Therapy
Start date of new anti-cancer therapy (drug, non-drug locoregional, radiation, surgery) is used 
for censoring in efficacy analyses (see Section 6.2.1).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment amongst the following:
•
Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ 
eCRF pages;


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•
Start date of anti-cancer non-drug locoregional therapy recorded in the eCRF pages
related to the follow-up non-drug locoregional treatments;
•
Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’;
•
Surgery date recorded in ‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF 
pages when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially Resected’.  
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied using ‘Follow-up Cancer Therapy’ eCRF 
page, eCRF pages related to the follow-up non-drug locoregional treatments, ‘Concomitant 
Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘Concomitant Surgery’, and ‘Follow-up 
Surgery’ eCRF pages.
5.2.7. Definition of On-treatment Period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years:
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:
•
Age [years]: 
(date of given informed consent - date of birth + 1) / 365.25
In case of missing day, day only: Age [years]: (year/month of given informed consent –
year/month of birth)
In case only year of birth is given: Age [years]: (year of given informed consent - year of 
birth)
The integer part of the calculated age will be used for reporting purposes. 
BMI (kg/m2) = weight (kg)/[height (m)]2


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For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer/first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 
5.5 to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled Visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits.
5.2.10. Adequate Baseline Tumor Assessment
Adequate baseline is defined using the following criteria:
All baseline assessments must be within 31 days prior to and including date of first dose of 
study treatment.
All documented lesions must have non-missing assessments (ie, non-missing measurements 
for target lesions and non-missing lesions assessment status at baseline for non-target 
lesions).
5.2.11. Adequate Post-baseline Tumor Assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.2.1.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’. 


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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.
All the concentration data will be listed but the summaries of Ctrough and Cmax, will not 
include concentrations associated with samples collected more than 20% before or after the 
planned time.  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
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:


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


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


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•
Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’);
•
Study drug start and end dates;
•
Withdrawal of consent date;
•
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up).
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will 
not be applied to derive the last contact date.
5.3.3.2. Death Date
Missing or partial death dates will be imputed based on the last contact date:
•
If the date is missing it will be imputed as the day after the date of last contact.
•
If the day or both day and month is missing, death will be imputed to the maximum of 
the full (non-imputed) day after the date of last contact and the following:
- Missing day:
1st day of the month and year of death
- Missing day and month:
January 1st of the year of death
5.3.3.3. Tumor Assessments
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates 
(eg, X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
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, non-drug 
locoregional therapy, radiation, surgery) will be imputed as follows and will be used for 
determining censoring dates for efficacy analyses and in the derivation of the end of 
on-treatment period.  PD date below refers to PD date by investigator assessment.
•
The end date of new anti-cancer therapy will be included in the imputations for start 
date of new anti-cancer therapy.  If the end date of new anti-cancer therapy is:
•
completely missing then it will be ignored in the imputations below;
•
partially missing with only year (YYYY) available then the imputations below 
will consider 31DECYYYY as the end date of the new anti-cancer therapy;
•
partially missing with only month and year available then the imputations below 
will consider the last day of the month for MMMYYYY as the end date of the 
new anti-cancer therapy.
•
For patients who have not discontinued study treatment at the analysis cut-off date, 
last dose of study treatment is set to the analysis cut-off date in the imputations 
below. 
•
If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is derived as follows:
•
Start date of new anti-cancer therapy is completely missing
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
•
Only year (YYYY) for start of anti-cancer therapy is available
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY; 
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 
1), end date of new anti-cancer therapy];
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 
1), end date of new anti-cancer therapy];
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 
1), end date of new anti-cancer therapy];
THEN imputed start date = 01JANYYYY.


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


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ELSE IF
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy];
THEN 
imputed start date = 01 MMM YYYY.
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology. 
6.1. Primary Endpoints
6.1.1. Adverse Events and Laboratory Abnormalities
6.1.1.1. Primary Analysis
Refer to Sections 6.6.1, 6.6.2, 6.6.3, 6.6.4 and 6.6.5.
6.2. Secondary Endpoint(s)
6.2.1. Efficacy Endpoints
The following analyses will be based on the FAS by treatment group.  Assessment of 
response will be made using RECIST v1.1. Tumor-related endpoints will be analyzed
separately based on investigator assessment and BICR assessment.
6.2.1.1. Objective Response
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the first dose of study treatment until the first 
documentation of PD, according to the following rules. Only tumor assessments performed 
on or before the start date of any further anti-cancer therapies will be considered in the 
assessment of BOR.  Clinical deterioration will not be considered as documentation of 
disease progression.
BOR Based on Confirmed Responses: 
•
CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD.
•
PR = at least two determinations of PR or better (PR followed by PR or PR followed 
by CR) at least 4 weeks apart and before first documentation of PD (and not 
qualifying for a CR).
•
SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥8 weeks after first dose of study treatment and before first 
documentation of PD (and not qualifying for CR or PR). 


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•
Non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline) = at least one non-CR/non-PD assessment (or better) ≥8 weeks after first 
dose of study treatment and before first documentation of PD (and not qualifying for 
CR or PR).
•
PD = first documentation of PD ≤16 weeks after first dose of study treatment (and not 
qualifying for CR, PR, SD or non-CR/non-PD).
•
NE: all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence 
PR-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 a confirmed BOR of CR, 
PR, SD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), PD and NE will be tabulated. Patients with confirmed BOR of NE will be 
summarized by reason for having NE status. The following reasons will be used:
•
No baseline assessment;
•
No post-baseline assessments due to death;
•
No post-baseline assessments due to other reasons;
•
All post-baseline assessments have overall response NE;
•
New anti-cancer therapy started before first post-baseline assessment;
•
SD of insufficient duration (<8 weeks after first dose of study treatment);
•
PD too late (>16 weeks after first dose of study treatment).


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Special and rare cases where BOR is NE due to both early SD and late PD will be classified 
as ‘SD too early’ (ie, SD of insufficient duration).
6.2.1.2. Tumor shrinkage from Baseline
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:
•
((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100.
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:
•
Minimum of ((sum of target lesions at week XX – sum of target lesions at 
baseline)/sum of target lesions at baseline) × 100.
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment group. 
These plots will display the best percentage change from baseline in the sum of the diameter 
of all target lesions for each patient with measurable disease at baseline and at least one
post-baseline assessment.
6.2.1.3. 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.
6.2.1.4. 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 6.
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 2, 4, 6, 8, 12 and 16 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 


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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.
6.2.1.5. Time to Response
Time to response (TTR) is defined, for patients with OR, as the time from the date of first 
dose of study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
TTR (in months) = [first date of OR – date of first dose of study treatment +1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.1.6. Time to Progression
Time to progression (TTP) is defined as the time from the date of first dose of study 
treatment to the date of the first documentation of PD. 
TTP data will be censored on the date the last adequate tumor assessment for patients without 
PD, for patients who start new anti-cancer therapy prior to PD (see Section 5.2.6), for 
patients who die without PD, or for patients with PD after 2 or more missing tumor 
assessments.  Patients who do not have a baseline tumor assessment or who do not have any 
post-baseline tumor assessments will be censored on the date of first dose of study treatment.
The censoring and event date options to be considered for the TTP analysis are presented in
Table 4. 
TTP (months) = [date of event or censoring– date of first dose of study treatment
+1]/30.4375
Table 4.
TTP Outcome and Event Dates
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of first dose of study treatment
Censored
PD
-
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR
-
≤16 weeks after first dose of 
study treatment
Date of PD
Event
PD after 2 or more missing or 
inadequate post-baseline tumor 
assessments
Date of last adequate tumor assessmenta
documenting no PD before new 
anti-cancer therapy is given or missed 
tumor assessments
Censored
No PD
Censored


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Table 4.
TTP Outcome and Event Dates
Scenario
Date of event/censoring
Outcome
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 assessmenta
documenting no PD before new 
anti-cancer therapy is given or missed 
tumor assessments
Censored
Death due to any cause
a.
If there are no adequate post-baseline assessments prior to the PD, then the time without adequate 
assessment should be measured from the first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median TTP time with 2-sided 
95% CIs.  In particular, the TTP rate at 2, 4, 6, 8, 12 and 16 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 event 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.
Table 5.
TTP 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 PD 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate 
post-baseline tumor assessment/first dose of study 
treatment
Event after missing assessmentsa
4
Death without documented PD
Death for reasons other than PD
5
No PD and [withdrawal of consent date ≥date of first 
dose of study treatment OR End of study (EOS) = 
Subject refused further follow-up]
Withdrawal of consent
6
No PD and lost to follow-up in any disposition page 
Lost to follow-up
7
No PD 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 post-baseline tumor 
assessment
8
No PD 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.


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The TTP time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for TTP
A Kaplan-Meier plot for TTP follow-up duration will also be generated to assess the 
follow-up time in the treatment groups reversing the TTP 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 
TTP with 2-sided 95% CIs.  In particular, the rate at 2, 4, 6, 8, 12 and 16 months will be 
estimated with corresponding 2-sided 95% CIs.
6.2.1.7. Progression-free Survival
Progression-Free Survival (PFS) is defined as the time from date of first dose of study 
treatment to the date of the first documentation of PD or death due to any cause, whichever 
occurs first.   
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.  Patients who do not have an adequate baseline tumor assessment or who do not 
have an adequate post-baseline tumor assessment will be censored on the date of first dose of 
study treatment unless death occurred on or before the time of the second planned tumor 
assessment (ie, ≤16 weeks after date of first dose of study treatment) in which case the death 
will be considered an event. 
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 6.  
PFS (months) = [date of event or censoring – date of first dose of study treatment
+1]/30.4375
Table 6.
Outcome and event dates for PFS and DR analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
date of first dose of study 
treatmenta
Censoreda
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤16 weeks after date of first dose of 
study treatment
Date of PD or death
Event
PD or death after 2 or more missing or 
inadequate post-baseline tumor assessments
Date of last adequate tumor 
assessmentb 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
assessmentb documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored


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Scenario
Date of event/censoring
Outcome
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived based 
on documented progression 
only
New anti-cancer therapy given 
Date of last adequate tumor 
assessmentb documenting no 
PD before new anti-cancer 
therapy is given or missed 
tumor assessments
Censored
a.
However if the patient dies ≤16 weeks after date of first dose of study treatment the death is an event with 
date on death date.
b.
If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided 
95% CIs.  In particular, the PFS rate at 2, 4, 6, 8, 12 and 16 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 7 following the hierarchy shown.
Table 7.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline 
assessment
2
Start of new anti-cancer therapy 
Start of new anti-cancer 
therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of first dose of study treatment
Event after missing 
assessmentsa
4
No event and [withdrawal of consent date ≥date of first 
dose of study treatment 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. 


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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 2, 4, 6, 8, 12 and 
16 months will be estimated with corresponding 2-sided 95% CIs.
6.2.1.8. Overall Survival
Overall survival (OS) is defined as the time from date of first dose of study treatment to the 
date of death due to any cause. Patients last known to be alive will be censored at date of last 
contact.
OS (months) = [date of death or censoring– date of first dose of study treatment
+1]/30.4375
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rate at 2, 4, 6, 8, 12, 16, 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 an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according 
to the categories in Table 8 following the hierarchy shown.
Table 8.
OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥date of first 
dose of study treatment OR End of study (EOS) = 
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 >104 days]
Lost to follow-up
3
No event and none of the conditions in the prior 
hierarchy are met 
Alive


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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 2, 4, 6, 8, 12, 16, 18 and 24 months will be estimated with 
corresponding 2-sided 95% CIs.
6.2.2. Pharmacokinetic Endpoints
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.
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 from concentration-time data as described in Section 3.2.2.
Presentation of pharmacokinetic data will include:
•
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of 
concentrations 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 avelumab and axitinib pharmacokinetic parameters.
•
Linear-linear plots of mean and median concentrations by nominal time for avelumab 
and axitinib will be presented for PK sampling days by treatment group, cycle, and 
study day. Similar plots will be presented for each individual patient concentration. 
Patients who have undergone intrapatient dose reduction or escalation will be 
excluded from the median concentration-time plots.
•
Pharmacokinetic parameters for avelumab and axitinib will be listed and summarized 
by treatment group/dose level, cycle and study day using descriptive statistics 
(n, mean, SD, %CV, median, minimum, maximum, geometric mean and its 
associated %CV, and 95% CI).  In addition, dose-normalized Cmax and Ctrough will be 
summarized (as described above) using data pooled across treatment groups in which 
different avelumab and axitinib doses were administered.


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•
Ctrough and Cmax for avelumab will be plotted for each treatment group using a box-
whisker plot by cycle and day within cycle.
6.2.3. 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 from the clinical study report.
6.2.4. Biomarker Endpoints
Biomarkers will be summarized at all timepoints described below:
•
Archived tumor biospecimens and de novo Tumor Biopsy: Screening and EOT.
Summary statistics, using descriptive statistics (mean, SD, median, Q1, Q3, minimum, and 
maximum), at each timepoint, ratio to screening and percent change from the value at 
screening/C1D1 if available (for continuous markers) will be provided by treatment group.
6.2.5. Endpoints for Immunogenicity Data of Avelumab
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 
8 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.
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 9.  
C
C


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Table 9
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 10. 
For nAb, treatment-boosted is not applicable since no titer result is available.


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Table 10
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. 
6.2.5.1. Time to and Duration of ADA and nAb Response 
The ADA and nAb analyses described below will include patients with treatment-induced 
ADA or nAb, respectively.  
Time (weeks) to ADA response is defined as:
(Date of first positive ADA result – date of first dose of avelumab + 1)/7. 
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).
Duration (weeks) of ADA response is defined as:
(Date of last positive ADA result – date of first positive ADA result + 1)/7. 
Duration of ADA response will be censored if: 
•
the last ADA assessment is positive AND patient is ongoing treatment with 
avelumab, or


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•
the last ADA assessment is positive AND patient discontinued treatment with 
avelumab AND the last planned ADA assessment (day 30 follow-up visit) is after the 
cut-off date.
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result. 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley
(1982) 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. 
6.2.5.2. ADA Titer
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value 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. 
6.2.5.3. Analysis of PK, Safety and Efficacy by Immunogenicity Status
The following ADA and nAb status will be used for the analyses described below.
ADA
•
ADA ever-positive versus ADA never-positive;
•
ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive.


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nAb 
•
nAb ever-positive versus nAb never-positive;
•
nAb: treatment-induced nAb versus nAb never-positive or baseline nAb positive.
Data listings will include immunogenicity data together with relevant PK, safety and efficacy 
data.
PK parameters and immunogenicity status
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax.  
Blood samples for avelumab PK will be collected 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 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 plots of mean and 
median for Ctrough and Cmax over relative PK day will be presented. 
As data permit, the analyses described above will be repeated for nAb.
Safety and immunogenicity status
The following analyses will include patients in the immunogenicity analysis set.
The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status.
•
TEAEs, by SOC and PT;
•
TEAEs leading to dose reduction of avelumab, by SOC and PT;


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•
TEAEs leading to discontinuation of avelumab, by SOC and PT;
•
TEAEs leading to discontinuation of study treatment by SOC and PT;
•
Grade ≥3 TEAEs, by SOC and PT;
•
SAEs, by SOC and PT;
•
IRRs, by PT.
For patients who had at least one IRR and have treatment-induced ADA, time related to first 
onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later) will be summarized 
taking into account whether the IRR occurred on or after the first ADA positive assessment 
or whether the IRR occurred before the first ADA positive assessment.  
As data permit, the analyses described above will be repeated for nAb.
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.
 
 
 
 
6.4. Subset Analyses
Subset analyses using PD-L1 status (thresholds are <1%/≥1% and <10%/≥10%) at baseline
will be performed for OR and PFS per investigator assessment and BICR assessment based 
on RECIST v1.1
, and for OS, based on the FAS.
CCI
CCI


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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
The following analyses will be based on the FAS overall and separately by treatment group.  
Demographic characteristics except for physical measurements (see Section 6.5.1.1), 
significant medical history (see Section 6.5.1.2) and disease characteristics (Barcelona Clinic 
Liver Cancer [BCLC], vascular invasion, extrahepatic spread, intrahepatic tumor,
extrahepatic spread and intrahepatic tumor and baseline AFP level; see Section 6.5.1.3) will
be also summarized by PD-L1 status at baseline based on the FAS.
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.  
•
Demographic characteristics:
•
Gender: Male, Female;
•
Race: White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander, Multiracial, Not Reported;
•
Racial Designation: Japanese, Korean, Chinese, Other;
•
Ethnic origin: Hispanic/Latino (Yes/No), Not Reported;
•
Age (years): summary statistics;
•
Age categories: 
•
<65 years, ≥65 years;
•
<65, 65-<75, 75-<85, ≥85 years;
•
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3,
and 4.
•
Physical measurements:
•
Height (cm);
•
Weight (kg);
•
Body Mass Index (BMI) (kg/m2).
•
Child-Pugh score:
•
Child-Pugh score (summarized as qualitative variable).


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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), ECOG performance status, and Child-Pugh score.
6.5.1.2. Medical History
•
Medical history
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.
•
Significant medical history
Significant medical history will be summarized by treatment group using the following 
information from the ‘Significant Medical History’ eCRF pages.
•
Hepatitis B: Yes, No
•
Hepatitis C: Yes, No
•
Alcoholic hepatitis: Yes, No
•
Non-alcoholic steatohepatitis: Yes, No
6.5.1.3. Disease Characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Subject 
Stratification’, ‘Substance Use’, ‘RECIST’ and ‘Laboratory Data’ eCRF pages will be 
summarized overall and by treatment group. Summary statistics will be presented for the 
following.
From the ‘Primary Diagnosis’ eCRF page:
•
Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’
eCRF page);
•
Method of primary diagnosis: Histology, Cytology, Non-invasive;
•
BCLC: A, B, C, D, Unknown;
•
Histopathological grade: Grade 1, 2, 3, 4;
•
TNM current stage: Stage I, Stage II, Stage IIIA, Stage IIIB, Stage IIIC, Stage IVA, 
Stage IVB, Unknown;


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•
Time since initial diagnosis to date of first dose of study treatment (months), defined 
as (date of first dose of study treatment – date of initial diagnosis)/30.4375;
•
Time since histopathological diagnosis to first dose of study treatment (months), 
defined as (date of first dose of study treatment – date of histopathological
diagnosis)/30.4375;
•
Time since recurrence/metastatic of disease to first dose of study treatment (months), 
defined as (date of first dose of study treatment – date of recurrence/metastatic of 
disease)/30.4375;
•
Time since diagnosis of local/regional recurrence of disease (months), defined as 
(date of first dose of study treatment – date of diagnosis of local/regional recurrence 
of disease)/30.4375.
From the Subject Stratification eCRF page:
•
Vascular invasion: Yes, No;
•
Extrahepatic spread: Yes, No;
•
Intrahepatic tumor: Yes, No;
•
Extrahepatic spread and intrahepatic tumor: Both, Extrahepatic spread only, 
Intrahepatic tumor only, None.
From the RECIST eCRF page:
•
Measurable disease (lesions) at baseline (Yes, No);
•
Involved tumor sites at baseline.
From Laboratory page: 
•
Baseline AFP <100 ng/mL, ≥100 - <200 ng/mL, ≥200 - <400 ng/mL, ≥400 ng/mL;
•
Number of patients who was diagnosed by imaging method by AFP level 
<400 ng/mL, ≥400 ng/mL.
From the ‘Substance Use’ eCRF page:
•
Smoking history:
•
Never smoker vs current vs former smoker;
•
Smoking exposure (pack-years): 0, <20, 20-<40, ≥40 and summary statistics;


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•
Years since quitting: never smoker, current smoker, <5, 5-<10, ≥10 and summary 
statistics.
Specifications for computation:
•
Cigarette equivalents are calculated as follows: one cigar is regarded equivalent to 
5 cigarettes and 1 pipe is regarded equivalent to 3 cigarettes.
•
Duration of nicotine consumption [years]:
(end of nicotine consumption – start of nicotine consumption + 1) / 365.25.
•
Pack-years:
•
calculate cigarette equivalents per day using the conversion factors given above;
•
convert to packs per day where 20 cigarettes are regarded as 1 pack;
•
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’, ‘Subject Stratification’, ‘Substance Use’, ‘RECIST’ and ‘Laboratory Data’ eCRF 
pages) and derived variables as above.
6.5.1.4. Prior Anti-cancer Therapies
The prior anti-cancer therapies are collected under the eCRF page related to prior non-drug 
locoregional treatment and ‘Prior Cancer Therapy’, ‘Prior Radiation Therapy’ and ‘Prior 
Surgery’ eCRF pages.
The prior anti-cancer locoregional therapies are collected under the eCRF page related to 
prior non-drug locoregional treatment and ‘Prior Cancer Therapy’ eCRF pages.  
•
Locoregional therapies with drug are extracted by verbatim term of ‘Reason for 
Administration’ in ‘Prior Cancer Therapy’ eCRF pages as below:
•
Transcatheter arterial chemoembolization;
•
Hepatic arterial infusion;
•
Percutaneous ethanol injection;
•
Others (‘Locoregional therapy’ as verbatim term).
•
Locoregional therapies without drug are extracted by verbatim term of ‘Treatment’ in
the eCRF page related to prior non-drug locoregional treatment as below:
•
Transcatheter arterial embolization;
•
Radiofrequency ablation;


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•
Cryotherapy;
•
Others (verbatim terms other than the above).
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:
•
Patients with at least one type of prior anti-cancer treatment;
•
Patients with at least one prior anti-cancer locoregional therapy;
•
Patients with at least one prior anti-cancer drug therapy other than locoregional 
therapy (other than locoregional therapy from ‘Prior Cancer Therapy’ eCRF page);
•
Patients with at least one prior anti-cancer radiotherapy;
•
Patients with at least one prior anti-cancer surgery.
Prior anti-cancer locoregional therapy with/without drug will be summarized as follows 
based on the number and percentage of patients with the following:
•
At least one prior anti-cancer locoregional therapy;
•
Number of times of prior transcatheter arterial chemoembolization (TACE): missing,
0, 1, 2, 3, ≥4;
•
Locoregional therapy: Transcatheter arterial embolization (TAE), TACE, Hepatic 
arterial infusion (HAI), Percutaneous ethanol injection (PEI), Radiofrequency 
ablation (RFA), Cryotherapy, Others.
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:
•
At least one prior anti-cancer drug therapy;
•
Number of prior anti-cancer drug therapy regimens: missing, 0, 1, 2, 3, ≥4;
•
Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced-Metastatic,
Locoregional Disease-Recurrence;
•
Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived 
from the last treatment regimen.
The drugs for prior anti-cancer locoregional therapies and prior anti-cancer drug therapies 
will also be summarized based on the number and percentage of patients by the drug class 
and preferred term, respectively. A patient will be counted only once within a given drug 
class and within a given drug name, even if he/she received the same medication at different 
times. The summary will be sorted on decreasing frequency of drug class and decreasing 


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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.
The combined preferred term of drug for prior anti-cancer locoregional therapies, 
eg, epirubicin/mitomycin, and prior anti-cancer drug therapies will also be summarized based 
on the number and percentage of patients. A patient will be counted only once within a given 
clustered drug name, even if he/she received the same medication at different times. The 
summary will be sorted on decreasing frequency of clustered drug. In case of equal 
frequency, alphabetical order will be used.
Prior anti-cancer therapies will be included in the listings that follow with a flag to identify 
prior therapies. These will include the patient identification number, and all the relevant 
collected data-fields on the corresponding eCRF pages.
•
Listing of anti-cancer locoregional therapies with drug, including responses to 
regimen;
•
Listing of anti-cancer locoregional therapies without drug, including responses to 
regimen;
•
Listing of anti-cancer drug therapies, including responses to regimen;
•
Listing of anti-cancer radiotherapy;
•
Listing of anti-cancer surgeries.
6.5.2. Study Conduct and Patient Disposition
The following analyses will be performed based on the FAS overall and separately by
treatment group.
6.5.2.1. Patient Disposition
The percentages below will be calculated based on the number of patients in the FAS.
•
Total number of patients screened overall;
•
Number of patients who discontinued from the study prior to treatment with study 
drug overall and by the main reason for discontinuation;
•
Number and percentage of treated patients in each of the analysis sets defined in 
Section 4;
•
Number and percentage of patients with study drug ongoing (separately for each 
study drug when administered in combination);
•
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 when 
administered in combination);


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•
Number and percentage of patients who entered follow-up;
•
Number and percentage of patients who discontinued follow-up overall and by the 
main reason for discontinuation;
•
Number and percentage of patients who entered long-term follow-up;
•
Number and percentage of patients who discontinued long-term follow-up overall and 
by the main reason for discontinuation.
In addition the following will be summarized:
•
Number and percentage of treated patients by center.
In addition, a cross tabulation of patients who have discontinued/are ongoing treatment with 
avelumab vs patients who have discontinued/are ongoing treatment with axitinib will also be 
provided. 
6.5.2.2. Protocol Deviations
All protocol violations that impact the safety of the patients and/or the conduct of the study 
and/or its evaluation will be reported. These include:
•
Patients who are dosed on the study despite not satisfying the inclusion criteria;
•
Patients who develop withdrawal criteria whilst on the study but are not withdrawn;
•
Patients who receive the wrong treatment or an incorrect dose;
•
Patients who receive an excluded concomitant medication;
•
Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study Treatment Compliance and Exposure
The following analyses will be based on the safety analysis set by treatment group.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  
For Cycle X, actual cycle start date for each patient is:
•
the earliest start date of dosing in the Cycle X Day 1 visit eCRF exposure page, if the 
patient received study treatment on that visit (ie, any study drug with dose >0 at that 
visit);


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•
the first day of assessments in the Cycle X Day 1 visit, if the patient did not receive 
study treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start 
date in the exposure page if available; if start date is not available then use date of 
collection of vital signs on Cycle X Day 1 visit.
Actual cycle end date for each patient is, 
•
for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start 
date – 1 day;
•
for the last cycle, actual cycle end date = actual cycle start date + intended cycle 
duration (in days) – 1 day.
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7 
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.
Exposure may be summarized (per cycle and/or overall) as dose received (cumulative dose, 
actual dose intensity) and as dose received relative to intended dose (relative dose intensity 
[RDI]).  
The information that will be summarized depends on how the study drug is dosed 
(eg, infusion cyclical, oral daily, oral cyclical).
The formulae below should be applied to each study drug separately even when study drugs 
are administered in combination.
The derivations below are provided assuming 1 cycle = 2 weeks and for the following study 
drugs (administered alone or in combination):
•
Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg once every 
2 weeks in 2-week cycles. 
•
Axitinib administered orally BID PO at a dose of 5 mg. 
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 study drug + 1)/7, 
where end date = start date of last cycle with non-zero dose of study drug + 14 – 1.


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


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Relative Dose Intensity (RDI)  
•
RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of study drug to last dose of study drug] 
= 100 × [overall cumulative dose] / [7 ×2 × 5 × duration of exposure to axitinib in 
weeks]
6.5.3.3. Dose Reductions 
Applicable to avelumab.  Dose reduction is defined as actual non-zero dose <90% of the 
planned dose. 
Applicable to axitinib.  Dose reduction is defined as a change to a non-zero dose level lower 
than that planned in the protocol.
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized. 
For axitinib, patients experiencing dose reduction to 3 mg and to 2 mg are also summarized.
6.5.3.4. Dose Escalations
Applicable to axitinib.
Dose escalation is defined as a change to a non-zero dose level upper than that planned in the 
protocol.
The number and percentage of patients with at least one dose escalations as well as a 
breakdown of the number of dose escalations (1, 2, 3, ≥4) will be summarized. 
Patients experiencing dose escalations to 7 mg and to 10 mg are also summarized.
6.5.3.5. Dose Interruptions
Applicable to axitinib.  
An interruption is defined a 0 mg dose administered on one or more days for axitinib. What 
follows defines how dose interruptions will be counted in the case of multiple dose 
interruptions.
•
If an interruption occurs consecutively for at least two days 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).


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•
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). 
•
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). 
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.
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses. 
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – 14. 
Dose delays will be grouped into the following categories: 
•
No delay;
•
1-3 days delay;
•
4-6 days delay;
•
7 or more days delay.
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16, 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. 


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6.5.3.7. Infusion Rate Reductions
Applicable to avelumab.
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized.
6.5.3.8. Infusion Interruptions
Applicable to avelumab.
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.


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All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’. 
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page.
6.5.5. Subsequent Anti-cancer Therapies
The following analyses will be based on the FAS by treatment group.
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’ eCRF page, eCRF pages related to the follow-up non-drug locoregional 
treatments, ‘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’ eCRF page, eCRF pages related to the follow-up non-drug locoregional 
treatments, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages. 
Number and percentage of patients with 2nd line systemic or locoregional treatment will be 
tabulated by type of therapy based on the data collected from the ‘Follow-up Cancer 
Therapy’ eCRF page and eCRF pages related to the follow-up non-drug locoregional 
treatments.
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 will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings.
•
Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) 
reported by the investigator and those of unknown relationship (ie, no answer to the 
question ‘Relationship with study treatment’). Related AEs are those related to any 
study drug (ie, at least one of the study drugs).
•
Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).


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•
Adverse Events Leading to Dose Reduction: adverse events leading to dose 
reduction of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug reduced).
•
Adverse Events Leading to Interruption of Study Treatment: adverse events 
leading to dose interruption of study treatment (as recorded on the AE eCRF page, 
Action taken with study treatment = Drug interrupted). The eCRF does not allow for 
a clear separation between interruption of an infusion and delays of administration for 
a parenteral drug as both are recorded using the same term on the eCRF (“Drug 
interrupted”).  IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion.
•
Adverse Events Leading to Permanent Treatment Discontinuation: adverse 
events leading to permanent discontinuation of study treatment (as recorded on the 
AE eCRF page, Action taken with study treatment = Drug withdrawn).
•
Adverse Events Leading to Death: adverse event leading to death (as recorded on 
the AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5).
•
Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan and finalized for analysis of the current 
studies data prior to DB lock).
•
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 based on the frequencies observed for the avelumab 
10 mg/kg in combination with axitinib 5 mg group. 
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 v.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. 


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The following tables will be created: 
•
The overall summary of AEs table will include the frequency (number and 
percentage) of patients with each of the following by treatment group:
•
TEAEs;
•
TEAEs, Grade ≥3;
•
Related TEAEs;
•
Related TEAEs, Grade ≥3;
•
TEAEs leading to dose reduction of avelumab;
•
TEAEs leading to dose reduction of axitinib;
•
TEAEs leading to interruption of avelumab;
•
TEAEs leading to interruption of axitinib;
•
TEAEs leading to discontinuation of avelumab;
•
TEAEs leading to discontinuation of axitinib;
•
TEAEs leading to discontinuation of any study drug;
•
TEAEs leading to discontinuation of all study drugs;
•
Related TEAEs leading to discontinuation of avelumab;
•
Related TEAEs leading to discontinuation of axitinib;
•
Related TEAEs leading to discontinuation of any study drug;
•
Related  TEAEs leading to discontinuation of all study drugs;
•
Serious TEAEs;
•
Related Serious TEAEs;
•
TEAEs leading to death;
•
Related TEAEs leading to death;
•
irAEs;
•
IRRs.


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•
TEAEs by SOC and PT and worst grade;
•
Related TEAEs by SOC and PT and worst grade;
•
TEAEs leading to death by SOC and PT;
•
Related TEAEs leading to death by SOC and PT;
•
TEAEs by SOC and PT: displaying in separate columns the All TEAEs / Related 
TEAEs / Grade ≥3 TEAEs / Related Grade ≥3 TEAEs;
•
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:
•
TEAEs leading to dose reduction of avelumab by SOC and PT;
•
TEAEs leading to dose reduction of axitinib by SOC and PT.
The listing of all AEs leading to dose reduction will also be provided with the relevant 
information.
6.6.1.3. Adverse Events Leading to Interruption of Study Treatment
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).  IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay). 
As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding 
•
IRRs that occurred on the day of infusion with ≥90% of the planned dose given 
(ie, IRRs that did not lead to a dose reduction) and subsequent administration of study 
drug had no delay (as defined in Section 6.5.3.6). These IRRs will be considered as 
IRRs leading to interruption of infusion.
•
IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.6).
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment group:
•
TEAEs leading to interruption of avelumab by SOC and PT;


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•
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:
•
TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT;
•
TEAEs leading to both interruption and dose reduction of axitinib by SOC and PT.
This summary will take into account PTs with both actions as defined in Section 6.6.1, 
eventhough the actions may be captured for different PT records (ie, different onset for the 
PT with action “drug interrupted” and the PT with action “dose reduced”.  
6.6.1.4. Adverse Events Leading to Discontinuation of Study Treatment
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment, by treatment group:
•
TEAEs leading to discontinuation of avelumab by SOC and PT;
•
Related TEAEs leading to discontinuation of avelumab by SOC and PT;
•
TEAEs leading to discontinuation of axitinib by SOC and PT;
•
Related TEAEs leading to discontinuation of axitinib by SOC and PT;
•
TEAEs leading to discontinuation of any study drug by SOC and PT;
•
Related TEAEs leading to discontinuation of any study drug by SOC and PT;
•
TEAEs leading to discontinuation of all study drugs by SOC and PT;
•
Related TEAEs leading to discontinuation of all study drugs by SOC and PT.
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’
eCRFs, by treatment group.  
•
All deaths;
•
Deaths within 30 days after last dose of study treatment;


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•
Reason for Death:
•
Disease progression;
•
Study treatment toxicity;
•
AE not related to study treatment;
•
Unknown;
•
Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first/last administration, 
dose) and will include the following information:
•
AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as 
AEs of Grade 5), 
•
Flag for death within 30 days of last dose of study treatment.
6.6.3. Serious Adverse Events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group:
•
SAEs by SOC and PT;
•
Related SAEs by SOC and PT.
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other Significant Adverse Events
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group:
•
irAEs leading to death, by Cluster and PT;
•
irAEs, by Cluster and PT;
•
irAEs, Grade ≥3, by Cluster and PT;
•
irAEs leading to discontinuation of avelumab, by Cluster and PT;
•
irAEs leading to discontinuation of axitinib, by Cluster and PT; 
•
irAEs leading to discontinuation of any study drug, by Cluster and PT; 


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•
irAEs leading to discontinuation of all study drugs, by Cluster and PT; 
•
Serious irAEs, by Cluster and PT.
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group:
•
IRRs leading to death, by PT;
•
IRRs, by PT;
•
IRRs, Grade ≥3, by PT;
•
IRRs leading to discontinuation of avelumab, by PT;
•
Serious IRRs, by PT;
•
Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later).
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
6.6.5. Laboratory Data
6.6.5.1. Hematology and Chemistry Parameters
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. 
Non-numerical qualifiers (with the exception of fasting flags) will not be taken into 
consideration in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are 
only distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9). End of Treatment visit laboratory results will be 
summarized separately. The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories 
(ie, Low, Normal, High). 


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


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•
AST ≥3×ULN, AST ≥5×ULN, AST ≥10×ULN, AST ≥20×ULN;
•
(ALT or AST) ≥3×ULN, (ALT or AST) ≥5×ULN, (ALT or AST) ≥10×ULN, (ALT 
or AST) ≥20×ULN;
•
TBILI ≥2×ULN;
•
Concurrent ALT ≥3×ULN and TBILI ≥2×ULN;
•
Concurrent AST ≥3×ULN and TBILI ≥2×ULN;
•
Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN;
•
Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP >2×ULN;
•
Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and (ALP ≤2×ULN or 
missing).
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying.
•
peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at
ALT=3×ULN and total bilirubin =2×ULN. 
•
peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at
AST=3×ULN and total bilirubin =2×ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a 
post-baseline TBILI ≥2×ULN, ALT ≥3×ULN or AST ≥3×ULN will be provided.
Parameters with NCI-CTC grades available: 
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie, those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).
•
The summary of laboratory parameters by CTCAE grade table will include number 
and percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade
(Grades 1-4), laboratory abnormalities during the on-treatment period.


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•
The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is 
considered as the worst grade for the summary. 
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie:
•
Hematology: 
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils/Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased).
•
Serum Chemistry:
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased), Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine Kinase 
(CPK increased), Potassium (hypokalemia/hyperkalemia), Sodium (hyponatremia/ 
hypernatremia), Magnesium (hypomagnesemia/hypermagnesemia), Calcium (hypocalcemia/ 
hypercalcemia), Glucose (hypoglycemia/hyperglycemia), Gamma Glutamyl Transferase 
(GGT) (GGT increased), Lipase (lipase increased), Phosphates (hypophosphatemia), 
Triglycerides (hypertriglyceridemia).
Parameters with NCI-CTC grades not available:
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with: 
•
shifts from baseline normal to at least one result above normal during on-treatment 
period;
•
shifts from baseline normal to at least one result below normal during on-treatment 
period.
In this study, these apply to the following parameters:
•
Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils;
•
Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH), troponin (I and T).
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. 


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•
Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time 
(INR);
•
Urinalysis: all urinalysis parameters;
•
Other parameters: hormone (TSH, free T4, ACTH), and immunology parameters
(HBV, HCV), AFP, PIVKA-II;
•
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.  
The average of the replicate measurements should be determined at each time point prior to 
summarizing the data.  All vital sign assessments will be listed, and those collected outside 
the on-treatment period will be flagged in the listing. 
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed 
will be the differences from baseline.
6.6.7. Electrocardiogram
ECG summaries will include all ECG assessments from the on-treatment period.  All ECG 
assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing. QTcB and QTcF will be derived based on RR and QT (see below). The 
average of the replicate measurements should be determined after the derivation of the 
individual parameter at each time point.


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Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB =
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF =
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions. If QTcB and 
QTcF methods do not adequately correct for HR and there are a sufficient number of patients 
(eg, >30) with baseline ECGs, an alternate correction to achieve the goal of getting 
uncorrelated QTc and RR is based on a linear regression methods which yields, theoretically, 
uncorrelated QTc and RR.
Linear regression method:
•
Fit a model QT = a + b × RR to baseline data 
•
Use the estimated slope, 
^
b , to correct QT
•
Corrected QT for heart rate will be computed as follows:
QTcP = QT + 
^
b × (1- RR)
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.
•
Pearson correlation between QT and HR, QTc (QTcB, QTcF and, if applicable, 
QTcP) and HR using individual (non-averaged) baseline assessments;
•
For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at 
each post-baseline time point;
•
Frequency (number and percentage) of patients with notable ECG values according to 
the following categories: 
•
QT/QTc increase from baseline >30 ms, >60 ms;
•
QT/QTc >450 ms, >480 ms, >500 ms;
•
HR ≤50 bpm and decrease from baseline ≥20 bpm;
•
HR ≥120 bpm and increase from baseline ≥20 bpm;
•
PR ≥220 ms and increase from baseline ≥20 ms;
•
QRS ≥120 ms.
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings.
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters.
6.6.8. MUGA/ECHO
LVEF% will be summarized using simple descriptive statistics (mean, SD, median, Q1, Q3, 
minimum, and maximum) of actual values and changes from baseline for each nominal visit 
over time.  In addition, LVEF% will be summarized as frequency (number and percentage) 
of patients with: 
•
a shift from baseline normal to at least one result below the institutional lower limit of 
normal during the on-treatment period;
•
≥10-point decrease from baseline in LVEF% during the on-treatment period;


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•
≥10-point decrease from baseline in LVEF% to a post-baseline value < LLN during 
the on-treatment period;
•
≥15-point decrease from baseline in LVEF% during the on-treatment period;
•
≥15-point decrease from baseline in LVEF% to a post-baseline value < LLN during 
the on-treatment period.
Clinically significant findings will be listed.
6.6.9. Physical Examination
The findings of the significant change since the previous physical examination will be 
presented in a data listing.
6.6.10. 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
No formal interim analysis will be conducted for this study. 


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8. REFERENCES
1.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
2.
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika; 26, 404-413.
3.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
4.
Collett D (1994). Modelling survival data in medical research. London, Chapman & 
Hall.
5.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience.  


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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 11.  
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step.  
Table 11.
Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs 
if A) OR B) OR C) below are met then the AE is in 
for the next step
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA, L04AB, 
L04AC, L04AD, L04AX A07EA) and AE PT 
is in any of the irAE clusters.
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters associated with 
“Immune-mediated endocrinopathies”
C) conmed ATC code is A10A and AE PT is in 
the irAE cluster associated with “Immune-
mediated endocrinopathies: Type I Diabetes 
Mellitus”


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


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Appendix 2. Infusion Related Reactions
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered. 
•
All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or 
after infusion) and the event resolved with end date within 2 days after onset. 
•
All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, 
will be considered potential IRRs when onset is on the day of study drug infusion 
(during or after the infusion) or the day after the study drug infusion (irrespective of 
resolution date).
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab. 
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 12
and will be identified for IV drugs only.
Table 12.
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs
Condition
Selection criterion
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)] then AE is classified as an IRR
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list 
2
•
AE onset date = date of infusion of study drug AND
•
AE timing related to study drug (‘DURING’, ‘AFTER’) AND
•
AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND
•
AE end date – AE onset date <=2 
3
PT is included in the ‘IRRs CORE’ list 
4A
•
AE onset date = date of infusion of study drug AND
•
AE timing related to study drug in (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion