A PHASE 3, MULTICENTER, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) PLUS BEST SUPPORTIVE CARE VERSUS BEST SUPPORTIVE CARE ALONE AS A MAINTENANCE TREATMENT IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL CANCER WHOSE DISEASE DID NOT PROGRESS AFTER COMPLETION OF FIRST-LINE PLATINUM-CONTAINING CHEMOTHERAPY
Phase: PHASE3
Conditions: Urothelial Cancer
Sponsor: Pfizer

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CLINICAL PROTOCOL
JAVELIN BLADDER 100
A PHASE 3, MULTICENTER, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, 
PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) PLUS BEST 
SUPPORTIVE CARE VERSUS BEST SUPPORTIVE CARE ALONE AS A 
MAINTENANCE TREATMENT IN PATIENTS WITH LOCALLY ADVANCED OR 
METASTATIC UROTHELIAL CANCER WHOSE DISEASE DID NOT PROGRESS 
AFTER COMPLETION OF FIRST-LINE PLATINUM-CONTAINING 
CHEMOTHERAPY 
Compound:
MSB0010718C
Compound Name:
Avelumab
United States (US) Investigational New 
Drug (IND) Number:
126,217
European Clinical Trials Database 
(EudraCT) Number:
2015-003262-86
Protocol Number:
B9991001
Phase:
3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.

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Document History
Document
Version Date
Summary of Changes
Amendment 6
08 March 2021
As the primary objective for the study was 
met at the pre-specified interim analysis 
(Section 9.6), the frequency of study 
procedures will be reduced while providing 
continued treatment for patients actively 
receiving avelumab and study participation 
will be ended for all patients not actively 
receiving avelumab (ie, Arm A patients in 
long-term follow-up and all Arm B patients 
who have not crossed over to receive 
avelumab). These changes will be 
implemented following a final overall 
survival (OS) update conducted after the 
target number of OS events has been reached
(see Section 9.1).  
Key changes implemented by Amendment 6 
include:

A new Schedule of Activities (SoA) table 
and a new Required Laboratory Tests 
table (Table 7) were added.

Blinded independent central review 
(BICR) tumor assessments will no longer 
be performed.

Arm B patients who are eligible to 
crossover to avelumab plus best 
supportive care (BSC) as per Supplement 
1 will be permitted to do so until 60 days 
after the final OS update or approval of 
Amendment 6, whichever is later. 

CRF data collection will be reduced to 
those items relating to study drug 
exposure and adverse events.
The following sections were modified based 
on the above:

Protocol Summary (Study Design, Study 
Treatment)

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
1.2.3.3 Rationale for Study Design

3.1 Study Overview

3.1.1 Study Treatment

3.1.2 Tumor Assessments

5.4.1 Treatment after Initial Evidence of 
Radiologic Disease Progression

5.9 Concomitant Treatments

6.2 Treatment Period

6.3 End of Treatment/Withdrawal and 
Follow-up Visits

6.5 Patient Withdrawal

7.1.1 Pregnancy Testing

7.1.3 Laboratory Safety Assessments

7.1.4 Physical Examinations and Vital 
Signs

7.1.5 (12-Lead) Electrocardiograms

7.2 Patient-Reported Outcome 
Assessments

7.3 Pharmacokinetics Assessments

7.4 Immunogenicity Assessment

7.5.2 Peripheral Blood

7.7 Tumor Assessments

7.8 Expedited Blinded Independent
Central Review for Disease Progression

9.7 External Data Monitoring Committee

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
Section 17 SUPPLEMENT 1: Crossover 
from BSC ALONE (ARM B) to 
Avelumab plus Best Supportive Care.
Additional changes:

For consistency with changes 
implemented by Protocol Amendment 3, 
the following sentence was removed from 
Footnote #3 of the Prior to Protocol 
Amendment 6: Schedule of Activities for 
End of Treatment/Withdrawal and 
Follow-up Periods: “During the post-
treatment safety follow-up (beyond 30 
days through 90 calendar days after last 
study administration), AEs (serious or 
non-serious) that the investigator believes 
have at least a reasonable possibility of 
being related to study drug are to be 
recorded on the case report form (CRF).” 

As per Protocol Administrative Change
Letter dated 02 Jul 2020, footnote #6 of 
the Prior to Protocol Amendment 6: 
Schedule of Activities for Screening and 
Study Treatment Periods, footnote #5 of 
the Schedule of Activities for patients 
who Crossover from Arm B to Avelumab 
Plus BSC (Supplement 1) and Section 
7.1.4 Physical Examinations and Vital 
Signs were updated to clarify that vital 
signs should be taken before study drug 
dosing.

8.14.2 Non-Serious Adverse Event 
Reporting Requirements was updated to 
include an administrative change 
implemented through a country specific 
(Japan) Protocol Administrative Change 
Letter dated 02 July 2020. 

As per country specific (Japan) Protocol 
Administrative Change Letter dated 02 
July 2020: Section 12.2 Ethical Conduct 

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of the Study was updated to clarify that 
after approval of avelumab for advanced 
urothelial carcinoma by the Japanese 
Ministry of Health, Labor and Welfare 
(MHLW), this study will be conducted 
according to Good Post-Marketing 
Surveillance Practices (GPSP) in addition 
to Good Clinical Practice (GCP).

As per the Protocol Administrative 
Change Letters dated 03 Apr 2020 and 15 
Apr 2020, and updated according to the 
current protocol appendix template for
public health emergencies: Appendix 6
Alternative Measures During Public 
Emergencies was added in response to the 
ongoing global pandemic COVID-19, and 
the increasing restrictions on travel, 
investigational site access issues and 
concerns on public health in order to 
clarify alternative solutions that will 
accommodate study procedures during 
the COVID-19 pandemic.

Per current best practice, copies of quality 
of life (QOL) questionnaires (formerly 
Appendix 5 and Appendix 6) were 
removed.

Additional minor edits were made 
throughout the document for clarity and 
consistency.
Amendment 5
13 February 2020
At the pre-specified interim analysis (Section 
9.6), this study met the primary objective and 
demonstrated that avelumab plus BSC 
significantly prolongs OS compared to BSC 
alone in both co-primary populations (ie, in 
all randomized patients and in patients with 
PD-L1-positive tumors). 
Based on this result, the External-Data 
Monitoring Committee (E-DMC) 
recommended that remaining patients on 

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Arm B who are progression-free be offered 
crossover to avelumab.  
The purpose of this protocol amendment is to 
implement the E-DMC recommendation.
1. The following sections were modified 
based on the above:

Protocol Summary (Study Design);

1.2.3.3 Rationale for Study Design;

1.3 Summary of Benefit Risk 
Assessment;

3.1 Study Overview;

5.1 Allocation to Treatment.
2. Added Section 17, Supplement 1: 
Crossover from BSC alone (Arm B) to 
Avelumab Plus Best Supportive Care.
This supplement provides details for Arm 
B patients who crossover to receive 
avelumab plus BSC including required 
eligibility criteria, general treatment/study 
plan, and schedule of activities for 
screening, treatment period, end of 
treatment/withdrawal and short and long-
term follow-up.  
Amendment 4
28 March 2019
1. Given the lack of standardization, 
immune-related Response Criteria 
(irRECIST) has been removed as an 
exploratory endpoint and required study 
assessment.  Associated elements were 
revised or removed accordingly in 
Section 3.1.2 and throughout the 
document as appropriate.  This includes:

The requirement for repeat tumor 
assessment to confirm progressive 
disease (PD) was removed.  

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(Section 7.7 and throughout the 
document as appropriate).

Treatment after PD section was 
updated as a result of removing the 
requirement to confirm PD.  
(Section 5.4.1). 
2. Management of avelumab-related toxicity 
has been updated to reflect current 
avelumab program standard 
recommendations (Section 5.4.3).  This 
includes:

Specific recommendations for 
avelumab-related toxicity provided in 
Tables 3, 4 and 5 were updated.

Text in the management of avelumab
immune-related adverse events and 
hypersensitivity reactions sections 
were removed, as the information 
provided is now covered in other 
sections. 

A 2-hour post-dose observation 
period is no longer required. 

Premedications to mitigate avelumab 
infusion-related reactions were 
revised such that premedication is 
only required for the first 4 infusions.  
(Section 5.4.3.1. and throughout the 
document as appropriate).

The avelumab infusion rate may be 
returned to the baseline rate following 
a previous reduction due to an 
infusion-related reaction (Table 4).
3. Contraception requirements have been 
updated for females and males in 
accordance with the current Pfizer and 
avelumab program standards.  

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(Section 4.3.1 and throughout the 
document as appropriate).
4. The contraception check and pregnancy 
test were removed as required study 
procedures at the 60 Day Follow-up visit, 
in accordance with the current avelumab 
program standard.  (Section 7.1.1 and 
throughout the document as appropriate).
5. It has been added that if new cancer 
therapy is started, reporting of 
concomitant medications should end at 
the time the new cancer therapy starts in 
order to match the AE reporting period, 
and in accordance with the current 
avelumab program standard.  (Section 5.9 
and throughout the document as 
appropriate).
6. The section for rational for 
immunotherapy treatments in 
maintenance of UC was updated to 
include recently published results from a 
pooled analysis of study EMR 100070-
001.  (Section 1.2.3.2).
7. Survival assessments for long-term 
follow-up (every 3 months) were clarified 
to begin after the last study clinic visit, 
and to allow additional timepoints at 
Sponsor request in preparation for interim 
and final analyses in order to update 
survival information and add uniformity 
in the time since most recent contact.  
(Footnotes in SOA table).
8. Clarifications have been made as follows:

The frequency of bone imaging 
requirements was clarified to be every 
16 weeks for the first year after 
randomization and every 24 weeks 
thereafter (ie, at every other tumor 
assessment).  (Section 7.7 and 

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throughout the document as 
appropriate).

Text was added to clarify that 
intranasal, inhaled, and topical 
steroids; local steroid injections; and 
all inactive vaccines are permitted.  
(Section 5.9.3 and throughout the 
document as appropriate).

The list of required lab tests was 
updated to clarify that glucose testing 
can be done in a fasted or non-fasted 
status.  (Section 7.1.3).

Clarification was added that the 
archival tumor tissue sample is not 
mandatory, in consistency with other 
sections of the protocol.  (SOA table 
and throughout the document as 
appropriate).

A window of ±3 days was specified 
for the radiological tumor 
assessments to provide clarity for 
scheduling purposes.  (Footnotes in 
SOA tables).

The reporting of AEs and recording 
of concomitant medications was 
clarified for Arm B to end 90 days 
after the End of Treatment (EOT) 
visit, instead of 90 days after the last 
dose of study drug.  (SOA tables and 
throughout the document as 
appropriate).
9. Additional minor edits were made 
throughout the document for clarity and 
consistency.
Amendment 3
19 December 2016
1. Removed a footnote stating “avelumab is 
the proposed International 
Nonproprietary Name (INN)…” as this 

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has been endorsed by the governing 
authorities (Cover Page, Protocol 
Summary, and Section 1.1). 
2. Following the accelerated approval of 
atezolizumab by the United States FDA, a 
sentence stating “there are no second-line 
therapies approved in the United States” 
was deleted (Protocol Summary and 
Section 1.2.3.1).
3. To mitigate the potential for bias in 
determining disease progression, an 
expedited blinded independent central 
review (BICR) for investigator-assessed 
disease progression was added 
(Section 7.8 and throughout text as 
appropriate).  
4. For patient convenience and to optimize 
trial logistics, revised text to allow 
patients to provide informed consent 
during or after first-line chemotherapy
(Protocol Summary, Schedule of 
Activities for Screening footnote 2, and 
Section 3.1).
5. To optimize trial logistics, removed the 
requirement for central eligibility review 
of first-line chemotherapy response 
(Protocol Summary; Schedule of 
Activities for Screening footnotes 16 and 
21; Section 3.1; Section 4.1 inclusion 
criterion 3.a; and Section 7.7).
6. Clarified that the ‘FACT Bladder 
Symptom Index (FBlSI)’ is the 
‘NCCN-FACT FBlSI-18’.  This change is 
indicated in Section 3.1.4 and throughout 
text where appropriate.
7. For patient/investigator convenience, 
added a note allowing that laboratory 
tests may be performed up to 3 days prior 
to the scheduled clinic visit so that results 
will be available for review (Schedule of 

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Activities for Study Treatment Period 
footnote 1 and Follow-up Period 
footnote 1).
8. Per United States FDA request, to assess 
the utility of serum troponin 
measurements in early detection of 
myocarditis, a rare and potentially fatal 
risk associated with avelumab and other 
check-point inhibitors, the following 
additions were made to both study arms:

Mandatory measurement of cardiac 
troponin levels at screening and at 
each clinic visit ending on Cycle 4 
Day 1 (ie, for a total of 12 weeks), 
and as clinically indicated (Schedule 
of Assessments for Study Treatment 
footnote 12, and Table 6).

Management guidelines for 
myocarditis (Table 5).

Further information and rationale for 
this addition in Section 1.2.2.1.
9. To adequately monitor for disease 
progression, clarified that chest, 
abdomen, and pelvic CT or MRI scans 
are required at each tumor assessment 
time point and for all patients (Schedule 
of Activities for Study Treatment Period 
footnote 16 and Follow-up Period 
footnote 13; and Sections 3.1.2 and 7.7).
10. Revised the requirement for a screening 
bone scan (or 18FDG-PET scan) to allow 
alternate modalities (eg, MRI) per local 
standard of care, as 18FDG-PET scan is 
not a permissible alternate for bone 
imaging at some centers and MRI in 
some countries is the preferred method 
for bone imaging instead of bone scans 
(Schedule of Activities for Study 
Treatment Period footnote 16 and 

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Follow-up Period footnote 13; and 
Sections 3.1.2 and 7.7).   
11. As asymptomatic brain metastases are 
infrequent in the study population, the 
requirement for a screening brain scan 
was changed to apply only to patients 
with a history of brain metastases or for 
whom brain metastases are suspected 
(Schedule of Activities for Study 
Treatment Period footnote 16 and 
Follow-up Period footnote 13; and 
Sections 3.1.2 and 7.7). 
12. Per the current standard for the avelumab 
program, extended the adverse event 
(AE) collection period for all AEs 
regardless of causality to 90 calendar 
days (rather than 30 days) after the last 
administration of study drug (Schedule of 
Activities for Study Treatment Period 
footnote 17 and Follow-up Period 
footnote 14; and Section 8.2).
13. Clarified and modified requirements 
relating to the collection of tumor tissue 
biospecimens (Schedule of Activities for 
Study Treatment Period footnotes 24 and 
25; Schedule of Activities for Follow-up 
Period footnote 19; inclusion criterion 4; 
and Section 6.1.1).

Permitted the submission of freshly 
cut slides in place of tissue blocks for 
the recent tumor tissue sample and the 
End of Treatment biopsy, as some 
investigative centers are not able to 
submit tissue blocks due to local 
policy or regulations.

To facilitate patient enrollment, 
allowed that the recent tumor tissue 
sample may have been obtained 

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within 24 months prior to 
randomization (instead of 1 year).

Added that tumor tissue samples 
obtained from bone metastases are not 
acceptable, as the processing required 
for these samples (decalcification) is 
not compatible with planned analyses.

Clarified the time point for the 
archival tumor tissue sample collected 
at the time of the primary diagnosis or
first tumor resection (if different from 
the most recent tumor tissue sample), 
and removed the availability of this 
sample as an eligibility requirement to 
facilitate patient enrollment.
14. Removed ECOG performance status as a 
survival follow-up procedure as this data 
is not required for survival analyses and 
is difficult to reliably collect during 
long-term follow-up (Schedule of 
Activities for Follow-up Period footnote 
3). 
15. Clarified and modified eligibility criteria 
(Section 4.1 and Section 4.2) to ensure 
protocol compliance and facilitate patient 
enrollment:

Clarified eligible tumor stage listed in 
inclusion criterion 1b and added 
reference to TNM tumor classification 
(Section 16).

Clarified that first-line chemotherapy 
must have been completed no less 
than 4 weeks and no more than 
10 weeks prior to randomization 
(inclusion criterion 2a).

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
Revised inclusion criterion 4 relating 
to tumor sample requirements (as 
described above).

Revised inclusion criterion 11 to 
allow alternate methods for 
estimating creatinine clearance.

Added a higher eligibility limit for 
AST and ALT elevations in patients 
with liver metastases consistent with 
updated inclusion criteria across 
avelumab program.

Clarified exclusion criterion 2 as 
being applicable to systemic 
treatments.

Added exceptions for persisting 
toxicity related to prior therapy to 
exclusion criterion 6.

Added exception for patients with 
resected prostate cancer to exclusion 
criterion 7.

Revised exclusion criterion 10 
relating to prior cardiovascular 
disease to facilitate patient enrollment 
and to match the current standard 
template for avelumab protocols.

Revised exclusion criterion 17 
relating to hepatitis B or C for clarity 
and to match the current standard 
template for avelumab protocols.
16. Removed a 120 minute maximum limit 
on the total duration of avelumab 
infusions as this limit is unnecessary 
(Protocol Summary, Section 3.1.1, 
Section 5.4.3.2, and Table 4).

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17. Removed requirement for testing urine 
albumin levels (Table 6) as this is not 
standardly available (eg, in routinely used 
urine test strips) and is not required as a 
safety assessment.
18. Removed measurement of avelumab 
metabolite(s) as this is not a planned 
pharmacokinetic analysis (Section 7.3).
19. Modified analysis of disease control 
(Section 9.3.2) as follows:

Added non-CR/non-PD as a response 
category since patients without 
measurable disease per RECIST v1.1 
are eligible for study participation.   

Noted that CR and PR must be 
confirmed by a repeat assessment, and 
that the criterion for SD must have 
been met at least 6 weeks after the 
date of randomization. 

Removed an analysis of the disease 
control rate at 24 weeks as this is best 
assessed based on Kaplan-Meier 
methodology for estimation of 
progression-free survival rates.
20. In Appendix 3, revised “index” lesions to 
be “target” lesions for consistency.
21. In Appendix 8, added abbreviations for 
EuroQol 5 dimension 5 level 
questionnaire (EQ-5D-5L) and cardiac 
troponin, and corrected the abbreviation 
for single reference safety document 
(SRSD). 
22. Minor edits for clarity were made where 
appropriate throughout text.
Amendment 2
24 March 2016
Per Voluntary Harmonisation Procedure 
Clinical Trial Application assessment:

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1. Added an HIV screening test unless not 
permitted by local laws and regulations 
(Schedule of Activities table and footnote 
#12; and Table 6, Section 7.1.3) and 
exclusion of HIV positive patients 
(exclusion criterion #16, Section 4.2). 
2. Clarified that exclusion criterion #21 
(Section 4.2) includes but is not limited to 
those medical conditions listed, and add 
‘pulmonary fibrosis’ as a listed condition.
3. Clarified in Section 7.1.3 that the 
requirement to repeat abnormal 
laboratory test results applies only for 
clinically significant abnormal results.
4. Clarified in Section 9.6 the stopping rules 
for efficacy and futility.  
Amendment 1
17 December 2015
1. Per FDA request, implemented 
clarifications in Section 5.4.3.5, Table 5 
Management of Avelumab Immune-
Related Adverse Events (irAEs):

Clarified requirement for delaying or 
discontinuing avelumab for Grade 3 
or 4 dermatological irAEs.

Clarified requirement to delay or 
discontinue avelumab therapy for 
suspicion of adrenal crisis. 
2. Per FDA request, added a requirement in 
Section 5.4.3.5, Table 5, to permanently 
discontinue avelumab therapy for patients 
with AST/ALT >3 x ULN with 
concurrent elevation of total bilirubin >2 
x ULN without another obvious cause.
3. Revised Table 3 (Section 5.4.3) to 
remove redundant items.
4. Section 4.1, inclusion criterion #11 was 
revised to allow enrollment of patients 
with a creatinine clearance (CrCl) 

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≥30 mL/min (changed from ≥50 
mL/min).

Patients with a CrCl of <60 mL/min 
are considered to be candidates for 
first-line gemcitabine+carboplatin 
chemotherapy.  A proportion of these 
patients would be commonly 
excluded by a ≥50 mL/min CrCl 
requirement.  Also, patients who 
initially have a value of >50 could 
drop to below 50 after completion of 
platinum based first-line treatment.  
This lower (but still ≥30 mL/min) 
permissible inclusion value is 
anticipated to be safe based on the 
low incidence of renal toxicity 
observed in the avelumab studies to-
date.
5. Correction of minor errors and internal 
inconsistencies.
6. Figure 1 (study schema) was corrected to 
remove reference to Blinded Independent 
Central Review (BICR).  

Patient withdrawal due to disease 
progression will be based on the 
investigator’s tumor response 
assessment, rather than BICR.
7. Section 9.3.2 was corrected to reflect that 
worsening of symptoms in the 
FBlSI-DRS-P subscale is measured as a 
decreased score (not an increase).  In 
addition, the formal comparison of the 
Time to Deterioration endpoint between 
the two treatment arms for each of the 
co-primary populations was deleted so as 
not to inflate the overall type I error in the 
study. 
8. Section 9.6 Interim Analysis was 
corrected to reflect that the timing of the 

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analysis will be based on deaths event 
and not disease progression events.
Original protocol
29 October 2015
Not Applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.  

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PROTOCOL SUMMARY
Background and Rationale:
Urothelial cancer (UC) includes tumors originating from the urothelial cells lining the 
bladder, renal pelvis, ureter, and urethra.1  Bladder cancer alone accounts for 90% of UC,1
and is the ninth most prevalent cancer worldwide, with approximately 400,000 new cases 
diagnosed and 150,000 deaths attributed to this disease each year.2  UC occurs more 
frequently in developed countries; in Europe it is the eighth most common cause of mortality 
due to cancer, and in the United States, it also occurs at a very high annual incidence rate 
(20.5 per 100,000 persons).3,4  The incidence and mortality of bladder cancer have remained 
unchanged over the last 25 years.2
Combination chemotherapy with platinum-based regimens is the standard of care for locally 
advanced or metastatic bladder cancer.  Despite the favorable response and survival rates 
associated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin 
(MVAC),10,11,12 toxicities associated with this regimen can be significant and lead to death in 
3-4% of patients.12,13  Subsequently, the combinations of gemcitabine + cisplatin and 
gemcitabine + carboplatin were shown to have comparable efficacy and an improved safety 
compared to MVAC,14,15,16 with the latter combination used in the 30-50% of patients 
ineligible for cisplatin-based chemotherapy due to renal impairment.17  As such, these two 
regimens are now the preferred regimens for the initial treatment of patients with locally 
advanced or metastatic UC.
Durable and complete responses following first-line chemotherapy in patients with advanced 
UC are uncommon.  Complicated treatment regimens and severe side effects limit long-term 
use of these agents and most patients will ultimately experience disease progression within 
9 months after initial response.14  Optimal treatment in the second-line treatment setting still 
needs to be determined.27  Single and combination agents evaluated in this treatment setting 
have been associated with low median progression-free survival (PFS, 1.5-3.0 months) and 
overall survival (OS, 4.6.-6.9 months), and are also associated with significant 
toxicities.28,29,30
In 2009, vinflunine was approved in Europe for the second-line treatment of UC after failure 
of first-line platinum-based therapy.28,31
The current “watch-and-wait” approach for the management of metastatic UC following 
response to first-line chemotherapy prior to initiation of second-line treatment has not proven 
to be effective because almost all patients eventually relapse.  A multicenter Phase 2 study of 
sunitinib as maintenance therapy in patients with advanced UC was recently reported.32  
Although the study terminated prematurely due to low patient recruitment, it provided a 
different perspective on the treatment of this disease (ie, maintenance therapy following 
response to first-line chemotherapy in an attempt to improve the durability of the initial 
response).  Recently, Powles et al reported the results of a Phase 2/3 study of lapatinib as 
maintenance treatment after first-line chemotherapy in patients with HER1/HER2-positive 
UC.33  The median PFS, median OS, and objective response rate (ORR) for patients 
receiving lapatinib (n = 116) vs. placebo (n = 116) were 4.6 months (95% confidence interval 

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[CI]: 2.8 – 5.4) vs. 5.3 months (95% CI: 3.0 – 5.9) (hazard ratio [HR] 1.04 [95% CI: 0.79 –
1.39] p = 0.77), and 12.6 months (95% CI: 9.5 - 16.2) vs. 11.9 months (95% CI: 10.6 – 15.8) 
(HR 0.98 [95% CI: 0.71 – 1.35] p = 0.89); and 13.8% vs. 7.8%, respectively (p = 0.14).  In 
addition, a study evaluating vinflunine34,35 as a maintenance UC treatment is currently 
ongoing.
There is a strong rationale for considering immunotherapy in patients with advanced UC.  
Urologists led the way in the use of immunotherapy in cancer in 1976, having introduced the 
tuberculosis vaccine bacille Calmette-Guérin (BCG), which stimulates a robust immune 
response in most patients and has become the standard of care as locoregional therapy after 
surgical resection of non-muscle-invasive disease.36,37  Multiple immunotherapies including 
interferon (IFN)-α, interleukin (IL)-2, IL-12, and IL-10 have been investigated, either as 
adjuncts with BCG or as a solo replacement therapy.38,39  Over the past 40 years, progress 
evaluating immunotherapy for bladder cancer has been slow.  Subsequently, the programmed 
cell death-1 (PD-1) / programmed death ligand 1 (PD-L1) pathway has emerged as an 
important biological pathway in UC.40,41,42  PD-1, an immunoinhibitory receptor of the CD28 
family, plays an important role in tumor immune escape.43,44  The PD-1/PD-L1 interaction 
inhibits T-lymphocyte activation, proliferation, survival and effector functions during 
anti-cancer immune response.  Several tumors, including UC, present with high rates of 
somatic mutations,45,46,47 possibly enhancing the host immune system’s ability to recognize 
tumor cells as foreign owing to an increased number of antigens and stimulate T-cell 
response.48  However, these cancers may also elude immune surveillance and eradication 
through the expression of PD-L1 in the tumor microenvironment,49 which then becomes an 
important target for anti-PD-L1 antibodies.  Indeed, antibodies blocking PD-1 and PD-L1 
have demonstrated significant and durable response in patients with advanced UC.  In a 
Phase 1b study of anti-PD-1 mAb pembrolizumab in heavily pre-treated patients with 
advanced UC,40 the ORR was 24% (10% complete response [CR] rate) among 33 treated 
patients with median follow-up duration of 11 months (range 10-13).  The responses 
observed were durable, ranging from 16 to 40+ weeks (median not reached), with several 
responses ongoing at the time of analysis.
Similarly, an anti-PD-L1 mAb, MPDL-3280A, recently demonstrated significant durable 
response in heavily pre-treated patients with UC.41,42  Preliminary data presented at the 
American Society of Clinical Oncology (ASCO) 2014 Annual Meeting from a Phase 1 study 
of MPDL3280A as second-line treatment of patients with UC demonstrated noteworthy 
activity in 20 evaluable patients with an ORR of 50%, including 1 CR and 9 partial responses 
(PRs).41  Durable responses were also demonstrated with this agent in heavily pre-treated 
patients with advanced stage UC,41,42 with an ORR of 54% in 68 patients with 
PD-L1-positive tumors, with durable ongoing responses up to 30.3 weeks reported.41  
Updated data from these studies with MPDL-3280A and pembrolizumab in patients with 
recurrent or metastatic PD-L1-positive UC further indicated durable responses with 
promising PFS and OS in patients with PD-L1-positive tumors, local immune/inflammatory 
cells, or stroma.  Among 85 patients (46 PD-L1 immunohistochemistry [IHC] 2/3 and 
38 IHC 0/1) with UC who received MPDL-3280A, the ORR for PD-L1 IHC 2+/3+ UC 
patients was 46% (95% CI: 31-61%; 6 CRs, 15 PRs) and IHC 0/1+ UC patients was 
16% (95% CI 6-31%; 6 PRs); median response durations not reached (IHC 2/3 0+ to 54+ 

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weeks; IHC 0/1 4+ to 33+ weeks).  Median PFS for IHC 2+/3+ UC patients was 24 weeks 
(95% CI 12-NE) and for IHC 0/1+ UC patients was 8 weeks (95% CI 6-12).50  Among 
33 patients enrolled with 1% PD-L1-positive cells in tumor nests or a PD-L1-positive band 
in stroma by IHC to receive pembrolizumab, 28 had measurable disease at baseline.  In these 
evaluable patients, the ORR was 25% (95% CI: 11-45), with 3 (11%) CR and 4 (14%) PR, 
with durations ranging from 16 to 50+ weeks (median not reached at time of analysis).51  
Avelumab (MSB0010718C), a potent and highly selective fully human mAb of the 
immunoglobulin (Ig) G1 isotype, targets and binds PD-L1, the ligand for PD-1 and B7.1, 
thereby blocking the interaction between PD-L1 and PD-1 and B7.1, removing the 
suppressive effects of PD-L1 on anti-tumor CD8+ T cells and resulting in restoration of the 
cytotoxic T-cell response.19
In the Phase 1 study EMR 100070-001, 53 patients have been treated with avelumab doses of 
1.0, 3.0, 10.0, and 20.0 mg/kg administered intravenous (IV) Q2W in the dose escalation 
phase.  The 10 mg/kg dose level was selected for further study and a summary of pooled 
safety data from 1738 patients treated at this dose level in studies EMR 100070-001 and 
EMR 100070-003 (N=1738) is available with a data cutoff date of 09 June 2016.19  The most 
frequently reported (incidence >5%) treatment-related adverse events were fatigue (17.7%), 
infusion-related reaction (17.0%), nausea (8.6%), diarrhea (7.1%), chills (6.7%), pyrexia 
(6.1%), decreased appetite (5.2%), and hypothyroidism (5.0%). 
Updated data from a pooled analysis of 249 patients enrolled in two advanced UC expansion 
cohorts in study EMR 100070-001 was recently published.75  Patients were included 
regardless of PD-L1 expression levels. The median age was 68 years and 124 (50%) patients 
received 2 or more prior treatments for advanced or metastatic disease.  At the time of the 
analysis (09 June 2016 data cut-off), the median follow-up was 9.9 months (range 
4.3-12.1 months) and 60 (24%) patients were still on treatment.  Among 161 post-platinum 
treated patients with at least 6 months of follow-up, the ORR was 17% (95% CI: 11-24%), 
including 9 CRs and 18 PRs.  The disease control rate (DCR) was 40%, including 37 patients 
who had SD as their best response.  An analysis using a cut-off of 5% for the expression of 
PD-L1 on tumor cells in 139 evaluable patients showed a 24% (15/63) ORR in the PD-L1 
positive population and 13% (10/76) in the PD-L1 negative population, supporting that 
avelumab has anti-tumor activity in both the PD-L1 positive and negative populations.  The 
median PFS was 11.9 weeks (95% CI: 6.1-18.0 weeks) and 6.1 weeks (95% CI: 5.9-8.0 
weeks) in the PD-L1 positive and negative populations, respectively.  The median OS was 
8.2 months (95% CI: 5.7-13.7 months) and 6.2 months (95% CI: 4.3-14.0 months) in patients 
with PD-L1 positive and negative tumors, respectively.
These data support further evaluation of avelumab for the treatment of patients with 
advanced stage UC.  Given the poor prognosis for patients with advanced UC whose disease 
progresses after first-line chemotherapy, where patient outcomes are ultimately very 
poor,30,53,75 a maintenance treatment with avelumab after first-line platinum-based 
chemotherapy may provide additional clinical benefit compared to the current 
watch-and-wait standard of care after chemotherapy.  The safety and efficacy of avelumab 
plus best supportive care (BSC, Arm A) and BSC alone (Arm B) will be evaluated in two 

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coprimary populations: 1) patients with PD-L1-positive tumors (including infiltrating 
immune cells) confirmed by a verified Good Manufacturing Practice (GMP) PD-L1 IHC test, 
and 2) all randomized patients to assess the effects of avelumab in this therapeutic setting.  
Study Objectives:
Primary Objective
To demonstrate the benefit of maintenance treatment with avelumab plus BSC vs. BSC alone 
in prolonging overall survival (OS) in patients with unresectable locally advanced or 
metastatic UC whose disease did not progress on or following completion of first-line 
platinum-containing chemotherapy in each co-primary UC patient population: 1) patients 
determined to have PD-L1-positive tumors (including infiltrating immune cells) by a verified 
GMP PD-L1 IHC test, and 2) all randomized patients. 
Secondary Objectives

To compare the PFS of avelumab plus BSC vs. BSC alone in patients determined to 
have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP 
PD-L1 IHC test, and in all randomized patients.

To evaluate the anti-tumor activity of avelumab plus BSC and BSC alone according 
to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients 
determined to have PD-L1-positive tumors (including infiltrating immune cells) by a 
verified GMP PD-L1 IHC test, and in all randomized patients.

To evaluate the overall safety profile of avelumab plus BSC and BSC alone.

To evaluate the pharmacokinetics (PK) of avelumab in each of the co-primary 
populations treated with avelumab. 

To assess the immunogenicity of avelumab in each of the co-primary populations 
treated with avelumab.

To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab
in pre-treatment tumor tissue in each of the co-primary populations treated with 
avelumab.

To evaluate the effect of avelumab plus BSC and BSC alone on patient-reported 
outcomes (PROs) in each of the co-primary populations.
Exploratory Objectives

To explore the predictive and/or pharmacodynamic (PD) characteristics of peripheral 
blood and additional tumor tissue biomarkers relevant to the mechanism of action of 
or resistance to avelumab.

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Study Endpoints:
Primary Endpoint

Overall Survival (OS).
Secondary Endpoints

Progression-free survival (PFS) based on Blinded Independent Central Review 
(BICR) assessment per RECIST v1.1.

Investigator-assessed Progression-Free Survival (PFS).  Objective Response (OR), 
Time to Tumor Response (TTR), Duration of Response (DR), and Disease Control 
(DC), as assessed per RECIST v1.1 by BICR and investigator.

Safety: Adverse events (AEs) and laboratory abnormalities as graded by National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v.4.03; vital signs (blood pressure, pulse rate). 

Pharmacokinetics (PK): maximum concentrations (Cmax) and trough concentrations 
(Ctrough) for avelumab.

Immunogenicity: Anti-drug antibodies (ADA; neutralizing antibody [Nab]) against 
avelumab.

Biomarkers: Tumor tissue biomarkers including, but not limited to, PD-L1 expression 
and tumor-infiltrating CD8+ T lymphocytes.

Patient-Reported Outcomes: patient-reported bladder cancer symptom, functioning, 
global quality of life (QOL), and Time to Deterioration (TTD) using the 
NCCN-FACT FBlSI-18; and health status using the EQ-5D-5L.
Exploratory Endpoints

Biomarkers: Peripheral blood and additional tumor tissue biomarkers consisting of 
the levels of cells, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or proteins 
that may be related to anti-tumor immune response and/or response to or disease 
progression on avelumab, such as genes related to IFN-or transforming growth 
factor (TGF)-.
Study Design:
This is a Phase 3, multicenter, multinational, randomized, open-label, parallel-arm efficacy 
and safety study of avelumab plus BSC compared to BSC alone as a maintenance treatment 
after completion of first-line platinum-based chemotherapy (gemcitabine + cisplatin or 
gemcitabine + carboplatin) without evidence of disease progression in adult patients with 
unresectable locally advanced or metastatic UC.

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The study design is illustrated in the following figure. 
Patients may sign informed consent at any time during or after completion of chemotherapy 
and prior to any study specific procedures, however must meet all eligibility requirements to 
be randomized in the study. 

A total of approximately 668 patients without progressive disease as per RECIST 
v1.1 guidelines (ie, with ongoing CR, PR, or SD) after 1st line chemotherapy will be 
allowed to be randomized in this study.  It is estimated that at least 334 patients with 
confirmed PD-L1-positive tumors (including infiltrating immune cells) will be 
randomized in this study.  

Patients will be randomized in a 1:1 ratio into two study arms: avelumab plus BSC 
(Arm A) or BSC alone (Arm B).  

Patients must have received at least 4 cycles, but not more than 6 cycles of a first-line 
chemotherapy regimen consisting of either gemcitabine + cisplatin or gemcitabine + 
carboplatin before randomization into this study.  No other chemotherapy regimen is 
allowed as the first line chemotherapy for inclusion in this clinical trial (please see 
Section 4.1, Inclusion Criterion #2). 

Randomization must occur at least 4 but not more than 10 weeks after the date of 
administration of the last dose of chemotherapy.  Patients will initiate study treatment 
(Cycle 1 Day 1) within 3 days after randomization.

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
Only patients without progressive disease as per RECIST v1.1 guidelines (ie, with 
ongoing CR, PR, or SD) after 4-6 cycles of chemotherapy will be allowed to be 
randomized in this study.  

Post-chemotherapy confirmatory scan(s) (computed tomography (CT)/magnetic 
resonance imaging (MRI)) for eligibility must be performed within 28 days prior 
to the date of randomization to assess response status following first-line 
chemotherapy.  

Based on the post-chemotherapy confirmatory scan(s), the investigator should 
assess patient eligibility (ie, CR, PR, or SD) before randomization.

This study is designed with two co-primary populations: 1) patients determined to 
have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP 
PD-L1 IHC test, and 2) all randomized patients. 

Randomization will be stratified by (i) best response to first-line chemotherapy 
(CR/PR vs. SD), and (ii) metastatic disease site (visceral vs. non-visceral) at the time 
of initiating first-line chemotherapy.  

Radiological tumor assessments will be conducted during the study at baseline as the 
post-chemotherapy confirmatory scan (as described above, within 28 days prior to 
randomization), at 8 weeks after randomization, then every 8 (±3 days) weeks for up 
to 1 year from randomization, and every 12 (±3 days) weeks thereafter until 
documented disease progression as assessed by BICR regardless of initiation of 
subsequent anti-cancer therapy.  Additional radiological tumor assessments should 
also be conducted whenever disease progression is suspected (eg, symptomatic 
deterioration).  Please see Section 3.1.2, Tumor Assessments for additional 
information.

All patients will be followed for survival until death, end of the study, or patient 
withdrawal of consent, whichever comes first, regardless of initiation of new 
anti-cancer therapy(ies).  Long-term follow-up survival assessments (every 3 months) 
may be completed at the investigative site or by telephone contact.

Upon approval of protocol Amendment 5, patients assigned to Arm B (BSC alone) 
who are progression-free and have not yet completed the End of Treatment (EOT) 
visit will be offered treatment with avelumab plus BSC maintenance therapy.  For 
additional information, including Schedule of Activities for those patients who 
crossover to avelumab, please refer to Supplement 1.  

Arm B patients who do not crossover to avelumab plus BSC will continue 
assessments as per protocol.

As per Protocol Amendment 6, following the final OS update, the frequency of study 
procedures will be reduced while providing continued treatment for patients actively 

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receiving avelumab and ending study participation for all patients who are not 
actively receiving avelumab (ie, Arm A patients in long-term follow-up and all Arm 
B patients who have not crossed over to receive avelumab).
Study Treatment:

For the purpose of this study, “study treatment” refers to both the investigational 
product (avelumab) plus BSC and BSC alone administered to patients during 
participation in this study.  

Study treatments may continue until confirmed disease progression as assessed by 
BICR, patient refusal, patient lost to follow up, unacceptable toxicity, or the study is 
terminated by the sponsor, whichever comes first (see Section 6.5 Patient 
Withdrawal).  

According to the opinion of an investigator, if a patient in Arm A is still experiencing 
clinical benefit at the time of confirmed disease progression, the patient will be 
eligible for continued treatment with avelumab plus BSC, provided the treating 
physician has determined that the benefit/risk for doing so is favorable (see 
Section 5.4.1 Treatment after Initial Evidence of Radiologic Disease Progression).  
Radiological tumor assessments will be continued in these patients as described in the 
Section 3.1.2, Tumor Assessments. 

If a patient starts a new anti-cancer therapy before documented disease progression, 
then tumor assessments should be continued per the Schedule of Activities (unless not 
feasible) until documentation of disease progression or death, whichever occurs first.

After review of radiologic images by BICR is stopped as per Protocol Amendment 6,   
following the final OS update, study treatment may continue until disease progression 
is assessed by the investigator, patient refusal, patient lost to follow-up, unacceptable 
toxicity, or the study is terminated by the sponsor, whichever comes first (see 
Section 6.5 Patient Withdrawal).    
Arm A: Avelumab (MSB0010718C) Plus Best Supportive Care
Patients randomized to avelumab plus BSC (Arm A) will be administered avelumab 
as a 1-hour intravenous (IV) infusion at a dose of 10 mg/kg once every 2 weeks 
(Q2W) together with BSC (see below).
To mitigate potential infusion-related reactions, patients in Arm A will be 
premedicated prior to avelumab administration as described in Section 5.4.3.1.  If an 
infusion-related reaction is observed, the infusion rate should be decreased or stopped 
depending on the severity of the event; please refer to Section 5.4.3.2 for further 
guidance.

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Arm B: Best Supportive Care Alone
Patients randomized to BSC alone (Arm B) will be cared for as deemed appropriate 
by the treating physician.  This could include treatment with antibiotics, nutritional 
support, correction of metabolic disorders, optimal symptom control and pain 
management (including palliative radiotherapy), etc.  BSC does not include any 
active anti-tumor therapy (see Section 5.8), however local radiotherapy of isolated 
lesions with palliative intent is acceptable as described in Section 5.9.2.
Statistical Methods:
The primary objective of this study is to demonstrate the benefit of maintenance treatment 
with avelumab plus BSC vs. BSC alone in prolonging OS in patients with unresectable 
locally advanced or metastatic UC whose disease did not progress on or following 
completion of first-line platinum-containing chemotherapy in each co-primary UC patient 
populations: 1) patients determined to have PD-L1-positive tumors (including infiltrating 
immune cells) by a verified GMP PD-L1 IHC test, and 2) all randomized patients. 
The study will randomize a total of approximately 668 patients, with at least 334 patients 
with confirmed PD-L1-positive tumors, using 1:1 randomization, stratified by best response 
to chemotherapy (CR/PR vs. SD) and site of metastasis (visceral vs. non-visceral) at time of 
initiating first-line chemotherapy. 
The sample size for this study is determined based on the following assumptions: 

For all patients and patients with PD-L1-positive tumors receiving BSC alone after 
first-line chemotherapy, the median OS is 12 months.33

For all patients receiving avelumab plus BSC after first-line chemotherapy, the 
median OS is assumed to be 17.1 months.

For patients with PD-L1-positive tumors receiving avelumab plus BSC after first-line 
chemotherapy, the median OS is assumed to be 18.5 months.
This corresponds to a hazard ratio (HR) of 0.7 for all patients and 0.65 for patients with 
PD-L1-positive tumors under the exponential model assumption. 
For all patients, if the true HR is 0.7 under the alternative hypothesis, a total of 425 OS 
events will be required to have 93% power to detect a HR of 0.7 using a one-sided log rank 
test at a significance level of 0.015 and a 2-look group-sequential design with Lan-DeMets 
(O’Brien-Fleming)71 -spending function to determine the efficacy boundary and a Gamma 
Family (-8) -spending function to determine the non-binding futility boundary. 
For patients with PD-L1 positive tumors, if the true HR is 0.65 under the alternative 
hypothesis, then a total of 219 OS events will be required to have 80% power to detect a HR 
of 0.65 using a one-sided log rank test at a significance level of 0.01 and a 2-look group 
sequential design with Lan-DeMets (O’Brien-Fleming)71 -spending function to determine 

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the efficacy boundary and a Gamma Family (-8) -spending function to determine the 
non-binding futility boundary.
The sample size further assumes a 5% drop-out rate for OS on either treatment arm, a 
non-uniform patient accrual accomplished over a 28-month period, and follow-up for about 
11 months after the last patient is randomized.  The data cutoff for the primary OS analysis 
will occur after the target number of events has been reached in both co-primary populations 
and the last patient randomized in the study has been followed for at least 12 months after 
randomization.
The study will be considered positive if the stratified log-rank test for OS is significant at the 
respective levels specified above at the time of the final analysis for either of the two 
co-primary populations. 
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. 
If deemed clinically necessary, the investigator may schedule visits in addition to those listed 
in the Schedule of Activities table (unplanned visits) at any time to conduct evaluations or 
assessments required to protect the well-being of the patient.

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PRIOR TO PROTOCOL AMENDMENT 6: SCHEDULE OF ACTIVITIES FOR SCREENING AND STUDY TREATMENT 
PERIODS
Visit Identifiers1
Screening
Study Treatment
(1 cycle = 4 weeks)
Arm A
Arm B
Within 28 Days 
Prior to 
Randomization
Cycle 1 Day 1
Cycle 2 Day 1 (3 days)
Day 15 (3 days)
All Cycles
Cycle 1 Day 1
Cycle 2 Day 1 (3 days)
Day 15 (3 days)
All Cycles
Clinical Assessments
Informed Consent2
X
Medical/Oncological History3
X
Baseline Signs/Symptoms4
X (Cycle 1 only)
X (Cycle 1 only)
Physical Examination5
X
X
X
ECOG Performance Status
X
X
X
Vital Signs and Weight6
X
X
X
X
Contraception Check7
X
X
X
Laboratory Studies
Coagulation8
X
X
X
X
Hematology8
X
X
X
X
Blood Chemistry (full and core)8,9
X
X8,9
X8,9
X8,9
Thyroid Function and ACTH Tests10
X
X (at Cycles 3, 5, 7, etc.)
X (at Cycles 3, 5, 7, etc.)
Serum/Urine Pregnancy Test11
X
X 
X
Troponin12
X
X (Cycles 1-4 and as 
clinically indicated)
X (Cycles 1-3 
and as clinically 
indicated)
X (Cycles 1-4 and as 
clinically indicated)
HBV, HCV Tests
X
If clinically indicated
If clinically indicated
HIV test13
X
Urinalysis14
X
If clinically indicated
If clinically indicated
12-Lead ECG15
X
If clinically indicated
If clinically indicated
Disease Assessments
Tumor Assessments (including 
scans)16
X
X (Q8W for the 1st yr after randomization and 
Q12W thereafter)
X (Q8W for the 1st yr after randomization and 
Q12W thereafter)
Other Clinical Assessments
Adverse Events17
X
X
X
X18
Concomitant 
Medications/Treatments19
X
X
X
X
X18

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Visit Identifiers1
Screening
Study Treatment
(1 cycle = 4 weeks)
Arm A
Arm B
Within 28 Days 
Prior to 
Randomization
Cycle 1 Day 1
Cycle 2 Day 1 (3 days)
Day 15 (3 days)
All Cycles
Cycle 1 Day 1
Cycle 2 Day 1 (3 days)
Day 15 (3 days)
All Cycles
Patient Reported Outcomes 
(NCCN-FACT FBlSI-18, EQ-5D-
5L)20
X
X
Randomization & Study Treatment
Randomization21
X
Avelumab (Arm A only)22
X
X
Best Supportive Care (BSC)23
X (Throughout study treatment)
X (Throughout study treatment)
Other Samplings
Archival FFPE Tumor Tissue24
X
Mandatory Recent FFPE Tumor 
Tissue Block or de novo biopsy25
X
Banked Blood Biospecimen for 
Genotyping26
X (Cycle 1 only)
X (Cycle 1 only)
Banked Blood Biospecimens for 
Exploratory Assessments27
X (Cycle 1, 2, 3 & 5)
X (Cycle 1 only)
X (Cycle 1, 2, 3 & 5)
Pharmacokinetics28
X
(Cycles 1-3, 5, 7, 9, 11 & 13)
X 
(Cycles 1-3)
Anti-Avelumab Antibodies and 
Neutralizing Antibodies29
X
(Cycles 1-3, 5, 7, 9, 11 & 13)
X
(Cycles 1-3)
ACTH = adrenocorticotropic hormone; BSC = best supportive care; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
FFPE = formalin-fixed and paraffin-embedded; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
PK = pharmacokinetics; Q12W = every 12 weeks
Footnotes for PRIOR TO PROTOCOL AMENDMENT 6: SCHEDULE OF ACTIVITIES FOR SCREENING AND STUDY TREATMENT 
PERIODS
1.
Visit Identifiers: All assessments should be performed prior to dosing with study treatments unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headers.  Note: laboratory tests may be performed up to 3 days prior to the scheduled clinic visit 
so that results will be available for review.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure.  May be obtained at any time during or after completion of first-
line chemotherapy (ie, prior to 28-day screening period).

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3.
Medical/Oncological History: To include information on prior adjuvant or neoadjuvant treatments, surgery, and radiation therapy.  Information for the 
first-line chemotherapy regimen for advanced/metastatic disease will include planned doses, actual doses, and dates of administration.  All sites of 
disease prior to first-line chemotherapy must also be documented.
4.
Baseline Signs/Symptoms: To be recorded on Cycle 1 Day 1.  Patients will be asked about any signs and symptoms experienced within the 14 days prior 
to randomization.
5.
Physical Examination: Includes an examination of major body systems (height included at screening only).  
6.
Vital Signs and Weight: Vital signs to include blood pressure and pulse rate, which should be taken prior to study drug dosing (if applicable) and with 
the patient in the seated position after the patient has been sitting quietly for at least 5 minutes.  
Weight should be measured at each visit as indicated.  For Arm A patients, weight should be measured within 3 days prior to each dose of avelumab (for 
determination of the avelumab dose [mg]).
7.
Contraception Check: Female patients who are of childbearing potential will need to affirm that they meet the criteria for correct use of the selected 
methods of contraception.  The investigator or his or her designee will discuss with the patient the need to use the selected contraception methods 
consistently and correctly and document such conversations in the patient’s chart.  In addition, the investigator or his or her designee will instruct the 
patient to call immediately if the selected contraception methods are discontinued, or if pregnancy is known or suspected in the patient or the male 
patient’s partner.  After randomization, contraception checks will be performed only for Arm A patients.  See Section 4.3.1.
8.
Coagulation, Hematology, and Blood Chemistry (full panel): Required tests are listed in Table 6.  Full chemistry panel is required at Screening, 
Cycle 1 Day 1, Cycle 1 Day 15 (Arm A patients), Cycle 2 Day 1, Cycle 3 Day 1, and Day 1 of every 2 cycles (8 weeks) thereafter.  May also be 
performed when clinically indicated.  If full and core chemistry panels are scheduled at the same visit, only the full chemistry will be performed.  
9.
Blood Chemistry (core panel): Core chemistry panel (required tests are listed in Table 6) is required at each clinic visit at which a full chemistry panel 
is not required. 
10. Thyroid Function and ACTH Tests: Free T4, TSH, and ACTH tests will be performed at screening, Cycle 3 Day 1, and Day 1 of every 2 cycles 
(8 weeks) thereafter.  Additional tests should be performed when clinically indicated.  See Table 6.
11. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed on two occasions prior to starting study treatment: once at the start of screening and once at the Cycle 1 Day 1 visit for Arm A patients 
immediately before study treatment administration.  Additional pregnancy tests (serum or urine) will also be routinely repeated for Arm A patients prior 
to each avelumab dose during the active treatment period, at the End of Treatment/Withdrawal visit, and additionally whenever one menstrual cycle is 
missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by Institutional Review 
Board (IRB)/Ethics Committees (ECs) or if required by local regulations.  Results of the pregnancy test should be available prior to each dosing.  After 
randomization, pregnancy tests will be performed only for Arm A patients.  See Section 7.1.1.
12. Cardiac Troponin (cTn): Measurement of cTnT is preferred; however, cTnI may be substituted where cTnT is not available at the local laboratory.  The 
same subunit (cTnT or cTnI) measured during screening should be measured consistently throughout the study for any given patient.  During screening, 
clinically significant positive results should be further assessed as per local standard of care to rule out concurrent cardiac conditions which could make the 
patient ineligible for the study per the exclusion criteria.  During the study, clinically significant new elevations suggestive of myocarditis should be 
assessed as per Table 5.  Additional tests should also be performed when clinically indicated.  See Table 6.
13. HIV test: HIV serology test is required at screening unless not permitted by local laws and regulations.  If indicated, supplemental testing may be 
performed per standard practice to confirm an HIV infection.
14. Urinalysis: Required only at Screening and End of Treatment.  To be performed as clinically indicated at other time points.  Required tests are listed in
Table 6.

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15. 12-Lead Electrocardiogram (ECG): All patients require a single ECG measurement at screening.  Additional ECGs may be performed as clinically 
indicated.  Clinically significant new findings seen on follow-up ECGs should be recorded as adverse events.
16. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging will include chest, abdomen, and pelvis computed 
tomography (CT) or magnetic resonance imaging (MRI) scans.  Bone imaging, eg, bone scans or other methods considered standard of care locally, such as 
18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET) or MRI, are required at baseline.  (Note: 18FDG-PET may not be a permissible 
alternate for bone imaging at some centers or countries (eg, investigative sites in Canada)).  Bone lesion(s) identified at baseline by bone scan will be 
further assessed by CT or MRI as per local practice (where bone scans are not used as a routine restaging tool) and subsequently re-assessed by CT or MRI 
as per the tumor assessment schedule as an alternative to bone scans.  Bone imaging will only be repeated during study as clinically indicated (eg, patient 
describes new or worsening bone pain, or has increasing alkaline phosphatase level, or other signs and symptoms of new/progressing bone metastases), at 
the time of complete response (CR) confirmation, and at every other tumor assessment visit (ie, every 16 weeks for the first year after randomization and 
every 24 weeks thereafter) if considered local standard of care.  
Brain imaging (eg, MRI) is required at baseline for patients who have a history of brain metastases or for whom brain metastases are suspected during 
screening.  Brain must be included in subsequent tumor assessments if a patient has brain metastases at baseline; otherwise brain will only be evaluated 
when clinically indicated. 
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.  All radiographic images from the time 
of the most recent tumor assessment prior to first-line chemotherapy until documented disease progression will be submitted to an independent third-
party core imaging laboratory for Blinded Independent Central Review (BICR) as described in the Study Manual.  
For all patients, anti-tumor activity will be assessed through radiological tumor assessments conducted at baseline (including chest, abdomen, and pelvic 
CT or MRI scans), at 8 weeks after randomization, then every 8 (±3 days) weeks for up to 1 year from randomization, and every 12 weeks (±3 days) 
thereafter until documented disease progression as assessed by BICR regardless of initiation of subsequent anti-cancer therapy.  Additional radiological 
tumor assessments should also be conducted whenever disease progression is suspected (eg, symptomatic deterioration).  
Assessment of response will be made using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 (Appendix 2).  Complete response (CR) and 
partial response (PR) must be confirmed with repeated imaging performed at least 4 weeks after initial documentation of response.  See Section 7.7 for 
additional information. 
17. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated 
representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior 
to undergoing any study-related procedure and/or receiving study treatment, through and including 90 calendar days after the last administration of the 
study treatment (Arm A) or 90 days after the End of Treatment (EOT) visit (Arm B).  SAEs occurring to a patient after the active reporting period has 
ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to study treatment are to be reported to the sponsor.
AEs (serious and non-serious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of study treatment 
(Arm A) or from Cycle 1 Day 1(Arm B), through and including 90 calendar days after the last administration of the study drug (Arm A) or 90 days after 
the EOT visit (Arm B).

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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 treatment, irrespective of any intervening treatment.
18. Day 15 Assessments for Arm B: Remote contact (eg, telephone) or in-clinic visit for collection of interim AEs and changes in concomitant medications 
and treatments, if any.  A follow-up in-clinic visit should be scheduled if clinically indicated.
19. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded for all patients from 28 days prior to the start of study 
treatment and up to 90 days after the last dose of study treatment (Arm A) or 90 days after the EOT visit (Arm B).  If a patient begins a new anti-cancer 
therapy, reporting of concomitant medications should end at the time the new cancer therapy is started; see Section 5.9 for additional details.  All 
concomitant medications will 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).  Concomitant medications should be reviewed at each study 
visit, and any prohibited treatments (as described in Section 5.9) should be discussed with the patient and appropriately managed. 
20. NCCN-FACT FBlSI-18, EQ-5D-5L: All patients will complete these self-administered questionnaires on Day 1 of each cycle.  Patients must complete 
each questionnaire at the clinic prior to any study or medical procedure.
21. Randomization: An interactive response technology (IRT) system will be used for randomization to a treatment arm as described in Section 5.1.  
Patients meeting all entry criteria will be randomized and, if randomized to Arm A, will be administered the first dose of avelumab within 3 days after 
randomization.  
22. Avelumab Study Treatment (Arm A): For patients randomized to Arm A, avelumab (10 mg/kg) will be given as a 1-hour intravenous infusion every 
2 weeks.  Patients should be weighed within 3 days prior to each dose of avelumab (for determination of the avelumab dose [mg]).  All safety 
assessments must be performed and results reviewed by the treating physician prior to study treatment administration.  Patients with disease progression 
who are continuing to derive clinical benefit from study treatment will be eligible to continue with avelumab provided that the treating physician has 
determined that the benefit/risk for doing so is favorable (See Section 5.4.1). 
23. Best supportive care (BSC): All patients (Arm A and Arm B) will receive BSC during this study, as described in Section 5.8.  All BSC components 
must comply with the permitted medications described in this protocol (see Section 5.9).
24. Archival FFPE Tumor Tissue: An archival formalin fixed, paraffin embedded (FFPE) tumor tissue block (or subsection thereof) collected at the time of 
primary diagnosis or first tumor resection (if different from the most recent sample described in footnote 25) is strongly encouraged to assess changes in 
the tumor microenvironment relative to the most recent sample.  If an FFPE tissue block cannot be provided, 15 freshly cut unstained slides (10 
minimum) will be acceptable.  A sample from a later timepoint that is still prior to the most recent tumor tissue sample (see footnote 25) may be 
substituted, if necessary.  Tumor tissue from cytologic samples (eg, FFPE cell pellet from Fine Needle Aspiration biopsy) or bone metastases are not 
acceptable.  See Section 6.1.1 and Section 7.5.1.
25. Mandatory Recent FFPE Tumor Tissue Block or de novo biopsy: All patients must provide an FFPE tumor tissue block (or subsection thereof) from 
the most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first line chemotherapy but within 24 months prior to 
randomization, with no intervening systemic anti-cancer therapy between the time the tissue was obtained and initiation of first-line chemotherapy.  If an 
FFPE tissue block cannot be provided, 15 freshly cut unstained slides (10 minimum) will be acceptable.  Tumor tissue from cytologic sampling (eg, fine 
needle aspiration, including FFPE cell pellet material) or bone metastases is not adequate and should not be submitted.  If a suitable tissue sample is not 
otherwise available, then an FFPE tissue sample from a de novo biopsy (core needle or excisional) must be obtained for research purposes (ie, after 
informed consent has been obtained and prior to randomization).  See Section 6.1.1 and Section 7.5.1.
Note: This mandatory tumor tissue sample must be submitted to the Central Laboratory prior to randomization.  

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26. Banked Blood Biospecimen for Genotyping: A single 4-mL blood sample will be collected on or prior to Cycle 1 Day 1 (prior to dosing for Arm A 
patients and at any time for Arm B patients) and retained in a biobank for possible pharmacogenetic assessments (ie, genotyping), unless prohibited by 
local regulations or by decision of the institutional review board or ethics committee.  See Section 7.6 for further details.
27. Banked Blood Biospecimens for Exploratory Assessments: Blood biospecimens (~24 mL) will be collected and retained as whole blood, plasma, and 
serum specimens (Prep D1: 4 mL K2 EDTA whole blood collection optimized for DNA analysis; Prep B1: 10 mL K2 EDTA blood for plasma 
preparation, and Prep B2: 10 mL blood for serum preparation) in a biobank for exploratory biomarker assessments, unless prohibited by local regulation 
or by decision of the Institutional Review Board or Ethics Committee.  For all patients, samples will be collected on or prior to Cycle 1 Day 1, and on 
Day 1 of Cycles 2, 3, and 5 (all pre-dose).  An additional sample timepoint will include pre-dose on Cycle 1 Day 15 for Arm A patients.  See 
Section 7.5.2 and Section 7.6.
28. Pharmacokinetics: ARM A ONLY: Blood samples (3.5 mL) for avelumab PK will be collected pre-dose and at the end of infusion (immediately before 
the end of avelumab infusion) on Day 1 and Day 15 of Cycles 1 – 3, and then pre-dose and at the end of infusion (immediately before the end of 
avelumab infusion) on Day 1 of Cycle 5, 7, 9, 11 and 13.  Do not collect blood from the same arm being infused.  See Section 7.3 for further details. 
29. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): Arm A ONLY: One blood sample (3.5 mL) for 
anti-avelumab antibodies will be collected pre-dose on Day 1 and Day 15 of Cycles 1 – 3, and then on Day 1 of Cycle 5, 7, 9, 11 and 13.  All samples 
should be drawn within 2 hours before the start of avelumab infusion.  All samples that are positive for ADA may also undergo characterization for Nab.  
See Section 7.4.

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PRIOR TO PROTOCOL AMENDMENT 6: SCHEDULE OF ACTIVITIES FOR END OF TREATMENT/WITHDRAWAL 
AND FOLLOW-UP PERIODS
Visit Identifiers1
End of 
Treatment/
Withdrawal
(±3 days)2
Follow-up3
Short-Term
Long-Term
every 3 months 
14 days)
30 days (±3 days)
After 
Last Dose (Arm A) 
or EOT/Withdrawal 
Visit (Arm B)
60 days (±3 days) 
After 
Last Dose (Arm A) 
or EOT/Withdrawal 
Visit (Arm B)
90 days (±3 days) 
After 
Last Dose (Arm A) 
or EOT/Withdrawal 
Visit (Arm B)
Documentation
Physical Examination4
X
X
X
X
ECOG Performance Status
X
X
X
X
Vital Signs and Weight5
X
X
X
X
Contraception Check (Arm A ONLY)6
X
X
Laboratory Studies
Hematology7
X
X
X
X
Blood Chemistry (full panel)8
X
X
X
X
Coagulation7
X
X
X
X
Thyroid Function Tests and ACTH9
X
X
X
X
Serum/Urine Pregnancy Test (Arm A 
ONLY)10
X
X
Urinalysis11
X
12-lead ECG12
If clinically indicated
Disease Assessments
Tumor Assessments (including scans)13
X (Q8W for the 1st year after randomization and Q12W thereafter)
Other Clinical Assessments
Adverse Events14
X
X
X
X
Concomitant Medications/Treatments15
X
X
X
X
New Systemic Anticancer Treatment
X
X
X
X
X
Survival Assessment16
X
X
X
X
Patient-Reported Outcomes 
(NCCN-FACT FBlSI-18, EQ-5D-5L)17
X
X
X
X
Other Samplings
Banked Blood Biospecimens for 
Exploratory Assessments18
X
De Novo Tumor Biopsy19
X

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Visit Identifiers1
End of 
Treatment/
Withdrawal
(±3 days)2
Follow-up3
Short-Term
Long-Term
every 3 months 
14 days)
30 days (±3 days)
After 
Last Dose (Arm A) 
or EOT/Withdrawal 
Visit (Arm B)
60 days (±3 days) 
After 
Last Dose (Arm A) 
or EOT/Withdrawal 
Visit (Arm B)
90 days (±3 days) 
After 
Last Dose (Arm A) 
or EOT/Withdrawal 
Visit (Arm B)
Pharmacokinetics20 (Arm A ONLY)
X
X
Anti-Avelumab Antibodies and 
Neutralizing21 (Arm A ONLY)
X
X
ACTH = adrenocorticotropic hormone; BSC = best supportive care; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = 
formalin-fixed and paraffin-embedded; Q12W = every 12 weeks
Footnotes for PRIOR TO PROTOCOL AMENDMENT 6: SCHEDULE OF ACTIVITIES FOR END OF TREATMENT/WITHDRAWAL AND 
FOLLOW-UP PERIODS
1.
Visit Identifiers: Acceptable time windows for performing each assessment are described in the column headers.  Per the visit time window, laboratory 
tests may be performed up to 3 days prior to the scheduled clinic visit so that results will be available for review.
2.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated 
if performed within the prior 6 weeks.
3.
Short- and Long-Term Follow-up: All patients will be followed for safety every 30 days (±3 days) through 90 days after the last dose of study 
treatment (Arm A) or 30 through 90 days after the End of Treatment (EOT) visit (Arm B), or until the time of initiation of new anticancer treatment.   
Beyond the 90 days until the end of the study (long-term follow-up), all patients will be followed every 3 months after the last study clinic visit (14 
days) for survival, tumor assessment, and new systemic anticancer treatment; additional timepoints to collect survival information may be requested by 
the Sponsor in preparation for interim and final analyses.
4.
Physical Examination: Includes an examination of major body systems.
5.
Vital Signs and Weight: 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.  
6.
Contraception Check (Arm A patients): Female patients who are of childbearing potential will need to affirm that they meet the criteria for correct use 
of the selected methods of contraception until at least 30 days after the last dose of study treatment.  The investigator or his or her designee will discuss 
with the patient the need to use the selected contraception methods consistently and correctly and document such conversations in the patient’s chart.  In 
addition, the investigator or his or her designee will instruct the patient to call immediately if the selected contraception methods are discontinued, or if 
pregnancy is known or suspected in the patient or the male patient’s partner.  See Section 4.3.1.
7.
Hematology, Blood Chemistry, and Coagulation: Required tests are listed in Table 6.  May also be performed when clinically indicated. 
8.
Blood Chemistry: Full chemistry panel (see Table 6) is required at End of Treatment/Withdrawal and during short-term follow-up visits (Days 30 3, 
60 3, 90 3 after last dose).   
9.
Thyroid Function Tests: Free T4, TSH, and ACTH will be performed at the End of Treatment/Withdrawal and at Follow-up visits at 30±3, 60±3, and 
90 3 days after last dose.  Additional tests should be performed when clinically indicated.  See Table 6.

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10. Serum/Urine Pregnancy Test (Arm A patients): For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at the End of Treatment/Withdrawal visit and at the 30-Day Follow-up visit, and additionally whenever one 
menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by 
Institutional Review Board (IRB)/Ethics Committees (ECs) or if required by local regulations.  See Section 7.1.1.
11. Urinalysis: Required only at the End of Treatment/Withdrawal.  To be performed as clinically indicated at other time points.  Required tests are listed in 
Table 6.
12. 12-Lead Electrocardiogram (ECG): When clinically-indicated. Clinically significant new findings seen on follow-up ECGs should be recorded as 
adverse events.  See Section 7.1.5 for further details.
13. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging will include chest, abdomen, and pelvis computed 
tomography (CT) or magnetic resonance imaging (MRI) scans.  Bone lesion(s) identified at baseline by bone scan will be further assessed by CT or MRI 
as per local practice (where bone scans are not used as a routine restaging tool) and subsequently re-assessed by CT or MRI as per the tumor assessment 
schedule as an alternative to bone scans.  Bone imaging (eg, bone scans or other methods considered standard of care locally, such as 18FDG-PET or 
MRI) will only be repeated during study as clinically indicated (eg, patient describes new or worsening bone pain, or has increasing alkaline phosphatase 
level, or other signs and symptoms of new/progressing bone metastases), at the time of complete response (CR) confirmation, and at every other tumor
assessment visit (ie, every 16 weeks for the first year after randomization and every 24 weeks thereafter) if considered local standard of care.  (Note: 
18FDG-PET may not be a permissible alternate for bone imaging at some centers or countries (eg, investigative sites in Canada).   
Brain must be included in subsequent tumor assessments if a patient has brain metastases at baseline; otherwise brain will only be evaluated when 
clinically indicated.  
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.  All radiographic images from the time 
of the most recent tumor assessment prior to first-line chemotherapy until documented disease progression will be submitted to an independent third-
party core imaging laboratory as described in the Study Manual.  
For all patients, anti-tumor activity will be assessed through radiological tumor assessments (including chest, abdomen, and pelvic CT or MRI scans) 
conducted every 8 weeks (± 3 days) for up to 1 year from randomization and every 12 weeks (±3 days) thereafter until documented disease progression as 
assessed by BICR regardless of initiation of subsequent anti-cancer therapy.  Additional radiological tumor assessments should also be conducted 
whenever disease progression is suspected (eg, symptomatic deterioration).
Assessment of response will be made using RECIST v.1.1 (Appendix 2).  Complete response (CR) and partial response (PR) must be confirmed with 
repeated imaging performed at least 4 weeks after initial documentation of response.  See Section 7.7 for additional information.
14. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated 
representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior 
to undergoing any study-related procedure and/or receiving study treatment, through and including 90 calendar days after the last administration of the 
study treatment (Arm A) or 90 days after the EOT visit (Arm B).  SAEs occurring to a patient after the active reporting period has ended should be 
reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable 
possibility of being related to study treatment are to be reported to the sponsor.

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AEs (serious and non-serious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of study treatment 
(Arm A) or from Cycle 1 Day 1 (Arm B), through and including 90 calendar days after the last administration of the study treatment (Arm A) or 90 days 
after the EOT visit (Arm B).  
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 treatment, irrespective of any intervening treatment.
15. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded for all patients from 28 days prior to the start of study 
treatment and up to 90 days after the last dose of study treatment (Arm A) or 90 days after the EOT visit (Arm B).  If a patient begins a new anti-cancer 
therapy, reporting of concomitant medications should end at the time the new cancer therapy is started; see Section 5.9 for additional details.  All 
concomitant medications will 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). 
16. Survival Assessment: All patients will be followed for survival and subsequent anticancer therapies every 3 months (±14 days) after the last study clinic 
visit until death, end of the study, or patient withdrawal of consent, whichever comes first.  These visits may be conducted in-clinic or by remote contact 
(eg, telephone).  Additional timepoints to collect survival information may be requested by the Sponsor in preparation for interim and final analyses.
17. Patient-Reported Outcome Questionnaire: NCCN-FACT FBlSI-18 and EQ-5D-5L are to be administered at the End of Treatment/Withdrawal visit 
and at the 30, 60 and 90 Day Follow-up Visits.
18. Banked Blood Biospecimens for Exploratory Assessments: Blood biospecimens (~24 mL) will be collected at the End of Treatment/Withdrawal visit 
and retained as whole blood, plasma, and serum (Prep D1: 4 mL K2 EDTA whole blood collection optimized for DNA analysis; Prep B1: 10 mL 
K2 EDTA blood for plasma preparation, and Prep B2: 10 mL blood for serum preparation), and retained in a biobank for exploratory biomarker 
assessments, unless prohibited by local regulation or by decision of the Institutional Review Board or Ethics Committee.  See Section 7.5.2 and 
Section 7.6.
19. De Novo Tumor Biopsy: A de novo (ie, fresh biopsy) tumor sample should also be collected at End of Treatment/Withdrawal visit, unless clinically 
contraindicated.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including formalin fixed, paraffin embedded [FFPE] cell pellet 
material) or bone metastases is not adequate and should not be submitted.  The de novo biopsy should be formalin-fixed and paraffin-embedded as per 
routine procedures (see Laboratory Manual), and the resulting FFPE tissue block(s) should be submitted to the Central Laboratory.  If an FFPE tissue 
block cannot be provided, 15 freshly cut unstained slides (10 minimum) will be acceptable.
20. Pharmacokinetics: Arm A ONLY: Blood samples (3.5 mL) for avelumab PK will be taken at the End of Treatment and 30 day Follow-up visits.  Details 
are outlined in Section 7.3.
21. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): Arm A ONLY.  One blood sample (3.5 mL) for 
anti-avelumab antibodies (and simultaneous pharmacokinetic draws for measurement of avelumab) will be collected at the End of Treatment and 30 day 
Follow-up visits.  All the samples that are positive for ADA may also undergo characterization for Nab.  

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PROTOCOL AMENDMENT 6:  SCHEDULE OF ACTIVITIES FOR STUDY TREATMENT, END OF TREATMENT AND 
FOLLOW-UP PERIODS
Visit Identifiers1
Avelumab plus BSC
(1 cycle = 4 weeks)
End of Treatment/
Withdrawal
(±3 days)2
Short-Term Follow-Up3
Day 1
(3 days)
Day 15 
(3 days)
30 days (±3 days)
After 
Last Dose of 
Avelumab
60 days (±3 days) 
After 
Last Dose of 
Avelumab
90 days (±3 days) 
After 
Last Dose of 
Avelumab
Clinical Assessments
Physical Examination4
Assessment not required per protocol but may be performed as clinically necessary
ECOG Performance 
Status4
Assessment not required per protocol but may be performed as clinically necessary
Vital Signs 4
Assessment not required per protocol but may be performed as clinically necessary
Weight5
X
X
Contraception Check4,6
X
X
X
X
Laboratory Studies
Hematology4,7
X
X
X
X
X
X
Blood Chemistry4,7
X 
X
X
X
X
X
Thyroid Function and 
ACTH Tests4,8
X (at odd number 
cycle only)
X
X
X
X
Serum/Urine Pregnancy 
Test4,9
X 
X
X
X
Urinalysis4
Assessment not required per protocol but may be performed as clinically necessary
12-Lead ECG4,10
Assessment not required per protocol but may be performed as clinically necessary
Other Assessments
Tumor Assessments 
(including scans)11
As per local standard of care and when progression is suspected
Adverse Events12
X
X
X
X
X
X
Concomitant 
Medications/Treatments13
Assessment not required per protocol but may be performed as clinically necessary
Study Treatment
Avelumab14
X
X
ACTH = adrenocorticotropic hormone; BSC = best supportive care; CR = crossover; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group 
Footnotes for PROTOCOL AMENDMENT 6: SCHEDULE OF ACTIVITIES FOR SCREENING AND STUDY TREATMENT PERIOD

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1.
Visit Identifiers: All assessments will be performed prior to dosing with avelumab unless otherwise indicated.  Acceptable time windows for performing each assessment 
are described in the column headers.  Note: laboratory tests may be performed up to 3 days prior to the scheduled clinic visit so that results will be available for review.
2.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week.
3.
Short-Term Follow-up: All patients will be followed for safety every 30 days (±3 days) through 90 days after the last dose of avelumab or until the time of initiation of a 
new anticancer treatment, whichever occurs first.
4.
These data will not be captured in the CRF unless the findings support the reporting of an AE.
5.
Weight: Weight should be measured within 3 days prior to each dose of avelumab (for determination of the avelumab dose [mg]).
6.
Contraception Check: Female patients who are of childbearing potential will need to affirm that they meet the criteria for correct use of the selected methods of 
contraception.  The investigator or his or her designee will discuss with the patient the need to use the selected contraception methods consistently and correctly and 
document such conversations in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if the selected 
contraception methods are discontinued, or if pregnancy is known or suspected in the patient or the male patient’s partner.  See Section 4.3.1.
7.
Hematology and Blood Chemistry: Required tests are listed in Table 7.  May also be performed when clinically indicated.  
8.
Thyroid Function and ACTH Tests: Free T4, TSH, and ACTH tests will be performed on Day 1 of every 2 cycles (8 weeks).  Additional tests should be performed 
when clinically indicated.  See Table 7.
9.
Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be routinely 
repeated prior to each avelumab dose during the active treatment period, at the End of Treatment/Withdrawal visit, and additionally whenever one menstrual cycle is 
missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by Institutional Review Board (IRB)/Ethics 
Committees (ECs) or if required by local regulations.  Results of the pregnancy test should be available prior to each dosing.  See Section 7.1.1.
10. 12-Lead Electrocardiogram (ECG): To be performed as clinically indicated.  Clinically significant new findings seen on follow-up ECGs should be recorded as adverse 
events.
11. Tumor Assessments: Tumor assessments will be performed at a frequency as per local standard of care and when progression is suspected. The tumor assessment data will 
no longer be entered into the CRF and radiologic images will no longer be submitted for central imaging review.
12. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the 
patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
study treatment, through and including 90 calendar days after the last administration of the study treatment.  SAEs occurring to a patient after the active reporting period 
has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable 
possibility of being related to study treatment are to be reported to the sponsor.
AEs (serious and non-serious) should continue to be recorded on the Case Report Form (CRF) through and including 90 calendar days after the last administration of 
avelumab.
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 treatment, irrespective of any intervening treatment.
13. Concomitant Medications/Treatments: Concomitant medications and treatments should only be recorded in the CRF if associated with treatment for an AE.
14. Avelumab Treatment: Avelumab (10 mg/kg) will be given as a 1 hour intravenous infusion every 2 weeks.  Patients should be weighed within 3 days prior to each dose 
of avelumab (for determination of the avelumab dose [mg]).  All safety assessments must be performed and results reviewed by the treating physician prior to avelumab 
administration.  Patients with disease progression who are continuing to derive clinical benefit from study treatment will be eligible to continue with avelumab provided 
that the treating physician has determined that the benefit/risk for doing so is favorable (See Section 5.4.1). 

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TABLE OF CONTENTS
PROTOCOL SUMMARY.......................................................................................................19
SCHEDULE OF ACTIVITIES................................................................................................28
LIST OF TABLES...................................................................................................................46
LIST OF FIGURES .................................................................................................................46
APPENDICES .........................................................................................................................47
1. INTRODUCTION ...............................................................................................................48
1.1. Mechanism of Action/Indication.............................................................................48
1.2. Background and Rationale ......................................................................................48
1.2.1. Urothelial Cancer........................................................................................48
1.2.2. Pharmaceutical and Therapeutic Background ............................................48
1.2.2.1. Avelumab (MSB0010718C) .....................................................48
1.2.2.2. Rationale for Best Supportive Care as Comparator Arm..........53
1.2.3. Rationale for Studying Avelumab plus Best Supportive Care in 
Patients with Advanced Urothelial Cancer......................................................53
1.2.3.1. Medical Need ............................................................................53
1.2.3.2. Rationale for Immunotherapy for Maintenance Treatment 
of Urothelial Cancer ..........................................................................54
1.2.3.3. Rationale for Study Design .......................................................57
1.2.4. Rationale for Avelumab Dose and Best Supportive Care Regimens .........57
1.3. Summary of Benefit-Risk Assessment....................................................................58
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................59
2.1. Objectives................................................................................................................59
2.2. Endpoints.................................................................................................................60
3. STUDY DESIGN.................................................................................................................60
3.1. Study Overview.......................................................................................................60
3.1.1. Study Treatment..........................................................................................63
3.1.2. Tumor Assessments....................................................................................64
3.1.3. Safety Assessment ......................................................................................65
3.1.4. Patient-Reported Outcomes........................................................................65
3.1.5. Pharmacokinetic/Immunogenicity Assessments ........................................66
3.1.6. Biomarker Assessments..............................................................................66
4. PATIENT SELECTION......................................................................................................66

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4.1. Inclusion Criteria.....................................................................................................66
4.2. Exclusion Criteria....................................................................................................68
4.3. Lifestyle Guidelines ................................................................................................71
4.3.1. Contraception..............................................................................................71
4.4. Sponsor Qualified Medical Personnel.....................................................................72
5. STUDY TREATMENTS.....................................................................................................73
5.1. Allocation to Treatment ..........................................................................................73
5.2. Patient Compliance with Avelumab Study Treatment............................................74
5.3. Investigational Product Supplies.............................................................................74
5.3.1. Avelumab Dosage Form(s) and Packaging ................................................74
5.3.2. Avelumab Preparation and Dispensing ......................................................74
5.4. Avelumab Administration.......................................................................................75
5.4.1. Treatment after Initial Evidence of Radiologic Disease Progression.........76
5.4.2. Food Requirements.....................................................................................77
5.4.3. Recommended Dose Modifications............................................................77
5.4.3.1. Special Precautions for Avelumab Administration...................77
5.4.3.2. Management of Avelumab Infusion-Related 
Reactions/Hypersensitivity Reactions...............................................78
5.4.3.3. Management of Avelumab-Related Tumor Lysis 
Syndrome...........................................................................................79
5.4.3.4. Management of Avelumab Immune-Related Adverse 
Events ................................................................................................81
5.5. Investigational Product Storage ..............................................................................88
5.6. Investigational Product Accountability...................................................................89
5.7. Destruction of Investigational Product Supplies.....................................................89
5.8. Best Supportive Care...............................................................................................89
5.9. Concomitant Treatments .........................................................................................89
5.9.1. Concomitant Surgery..................................................................................90
5.9.2. Concomitant Radiotherapy.........................................................................90
5.9.3. Other Prohibited Concomitant Medications and Therapies........................91
5.10. Rescue Medications and Supportive Care.............................................................92
5.10.1. Supportive Care Guidelines......................................................................92
6. STUDY PROCEDURES .....................................................................................................93

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6.1. Screening.................................................................................................................93
6.1.1. Tumor Biospecimens..................................................................................93
6.2. Treatment Period.....................................................................................................94
6.3. End of Treatment/Withdrawal and Follow-up Visits..............................................94
6.4. End of the Study......................................................................................................94
6.5. Patient Withdrawal..................................................................................................94
7. ASSESSMENTS..................................................................................................................96
7.1. Safety Assessment...................................................................................................96
7.1.1. Pregnancy Testing ......................................................................................96
7.1.2. Adverse Events...........................................................................................96
7.1.3. Laboratory Safety Assessments..................................................................96
7.1.4. Physical Examinations and Vital Signs......................................................98
7.1.5. (12-Lead) Electrocardiograms....................................................................99
7.2. Patient-Reported Outcome Assessments.................................................................99
7.3. Pharmacokinetics Assessments...............................................................................99
7.4. Immunogenicity Assessment.................................................................................100
7.5. Translational and Pharmacodynamic Assessments...............................................100
7.5.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies...............100
7.5.2. Peripheral Blood.......................................................................................101
7.6. Banked Biospecimens ...........................................................................................101
7.6.1. Markers of Drug Response.......................................................................101
7.6.2. Additional Research..................................................................................103
7.7. Tumor Assessments...............................................................................................103
7.8. Expedited Blinded Independent Central Review for Disease Progression ...........104
8. ADVERSE EVENT REPORTING....................................................................................105
8.1. Adverse Events......................................................................................................105
8.2. Reporting Period ...................................................................................................105
8.3. Definition of an Adverse Event.............................................................................105
8.3.1. Avelumab Adverse Events of Special Interest .........................................106
8.4. Medication Errors..................................................................................................106
8.5. Abnormal Test Findings........................................................................................107
8.6. Serious Adverse Events.........................................................................................108

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8.6.1. Protocol-Specified Serious Adverse Events.............................................108
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................108
8.7. Hospitalization ......................................................................................................109
8.8. Severity Assessment..............................................................................................111
8.9. Causality Assessment............................................................................................111
8.10. Exposure During Pregnancy................................................................................111
8.11. Occupational Exposure .......................................................................................113
8.12. Withdrawal Due to Adverse Events (also see Section 6.5 Patient 
Withdrawal).............................................................................................................113
8.13. Eliciting Adverse Event Information ..................................................................113
8.14. Reporting Requirements......................................................................................113
8.14.1. Serious Adverse Event Reporting Requirements ...................................113
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................114
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............114
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................114
9.1. Sample Size Determination...................................................................................115
9.2. Analysis Populations.............................................................................................116
9.2.1. Full Analysis Set.......................................................................................116
9.2.2. Per-Protocol Analysis Set.........................................................................116
9.2.3. Safety Analysis Set...................................................................................116
9.2.4. PK Analysis Set ........................................................................................116
9.2.5. Immunogenicity Analysis Set...................................................................117
9.2.6. Biomarker Analysis Set............................................................................117
9.3. Efficacy Analysis ..................................................................................................117
9.3.1. Analysis of Primary Endpoint ..................................................................117
9.3.2. Analysis of Secondary Endpoints.............................................................117
9.4. Analysis of Other Endpoints .................................................................................121
9.4.1. Statistical Analysis of Biomarker Endpoints............................................121
9.4.2. Exploratory Endpoints..............................................................................121
9.5. Safety Analysis......................................................................................................121
9.6. Interim Analysis ....................................................................................................122
9.7. External Data Monitoring Committee...................................................................123

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10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................123
11. DATA HANDLING AND RECORD KEEPING ...........................................................124
11.1. Case Report Forms/Electronic Data Record .......................................................124
11.2. Record Retention.................................................................................................125
12. ETHICS............................................................................................................................125
12.1. Institutional Review Board/Ethics Committee....................................................125
12.2. Ethical Conduct of the Study ..............................................................................125
12.3. Patient Information and Consent.........................................................................126
12.4. Patient Recruitment.............................................................................................127
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................127
13. DEFINITION OF END OF TRIAL.................................................................................127
13.1. End of Trial in a Member State...........................................................................127
13.2. End of Trial in all other Participating Countries.................................................127
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................127
15. PUBLICATION OF STUDY RESULTS........................................................................128
15.1. Communication of Results by Pfizer ..................................................................128
15.2. Publications by Investigators ..............................................................................128
16. REFERENCES ................................................................................................................130
17. SUPPLEMENT 1: CROSSOVER FROM BSC ALONE (ARM B) TO 
AVELUMAB PLUS BEST SUPPORTIVE CARE..........................................................151

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LIST OF TABLES
Table 1.
Most Frequently Reported (Incidence 5%) Treatment-Related 
TEAEs in the Pooled Expansion Cohorts (Any Grade)............................50
Table 2.
Most Frequently Reported (in 3 Patients) Grade 3 Investigational 
Product-Related TEAEs in the Pooled Expansion Cohorts......................50
Table 3.
Avelumab Infusion Omissions for Avelumab Product-Related 
Toxicity.....................................................................................................77
Table 4.
Treatment Modification for Symptoms of Avelumab Infusion-
Related Reactions .....................................................................................78
Table 5.
Management of Avelumab Immune-Related Adverse Events .................81
Table 6.
Prior to Protocol Amendment 6: Required Laboratory Tests...................97
Table 7.
Protocol Amendment 6: Required Laboratory Tests................................98
Table 8.
Stopping Boundaries for Overall Survival .............................................123
Table 9.
Objective Response Status at each Evaluation.......................................141
Table 10.
Objective Response Status at each Evaluation for Patients with Non 
Target Disease Only ...............................................................................141
LIST OF FIGURES
Figure 1
Study B9991001 Design...........................................................................61
Figure 2
Assessment and Initial Management of Tumor Lysis Syndrome 
(TLS).........................................................................................................80

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APPENDICES
Appendix 1. ECOG Performance Status................................................................................136
Appendix 2. Response Evaluation Criteria in Solid Tumors Version 1.1 .............................137
Appendix 3. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ......................................................................142
Appendix 4. Cockcroft-Gault Formula..................................................................................143
Appendix 5. Abbreviations and Definitions of Term ............................................................144
Appendix 6. Alternative Measures During Public Emergencies ...........................................147

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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Avelumab selectively binds to programmed death-ligand 1 (PD-L1) and competitively blocks 
its interaction with programmed death protein 1 (PD-1).  The mechanism of avelumab action 
is further described in Section 1.2.2.1.
The indication under study is the maintenance treatment of unresectable locally advanced or 
metastatic urothelial cancer (UC) after standard first-line platinum containing chemotherapy. 
1.2. Background and Rationale
1.2.1. Urothelial Cancer
UC includes tumors originating from the urothelial cells lining the bladder, renal pelvis, 
ureter, and urethra.1  Bladder cancer alone accounts for 90% of UC,1 and is the ninth most 
prevalent cancer worldwide, with approximately 400,000 new cases diagnosed and 
150,000 deaths attributed to this disease each year.2  UC occurs more frequently in developed 
countries; in Europe it is the eighth most common cause of mortality due to cancer and 
occurs at a very high annual incidence rate (20.5 per 100,000 persons) in the United States.3,4  
The incidence and mortality of bladder cancer have remained unchanged over the last 
25 years.2
Approximately 30% of patients with newly diagnosed UC present with muscle-invasive UC 
of the bladder,5 a high-grade, typically aggressive disease requiring multimodal therapy 
including radical cystectomy and chemotherapy.1,6,7  Metastatic disease is observed in 5% of 
patients at the time of diagnosis6 or, if localized at diagnosis, metastasis develops within 
2 years when treated with radical cystectomy alone.8,9
Combination chemotherapy with platinum-based regimens is the standard of care for locally 
advanced or metastatic bladder cancer.  Despite the favorable response and survival rates 
associated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin 
(MVAC),10,11,12 toxicities associated with this regimen can be significant and lead to death in 
3-4% of patients.12,13  Subsequently, the combinations of gemcitabine + cisplatin and 
gemcitabine + carboplatin were shown to have comparable efficacy and an improved safety 
compared to MVAC,14,15,16 with the latter combination used in the 30-50% of patients 
ineligible for cisplatin-based chemotherapy due to renal impairment.17  As such, these two 
regimens are now the preferred regimens for the initial treatment of patients with locally 
advanced or metastatic UC.
1.2.2. Pharmaceutical and Therapeutic Background 
1.2.2.1. Avelumab (MSB0010718C)
The investigational product 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.18  For complete details of the in vitro and nonclinical studies, refer 
to the Avelumab Investigator’s Brochure.19
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, and urothelial cancer.  
Trial EMR100070-001 is a Phase 1, open-label, multiple-ascending dose clinical study aimed 
to investigate the safety, tolerability, pharmacokinetics (PK), biological activity, and clinical 
activity of avelumab in patients with metastatic or locally advanced solid tumors.  This trial 
consists of 2 parts, a dose-escalation phase and a dose-expansion phase, which is performed 
in selected tumor indications.  Avelumab is administered intravenously (IV) at the assigned 
dose level as a 1-hour infusion once every 2 weeks (Q2W).  The following dose levels have 
been investigated: 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, and 20.0 mg/kg.
As of 01 June 2015, 53 patients were treated in the dose-escalation phase of the 
EMR10070-001, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3, 10, and 
20 mg/kg, respectively.  None of the patients treated with doses up to 10 mg/kg experienced 
a dose-limiting toxicity (DLT), and the 10 mg/kg dose of avelumab was thus considered a 
safe and well-tolerated dose for further investigation in the dose-expansion cohorts.  One 
DLT (a Grade 3 immune-related adverse event characterized by increased creatine kinase,
myositis, and myocarditis) was observed in 1 patient at the dose of 20 mg/kg.
As of 01 June 2015, 717 patients have been enrolled in the tumor type specific expansion 
cohorts and treated with the recommended dose of 10 mg/kg avelumab (Q2W); safety data 
were available for all of these patients as of the data cut-off date and are briefly summarized 
here. 
Treatment-related treatment emergent adverse events (TEAEs) were observed in 498 (69.5%) 
subjects in the pooled expansion cohorts.  The most frequently observed treatment-related 
TEAEs (with an incidence of 5%) of any grade were infusion-related reaction (18.7%), 
fatigue (18.1%), nausea (10.3%), diarrhea (6.8%), chills (6.7%), and decreased appetite 
(5.2%).  The most frequently reported (incidence 5%) treatment-related TEAEs (any grade) 
in the pooled expansion cohort are summarized in Table 1.  The most frequently reported 
(occurring in at least 3 patients) Grade 3 treatment-related TEAEs in the pooled expansion 
cohorts are presented in Table 2.

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Table 1.
Most Frequently Reported (Incidence ≥5%) Treatment-Related TEAEs in 
the Pooled Expansion Cohorts (Any Grade)
MedDRA Preferred Term
Pooled Expansion Cohort Patients (n=717)
n (%)
Number of patients with at least 1 TEAE
498 (69.5%)
Infusion related reaction
134 (18.7%)
Fatigue
130 (18.1%)
Nausea
74 (10.3%)
Diarrhea
49 (6.8%)
Chills
48 (6.7%)
Decreased appetite
37 (5.2%)
Table 2.
Most Frequently Reported (in ≥3 Patients) Grade ≥3 Investigational 
Product-Related TEAEs in the Pooled Expansion Cohorts
MedDRA Preferred Term
Pooled Expansion Cohort Patients (n=717)
n (%)
Number of patients with at least 1 TEAE
77 (10.7%)
Gamma-glutamyltransferase increased
7 (1.0%)
Infusion related reaction
7 (1.0%)
Lipase increased
7 (1.0%)
Anemia
6 (0.8%)
Fatigue
5 (0.7%)
Aspartate aminotransferase increased
4 (0.6%)
Autoimmune hepatitis
4 (0.6%)
Alanine aminotransferase increased
3 (0.4%)
Lymphocyte count decreased
3 (0.4%)
Pneumonitis
3 (0.4%)
As of 01 June 2015, 289 of 717 patients (40.3%) in the pooled expansion cohorts had at least 
1 serious TEAE.  Treatment-related serious TEAEs were reported in 47 of these patients, and 
included infusion-related reaction and pneumonitis (each in 6 subjects; 0.8%), pyrexia 
(4 subjects; 0.6%), autoimmune hepatitis and dyspnea (each in 3 subjects; 0.4%), and colitis 
and non-cardiac chest pain (each in 2 subjects; 0.3%).  All other treatment-related serious 
TEAEs were reported in a single subject (0.1%) only.
Among the 717 patients, 290 patients (40.4%) have died, mostly due to disease progression 
(216 deaths; 30.1%).  Overall, a total of 4 deaths (0.6%) due to TEAEs related to study 
treatment were considered as the primary reason of the death by the investigator.  Two 
additional cases of death were reported and assessed as treatment-related, but the treatment 
related TEAEs were not considered as the primary reason of the death.  These 6 deaths due to 
TEAEs related to study treatment were attributed to the following events: pneumonitis 
radiation induced and dyspnea; acute liver failure associated with autoimmune hepatitis (no 
biopsy/autopsy performed); fatal anoxic brain injury (not related) after cardiac arrest 
(related); autoimmune hepatitis with hepatic failure and fatigue (no biopsy/autopsy 

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performed); respiratory distress and sepsis; and acute respiratory failure, acute exacerbation 
chronic obstructive pulmonary disease (COPD). 
A total of 139 patients (19.4%) in the dose expansion cohorts withdrew permanently from 
study treatment due to TEAEs.  In 60 (8.4%) of these patients, the TEAEs leading to study 
treatment discontinuation were considered to be related to study treatment by the 
investigator.  The most frequent (2 patients) treatment-related TEAEs leading to 
discontinuation were infusion-related reaction (19 patients; 2.6%), 
gamma-glutamyltransferase increased (5 patients; 0.7%), autoimmune hepatitis, blood 
creatine phosphokinase increased, and lipase increased (3 patients; 0.4%), and dyspnea 
(2 patients; 0.3%).
Immune-related Adverse Events: As of 01 June 2015, a cumulative review identified 
106 patients with potential immune-related adverse events (irAEs) out of 717 patients 
(14.8%) treated in the pooled expansion cohort of trial EMR 100070-001.  Treatment-related 
potential irAEs were observed in 71 of the 717 patients (9.9%).  Hypothyroidism was the 
most frequent treatment-related irAE, which occurred in 32 patients (4.5%) in the pooled 
expansion cohort.  The other frequent irAEs, which were considered as treatment-related, 
were pneumonitis (8 patients; 1.1%), autoimmune hepatitis and hyperthyroidism (4 patients; 
0.6%), and colitis and dry eye (3 patients each; 0.4%).  Additional treatment-related irAEs 
were seen in 2 or 1 patients in the pooled expansion cohort. 
Infusion-Related Reactions: Two suspected unexpected serious adverse reactions (SUSARs; 
anaphylactic reaction and infusion-related reaction) involving 2 patients were reported in 
December 2013 and triggered a cumulative review of serious and non-serious cases of 
infusion-related reactions and hypersensitivity across the avelumab program.  Following 
evaluation of safety signals, infusion-related reactions and hypersensitivity were classified as 
a newly identified risk (previously classified as a potential risk) and a mandatory 
premedication regimen of a histamine H1 receptor (H1) blocker plus 
acetaminophen/paracetamol was implemented for all trial patients starting 29 January 2014.
As of 01 June 2015, 138 of 717 patients (19.2%) in the pooled expansion cohort experienced 
at least 1 episode of infusion-related reaction.  Most of the events were Grade 1 (30 patients, 
4.2%) or Grade 2 (101 patients, 14.1%) in intensity, and Grade 3 (5 patients, 0.7%) or 
Grade 4 events (2 patients, 0.3%) were less frequent.  No Grade 5 events were reported.  
Most of the infusion-related reactions had an onset after the first (91 patients, 12.7%) or 
second (35 patients, 4.9%) avelumab infusion, and those with an onset after the third 
(9 patients, 1.3%) or fourth avelumab infusion (3 patients, 0.4%) were less frequent.  In 
17 patients (2.4%), avelumab treatment was discontinued because of infusion-related 
reaction. 
After introduction of the mandatory premedication on 29 January 2014, 35 and 677 patients 
in the dose escalation and the pooled expansion cohorts of Trial EMR 100070-001 received 
trial treatment, respectively.  Under this premedication procedure, 117 of 677 patients 
(17.3%) in the pooled expansion cohort experienced infusion-related reaction, with 
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(0.4%) having Grade 3 event.  No Grade 4 infusion-related reaction was observed after 
introduction of the mandatory premedication.  Three patients (8.6%) in the dose escalation 
cohort reported infusion-related reactions (all Grade 2) starting from 29 January 2014.
In addition to the aforementioned patients, 1 case of Grade 4 cardiac arrest occurred 
1.5 hours after the third infusion of avelumab (10 mg/kg).  The patient died due to anoxic 
brain injury 7 days later; no autopsy was performed. 
The management of infusion-related reactions and severe hypersensitivity reactions can be 
found in Section 5.4.3.2.  A complete guideline for the emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (United Kingdom) 
can be found at https://www.resus.org.uk/pages/reaction.pdf.
Myocarditis: As reported in the Investigator’s Brochure,19 three cases of myocarditis have 
been reported among patients receiving avelumab:

A case of fatal myocarditis (case no. E2B_80035746) occurred in a patient enrolled in 
study B9991002, a Phase I study of avelumab in combination with axitinib in renal 
cell carcinoma.  The event occurred 5 days after the second and 19 days after the first 
dose of avelumab (10 mg/kg).  

A case of non-fatal myocarditis (case no. 260076) was reported in the context of a 
Grade 3 autoimmune syndrome characterized by myositis and myocarditis in a patient 
enrolled in study EMR 100070-001, a Phase I study of avelumab in patients with 
advanced solid tumors.  The event occurred 18 days after the first dose of avelumab 
(20 mg/kg).

A fatal case of potential autoimmune myocarditis, acute cardiac failure and 
respiratory failure (case no. 8091934) occurred in a patient enrolled in study EMR 
100070-004, a Phase III study of avelumab as a second-line treatment for non-small 
cell lung cancer.  The events occurred 14 days after the first and only dose of 
avelumab (10 mg/kg).
Cases of severe or fatal myocarditis also have been reported with other immune checkpoint 
inhibitors, including pembrolizumab, nivolumab, and ipilimumab,20-24 either as single 
adverse events or in the context of more complex autoimmume syndromes.  For both 
ipilimumab and nivolumab, myocarditis is reported in the prescribing information with a 
frequency of <1%.25,26  
Given these reports, routine troponin measurements are being implemented in selected 
avelumab studies, including Protocol B9991001.  Cardiac troponin (cTn) is a sensitive 
marker of myocardial injury and may aid in the identification of patients potentially 
experiencing myocarditis; however, the utility of routine troponin monitoring for the early 
detection of myocarditis is currently unknown.  In addition to cTn monitoring, guidelines for 
the management of suspected or confirmed myocarditis and relevant avelumab management 
instructions are provided in Table 5. 

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Avelumab Pharmacokinetics: Avelumab pharmacokinetics and dose proportionality 
following the first 1-hour infusion have been characterized in 77 mainly Caucasian patients 
treated in the dose escalation and expansion cohorts of Study EMR 100070-001 by standard 
non-compartmental analysis.  This analysis revealed that the exposure parameters of Cmax and 
AUCτ increased with dose in a linear fashion across the 1, 3, 10 and 20 mg/kg doses.  The 
apparent half-life tends to increase with the dose, presumably linked to target-mediated 
disposition.  Taking into account the variability, the half-lives of the 10 and 20 mg/kg doses 
were similar (mean half-lives of 102 and 120 hours, respectively), indicating that target 
mediated elimination does not increase at these doses.  This implies that target occupancy is 
likely to be high at these two doses throughout the dosing interval. 
Target occupancy on peripheral blood CD3+ T-cells was investigated in human blood from 
8 healthy volunteers in vitro by flow cytometry after spiking of whole blood samples with 
avelumab over a concentration range of 0.003-10 g/mL.  Fifty percent (50%) receptor 
occupancy was observed at a drug concentration of 0.122 g/mL ±0.042 g/mL with a 
plateau indicating at least 95% receptor occupancy reached in all blood samples at 1 g/mL.  
PK profiles obtained from the dose escalation phase of Study EMR 100070-001 found all 
patients at 10 mg/kg dose reached or exceeded the serum level (median Ctrough 20-37 ug/ml) 
of avelumab required for >95% target occupancy.  For patients treated with 3 mg/kg of 
avelumab, 10 of 13 patients reached the required serum level (3.7 - 8.3 g/mL).
Complete information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the Avelumab Investigator’s Brochure.19
1.2.2.2. Rationale for Best Supportive Care as Comparator Arm
Currently, there are no approved therapeutic agents for the maintenance treatment of patients 
with unresectable UC who have completed prior systemic therapy with a platinum-based 
regimen.  Despite improvement of patient outcomes with these first-line therapies, durable 
and complete responses (CRs) in patients with advanced UC are uncommon and severe side 
effects limit long-term use of these agents.  Following completion of first-line therapy, 
patients are managed with best supportive care (BSC) until disease progression.  The 
“Guideline on the evaluation of anticancer medicinal products in man” (European Medicines 
Agency (EMA)/Committee for Medicinal Products for Human Use (CHMP)/205/95/Rev.4, 
Dec2012) indicates that BSC may be acceptable in cases where there is no well-documented 
reference regimen.  This guideline also defines BSC to include antibiotics, nutritional 
support, correction of metabolic disorders, optimal symptom control and pain management 
(including palliative radiotherapy), etc., but does not include active anti-tumor therapy.  
1.2.3. Rationale for Studying Avelumab plus Best Supportive Care in Patients with 
Advanced Urothelial Cancer
1.2.3.1. Medical Need
Durable CR following first-line chemotherapy in patients with advanced UC are uncommon.  
Complicated treatment regimens and severe side effects limit long-term use of these agents 
and most patients will ultimately experience disease progression within 9 months after initial 
response.14  Patients with stable disease (SD) or objective response (OR) are typically 

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managed with BSC alone after completion of first-line chemotherapy until progression of 
disease occurs and only then begin treatment with an alternate therapy.  While 
platinum-based combination chemotherapy leads to high response rates in patients with UC, 
most patients will ultimately experience disease progression.  Optimal treatment in the 
second-line treatment setting still needs to be determined.27  Single and combination agents 
evaluated in this treatment setting have been associated with low median progression-free 
survival (PFS, 1.5-3.0 months) and overall survival (OS, 4.6.-6.9 months), and are also 
associated with significant toxicities.28,29,30
In 2009, vinflunine was approved in Europe for the second-line treatment of UC after failure 
of first-line platinum-based therapy.28,31  Three hundred seventy (370) adult patients with 
advanced or metastatic transitional-cell carcinoma of the urothelial tract were randomly 
assigned 2:1 to vinflunine plus BSC or BSC alone in a Phase 3 trial.  Patients had previously 
received platinum-based therapy after which relapse had occurred.  In the intent-to-treat 
(ITT) population, the median OS was 6.9 months for vinflunine plus BSC vs 4.6 months for 
BSC alone.  In multivariate Cox analysis, the addition of vinflunine was independently 
correlated with improved survival (hazard ratio [HR]: 0.719; 95% confidence interval 
[CI]: 0.570-0.906, P =0.0052).28  However, the response rate with vinflunine is disappointing 
and it has not been formally compared with other commonly used agents such as taxanes.  
The current “watch-and-wait” approach for the management of metastatic UC following 
response to first-line chemotherapy prior to initiation of second-line treatment has not proven 
to be effective because almost all patients eventually relapse.  A multicenter Phase 2 study of 
sunitinib as maintenance therapy in patients with advanced UC was recently reported.32  
Although the study terminated prematurely due to low patient recruitment, it provided a 
different perspective on the treatment of this disease (ie, maintenance therapy following 
response to first-line chemotherapy in an attempt to improve the durability of the initial 
response).  Very recently, Powles et al reported the results of a Phase 2/3 study of lapatinib 
as maintenance treatment after first-line chemotherapy in patients with HER1/HER2-positive 
UC.33  Between 2007 and 2013, 455 patients were screened and 232 HER 1 or 2 positive 
patients randomized to lapatinib (n = 116) or placebo (n = 116).  The median PFS, median 
OS, and objective response rate (ORR) for lapatinib vs. placebo were 4.6 months (95% CI: 
2.8 – 5.4) vs. 5.3 months (95% CI: 3.0 – 5.9) (HR: 1.04 [95% CI: 0.79 – 1.39] p = 0.77); 
12.6 months (95% CI: 9.5 – 16.2) vs. 11.9 months (95% CI: 10.6 – 15.8) (HR 0.98 [95% CI: 
0.71 – 1.35] p = 0.89); and 13.8% vs. 7.8%, respectively (p = 0.14).  Subset analysis of 1) 
HER1/HER2 3+ positive UC patients on immunohistochemistry (IHC), 2) HER1-positive 
UC patients, and 3) HER2-positive UC patients showed no significant benefit for lapatinib 
compared to placebo in median PFS (HR 0.94, 0.99, and 1.19 respectively; p >0.05 for each) 
or median OS (HR: 0.76, 0.92, and 1.03 respectively; p >0.05 each).  In addition, a study 
evaluating vinflunine34,35 as a maintenance UC treatment is currently ongoing.
1.2.3.2. Rationale for Immunotherapy for Maintenance Treatment of Urothelial Cancer
There is a strong rationale for considering immunotherapy in patients with advanced UC.  
Urologists led the way in the use of immunotherapy in cancer in 1976, having introduced the 
tuberculosis vaccine bacille Calmette-Guérin (BCG), which stimulates a robust immune 
response in most patients and has become the standard of care as locoregional therapy after 

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surgical resection of non-muscle-invasive disease.36,37  Multiple immunotherapies including 
interferon (IFN)-α, interleukin (IL)-2, IL-12, and IL-10 have been investigated, either as 
adjuncts with BCG or as a solo replacement therapy.38,39  Over the past 40 years, progress 
evaluating immunotherapy for bladder cancer has been slow.  Subsequently, the PD-1/PD-L1 
pathway has emerged as an important biological pathway in UC.40,41,42  PD-1, an 
immunoinhibitory receptor of the CD28 family, plays an important role in tumor immune 
escape.43,44  The PD-1/PD-L1 interaction inhibits T-lymphocyte activation, proliferation, 
survival, and effector functions during anti-cancer immune response.  Several tumors, 
including UC, present with high rates of somatic mutations,45,46,47 possibly enhancing the 
host immune system’s ability to recognize tumor cells as foreign owing to an increased 
number of antigens and stimulate T-cell response.48  However, these cancers may also elude 
immune surveillance and eradication through the expression of PD-L1 in the tumor 
microenvironment,49 which then becomes an important target for anti-PD-L1 antibodies.  
Indeed, antibodies blocking PD-1 and PD-L1 have demonstrated significant and durable 
response in patients with advanced UC.  In a Phase 1b study of anti-PD-1 mAb 
pembrolizumab in heavily pre-treated patients with advanced UC,40 the ORR was 
24% (10% CR) among 33 treated patients with median follow-up duration of 11 months 
(range 10-13).  The responses observed were durable, ranging from 16 to 40+ weeks (median 
not reached), with several responses ongoing at the time of analysis.
Similarly, an anti-PD-L1 mAb, MPDL-3280A, recently demonstrated significant durable 
response in heavily pre-treated patients with UC.41,42  Preliminary data presented at the 
ASCO 2014 Annual Meeting from a Phase 1 study of MPDL-3280A as second-line treatment 
of patients with PD-L1 positive UC demonstrated noteworthy activity in 20 evaluable 
patients with an ORR of 50%, including 1 CR and 9 partial response (PRs).41  Durable 
responses were also demonstrated with this agent in heavily pre-treated patients with 
advanced stage UC,41,42 with an ORR of 54% in 68 patients with PD-L1-positive tumors, 
with durable ongoing responses up to 30.3 weeks reported.41  Updated data from these 
studies with MPDL-3280A and pembrolizumab in patients with recurrent or metastatic 
PD-L1-positive UC further indicated durable responses with promising PFS and OS in 
patients with PD-L1-positive tumors, local immune/inflammatory cells, or stroma.  Among 
85 patients (46 PD-L1 immunohistochemistry [IHC] 2/3 and 38 IHC 0/1) with UC who 
received MPDL-3280A, the ORR for PD-L1 IHC 2+/3+ UC patients was 46% (95% CI: 
31-61%; 6 CRs, 15 PRs) and IHC 0/1+ UC patients was 16% (95% CI 6-31%; 6 PRs); 
median response durations not reached (IHC 2/3 0+ to 54+ weeks; IHC 0/1 4+ to 33+weeks).  
Median PFS for IHC 2+/3+ UC patients was 24 weeks (95% CI 12-NE) and for IHC 0/1+ 
UC patients was 8 weeks (95% CI 6-12).50  Among 33 patients enrolled with 
≥1% PD-L1-positive cells in tumor nests or a PD-L1-positive band in stroma by IHC to 
receive pembrolizumab, 28 had measurable disease at baseline.  In these evaluable patients, 
the ORR was 25% (95% CI: 11-45), with 3 (11%) CR and 4 (14%) PR, with durations 
ranging from 16 to 50+ weeks (median not reached at time of analysis).51
Avelumab, a potent and highly selective fully human mAb of the Ig G1 isotype, targets and 
blocks PD-L1, the ligand for PD-1 and B7.1 receptors.  Avelumab binds PD-L1 and blocks 
the interaction between PD-L1 and PD-1 and B7.1, removing the suppressive effects of PD-
L1 on anti-tumor CD8+ T-cells and resulting in restoration of the cytotoxic T-cell response.19  

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Avelumab has demonstrated an efficacy and safety profile similar to other PD-1/PD-L1 
inhibitors.19,52
In the ongoing Phase 1 study EMR 100070-001, 53 patients were treated with avelumab 
doses of 1.0, 3.0, 10.0, and 20.0 mg/kg administered IV Q2W in the dose escalation phase.  
The 10 mg/kg dose level was selected for further study and a summary of pooled safety data 
from1738 patients treated at this dose level in studies EMR 100070-001 and EMR 
100070-003 (N=1738) is available with a data cutoff date of 09 June 2016.19  The most 
frequently reported (incidence >5%) treatment-related adverse events were fatigue (17.7%), 
infusion-related reaction (17.0%), nausea (8.6%), diarrhea (7.1%), chills (6.7%), pyrexia 
(6.1%), decreased appetite (5.2%), and hypothyroidism (5.0%).   
Updated data from a pooled analysis of 249 patients enrolled in two advanced UC expansion 
cohorts in study EMR 100070-001 was recently published.75  Patients were included 
regardless of PD-L1 expression levels. The median age was 68 years and 124 (50%) patients 
received 2 or more prior treatments for advanced or metastatic disease.  At the time of the 
analysis (09 June 2016 data cut-off), the median followup was 9.9 months (range 4.3-12.1 
months) and 60 (24%) patients were still on treatment. Among 161 post-platinum patients 
with at least 6 months of follow-up, the ORR was 17% (95% CI: 11-24%), including 9 CRs 
and 18 PRs.  The disease control rate (DCR) was 40%, including 37 patients who had SD as 
their best response.  An analysis using a cut-off of 5% for the expression of PD-L1 on 
tumor cells in 139 evaluable patients showed a 24% (15/63) ORR in the PD-L1 positive 
population and 13% (10/76) in the PD-L1 negative population, supporting that avelumab has 
anti-tumor activity in both the PD-L1 positive and negative populations.  The median PFS 
was 11.9 weeks (95% CI: 6.1-18.0 weeks) and 6.1 weeks (95% CI: 5.9-8.0 weeks) in the 
PD-L1 positive and negative populations, respectively.  The median OS was 8.2 months 
(95% CI: 5.7-13.7 months) and 6.2 months (95% CI: 4.3-14.0 months) in patients with 
PD-L1 positive and negative tumors, respectively.
These data support further evaluation of avelumab (MSB0010718C) for the treatment of 
patients with advanced stage UC.  Given the poor prognosis for patients with advanced UC 
whose disease progresses after first-line chemotherapy, where patient outcomes are 
ultimately very poor,30,53 a maintenance treatment with avelumab after first-line 
platinum-based chemotherapy may provide additional clinical benefit compared to the 
current watch-and-wait standard of care after chemotherapy.  The current treatment 
recommendation for the first-line treatment of advanced UC is platinum-based 
chemotherapy,1 which has been administered for a maximum of 6 cycles in previously 
completed clinical trials.12,14,15,54  Due to the toxicities associated with platinum-based 
chemotherapy, these therapies are not administered long term; patients who respond to 
first-line treatment are then managed with BSC until disease relapse or progression, when 
second-line treatments are considered.  The safety and efficacy of avelumab plus best 
supportive care (BSC, Arm A) and BSC alone (Arm B) will be evaluated in two coprimary 
populations: 1) patients with PD-L1-positive tumors (including infiltrating immune cells) 
confirmed by a verified Good Manufacturing Practice (GMP) PD-L1 IHC test, and 2) all 
randomized patients to assess the effects of avelumab in this therapeutic setting.  

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1.2.3.3. Rationale for Study Design
As described in the previous section, recent data demonstrate that immune checkpoint 
inhibitors, including avelumab, are capable of inducing objective tumor response in advanced 
UC patients and may provide further clinical benefit by prolonging overall survival.41,42,51,55  
The strategy of the proposed trial is to maintain or extend early clinical benefit following 
completion of first-line platinum-based chemotherapy in patients with advanced urothelial 
cancer by providing maintenance immunotherapy with avelumab.  In this study, patients 
assigned to receive avelumab may continue to do so until their disease progresses or they 
discontinue due to other reasons.  The potential benefits of avelumab maintenance therapy 
may include delay in the subsequent treatment with more toxic 2nd line chemotherapy as well 
as an improvement in overall survival.
An open-label design was chosen over a double-blind placebo-controlled design after 
assessment of risk-benefit considerations.  As the study medication (avelumab) is 
administered as a 1-hour infusion, the use of an intravenous placebo would be associated 
with some risks (eg, injection site reactions) and with no benefit to the patient.  Additionally, 
in order to preserve the blind, the use of a placebo infusion would require premedication with 
an H1 blocker and paracetamol prior to infusion as required for patients receiving avelumab 
to limit the incidence and severity of infusion-related reactions, an unnecessary practice for 
patients receiving placebo. 
Overall survival (OS) will be the primary endpoint.  PFS assessed by Blinded Independent 
Central Review (BICR) as well as the objective response as determined by RECIST v1.1 
guidelines, will be secondary endpoints. 
At the pre-specified interim analysis (Section 9.6), this study met the primary objective and 
demonstrated that avelumab plus BSC significantly prolongs OS compared to BSC alone in
both co-primary populations (ie, in all randomized patients and in patients with 
PD-L1-positive tumors).  Based on this result, the E-DMC recommended that remaining 
patients on Arm B who are progression-free be offered crossover to avelumab.  For 
additional information, please refer to Supplement 1.  
As the primary objective for the study was met (see above), a final OS update will be 
conducted after the target number of OS events has been reached (see Section 9.1; 425 OS 
events in all patients and 219 OS events in patients with PD-L1 positive tumors).  Following
this final OS update or approval of Protocol Amendment 6, whichever is later, the frequency 
of study procedures will be reduced for patients actively receiving avelumab and study 
participation for all others will be ended.  Investigators will be appropriately notified once 
the final OS update has been completed and Amendment 6 can be fully implemented.
1.2.4. Rationale for Avelumab Dose and Best Supportive Care Regimens
Arm A patients will receive avelumab plus BSC.  The avelumab dose will be 10 mg/kg 
administered as a 1-hour IV infusion every 2 weeks (Q2W).  This dose is the recommended 
dose administered to >700 patients in the ongoing dose-expansion phase of study EMR 
100070-001 (see Section 1.2.2.1 for details and the Avelumab Investigator’s Brochure).19

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Arm B patients will receive BSC as deemed appropriate by the treating physician (see 
Section 5.8).  Currently, there are no approved therapeutic agents for the maintenance 
treatment of patients with unresectable UC who have completed prior systemic 
platinum-based therapy without progression of disease.  Despite improvement of patient 
outcomes with these first-line therapies, durable and complete responses in patients with 
advanced UC are uncommon, and severe side effects limit long-term use of these agents.  
These patients are typically managed with BSC alone until progression of disease occurs, and 
only then are they treated with an alternate therapy.13,30  Salvage cytotoxic agents have not 
demonstrated meaningful improvements in survival.30  Initiation of maintenance therapy in 
an attempt to improve the durability of response and prolong time to progression is an 
alternate approach to management of this disease.32,34,35,56  The “Guideline on the evaluation
of anticancer medicinal products in man” (EMA/CHMP/205/95/Rev.4, Dec 2012) indicates 
that BSC may be an acceptable comparator in cases where there is no well-documented 
reference regimen.  
1.3. Summary of Benefit-Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
For single-agent avelumab, based on the nonclinical and Phase 1 trial EMR 100070-001 
clinical data available to date, the conduct of the trial with the proposed avelumab dosing 
regimen is considered justifiable.  
The anti-tumor activity of several PD-1/PD-L1 inhibitors,40,41,42 including avelumab in the 
cohort of pretreated patients with UC in Study EMR 100070-001, support the formal testing 
of avelumab in the maintenance treatment setting following first-line chemotherapy in 
patients with unresectable locally advanced or metastatic UC that did not progress on 
first-line chemotherapy.
Available adverse event and laboratory abnormality data from patients with advanced solid 
tumors treated with single agent avelumab suggest an acceptable safety profile for this agent.  
Most of the observed events were either in line with those expected in patients with advanced 
solid tumors or with similar class effects of monoclonal antibodies blocking the PD-1/PD-L1 
axis (see Section 1.2.2.1).  
Infusion-related reactions (including hypersensitivity) and immune related adverse events 
(irAEs)/autoimmune disorders have been identified as important risks for avelumab.  
Respective risk mitigation measures have been implemented in all ongoing clinical studies 
with avelumab, including this clinical trial protocol.  These include a treatment algorithm and 
guidelines for treatment interruption and discontinuation in case of irAEs, as well as 
instructions for mandatory pre-medication with a histamine H1 receptor (H1) blocker and 
acetaminophen before the first 4 avelumab infusions.  
Thus, the projected benefit/risk of avelumab administered in the first-line maintenance 
setting in patients with locally advanced or metastatic UC is anticipated to be favorable for 
investigation in this advanced cancer patient population.

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Patients assigned to Arm B (BSC alone) who are progression-free and have not yet 
completed the EOT visit will be offered treatment with avelumab plus BSC maintenance 
therapy.  For additional information, please refer to Supplement 1.  
Of note, the benefit of avelumab plus BSC compared to BSC alone was demonstrated in a 
study population who had completed first-line chemotherapy 4-10 weeks prior to 
randomization to study treatment.  The potential benefit of avelumab plus BSC is unknown 
for those in Arm B who might crossover to avelumab.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective
To demonstrate the benefit of maintenance treatment with avelumab plus BSC vs. BSC alone 
in prolonging overall survival (OS) in patients with unresectable locally advanced or 
metastatic UC whose disease did not progress on or following completion of first-line 
platinum-containing chemotherapy in each co-primary UC patient population: 1) patients 
determined to have PD-L1-positive tumors (including infiltrating immune cells) by a verified 
GMP PD-L1 IHC test, and 2) all randomized patients. 
Secondary Objectives

To compare the PFS of avelumab plus BSC vs. BSC alone in patients determined to 
have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP 
PD-L1 IHC test, and in all randomized patients.

To evaluate the anti-tumor activity of avelumab plus BSC and BSC alone according 
to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients 
determined to have PD-L1-positive tumors (including infiltrating immune cells) by a 
verified GMP PD-L1 IHC test, and in all randomized patients.

To evaluate the overall safety profile of avelumab plus BSC and BSC alone.

To evaluate the PK of avelumab in each of the co-primary UC patient populations
treated with avelumab. 

To assess the immunogenicity of avelumab in each of the co-primary UC patient 
populations treated with avelumab.

To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab 
in pre-treatment tumor tissue in each of the co-primary UC patient populations treated 
with avelumab.

To evaluate the effect of avelumab plus BSC and BSC alone on patient-reported 
outcomes (PROs) in each of the co-primary UC patient populations.

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Exploratory Objectives

To explore the predictive and/or pharmacodynamic (PD) characteristics of peripheral 
blood and additional tumor tissue biomarkers relevant to the mechanism of action of 
or resistance to avelumab.
2.2. Endpoints
Primary Endpoint

Overall Survival (OS).
Secondary Endpoints

Progression-free survival (PFS) based on BICR assessment per RECIST v1.1.

Investigator-assessed Progression-Free Survival (PFS). Objective Response (OR), 
Time to Tumor Response (TTR), Duration of Response (DR), and Disease Control 
(DC), as assessed per RECIST v1.1 by BICR and investigator.

Safety: Adverse events (AEs) and laboratory abnormalities as graded by National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v.4.03; vital signs (blood pressure, pulse rate). 

Pharmacokinetics (PK): maximum concentrations (Cmax) and trough concentrations 
(Ctrough) for avelumab.

Immunogenicity: Anti-drug antibodies (ADA; neutralizing antibody [Nab]) against 
avelumab.

Biomarkers: Tumor tissue biomarkers including, but not limited to, PD-L1 expression 
and tumor-infiltrating CD8+ T lymphocytes.

Patient-Reported Outcomes: patient-reported bladder cancer symptom, functioning, 
global quality of life (QOL), and Time to Deterioration (TTD) using the 
NCCN-FACT FBlSI-18; and health status using the EQ-5D-5L.
Exploratory Endpoints

Biomarkers: Peripheral blood and additional tumor tissue biomarkers consisting of 
the levels of cells, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or proteins 
that may be related to anti-tumor immune response and/or response to or disease 
progression on avelumab, such as genes related to IFN-or transforming growth 
factor (TGF)-.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 3, multicenter, multinational, randomized, open-label, parallel-arm efficacy 
and safety study of avelumab plus BSC compared to BSC alone as a maintenance treatment 

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after completion of first-line platinum-based chemotherapy without evidence of disease 
progression in adult patients with unresectable locally advanced or metastatic UC.  
The study design is illustrated in the following figure.
Figure 1
Study B9991001 Design

Patients may sign informed consent at any time during or after completion of 
chemotherapy and prior to any study specific procedures, however must meet all 
eligibility requirements to be randomized in the study. 

A total of approximately 668 patients without progressive disease as per 
RECIST v1.1 guidelines (ie, with ongoing CR, PR, or SD) after 1st line chemotherapy 
will be allowed to be randomized in this study.  It is estimated that at least 
334 patients with confirmed PD-L1-positive tumors (including infiltrating immune 
cells) will be randomized in this study.  

Patients will be randomized in a 1:1 ratio into two study arms: avelumab plus BSC 
(Arm A) or BSC alone (Arm B).  

Patients must have received at least 4 cycles, but not more than 6 cycles of a first-line 
chemotherapy regimen consisting of either gemcitabine + cisplatin or gemcitabine 
+ carboplatin before randomization into this study.  No other chemotherapy regimen 
is allowed as the first line chemotherapy for inclusion in this clinical trial (please see 
Section 4.1, Inclusion Criterion #2).

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
Randomization must occur at least 4 but not more than 10 weeks after the date of 
administration of the last dose of chemotherapy.  Patients will initiate study treatment 
(Cycle 1 Day 1) within 3 days after randomization.

Only patients without progressive disease as per RECIST v1.1 guidelines (ie, with 
ongoing CR, PR, or SD) after 4-6 cycles of chemotherapy will be allowed to be 
randomized in this study.  

Post-chemotherapy confirmatory scan(s) (CT/MRI) for eligibility must be 
performed within 28 days prior to the date of randomization to assess response 
status following first-line chemotherapy.  

Based on the post-chemotherapy confirmatory scan(s), the investigator should 
assess patient eligibility (ie, CR, PR, or SD) before randomization.

This study is designed with two co-primary populations: 1) patients determined to 
have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP 
PD-L1 IHC test, and 2) all randomized patients. 

Randomization will be stratified by (i) best response to first-line chemotherapy 
(CR/PR vs. SD), and (ii) metastatic disease site (visceral vs. non-visceral) at the time 
of initiating first-line chemotherapy.  

Radiological tumor assessments will be conducted during the study at baseline as the 
post-chemotherapy confirmatory scan (as described above, within 28 days prior to 
randomization), at 8 weeks after randomization, then every 8 (±3 days) weeks for up 
to 1 year from randomization, and every 12 (±3 days) weeks thereafter until 
documented disease progression as assessed by BICR regardless of initiation of 
subsequent anti-cancer therapy.  Additional radiological tumor assessments should 
also be conducted whenever disease progression is suspected (eg, symptomatic 
deterioration).  Please see Section 3.1.2, Tumor Assessments for additional 
information.

All patients will be followed for survival until death, end of the study, or patient 
withdrawal of consent, whichever comes first, regardless of initiation of anti-new 
cancer therapy(ies).  Long-term follow-up survival assessments (every 3 months) may 
be completed at the investigative site or by telephone contact.

Upon approval of protocol Amendment 5, patients assigned to Arm B (BSC alone) 
who are progression-free and have not yet completed the EOT visit will be offered 
treatment with avelumab plus BSC maintenance therapy.  For additional information, 
including Schedule of Activities for those patients who crossover to avelumab, please 
refer to Supplement 1.  

Arm B patients who do not crossover to avelumab plus BSC will continue 
assessments as per protocol.  

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
As per Protocol Amendment 6, following the final OS update, the frequency of study 
procedures will be reduced while providing continued treatment for patients actively 
receiving avelumab and ending study participation for all patients who are not 
actively receiving avelumab (ie, Arm A patients in long-term follow-up and all Arm 
B patients who have not crossed over to receive avelumab).
3.1.1. Study Treatment 

For the purpose of this study, “study treatment” refers to both the investigational 
product (avelumab) plus BSC and BSC alone administered to patients during 
participation in this study.  

Study treatments may continue until confirmed disease progression as assessed by 
BICR, patient refusal, patient lost to follow up, unacceptable toxicity, or the study is 
terminated by the sponsor, whichever comes first (see Section 6.5 Patient 
Withdrawal).  

According to the opinion of an investigator, if a patient in Arm A is still experiencing 
clinical benefit at the time of confirmed disease progression, the patient will be 
eligible for continued treatment with avelumab plus BSC, provided the treating 
physician has determined that the benefit/risk for doing so is favorable (see 
Section 5.4.1 Treatment after Initial Evidence of Radiologic Disease Progression).  
Radiological tumor assessments will be continued in these patients as described in the 
Section 3.1.2, Tumor Assessments.

If a patient starts a new anti-cancer therapy before documented disease progression, 
then tumor assessments should be continued per the Schedule of Activities (unless not 
feasible) until documentation of disease progression or death, whichever occurs first. 

After review of radiologic images by BICR is stopped as per Protocol Amendment 6, 
following the final OS update, study treatment may continue until disease progression 
is assessed by the investigator, patient refusal, patient lost to follow-up, unacceptable 
toxicity, or the study is terminated by the sponsor, whichever comes first (see 
Section 6.5 Patient Withdrawal).  

Arm A: Avelumab (MSB0010718C) plus Best Supportive Care
Patients randomized to avelumab plus BSC (Arm A) will be administered avelumab 
as a 1-hour IV infusion at a dose of 10 mg/kg once every 2 weeks together with BSC 
(see below).
To mitigate potential infusion-related reactions, patients in Arm A will be 
premedicated prior to avelumab administration as described in Section 5.4.3.1.  If an 
infusion-related reaction is observed, the infusion rate should be decreased or stopped 
depending on the severity of the event; please refer to Section 5.4.3.2 for further 
guidance.

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
Arm B: Best Supportive Care Alone
Patients randomized to BSC alone (Arm B) will be cared for as deemed appropriate 
by the treating physician.  This could include treatment with antibiotics, nutritional 
support, correction of metabolic disorders, optimal symptom control and pain 
management (including palliative radiotherapy), etc.  BSC does not include any 
active anti-tumor therapy (see Section 5.8), however local radiotherapy of isolated 
lesions with palliative intent is acceptable as described in Section 5.9.2.
3.1.2. Tumor Assessments
Anti-tumor activity will be assessed by radiological tumor assessments and will be based on 
RECIST v1.1 (Appendix 2).
Tumor assessments will include all known or suspected disease sites.  For all patients, 
imaging assessments will include chest, abdomen, and pelvis computerized tomography (CT) 
or magnetic resonance imaging (MRI) scans.  Bone imaging, eg, bone scans or other methods 
considered standard of care locally, such as 18-Fluorodeoxyglucose Positron Emission 
Tomography (18FDG-PET) or MRI, are required at baseline (28 day screening period).  
(Note: 18FDG-PET may not be a permissible alternate for bone imaging at some centers or 
countries (eg, investigative sites in Canada).  Bone lesion(s) identified at baseline by bone 
scan will be further assessed by CT or MRI as per local practice (where bone scans are not 
used as a routine restaging tool) and subsequently re-assessed by CT or MRI as per the tumor 
assessment schedule as an alternative to bone scans.  Bone imaging will only be repeated 
during study as clinically indicated (eg, patient describes new or worsening bone pain, or has 
increasing alkaline phosphatase level, or other signs and symptoms of new/progressing bone 
metastases), at the time of complete response (CR) confirmation, and at every other tumor 
assessment visit (ie, every 16 weeks for the first year after randomization and every 24 weeks 
thereafter) if considered local standard of care.  
Brain imaging (eg, MRI) is required at baseline for patients who have a history of brain 
metastases or for whom brain metastases are suspected during screening.  Brain must be 
included in subsequent tumor assessments if a patient has brain metastases at baseline; 
otherwise brain will only be evaluated when clinically indicated.  
Both pre-chemotherapy and post-chemotherapy scans must have been performed and be 
readily available during screening.  Post-chemotherapy confirmatory scan for eligibility must 
be performed within 28 days prior to the date of randomization to assess response status 
following first-line chemotherapy.  This scan will also be used as the baseline scan for the 
tumor assessments in this study.
For all patients, radiological tumor assessments (including chest, abdomen, and pelvic CT or 
MRI scans) will be conducted at baseline (ie, the post-chemotherapy confirmatory scan 
within 28 days prior to randomization), at 8 weeks after randomization, then every 
8 (±3 days) weeks for up to 1 year from randomization, and every 12 (±3 days) weeks 
thereafter until documented disease progression as assessed by BICR regardless of initiation 

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of subsequent anti-cancer therapy.  Additional radiological tumor assessments should also be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration).
CR and PR must be confirmed with repeat imaging performed at least 4 weeks after initial 
documentation of response.  In the absence of clinical deterioration, patients with PD should 
remain on the current study treatment until PD is confirmed by BICR.  Further details 
regarding tumor assessments are provided in Section 7.7.
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions unless an increase in size has been observed following completion of radiation 
therapy.
All radiographic images from the time of the most recent tumor assessment prior to first-line 
chemotherapy until documented disease progression will be submitted to an independent 
third-party core imaging laboratory for Blinded Independent Central Review (BICR) as 
described in the Study Manual.  
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.
As per Protocol Amendment 6, following the final OS update, tumor assessments will be 
performed by the study investigator at a frequency as per local standard of care and when 
progression is suspected. Radiologic images will no longer be submitted for independent 
central review or entered into the CRF.
3.1.3. Safety Assessment
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the Schedule of Activities table. 
3.1.4. Patient-Reported Outcomes 
PROs will be assessed using 2 published and validated instruments, NCCN-FACT FBlSI-18 
and EQ-5D-5L.
In the treatment of UC, delay of worsening of symptoms and maintenance of QOL is a 
treatment goal with the currently available non-curative therapies.57  To that end, Herman et 
al, (2004)58 demonstrated that the combination of gemcitabine with radiation therapy 
maintained overall QOL versus radiation alone, as indicated by the FACT-Bl.  The 
NCCN-FACT FBlSI-18 (a later version of the FACT-Bl) was developed to be part of the 
Functional Assessment of Chronic Illness Therapy (FACIT) system59,60 and was specifically 
created with input from the Food and Drug Administration (FDA) and validated in bladder 
cancer patients.61  The NCCN-FACT FBlSI-18 is designed to be a stand-alone instrument to 
measure symptoms and QoL in patients with UC and was created using inputs from patients 
and oncologists.62  The ‘Disease Related Symptoms-Physical’ subscale of the NCCN-FACT 
FBlSI-18 (FBlSI-DRS-P), uses a subset of physical symptoms which are considered to be 
specific to UC.61

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The EuroQol EQ-5D-5L is a 6-item patient-completed questionnaire designed to assess 
health status in terms of a single index value or utility score.63  There are 2 components to the 
EuroQol EQ-5D-5L, a Health State Profile which has individuals rate their level of problems 
(none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in 
which patients rate their overall health status from 0 (worst imaginable) to 100 (best 
imaginable).  Published weights are available that allow for the creation of a single summary 
score.64  Overall scores range from 0 to 1, with low scores representing a higher level of 
dysfunction.  
3.1.5. Pharmacokinetic/Immunogenicity Assessments
Sparse plasma/serum PK/immunogenicity sampling will be collected for avelumab and anti-
drug antibodies (ADA).  Sampling will only be done in patients randomized to Arm A.  Refer 
to the Schedule of Activities table and Sections 7.3 and 7.4 for additional details of the PK 
and immunogenicity collections.    
3.1.6. Biomarker Assessments 
Mandatory baseline (recent) tumor tissue, as well as archival tumor tissue, if available, will 
be collected from all patients to support investigation and, as appropriate, clinical validation 
of biomarkers that may predict response to treatment.  End of Treatment tumor tissue from a 
de novo biopsy should also be obtained unless clinically contraindicated to support an 
investigation of mechanisms of resistance.  Banked blood biospecimen will be collected from 
all patients at baseline, on treatment and at End of Treatment/Withdrawal to support 
exploratory investigation of possible markers predictive of clinical benefit, 
pharmacodynamic markers and/or markers of intrinsic or acquired resistance. 
Biomarker assessments are described in the Schedule of Activities table and in Section 7.5
and Section 7.6.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.

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Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Diagnosis:
a.
Histologically confirmed, unresectable locally advanced or metastatic transitional 
cell carcinoma of the urothelium.  
b. Documented Stage IV disease (per American Joint Committee on 
Cancer/International Union for Cancer Control Tumor Node Metastasis (TNM) 
system, 7th edition)65 at the start of first-line chemotherapy.
c.
Measurable disease prior to the start of first-line chemotherapy by RECIST v1.1.
2. Prior first-line chemotherapy must have consisted of at least 4 cycles and no more 
than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin.  No other 
chemotherapy regimens are allowed in this study.
a.
The last dose of first-line chemotherapy must have been received no less than 
4 weeks, and no more than 10 weeks, prior to randomization in the present study.
3. Patients without progressive disease as per RECIST v1.1 guidelines (ie, with an 
ongoing CR, PR, or SD) following completion of 4 to 6 cycles of first-line 
chemotherapy. 
a.
Eligibility based on this criterion will be determined by investigator review of 
pre-chemotherapy and post-chemotherapy radiological assessments (CT/MRI 
scans); see Study Overview, Section 3.1.
4. Provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block 
(or subsection thereof) from the most recent primary or metastatic tumor biopsy or 
resection obtained prior to treatment with first line chemotherapy but within 
24 months prior to randomization, with no intervening systemic anti-cancer therapy.  
If a FFPE tissue block cannot be provided, 15 freshly cut unstained slides 
(10 minimum) will be acceptable.
If a suitable tissue sample is not otherwise available, then a de novo biopsy (core 
needle or excisional) must have been obtained for research purposes prior to 
randomization in this study.  
Note: tumor tissue from cytologic sampling (eg, fine needle aspiration, including 
FFPE cell pellet material) or bone metastases are not acceptable and should not be 
submitted.
5. Evidence of a signed and dated informed consent document indicating that the patient 
(or a legally acceptable representative, as allowed by local guideline/practice) has 
been informed of all pertinent aspects of the study.

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6. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures.
7. Age 18 years (20 years in Japan).
8. Estimated life expectancy of at least 3 months. 
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 
1 (Appendix 1).
10. Adequate bone marrow function, including:
a.
Absolute neutrophil count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9 g/dL (may have been transfused).
11. Adequate renal function, defined as estimated creatinine clearance 30 mL/min as 
calculated using the Cockcroft-Gault equation (Appendix 4) or by 24-hour urine 
collection for creatinine clearance or according to the local institutional standard 
method.
12. Adequate liver function, including:
a.
Total serum bilirubin 1.5 x upper limit of normal (ULN); 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
2.5 x ULN, or, for patients with documented metastatic disease to the liver, AST 
and ALT levels ≤5 × ULN. 
13. Serum pregnancy test (for females of childbearing potential) negative at screening.
14. Female patients of childbearing potential and at risk for pregnancy must agree to use 
a highly effective method of contraception (Section 4.3.1) throughout the study and 
for at least 30 days after the last dose of assigned treatment. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients whose disease progressed by RECIST v1.1 on or after first-line 
chemotherapy for urothelial cancer. 
2. Prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization.

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3. Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or 
drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
4. Major surgery 4 weeks or major radiation therapy 2 weeks prior to randomization.  
Prior palliative radiotherapy is permitted, provided it has been completed at least 
48 hours prior to patient randomization.
5. Patients with known symptomatic central nervous system (CNS) metastases requiring 
steroids.  Patients with previously diagnosed CNS metastases are eligible if they have 
completed their treatment and have recovered from the acute effects of radiation 
therapy or surgery prior to randomization, have discontinued corticosteroid treatment 
for these metastases for at least 4 weeks, and are neurologically stable. 
6. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however, 
alopecia, sensory neuropathy Grade 2 is acceptable, or other Grade 2 adverse 
events not constituting a safety risk based on the investigator’s judgment are 
acceptable.
7. Diagnosis of any other malignancy within 5 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix, low-grade (Gleason 6) prostate cancer on surveillance
without any plans for treatment intervention (eg, surgery, radiation, or castration), or 
prostate cancer that has been adequately treated with prostatectomy or radiotherapy 
and currently with no evidence of disease or symptoms.
8. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
randomization.  Observational studies are permitted.
9. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or 
hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible.
10. Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring 
medication.
11. Active infection requiring systemic therapy.
12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3), any
history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma 
symptom control per the Global Initiative for Asthma 2015).66

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13. Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations.
14. Current or prior use of immunosuppressive medication within 7 days prior to 
randomization, 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). 
15. Diagnosis of prior immunodeficiency or organ transplant requiring 
immunosuppressive therapy.
16. Positive test for human immunodeficiency virus (HIV) infection or known acquired 
immunodeficiency syndrome (AIDS).
17. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).  
18. Vaccination within 4 weeks of the first dose of study treatment and while on trial is 
prohibited except for administration of inactivate vaccines (for example, inactivated 
influenza vaccines).
19. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
20. Pregnant female patients; breastfeeding female patients; and female patients of 
childbearing potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in the protocol for the duration of the study and for at least 
30 days after the last dose of investigational product.
21. Other severe acute or chronic medical conditions including but not limited to colitis, 
inflammatory bowel disease, pneumonitis, and pulmonary fibrosis; 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 study treatment 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.

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4.3. Lifestyle Guidelines
4.3.1. Contraception
Contraception use and pregnancy test will be evaluated in all patients at screening prior to 
randomization.  However, following assignment to treatment only patients assigned to 
Arm A (avelumab plus BSC) will be required to remain on contraception as described below.  
In Arm A of this study, female patients who are of childbearing potential will receive 
avelumab for which the teratogenic risk is currently unknown.  
All female patients of childbearing potential who are, in the opinion of the Investigator, 
sexually active and at risk for pregnancy must agree to use a highly effective contraception 
method, preferably with low user dependency, during treatment and for at least 30 days after 
the last dose.  The investigator or his or her designee, in consultation with the patient, will 
select an appropriate method of contraception for the individual patient from the list of 
permitted contraception methods (see below), and instruct the patient in its consistent and 
correct use. 
Patients need to affirm that they meet the criteria for the correct use of the selected method of 
contraception.  At time points indicated in the Schedule of Activities, the investigator or his 
or her designee will discuss with the patient the need to use the selected contraception 
method consistently and correctly and document such conversation, and the patient’s 
affirmation, in the patient’s chart.  In addition, the investigator or his or her designee will 
instruct the patient to call immediately if the selected contraception methods are 
discontinued, or if pregnancy is known or suspected in the patient or to the male patient’s 
partner. 
Contraception Methods
Highly Effective Methods of Contraception That Have Low User Dependence include the 
following: 
1. Implantable progestogen- only hormonal contraception associated with the inhibition 
of ovulation.
2. Intrauterine device (IUD).
3. Intra-uterine hormone-releasing system (IUS).
4. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
male partner is the sole sexual partner of the female of child-bearing potential and 
the absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  
5. Bilateral tubal occlusion.

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Highly Effective Methods of Contraception That Are User Dependent include the following: 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
2. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
3. Sexual abstinence.  

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention.  The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the participant.
Female patients of nonchildbearing potential must meet at least 1 of the following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as 60 years or older or no cessation of 
regular menses for at least 12 consecutive months with no alternative pathological 
or physiological cause.  Status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level test.
All other female patients (including females with tubal ligations) will be considered to be of 
childbearing potential.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual.
To facilitate access to appropriately-qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 

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at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however it should be used 
only in the event that the established communication pathways between the investigational
site and the study team are not available.  It is therefore intended to augment, but not replace 
the established communication pathways between the investigational site and 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 investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33).  
For the purpose of this study, the investigational product is avelumab (MSB0010718C).
For the purpose of this study, “study treatment” refers to both the investigational product 
(avelumab) plus BSC and BSC alone administered to patients during participation in this 
study.  Please see Section 5.8 for additional information regarding BSC. 
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular patient or affect the order in which patients are enrolled.
Qualified patients who have signed an Informed Consent Form and meet all eligibility 
criteria will be randomized in a 1:1 ratio to receive avelumab plus BSC (Arm A) or BSC 
alone (Arm B).  Allocation of patients will be stratified according to best response to 
first-line chemotherapy (CR/PR vs. SD) and site of metastases (visceral vs. non-visceral) at 
the time of initiating first-line chemotherapy.  The “non-visceral” stratum includes patients 
with locally-advanced disease as well as patients with only non-visceral disease.  This 
stratified randomization will be centrally allocated across all centers using an Interactive 
Response Technology (IRT) system (an interactive web-based response system).
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, patient identifiers and demographic information, and stratification factors.  
The site personnel will then be provided with a treatment assignment.  The IRT system will 
also provide a confirmation report containing the patient number; this confirmation report 
must be stored in the site’s files. 

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Study treatment (Cycle 1 Day 1) must start within 3 days after patient randomization.
There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues.  The study-specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system. 
Note: The IRT is the source of the patient number.  The IRT system will provide the patient 
number at the end of the first IRT patient transaction. 
Arm B patients who crossover to receive avelumab plus BSC will be assigned avelumab in 
the IRT system according to instructions provided by the Sponsor. 
5.2. Patient Compliance with Avelumab Study Treatment
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigational site.  
5.3. Investigational Product Supplies
Avelumab (MSB0010718C) 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. Avelumab Dosage Form(s) and Packaging
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20.0 mg/mL solution and will be supplied by the sponsor in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene 
flip-off seal.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines.  Avelumab will be packed in 
boxes each containing one vial.  The information on the study treatment will be in 
accordance with approved submission documents. 
Avelumab will be shipped in transport cool containers (2C to 8C) that are monitored with 
temperature monitoring devices.
5.3.2. Avelumab Preparation and Dispensing
See the Dosage and Administration Instructions (DAI), which is located in the 
Investigational Product 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, 

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physician’s assistant, practitioner, or pharmacist) as allowed by local, national, and 
institutional guidance.
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 
anticancer agents.
Avelumab will be administered 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 administration in this trial, avelumab drug product must be diluted with 0.9% sodium 
chloride (normal saline).  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 DAI.  During avelumab administration, tubing with in-line, low protein binding 
0.2 micron filter made with polyether sulfone (PES) must be used.   
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.
5.4. Avelumab Administration
Avelumab will be administered at the investigational site on an outpatient basis as detailed in 
the DAI.
Avelumab will be administered at 10 mg/kg on Day 1 and Day 15 of each 4-week treatment 
cycle after all procedures/assessments have been completed as described in the Schedule of 
Activities table.  All safety assessments must be performed, and results reviewed by the 
treating physician prior to study treatment administration.  
Avelumab will be administered as a 1-hour IV infusion.  In order to mitigate infusion-related 
reactions, premedication with an antihistamine and with paracetamol (acetaminophen) 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory (for 
example, 25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or 
oral equivalent).  Premedication should be administered for subsequent avelumab doses 
based upon clinical judgment and presence/severity of prior infusion reactions.  The 
premedication regimen may be modified based on local treatment standards and guidelines, 
as appropriate, provided it does not include systemic corticosteroids.  Sites should make 
every effort to target infusion timing to be as close to 1 hour as possible.  However, given the 
variability of infusion pumps from site to site, time windows of -10 minutes and +20 minutes 
is permitted (ie, infusion time is 60 minutes: -10 min/+20 min).  The exact duration of 
infusion should be recorded in both source documents and case report forms (CRFs).  

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Possible modifications of the infusion rate for the management of infusion-related reactions 
are described in Section 5.4.3.2.  
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 dose.  If the patient experienced either a weight loss or gain >10% compared 
to the weight used for the last dose calculation, the amount of study drug required for 
preparation and administration for the current dose must be recalculated using this most 
recent weight obtained.  For weight change less than 10%, the decision to recalculate the 
avelumab dose can be in accordance with institutional practice.  Avelumab dose reduction for 
toxicity management is not permitted, however the next dose administration may be omitted 
due to persisting toxicity as described in Table 3 and Section 5.4.3.
5.4.1. Treatment after Initial Evidence of Radiologic Disease Progression 
Immunotherapeutic agents such as avelumab may produce anti-tumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiologic imaging shows disease progression as assessed by BICR (or as assessed by 
Investigator as per Protocol Amendment 6, following the final OS update), after discussion 
between the Sponsor and Investigator, patients may continue to receive avelumab at the 
Investigator’s discretion if the following criteria are met: 

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.
Patients who stop avelumab 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 BSC since the last dose of avelumab, 2) the patient does not meet the 
safety withdrawal criteria, and 3) the trial is still open.
As per Protocol Amendment 6, following the final OS update, patients who stop avelumab 
treatment and subsequently experience radiologic disease progression, will no longer be 
eligible for re-treatment with avelumab.

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5.4.2. Food Requirements
Avelumab may be administered without regard for food.
5.4.3. Recommended Dose Modifications
Every effort should be made to administer study treatment on the planned dose and schedule.
For avelumab, no dose modifications are permitted in this study, but next infusion may be 
omitted based on persisting toxicity.  Recommended toxicity management guidelines with 
regard to avelumab infusion omissions are shown in Table 3.  
Table 3.
Avelumab Infusion Omissions for Avelumab Product-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Treatment Modification
Infusion-related 
Reaction / 
Hypersensitivity 
Grade 1-4

See Section 5.4.3.2 and Table 4.
Tumor lysis 
syndrome
Grade 1-4

See Section 5.4.3.3 and Figure 2.
Immune-related 
AE (irAE)
Grade 1-4

See Section 5.4.3.4 and Table 5.
Drug-related 
adverse reactions
(excluding 
infusion-related 
reaction / 
hypersensitivity 
and immune-
related AE)
Grade 1

Continue as per schedule. 
Grade 2

Continue as per schedule.
Grade 3

Withhold until recovery to Grade 1 or baseline.

Permanently discontinue if toxicities do not resolve to 
Grade 1 or baseline within 12 weeks of last administration 
or if the same Grade 3 toxicity recurs.
Exceptions are:

Laboratory values out of normal range that do not have any 
clinical correlate.    
Grade 4

Permanently discontinue. 
Exceptions are:

Laboratory values out of normal range that do not have any 
clinical correlate.    
Avelumab infusion-related reactions (including hypersensitivity) and irAEs should be 
handled according to guidelines in Section 5.4.3.2 Management of Avelumab Infusion-
Related Reactions and Section 5.4.3.4 Management of Avelumab Immune-Related Adverse 
Events.
5.4.3.1. Special Precautions for Avelumab Administration
In order to mitigate avelumab infusion-related reactions, premedication with an antihistamine 
and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to the first 
4 infusions of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 
500-650 mg paracetamol [acetaminophen] IV or oral equivalent).  Premedication should be 

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administered for subsequent avelumab doses based upon clinical judgement and 
presence/severity of prior infusion reactions.  The premedication regimen may be modified 
based on local treatment standards and guidelines, as appropriate, provided it does not 
include systemic corticosteroids. 
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications 
(IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access.
Infusion of avelumab will be stopped in case of Grade 2 infusion-related, allergic, or 
anaphylactic reactions.  Symptoms of avelumab infusion related reactions include, but are not 
limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal 
pain, and urticaria.  Management of avelumab infusion related reactions is described in 
Section 5.4.3.2.  Patients should be instructed to immediately report to the Investigator any 
delayed reactions that may occur after they leave the clinic.
5.4.3.2. Management of Avelumab Infusion-Related Reactions/Hypersensitivity 
Reactions 
Since avelumab is administered IV, infusion-related reactions may occur (with symptoms 
such as fever, chills, rigors, diaphoresis, and headache).  Treatment of the infusion-related 
reaction and modifications of avelumab infusion are mainly dependent upon severity, as 
indicated in Table 4. 
Table 4.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions
NCI CTCAE Grade
Treatment Modification for Avelumab
Grade 1 – mild

Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.

Decrease the avelumab infusion rate by 50%*
and monitor closely for any worsening.
Grade 2 – moderate

Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for 24 hours.

Temporarily discontinue avelumab infusion.

Resume infusion at 50% of previous rate*
once infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity. 
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.

Stop the avelumab infusion immediately and 
disconnect infusion bag and tubing from the 
patient.

Subjects have to be withdrawn immediately 
from avelumab treatment and must not receive 
any further avelumab treatment.

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Table 4.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions
NCI CTCAE Grade
Treatment Modification for Avelumab

Grade 4: Life-threatening consequences; urgent 
intervention indicated.
IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
*If the avelumab infusion rate has been decreased by 50% due to an infusion reaction, it must remain 
decreased for the next scheduled infusion.  If no infusion reaction is observed at the next scheduled infusion, 
at the Investigator’s discretion, the infusion rate may be returned to baseline at subsequent infusions.
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions: In the 
event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 4 (including reducing the infusion 
rate by 50%), the investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed for that dose.  At the next dose, the investigator may consider the 
addition of H2-blocker antihistamines (eg, famotidine or ranitidine), meperidine, or 
ibuprofen to the mandatory premedication.  Prophylactic steroids are NOT permitted.
5.4.3.3. Management of Avelumab-Related Tumor Lysis Syndrome
Avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), so there is a 
potential risk of tumor lysis syndrome.  Should this occur, patients should be treated as per 
local guidelines and the management algorithm (Figure 2) published by Howard et al.67

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

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5.4.3.4. Management of Avelumab Immune-Related Adverse Events
Treatment of irAEs should follow guidelines set forth in Table 5. 
Table 5.
Management of Avelumab Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Diarrhea: <4 stools/day over 
Baseline
Colitis: asymptomatic 
Continue avelumab therapy.
Symptomatic treatment 
(eg, loperamide).
Close monitoring for worsening 
symptoms.
Educate subject to report 
worsening immediately.
If worsens:
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated <24 
hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy.
Symptomatic treatment.
If improves to Grade ≤1: 
Resume avelumab therapy.
If persists >5-7 days or recurs:
Treat as Grade 3 or 4.
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 5mg/kg (if no 
contraindication).  Note: 
infliximab should not be used in 
cases of perforation or sepsis. 

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Table 5.
Management of Avelumab Immune-Related Adverse Events
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 Grade 2 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.
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 

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Table 5.
Management of Avelumab Immune-Related Adverse Events
Monitor symptoms daily; consider 
hospitalization. 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections. 
Consider bronchoscopy, lung 
biopsy. 
avelumab therapy following 
steroids taper. 
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia;
Grade 4: Life-threatening 
Permanently discontinue avelumab 
therapy.
Hospitalize.
Pulmonary and Infectious Disease 
consults.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider bronchoscopy, lung 
biopsy. 
If improves to Grade ≤1: 
Taper steroids over at least 
1 month. 
If not improving after 48 hours or 
worsening: 
Add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil). 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 3.0 
x ULN and/or Total bilirubin > 
ULN to 1.5 x ULN. 
Continue avelumab therapy.
Continue liver function 
monitoring. 
If worsens: 
Treat as Grade 2 or 3 to 4. 
Grade 2
AST or ALT >3.0 to ≤5 x ULN 
and/or total bilirubin >1.5 to ≤3 x 
ULN. 
Withhold avelumab therapy.
Increase frequency of monitoring 
to every 3 days.
If returns to Grade ≤1:
Resume routine monitoring; 
resume avelumab therapy.
If elevation persists >5 to 7 days 
or worsens: 
Treat as Grade 3 to 4.
Grade 3 to 4
AST or ALT >5 x ULN and/or total 
bilirubin >3 x ULN. 
Permanently discontinue avelumab 
therapy. 
Increase frequency of monitoring 
to every 1 to 2 days. 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections. 
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 

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Table 5.
Management of Avelumab Immune-Related Adverse Events
Consult 
gastroenterologist/hepatologist.
Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted. 
other immunosuppressants per 
local guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 
x ULN
Continue avelumab therapy.
Continue renal function 
monitoring.
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased >1.5 and ≤6 x 
ULN
Withhold avelumab therapy
Increase frequency of monitoring to 
every 3 days.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
If returns to Grade ≤1:
Taper steroids over at least 
1 month, and resume avelumab 
therapy following steroids taper.
If worsens: 
Treat as Grade 4.
Grade 4
Creatinine increased >6 x ULN
Permanently discontinue avelumab 
therapy.
Monitor creatinine daily.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
Nephrology consult.
If returns to Grade ≤1:
Taper steroids over at least 
1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations 
(eg, troponin, CK-MB, BNP) or 
cardiac imaging abnormalities 
suggestive of myocarditis. 
Withhold avelumab therapy.
Hospitalize.
In the presence of life threatening
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
arrhythmia management.
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 

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Table 5.
Management of Avelumab Immune-Related Adverse Events
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.
cardiology consult, manage as 
immune-mediated myocarditis.
Immune-mediated myocarditis
Permanently discontinue avelumab.
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Once improving, taper steroids 
over at least 1 month.
If no improvement or worsening, 
consider additional 
immunosuppressants 
(eg, azathioprine, cyclosporine
A).
*Local guidelines, or eg. European Society of Cardiology or American Heart Association guidelines 
European Society of Cardiology guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines.
American Heart Association guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, Type I diabetes 
mellitus)
Continue avelumab therapy.
Endocrinology consult if needed.
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or 
insulin (for Type I diabetes 
mellitus) as appropriate.  
Rule-out secondary 
endocrinopathies 
(ie, hypopituitarism/hypophysitis).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, Type I diabetes 
mellitus)
Withhold avelumab therapy.
Consider hospitalization.
Endocrinology consult.
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
Resume avelumab once 
symptoms and/or laboratory tests 
improve to Grade ≤1 (with or 
without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 

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Table 5.
Management of Avelumab Immune-Related Adverse Events
hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or 
insulin (for Type I diabetes 
mellitus) as appropriate.  
Rule-out secondary 
endocrinopathies 
(ie, hypopituitarism/hypophysitis).
monitoring of endocrine function 
as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or 
adrenal insufficiency is confirmed 
(ie, subnormal serum thyroxine 
with inappropriately low 
thyroid-stimulating hormone 
and/or low serum cortisol with 
inappropriately low 
adrenocorticotropic hormone):

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.

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Table 5.
Management of Avelumab Immune-Related Adverse Events
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold avelumab therapy 
pending clinical investigation.
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-
starting avelumab therapy
If irAE is confirmed, treat as 
Grade 2 or 3 irAE.
Grade 2 irAE or first occurrence 
of Grade 3 irAE
Withhold avelumab therapy.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.  
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult as appropriate.
If improves to Grade ≤1: 
Taper steroids over at least 
1 month and resume avelumab
therapy following steroids taper.
Recurrence of same Grade 3 
irAEs
Permanently discontinue avelumab 
therapy.
1.0 to 2.0 mg/kg/day.
prednisone or equivalent.
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult as appropriate.
If improves to Grade ≤1: 
Taper steroids over at least 
1 month.
Grade 4 
Permanently discontinue avelumab 
therapy.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent and/or other 
immunosuppressant as needed.
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult.
If improves to Grade ≤1: 
Taper steroids over at least 
1 month.
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Permanently discontinue avelumab 
therapy.
Specialty consult.
Abbreviations: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; ULN=upper limit of normal.

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5.5. Investigational Product Storage 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
label. See the DAI for storage conditions for avelumab once reconstituted and/or diluted.
Avelumab must be stored in the refrigerator at 2 – 8 C (36 – 46 F).  Do not freeze.  Protect 
from light.  Do not shake vigorously.   
Storage conditions stated in the SRSD (ie, Avelumab Investigator’s Brochure) will be 
superseded by the storage conditions stated on the label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  Storage 
temperatures must be captured from the time of investigational product receipt throughout 
the study.  Even for continuous monitoring systems, a log or site procedure that ensures 
active daily evaluation for excursions should be available.  The operation of the temperature 
monitoring device and storage unit (for example, refrigerator), as applicable, must be 
regularly inspected to ensure it is maintained in working order. 
Any excursions from the product label storage conditions must be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the label are not 
considered excursions. More specific details will be provided to the sites separately.  
All study drug supplies must be kept in a locked, limited access room.  The study drug must 
not be used outside the context of this protocol.  Under no circumstances should the 
investigator or other site personnel supply study drug to other Investigators, patients, or 
clinics, or allow supplies to be used other than directed by this protocol without prior 
authorization from the sponsor.  The investigator and or site staff must report any 
unacceptable condition of the investigational product to the site monitor. 

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5.6. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  The sponsor will provide 
instructions as to disposition of any unused investigational product if the investigative site is 
unable to destroy at site per local procedures. 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product-supplies.  
Pfizer may supply drug accountability forms that must be used or may approve use of 
standard institution forms.  In either case, the forms must identify the investigational product, 
including batch or code numbers, and account for its disposition on a patient-by-patient basis, 
including specific dates and quantities. 
The prescribed dose must be recorded in the patient’s medical records.  Drug dispensing 
needs to be verified and documented by a second individual and the forms must be signed by 
both the individual who dispensed the drug and the second individual who verified the 
dispensing.  Copies must be provided to Pfizer. 
5.7. Destruction of Investigational Product Supplies 
At the end of the trial, or at appropriate points during the trial, Pfizer or designee will provide 
instructions as to disposition of any unused investigational product.  If Pfizer or designee 
authorizes destruction at the trial 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.  All destruction must be adequately documented.  
If drug destruction is not permitted locally, Pfizer should be contacted for further directions.
5.8. Best Supportive Care
All patients will receive BSC during this study.  BSC will be prescribed and/or administered 
per current treatment practices at each investigational site and per individual patient needs 
and could include treatment with antibiotics, nutritional support, correction of metabolic 
disorders, optimal symptom control and pain management (including radiotherapy), etc.  
BSC does not include any active anti-tumor therapy; however, local radiotherapy of isolated 
lesions with palliative intent is acceptable as described in Section 5.9.2.  
All BSC components must comply with the permitted medications described in this protocol 
(see Section 5.9).
5.9. Concomitant Treatments
Medications or vaccinations specifically prohibited in the Exclusion Criteria are also not 
allowed during the active treatment period, except for administration of inactivated vaccines.
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 

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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.
Concomitant medications, blood products, non-drug interventions, 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 (Arm A) or 90 days after the End of 
Treatment (EOT) visit (Arm B).  
All concomitant medications will 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).  During study 
treatment, concomitant medications should be reviewed at each study visit, and any 
prohibited treatments should be discussed and appropriately managed.
Given that recording of non-serious AEs ends when a patient begins a new anti-cancer 
therapy (Section 8.2), recording of concomitant medications associated with these non-
serious AEs should also end.  However, given that SAEs must continue to be recorded up to 
90 days after the last dose of study treatment(s) even if the patient begins a new anti-cancer 
therapy, concomitant medications associated with these SAEs must also be recorded. 
As per Protocol Amendment 6, following the final OS update, concomitant 
medications/treatments will not be captured in the CRF unless they contribute to or are 
associated with the treatment for an AE. 
Concurrent anticancer therapy with agents is not allowed, other than avelumab in patients 
randomized to Arm A.  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 
flu-like symptoms, tumor lysis syndrome, and irAE are reported in Sections 5.4.3.2, 5.4.3.3, 
and 5.4.3.4, respectively. 
5.9.1. Concomitant Surgery 
In the case that a surgical procedure is required for palliative care, all attempts should be 
made to rule out disease progression beforehand.  
In the case of a surgical procedure, avelumab treatment should be withheld.  Postoperatively, 
the decision to reinitiate avelumab treatment should be discussed with the sponsor’s medical 
monitor. 
5.9.2. Concomitant Radiotherapy
Local radiotherapy of isolated lesions with palliative intent is acceptable (eg, bleeding, pain, 
compression), however all attempts should be made to rule out disease progression.  

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Palliative radiotherapy is permitted if considered medically necessary by the treating 
physician.  If palliative radiotherapy is needed to control pain, the site(s) of disease causing 
pain should also be present at baseline; otherwise, painful lesion(s) requiring radiotherapy 
will be considered as a sign of disease progression. 
5.9.3. Other Prohibited Concomitant Medications and Therapies 
All patients are prohibited from receiving the following therapies while receiving study 
treatment:

Anti-cancer systemic chemotherapy or biological therapyor investigational agents 
other than avelumab. 

Other experimental pharmaceutical products.
Patients enrolled on Arm A 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.  Intranasal, inhaled, topical 
steroids, or local steroid injections (eg, intra-articular injection) are allowed.

Any vaccine therapies for the prevention of infectious disease within 4 weeks of start 
of study treatment, except for inactivated vaccines (eg, influenza vaccine). 

Bisphosphonate or denosumab treatment unless it has been initiated more than 
14 days prior to receiving the first administration of avelumab.  

Growth factors (granulocyte colony stimulating factor or granulocyte macrophage 
colony stimulating factor). Exception: Erythropoietin and darbepoietin alpha may be 
prescribed at the investigator’s discretion).

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.68,69  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 agents indicate that short-term 
use of steroids may be employed without compromising clinical outcomes.70  Therefore, the 
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
Therapeutic use: for the treatment of infusion-related reactions and short-term 
treatment of irAEs, steroids are permitted according to the modalities indicated in 
Table 5.

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 prophylactic use prior to CT or MRI.

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular
injection) are permitted.
5.10. Rescue Medications and Supportive Care 
5.10.1. Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.

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 5.

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 for patients receiving avelumab.

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 factor Xa inhibitors) may be allowed; however, appropriate 
monitoring of prothrombin time/international normalized ratio (PT/INR) should be 
performed. 

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6. STUDY PROCEDURES 
6.1. Screening
For screening procedures, see Schedule of Activities (SOA) table and Assessments section 
(Section 7).  
6.1.1. Tumor Biospecimens
Provision of a tumor biospecimen will be required for randomization into the study as 
follows:
1. Recent tumor biospecimen: A mandatory FFPE tumor tissue block (or subsection 
thereof) must be obtained from all patients representing tumor tissue from the most 
recent primary or metastatic tumor biopsy or resection obtained prior to treatment 
with first line chemotherapy but within 24 months prior to randomization, with no 
intervening systemic anti-cancer therapy between the time the tissue was obtained 
and initiation of first-line chemotherapy.  If an FFPE tissue block cannot be provided 
due to local regulation or policy, 15 freshly cut unstained slides (10 minimum) will be 
acceptable.  
Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell 
pellet material) or bone metastases is not adequate and should not be submitted.  If a 
suitable tissue sample is not otherwise available, then an FFPE tissue sample from a 
de novo biopsy (core needle or excisional) must be obtained for research purposes 
during the screening period for this study (after informed consent has been obtained 
and prior to randomization).  
Note: This mandatory tumor tissue sample must be submitted to the Central 
Laboratory prior to randomization.  
2. Archival tumor biospecimen: An archival FFPE tumor tissue block (or subsection 
thereof) collected at the time of primary diagnosis or first tumor resection (if different 
from the most recent sample described above) is strongly encouraged to assess 
changes in the tumor microenvironment relative to the most recent sample (per 
above).  If an FFPE tissue block cannot be provided, 15 unstained slides 
(10 minimum) will be acceptable.  A sample from a later timepoint that is still prior to 
the most recent tumor tissue sample (per above) may be substituted, if necessary.  
Tumor tissue from cytologic samples (eg, FFPE cell pellet from Fine Needle 
Aspiration biopsy) or bone metastases are not acceptable.  
End of Treatment Tumor Biospecimen: A de novo tumor sample (ie, fresh biopsy) should 
also be collected at End of Treatment unless clinically contraindicated.  This de novo biopsy 
should be formalin-fixed and paraffin-embedded as per routine procedures (see Laboratory 
Manual), and the resulting FFPE tissue block(s) should be submitted to the Central 
Laboratory.  If an FFPE tissue block cannot be provided, 15 freshly cut unstained slides 
(10 minimum) will be acceptable.

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Please refer to Section 7.5.1 for planned analyses of tumor biospecimens.  Additional 
information on tumor biospecimen collection procedures is included in the Laboratory 
Manual.
6.2. Treatment Period
For treatment period procedures, see Schedule of Activities table and Assessments section 
(Section 7).  Patients who refuse to return to the site for evaluations should be contacted by 
telephone every 3 months as an alternative to site visits, as all patients will be followed for 
survival until death, end of the study, or patient withdrawal of consent, whichever comes 
first.
As per Protocol Amendment 6, following the final OS update, only patients receiving 
avelumab will continue in the treatment phase of this study. All Arm B patients who have not 
crossed over to receive avelumab and are still in the treatment phase will be discontinued.  
Please refer to the “Protocol Amendment 6: Schedule of Activities for Study Treatment, End 
of Treatment and Follow-up Periods” for study procedures to be performed for patients 
continuing to receive avelumab. 
6.3. End of Treatment/Withdrawal and Follow-up Visits
For follow-up procedures, see Schedule of Activities and Assessments section (Section 7). 
Beyond the 90 days until the end of the study (long-term follow-up), all patients will be 
followed every 3 months after the last study clinic visit (14 days) for survival, tumor 
assessment, and new systemic anticancer treatment; additional timepoints to collect survival 
information may be requested by the Sponsor in preparation for interim and final analyses.
As per Protocol Amendment 6, following the final OS update, only patients who received 
avelumab will be followed through the 90-day Short-term Follow-up Visit.  Patients who are 
receiving or have received BSC alone and are in the treatment or 90-day Short-term Follow-
up phase will be discontinued with no further follow-up.  No additional OS follow-up will be 
performed for any study patient.
6.4. End of the Study
The study will end when at least 425 and 219 OS events have occurred for all randomized 
patients and patients with PD-L1-positive tumors, respectively.
At the end of study, patients receiving avelumab plus BSC who are still deriving clinical 
benefit from the study treatment will be provided with an option for continued study 
treatment (eg, rollover study).
6.5. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol- required schedule of study 
visits or procedures at a given study site. 

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Reasons for withdrawal of study treatment may include:

Confirmed disease progression as assessed by BICR (or as assessed by Investigator as 
per Protocol Amendment 6, following the final OS update).  However, patients 
receiving avelumab with disease progression who are continuing to derive clinical 
benefit from study treatment will be eligible to continue with avelumab, provided that 
the treating physician has determined that the benefit/risk for doing so is favorable 
(see Section 5.4.1);

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment (follow-up permitted by patient);

Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs.
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.

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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, which may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions 
which he or she has taken to ensure that normal processes are adhered to as soon as possible.  
The sponsor’s study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of AEs, Serious Adverse Events (SAEs), vital 
signs, physical examination, laboratory assessments (including pregnancy tests), and 
verification of concomitant medications.  Further details of these assessments are described 
in the Schedule of Activities.  
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed on 2 occasions prior to starting study treatment: once at 
the start of screening, and once at the Cycle 1 Day 1 visit for Arm A patients immediately 
before the administration of study treatment.  Following a negative pregnancy test result at 
screening, appropriate contraception must be commenced and another negative pregnancy 
test result will then be required at the Cycle 1 Day 1 visit before the patient may receive 
avelumab study treatment.  For patients receiving avelumab study treatment, serum or urine 
pregnancy tests will also be routinely repeated as described in the Schedule of Activities
tables and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is 
otherwise suspected.  In the case of a positive human chorionic gonadotropin (hCG) test, the 
patient will be withdrawn from treatment but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by Institutional Review 
Board/Ethics Committees (IRB/ECs) or if required by local regulations.
As per Protocol Amendment 6, following the final OS update, negative pregnancy test results 
need not be recorded in the CRF.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by NCI 
CTCAE version 4.03, Appendix 3), timing, seriousness, and relatedness.  Adverse events that 
occur during the study will be recorded on the adverse events CRF page.
7.1.3. Laboratory Safety Assessments
Hematology, blood chemistry, and urinalysis will be collected at the time points described in 
the Schedule of Activities and analyzed at local laboratories.  They may also be performed 
when clinically indicated.  Clinically significant abnormal laboratory test results should be 

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repeated as soon as possible (preferably within 24-48 hours).  The required laboratory tests 
are listed in Table 6 and Table 7.  As per Protocol Amendment 6, following the final OS 
update, laboratory test results need not be recorded in the CRF unless the findings support an 
AE.
Table 6.
Prior to Protocol Amendment 6: Required Laboratory Tests
Hematology
Chemistry Panel
(* denotes core chemistry test)
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT*
Protein, 
glucose, 
blood
PT or INR
For female 
patients of 
childbearing 
potential, 
serum or urine 
Platelets
AST*
PTT or aPTT
WBC
Alkaline Phosphatase*
Absolute Neutrophils
Sodium*
Absolute Lymphocytes
Potassium*
Absolute Monocytes
Magnesium*
Absolute Eosinophils
Chloride*
Absolute Basophils
Total Calcium*
Total Bilirubin*$
BUN or Urea*
Creatinine*
Glucose*
Phosphorus or Phosphate*
Albumin
Total Protein
Uric Acid
Amylase
Gamma glutamyl transferase 
(GGT)
Cholesterol
Creatine kinase
C-reactive protein (CRP) 
Lactate dehydrogenase (LDH)
Lipase
Triglycerides
HBV, HCV testing
HIV serology
Thyroid Function Tests: TSH, 
free T4
Cardiac biomarkers:
Troponin (cTnT or cTnI)†
Other Tests: ACTH 
$. For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, PT/INR, 
alkaline phosphatase.
† Measurement of cTnT is preferred; however, cTnI may be substituted where cTnT is not available at the 
local laboratory.  The same subunit (cTnT or cTnI) measured during screening should be measured 
consistently throughout the study for any given patient.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin 
time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, cTnI= cardiac 
troponin subunit I, cTnT= cardiac troponin subunit T, GGT=gamma-glutamyltransferase, HBV= hepatitis B 

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virus (eg, HBsAg, Hepatitis B core antibody), HCV=hepatitis C virus (eg, Hep C antibody), HIV=human 
immunodeficiency virus, INR=international normalized ratio, LDH=lactate dehydrogenase, PT=prothrombin 
time, PTT=partial thromboplastin time, TSH=thyroid-stimulating hormone, WBC=white blood cell
Table 7.
Protocol Amendment 6: Required Laboratory Tests
Hematology
Chemistry Panel
Pregnancy Tests
Hemoglobin
ALT
For female patients of childbearing 
potential, serum or urine
Platelets
AST
WBC
ALP
Absolute Neutrophils
Total Bilirubin°
Absolute Lymphocytes
BUN or Urea
GGT
Amylase
Lipase
Creatinine
Potassium (if clinically indicated)
Sodium (if clinically indicated)
Total Calcium (if clinically indicated)
Creatine kinase
Glucose (non-fasted)
Thyroid Function Tests: Free T4, TSH
ACTH
° For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, PT/INR, 
alkaline phosphatase.
Abbreviations: ACTH=adrenocorticotropic hormone, ALP= alkaline phosphatase, ALT=alanine 
aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, GGT=gamma-glutamyl 
transferase, INR=international normalized ratio, PT=prothrombin time, T4=thyroxine, 
TSH=thyroid-stimulating hormone, WBC=white blood cell.
7.1.4. Physical Examinations and Vital Signs 
Physical examinations will be performed according to institutional guidelines on study days 
as described in the Schedule of Activities.  
The physical examination will include major body systems, height (height will be measured 
at screening only), and assessment of ECOG performance status.
Vital signs (blood pressure and pulse rate) and weight will be measured on study days as 
described in the Schedule of Activities.  Blood pressure and pulse rate should be taken prior 
to study drug dosing (if applicable) and with the patient in the seated position  after the 
patient has been sitting quietly for at least 5 minutes.  
As per Protocol Amendment 6, following the final OS update, physical examinations, vital 
signs, and ECOG performance status need not be recorded in the CRF unless the findings 
support an AE.  Clinically significant findings must be reported as AEs.

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7.1.5. (12-Lead) Electrocardiograms
A standard 12 lead (with a 10 second rhythm strip) tracing will be used for all 
electrocardiogram (ECG) assessments.   
All patients require a single ECG measurement at screening (clinically significant abnormal 
findings in baseline ECGs will be recorded as medical history).  On-treatment ECGs will be 
performed as clinically indicated. 
Clinically significant new findings seen on subsequent ECGs should be recorded as adverse 
events.  In case of QTc >500 msec (ie, > CTCAE Grade 2), ECG must be reviewed by 
qualified personnel at the site as soon as the finding is made, including verifying that the 
machine reading is accurate.  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 
concluding 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), the ECGs should be re-evaluated by a qualified person at the 
institution for confirmation and repeated as clinically indicated.
As per Protocol Amendment 6, following the final OS update, ECG results need not be 
recorded in the CRF unless the findings support an AE.  
7.2. Patient-Reported Outcome Assessments
The NCCN-FACT FBlSI-18 and EQ-5D-5L questionnaires will be administered at time 
points described in the Schedule of Activities.  The amount of time for a patient to complete 
the questionnaire is estimated to be about 3-5 minutes. 
As per Protocol Amendment 6, following the final OS update, Patient-Reported Outcome 
Assessments will no longer be performed/collected.  
7.3. Pharmacokinetics Assessments
Blood samples (3.5 mL serum separator (SST) tube per timepoint) for PK analyses will be 
collected from Arm A patients as outlined in the Schedule of Activities table.  Do not collect 
blood from the same arm being infused.  Where noted in the Schedule of Activities, PK 
blood samples will be collected at approximately the same time as other assessments 
wherever possible.

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For all PK blood sample collections, the actual time of avelumab dosing, as well as actual 
times of PK collections, will be recorded in the source document and CRF.
In addition to PK blood samples collected at the scheduled times, additional PK blood 
samples for avelumab should be collected from patients experiencing unexpected and/or 
serious AEs.  The date and time of blood sample collection and of the last dose of study 
treatment prior to PK collection must be 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 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 further evaluation of the bioanalytical methods for 
avelumab.  The results of such analyses may be included in the clinical report.
As per Protocol Amendment 6, following the final OS update, the collection of PK blood 
samples will no longer be performed/collected.  
7.4. Immunogenicity Assessment
Blood samples (3.5 mL SST tube per timepoint) for evaluation of avelumab immunogenicity 
will be collected from Arm A patients as outlined in the Schedule of Activities table.  
Immunogenicity blood samples will be assayed for anti avelumab antibodies using a 
validated analytical method.  All samples should be drawn within 2 hours before the start of 
avelumab infusion.  All of the samples that are positive for ADA may also undergo 
characterization for neutralizing antibodies.  Additional details regarding the collection, 
processing, storage, and shipping of the blood samples will be provided in the Study Manual.
As per Protocol Amendment 6, following the final OS update, the collection of 
immunogenicity blood samples will no longer be performed/collected.  
7.5. Translational and Pharmacodynamic Assessments
7.5.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies
Tumor biospecimens (see Section 6.1.1) will be used to analyze candidate DNA, RNA, or 
protein markers, or relevant signatures of markers for their ability to identify those patients 
who are most likely to benefit from treatment with the study drugs. 
Tumor tissue biomarker status will be determined by analytically validated tests developed 
by the sponsor; tumor tissue biomarkers analyzed may include, but may not necessarily be 
limited to, PD-L1 expression and quantitation of tumor-infiltrating CD8+ T-lymphocytes by 
IHC.  Optional tumor biopsies obtained at the End of Treatment/Withdrawal will be assessed 

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to the pre-treatment biopsies (archival or de novo) to investigate acquired mechanisms of 
resistance.  
Only core needle or excisional biopsies, or resection specimen are suitable.  Cytologic 
preparations, such as fine needle aspiration biopsies, are not acceptable.  Additional 
information on tissue collection procedures can be found in the Study Manual.
7.5.2. Peripheral Blood
Specimens will be retained as banked biospecimens (see Section 7.6) and will include whole 
blood, serum and plasma samples that will be retained in a biobank for exploratory 
assessments, unless prohibited by local regulation or by decision of the Institutional Review 
Board or Ethics Committee.  Samples may be used to identify or characterize cells, DNA, 
RNA, or protein markers known or suspected to be of relevance to the mechanisms of action, 
or the development of resistance to study treatment.  These include biomarkers that may aid 
in the identification of those patients who might preferentially benefit from treatment with 
avelumab plus BSC vs. BSC alone, including but not limited to biomarkers related to 
anti-tumor immune response or target modulation, such as soluble IL-8 or IFN, and/or tissue 
FoxP3, PD-1, PD-L2. 
As per Protocol Amendment 6, following the final OS update, the collection of biomarkers 
will no longer be performed/collected.  
7.6. Banked Biospecimens
7.6.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the DNA, RNA, protein, and 
metabolite variation patterns of patients who respond well and those who respond poorly to 
treatment may help to better define the most appropriate group of patients in which to target a 
given treatment.  Collecting biospecimens for exploratory pharmacogenomic/biomarker 
analyses and retaining them in the Pfizer BioBank makes it possible to better understand the 
drug’s mechanism of action and to seek explanations for differences in, for example, 
exposure, efficacy, tolerability, or safety not anticipated prior to the beginning of the study.  
Providing these biospecimens is a required study activity for study sites and patients, unless 
prohibited as such by local regulations or ethics committee decision. 
To protect patients’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the patient’s study ID number.  Samples will be kept in a facility 
accessible only by swiping a badge.  Data will be stored on password-protected computer 
systems.  The key between the code and the patient’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information.  Biospecimens will be 
used only for the purposes described here and in the informed consent document/patient 
information sheet; any other uses require additional ethical approval.  Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 

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stored indefinitely to allow for future research on the topics described here, including 
research conducted during the drug development process and also postmarketing research.  
Patients can withdraw their consent for the use of their biospecimens at any time by making a 
request to the investigator, in which case any remaining biospecimen will be destroyed; data 
already generated from the biospecimens will continue to be stored to protect the integrity of 
existing analyses.  It is very unlikely that results generated from the biospecimens will have 
any clinical, diagnostic, or therapeutic implications for the individual study participants.  
Patients are notified in the informed consent document/patient information sheet that their 
results will not be given to them, unless required by local laws or regulations, in which case 
results will be returned via the investigator.  Results will not be provided to family members 
or other physicians, nor will they be recorded in the patient’s medical record.  There is no 
intention to contact patients after completion of the clinical study.
A single 4 mL blood biospecimen Prep D1 (K2 edetic acid [ethylenediaminetetraacetic 
acid, EDTA] whole blood collection optimized for DNA analysis) will be collected on or 
prior to the Cycle 1 Day 1 visit (prior to dosing for Arm A patients and at any time for 
Arm B patients) to be retained for potential pharmacogenomic/biomarker analyses related to 
drug response, unless prohibited by local regulations or ethics committee decision.  For 
example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
examined.
Additional biospecimens to be retained for exploratory analyses in this study, as described in 
Section 7.6.2, include the following: 

Prep D1 (K2 EDTA whole blood collection optimized for DNA analysis): A 4 mL 
blood biospecimen will be collected on or prior to Cycle 1 Day 1; Cycle 1 Day 15 
(Arm A only); Day 1 of Cycles 2, 3, and 5; and at the End of Treatment/Withdrawal 
Visit.  All collections must be pre-dose.

Prep B2 (serum collection optimized for biomarker/proteomic/metabonomic 
analysis): A 10 mL blood biospecimen will be collected on or prior to Cycle 1 Day 1; 
Cycle 1 Day 15 (Arm A only); Day 1 of Cycles 2, 3, and 5; and at the End of 
Treatment/Withdrawal Visit.  All collections must be pre-dose.

Prep B1 (EDTA plasma collection optimized for biomarker/proteomic/
metabonomic analysis): A 10-mL blood biospecimen will be collected on or prior to 
Cycle 1 Day 1; Cycle 1 Day 15 (Arm A only); Day 1 of Cycles 2, 3, and 5; and at the 
End of Treatment/Withdrawal Visit.  All collections must be pre-dose.
The banked biospecimens will be collected from all patients unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage, and 
shipment instructions are provided in the central laboratory manual.

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It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.6.2. Additional Research
Unless prohibited by local regulations or ethics committee decision, patients will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:

Investigations of the disease under study in the clinical study, and related conditions.

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Markers of Drug Response section will be used.  Patients may 
still participate in the clinical study if they elect not to allow their Banked Biospecimens to 
be used for the additional purposes described in this section.
7.7. Tumor Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging will include 
chest, abdomen, and pelvis CT or MRI scans.  Bone imaging, eg, bone scans or other 
methods considered standard of care locally, such as 18FDG PET or MRI, are required at 
baseline (28 day screening period).  (Note: 18FDG-PET may not be a permissible alternate 
for bone imaging at some centers or countries (eg, investigative sites in Canada).)  Bone 
lesion(s) identified at baseline by bone scan will be further assessed by CT or MRI as per 
local practice (where bone scans are not used as a routine restaging tool) and subsequently 
re-assessed by CT or MRI as per the tumor assessment schedule as an alternative to bone 
scans.  Bone imaging will only be repeated during study as clinically indicated (eg, patient 
describes new or worsening bone pain, or has increasing alkaline phosphatase level, or other 
signs and symptoms of new/progressing bone metastases), at the time of complete response 
(CR) confirmation, and at every other tumor assessment visit (ie, every 16 weeks for the first 
year after randomization and every 24 weeks thereafter) if considered local standard of care.  
Brain imaging (eg, MRI) is required at baseline for patients who have a history of brain 
metastases or for whom brain metastases are suspected during screening.  Brain must be 
included in subsequent tumor assessments if a patient has brain metastases at baseline; 
otherwise brain will only be evaluated when clinically indicated.
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.

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Both pre-chemotherapy and post-chemotherapy scans must have been performed and be 
readily available during screening.  The post-chemotherapy confirmatory scan for eligibility 
must be performed within 28 days prior to the date of randomization to assess response status 
following first-line chemotherapy.  This scan will also be used as the baseline scan for tumor 
assessments in this study.
All radiographic images from the time of the most recent tumor assessment prior to first-line 
chemotherapy until documented disease progression will be submitted to an independent 
third-party core imaging laboratory for BICR as described in Study Manual.  
For all patients, anti-tumor activity will be assessed through radiological tumor assessments
(including chest, abdomen, and pelvic CT or MRI scans) conducted at baseline (ie, the 
post-chemotherapy confirmatory scan for randomization), every 8 weeks up to 1 year after 
randomization, and every 12 weeks thereafter until documented disease progression as 
assessed by BICR regardless of initiation of subsequent anti-cancer therapy.  Additional 
radiological tumor assessments should also be conducted whenever disease progression is 
suspected (eg, symptomatic deterioration).
Assessment of response will be made using RECIST version 1.1 (Appendix 2).  Measurable 
or evaluable lesions that have been previously irradiated will not be considered target lesions 
unless an increase in size has been observed following completion of radiation therapy.
CR and PR must be confirmed with repeat imaging performed at least 4 weeks after initial 
documentation of response.  In the absence of clinical deterioration, patients with PD should 
remain on the current study treatment until PD is confirmed by BICR.  For Arm A patients, 
please see Section 5.4.1 regarding continued avelumab study treatment after initial evidence 
of disease progression.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.
As per Protocol Amendment 6, following the final OS update, tumor assessments will be 
performed by the study investigator at a frequency as per local standard of care and when 
progression is suspected.  Radiologic images will no longer be submitted for independent 
central review or entered into the CRF.
7.8. Expedited Blinded Independent Central Review for Disease Progression
Prior to implementation of Protocol Amendment 6 and the final OS update, to mitigate the 
potential for bias in determining disease progression, expedited BICR will be performed for 
investigator-assessed disease progression.  Upon investigator-assessed disease progression, 
all radiographic images collected for a patient from baseline onwards will be submitted to the 
BICR for expedited review.  See the Study Manual for process details.  Every effort should 
be made to keep the patient on study treatment until the BICR has completed their imaging 
review. 

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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the study treatment(s) will be reported as described in the following sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any non-serious adverse event 
that is determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving study treatment, through and including 90 calendar days after the last 
administration of the study treatment (Arm A) or 90 days after the EOT visit (Arm B).  SAEs 
occurring to a patient after the active reporting period has ended should be reported to the 
sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to study treatment 
are to be reported to the sponsor. 
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of study treatment (Arm A) or from Cycle 1 Day 1 (Arm B) through and 
including 90 calendar days after the last administration of study treatment (Arm A) or 
90 days after the EOT visit (Arm B). 
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 treatment, irrespective of any intervening 
treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

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
Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.3.1. Avelumab Adverse Events of Special Interest
Any AE that is suspected to be a potential irAE is considered an AE of special interest 
(AESI). Specific guidance for the management of irAEs is provided in Section 5.4.3.4.  
AESIs are reported according to the general AE reporting rules specified in Section 8.1 and 
Section 8.2.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  

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Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the study treatment;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page. 
The guidance on reporting of medication errors also applies to the reporting of overdose.
For purposes of this study, an overdose of avelumab is defined as an increase 5% than the 
planned avelumab dose for that particular administration.  
There is no specific treatment for avelumab overdose.  In the event of overdose with 
avelumab, the patient should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided as clinically indicated.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal test finding should be reported as an AE 
are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.

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8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE (version 4.03) Grade 5 (see 
Section 8.8 Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention, to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section 8.14.1, Serious Adverse Event Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s law cases) and should always be considered important medical 
events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 

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present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available.

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with preexisting AST or ALT baseline values above the normal 
range, AST or ALT value 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).

Concurrent with

For patients with preexisting values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least 1 × ULN or if the 
value reaches 3 × ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), PT/INR, and alkaline phosphatase.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug, and supplement 
consumption, family history, occupational exposure, sexual history, travel history, history of 
contact with a jaundiced person, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or 
C infection and liver imaging (eg, biliary tract) may be warranted.  All cases confirmed on 
repeat testing as meeting the laboratory criteria defined above, with no other cause for Liver 
Function Test (LFT) abnormalities identified at the time should be considered potential Hy’s 
law cases irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs.  Such potential Hy’s law cases should be reported 
as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 

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however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.

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8.8. Severity Assessment
Grade
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse event reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the study treatment caused or contributed to 
an AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the study treatment caused the 
event, then the event will be handled as “related to study treatment” for reporting purposes, 
as defined by the sponsor (see Section 8.14, Reporting Requirements).  If the investigator's 
causality assessment is “unknown but not related to study treatment”, 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, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the study treatment; 
or the female becomes or is found to be pregnant after discontinuing and/or being 
exposed to the study treatment;

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

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the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (also see Section 6.5 Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient or legally acceptable representative.  In addition, each study patient or 
legally acceptable representative will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs,
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.

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For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy escalations must be submitted as soon as possible to Pfizer or 
its designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
For Investigative Sites in Japan Only: 
After avelumab is approved for treatment of advanced urothelial carcinoma by the Ministry 
of Health, Labour and Welfare (MHLW) in Japan, investigators in Japan may be requested 
by Pfizer to obtain specific additional follow-up information to be provided to 
Pharmaceuticals and Medical Devices Agency (PMDA) and/or MHLW if a reported 
treatment-related non-serious AE is found to be unexpected according to the Japanese 
Prescribing Information. If this occurs, the investigator will be required to pursue and 
provide the additional information to Pfizer; this information may be more detailed than the 
information captured on the adverse event case report form. In general, the information will 
include sufficient detail regarding the description of the adverse event to allow for a complete 
medical assessment of the case and independent determination of possible causality. 
Information regarding other possible causes of the adverse event, such as concomitant 
medications and illnesses, must also be provided.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
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9.1. Sample Size Determination
The primary objective of this study is to demonstrate the benefit of maintenance treatment 
with avelumab plus BSC vs. BSC alone in prolonging OS in patients with unresectable 
locally advanced or metastatic UC whose disease did not progress on or following 
completion of first-line platinum-containing chemotherapy in each co-primary UC patient 
populations: 1) patients determined to have PD-L1-positive tumors (including infiltrating 
immune cells) by a verified GMP PD-L1 IHC test, and 2) all randomized patients. 
The study will randomize a total of approximately 668 patients, with at least 334 patients 
with confirmed PD-L1-positive tumors, using 1:1 randomization, stratified by best response 
to chemotherapy (CR/PR vs. SD) and site of metastasis (visceral vs. non-visceral) at time of 
initiating first-line chemotherapy.  The “non-visceral” stratum includes patients with 
locally-advanced disease as well as patients with only non-visceral disease.  The type 1 error 
rate will be split between the co-primary populations to preserve the overall type 1 error rate 
for the study at 0.025 one-sided.  It is estimated that at least 50% of the randomized patients 
will have adequate tissue for analysis and be determined to have PD-L1-positive tumors.  
The sample size for this study is determined based on the following assumptions: 

For all patients and patients with PD-L1-positive tumors receiving BSC alone after 
first-line chemotherapy, the median OS is 12 months.33

For all patients receiving avelumab plus BSC after first-line chemotherapy, the 
median OS is assumed to be 17.1 months.

For patients with PD-L1-positive tumors receiving avelumab plus BSC after first-line 
chemotherapy, the median OS is assumed to be 18.5 months.
This corresponds to a hazard ratio (HR) of 0.7 for all patients and 0.65 for patients with 
PD-L1-positive tumors under the exponential model assumption. 
For all patients, if the true HR is 0.7 under the alternative hypothesis, a total of 425 OS 
events will be required to have 93% power to detect a HR of 0.7 using a one-sided log rank 
test at a significance level of 0.015 and a 2-look group-sequential design with Lan-DeMets 
(O’Brien-Fleming)71 -spending function to determine the efficacy boundary and a Gamma 
Family (-8) -spending function to determine the non-binding futility boundary. 
For patients with PD-L1 positive tumors, if the true HR is 0.65 under the alternative 
hypothesis, then a total of 219 OS events will be required to have 80% power to detect a HR 
of 0.65 using a one-sided log rank test at a significance level of 0.01 and a 2-look group 
sequential design with Lan-DeMets (O’Brien-Fleming) -spending function to determine the 
efficacy boundary and a Gamma Family (-8) -spending function to determine the non-
binding futility boundary (see Section 9.6 Interim Analysis for details).
The sample size further assumes a 5% drop-out rate for OS on either treatment arm, a 
non-uniform patient accrual accomplished over a 28-month period, and follow-up for about 

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11 months after the last patient is randomized.  The data cutoff for the primary OS analysis 
will occur after the target number of events has been reached in both co-primary populations 
and the last patient randomized in the study has been followed for at least 12 months after 
randomization.
The study will be considered positive if the stratified log rank test for OS is significant at the 
respective adjusted levels at the interim or at the final analyses, for either of the two 
co-primary populations. 
9.2. Analysis Populations
9.2.1. Full Analysis Set
The Full Analysis Set will include patients who are randomized.  Patients will be classified 
according to the treatment and stratum assigned at randomization.  The Full Analysis Set will 
be the primary analysis set for evaluating all efficacy endpoints and patient characteristics 
within each of the co-primary populations: 1) patients determined to have PD-L1-positive 
tumors (including infiltrating immune cells) by a verified GMP PD-L1 IHC test and 2) all 
randomized patients.
Patients to be included in the co-primary population defined by PD-L1 positive tumors will 
be determined by retrospective analysis of the mandatory recent FFPE tumor biospecimen 
(see Sections 4.1 and 6.1.1) using an analytically-validated and GMP-verified PD-L1 IHC 
assay with a pre-specified scoring algorithm defining PD-L1 positive status.  The PD-L1 IHC 
assay and scoring algorithm will be fully defined prior to initiation of sample analysis.
9.2.2. Per-Protocol Analysis Set
The Per-Protocol Analysis Set is a subset of the Full Analysis Set and will include patients 
who receive at least 1 dose of study treatment or who only receive BSC and do not have 
major protocol deviations expected to impact the primary objectives of the study.  Major 
protocol deviations will be pre-specified in the SAP.  The Per-Protocol Analysis Set will be 
used for sensitivity analyses for the primary efficacy endpoint.
9.2.3. Safety Analysis Set
The Safety Analysis Set will include all patients who receive at least 1 dose of avelumab or 
who only receive BSC.  Patients will be classified according to the treatment assigned at 
randomization unless the incorrect treatment(s) are received throughout the dosing period in 
which case patients will be classified according to the first treatment received.  The Safety 
Analysis Set will be the primary population for evaluating treatment 
administration/compliance and safety.
9.2.4. PK Analysis Set
The PK Concentration Analysis Set will include all treated patients who have at least 
1 concentration above the below limit of quantitation (BLQ) of avelumab.
The PK Parameter Analysis Set will include all treated patients who have at least 1 of the PK 
parameters of interest.

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9.2.5. Immunogenicity Analysis Set
The Immunogenicity Analysis Set will include all treated Arm A patients who have at least 
1 ADA sample collected.
9.2.6. Biomarker Analysis Set
The Biomarker Analysis Set will include all treated Arm A patients who have at least 
1 baseline biomarker assessment performed.
9.3. Efficacy Analysis
All efficacy analyses will be performed on the Full Analysis Set within each of the 
co-primary populations unless otherwise specified. 
All analyses will be performed by using SASVersion 9.1.3 or higher. 
All secondary endpoints based on radiological assessments of tumor burden (ie, PFS, OR, 
TTR, DR, DC) will be derived using the local radiologist’s/investigator’s assessment.  
Radiographic images and clinical information collected on study will also be reviewed by 
BICR to verify investigator reported tumor assessments and be used for primary analyses.
The primary analysis will be repeated on the Per-Protocol Analysis Set as a sensitivity 
analysis.  Further sensitivity analyses will be described in the SAP. 
9.3.1. Analysis of Primary Endpoint
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Patients last known to be alive will be censored at date of last contact.  
The primary analyses of OS will be performed based on the Full Analysis Set.  A stratified 
log-rank test (one-sided) stratified by stratification factors described in Section 3 will be used 
within each comparison at the interim and/or final analyses with the overall significance level 
preserved at its respective levels (one-sided 0.015 for all patients and one-sided 0.01 for 
patients with PD-L1-positive tumors).  OS time associated with each treatment arm will be 
summarized using the Kaplan-Meier method and displayed graphically where appropriate.  
Confidence intervals (CIs) for the 25th, 50th and 75th percentiles will be reported.  The Cox 
proportional hazards model will be fitted to compute the treatment hazard ratios and the 
corresponding 95% CI.  
OS will also be evaluated based on the PPS as a sensitivity analysis using the stratified 
log-rank test with the overall significance level preserved at its respective levels (one-sided 
0.015 for all patients and one-sided 0.01 for patients with PD-L1-positive tumors).
9.3.2. Analysis of Secondary Endpoints
All analyses will be performed using the Full Analysis Set separately for each co-primary
population.  The analysis of PFS using the Full Analysis Set described in Section 9.2.1 based 
on BICR assessment will be repeated based on the investigator’s assessment.

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The analyses of other tumor-related endpoints will be based on the investigator’s assessment, 
as well as on the BICR. 
Progression-Free Survival
PFS is defined as the time from randomization to the date of the first documentation of 
objective progression of disease (PD) or death due to any cause, whichever occurs first.  
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start new anti-cancer treatment prior to 
an event, or for patients with an event after two or more missing tumor assessments.  Patients 
who do not have a baseline tumor assessment or who do not have any post-baseline tumor 
assessments will be censored on the day of randomization, with a duration of 1 day, unless 
death occurred on or before the time of the second planned tumor assessment in which case 
the death will be considered an event.
Within each co-primary population PFS time will be summarized by treatment arm using the 
Kaplan-Meier method and displayed graphically where appropriate.  Confidence intervals 
(CIs) for the 25th, 50th, and 75th percentiles of the event-free time will be reported.  The Cox 
proportional hazards model will be fitted to compute the treatment hazard ratios and the 
corresponding 95% CI.
Objective Response (OR)
Objective response is defined as a CR or PR according to RECIST v1.1 (Appendix 2) 
recorded from randomization until disease progression or death due to any cause.  Both CR 
and PR must be confirmed by repeat assessments performed no less than 4 weeks after the 
criteria for response are first met.  A patient will be considered to have achieved an OR if the 
patient has a sustained CR or PR according to RECIST v1.1 definitions.  Otherwise, the 
patient will be considered as a non-responder in the ORR analysis.  Additionally, patients 
with inadequate data for tumor assessment (eg, no baseline assessment or no follow-up 
assessments) will be considered as non-responders in the ORR analysis. 
The ORR in each randomized treatment arm will be estimated by dividing the number of 
patients with confirmed objective response (CR or PR) by the number of patients randomized 
to the respective treatment arm.  The corresponding exact 2-sided 95% CIs will be provided 
by treatment arm. 
In addition, the best overall response for each patient will be summarized by treatment arm.
Time to Tumor Response (TTR)
Time to tumor response (TTR) is defined for patients with an objective response per RECIST 
v1.1 (Appendix 2) as the time from randomization to first documentation of objective tumor 
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TTR will be summarized by treatment arm using descriptive statistics (n, mean, median, 
standard deviation, minimum, and maximum).
Duration of Response (DR)
Duration of response (DR) is defined, for patients with an objective response per RECIST 
v1.1, as the time from the first documentation of objective tumor response (CR or PR) to the 
first documentation of objective tumor progression or death due to any cause, whichever 
occurs first.  Censoring rules for DR will follow those described above for PFS. 
DR will be summarized by treatment arm using Kaplan-Meier method and displayed 
graphically, where appropriate.  The median DR and 95% CI for the median will be provided 
for each treatment arm.
Disease Control (DC)
Disease control (DC) is defined as complete response (CR), partial response (PR), non-
CR/non-PD, or stable disease (SD) according to the RECIST v.1.1 (Appendix 2) recorded 
from randomization until disease progression or death due to any cause.  Both CR and PR 
must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.  Criterion for SD must have been met at least 6 weeks after the date of 
randomization. 
The DC rate (DCR) on each randomized treatment arm will be estimated by dividing the 
number of patients with CR, PR, non-CR/non-PR, or SD overall by the number of patients 
randomized to the treatment arm. The corresponding exact 2-sided 95% CIs for DCR will be 
provided by treatment arm. 
Patient Reported Outcomes (PRO) Endpoints
The FBlSI-DRS-P subscale will be used to determine the Time to Deterioration (TTD).  TTD 
is defined as the time from first dose (baseline) to the first time the patient’s score shows a 
3 point or higher decrease in the FBlSI-DRS-P subscale.  Patients will be censored at the last 
time when they completed a sub-scale assessment if they have not deteriorated. 
Kaplan-Meier plots will be used to display deterioration over time and a log-rank test will be 
used to compare the TTD between the two treatment arms.  The median time and 2-sided 
95% CI for the median will be provided based on the Brookmeyer Crowley method.72  
Yost & Eton (2005)73 established that a 3-point or a greater minimally important difference 
(MID) from baseline on the FACT scales would correlate with change in disease symptoms 
and status.  Thus, in the analysis of TTD, a MID of 3 points or greater is proposed within the 
FBlSI-DRS-P sub-scale of the NCCN-FACT FBlSI-18.  Additionally, symptom sub-scale 
improvement will be defined as an increase of at least 3 points in the mean FBlSI-DRS-P 
sub-scale score of the NCCN-FACT FBlSI-18.  Within group and between group 
comparisons to baseline in order to assess symptom improvement among treatment arms will 
also be performed.  To test the robustness of the MID of 3 points, sensitivity analyses using 
2 and 4 points will be explored.

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Patient reported disease/treatment related symptoms of bladder cancer, function/well-being, 
and general health status will also be assessed.  Summary statistics [mean (and SE), median, 
range and 95% CI] of absolute scores will be reported for all of the subscales of the 
NCCN-FACT FBlSI-18 questionnaire and the EQ-5D-5L VAS scale.  The mean change of 
absolute scores from baseline (and 95% CI) will also be assessed.  Line charts depicting the 
means and mean changes of items and subscales over time will be provided for each 
treatment arm.  Additional exploratory analyses may be performed, such as repeated 
measures mixed effects modeling and analyses of patients who experienced a complete 
response.
Pharmacokinetic Analysis of Avelumab 
Cmax and Ctrough for avelumab 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 using a box-whisker 
plot by cycle and day in order to assess the attainment of steady-state.
Immunogenicity Assessment
For the immunogenicity data, the percentage of patients receiving avelumab 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. 
Analysis of Biomarker Endpoints 
Analyses to evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab 
in addition to PD-L1 expression defining the co-primary population may also be performed 
in which biomarker status (ie, positive or negative) will be determined in all randomized 
patients by a predictive biomarker test with an established scoring algorithm defining 
positive and negative that is developed by the sponsor.  Analysis of primary and secondary 
efficacy endpoints in subgroups defined by biomarker status will be performed and reported 
as described above.  Comparisons will be made between biomarker subgroups (positive and 
negative) within treatment arms and between treatment arms within biomarker subgroups.
Exposure/Response Analysis
In addition, the relationship between exposure and efficacy and safety endpoints may be 
explored, as necessary, based on emerging efficacy and safety data.  Refer to the SAP for 
details.  The results of these modeling analyses may be reported separately from the clinical 
study report.

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9.4. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed 
graphically, where appropriate.
9.4.1. Statistical Analysis of Biomarker Endpoints
It is possible that, during the course of this study, emerging data and/or methods will suggest 
additional patient selection strategies beyond the verified GMP PD-L1 test used to define the 
co-primary populations.  Retrospective analysis of biomarkers such as PD-L1 (using a 
different method from the GMP test) and CD8 are planned as a secondary objective to enable 
refinements in patient selection strategy, whether via technical modifications or revised 
thresholds.  These methods may be single- or multi-analyte based on IHC or 
immunofluorescence.  Further exploratory analyses may also be performed to assess the 
predictive and/or pharmacodynamic utility of additional methods, such as profiling of gene 
expression signatures indicative of immune activation.  The Biomarker Analysis Set will be 
used for the analysis of biomarker endpoints.  
Biomarkers will be assessed separately for whole blood, serum, plasma, archival tumor 
tissue, and de novo tumor biopsies.  In each case, summaries of baseline levels, changes from 
baseline (where appropriate), gene alteration or biomarker signature status, will be reported.  
For continuous variables summary statistics may include the mean, ratio to baseline, standard 
deviation, median, 25th and 75th quartile, %CV and minimum/maximum levels of biomarker 
measures; for categorical variables, the summary may include number, percentage, and odds 
ratio, as appropriate.
Data from biomarker assays will be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach may examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
Regarding exploratory biomarkers, the data analysis will be conducted with the goal of 
identifying predictive and/or pharmacodynamic (ie, baseline and change from baseline 
values) biomarkers associated with clinical outcome, encompassing both safety and efficacy.  
Candidate biomarkers will be validated in subsequent trials.
9.4.2. Exploratory Endpoints
Details regarding exploratory endpoints (definitions and analyses) will be provided in the 
SAP.
9.5. Safety Analysis
The Safety Analysis Set will be the primary population for safety evaluation.  Summaries of 
AEs and other safety parameters will be provided, by treatment arm, as appropriate. 

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Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html).  The 
frequency of patients experiencing treatment emergent adverse events corresponding to body 
systems and MedDRA preferred term will be reported.  Adverse events will be graded by 
worst NCI CTCAE v4.03 Grade.  Adverse events will be summarized by cycle and by 
relatedness to study treatment. 
Emphasis in the analysis will be placed on AEs classified as treatment emergent.  Adverse 
events leading to death or discontinuation of study treatment, events classified as NCI 
CTCAE v4.0 Grade 3 or higher, trial drug-related events, and serious adverse events will be 
considered with special attention.  As appropriate, the difference in risk between treatment 
arms for AEs of clinical interest may be further assessed as described in the SAP.
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study treatment, action taken, and 
clinical outcome.
Laboratory Abnormalities
The laboratory abnormalities will be graded according to the NCI CTCAE v4.03 severity 
grade.  The frequency of patients with laboratory test abnormalities will be summarized 
according to the worst grade for each laboratory test. 
For laboratory tests without an NCI CTCAE grade definition, results will be categorized as 
normal (within normal ranges), abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory abnormalities. 
9.6. Interim Analysis
The interim analysis will be performed based on the Full Analysis Set. 
The purposes of the interim analysis are to: (i) allow early stopping of the study for futility, 
(ii) to allow early stopping of the study for efficacy, (iii) to assess safety of avelumab, and 
(iv) to potentially adjust the sample size.  The interim analysis for both co-primary 
populations will be performed at the same time.
The interim analysis of OS will be performed after at least 315 of all randomized patients 
have died (74% of the total OS events needed), and all of the following conditions have been 
met:
i.
All initially planned patients have been randomized; and 
ii.
At least 146 patients with PD-L1-positive tumors have died (approximately 66.7% of 
the total OS events expected in the PD-L1-positive tumor population).

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The efficacy and futility boundaries for the co-primary populations with the planned number 
of events at interim look are listed below in Table 8.  The boundary values will be updated 
using the pre-specified and spending functions with the observed number of events at the 
time of the interim analysis.  The study may be stopped if:

The futility boundary is crossed for both populations (all and PD-L1+); or

The efficacy boundary is crossed for both populations (all and PD-L1+); or

The futility boundary is crossed for one of the populations and the efficacy boundary 
is crossed for the other population.
Alternatively, as appropriate, the sample size of the study may be adjusted using the method 
outlined by Cui et al [1999].74  If the results of the interim analysis indicate serious safety 
concerns, the sponsor, in conjunction with the External Data Monitoring Committee 
(E-DMC), will communicate with the Health Authorities regarding stopping the clinical trial.
Table 8.
Stopping Boundaries for Overall Survival
Population
Number of 
Events
Efficacy
Futility
Z scale
p-value (one-sided)
Z scale
p-value (one-sided)
All patients
315
z < -2.595
p <0.005
z > -0.789
p >0.215
PD-L1-positive
146
z < -2.947
p <0.002
z > -0.397
p >0.346
9.7. External Data Monitoring Committee
This study will use an E-DMC. 
The E-DMC will be responsible for ongoing monitoring of the safety of patients in the study 
according to the charter.  The recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate.  
The E-DMC will convene to monitor safety in the study approximately every 6 months.  
Following the pre-planned interim analysis at which the primary objective was met, the E-
DMC had completed its study-specific activities and was therefore closed.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.

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

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11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to ICH guidelines, local regulations, or as specified in 
the Clinical Study Agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.

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For Investigative Sites in Japan Only: 
After avelumab is approved for treatment of advanced urothelial carcinoma by the MHLW in 
Japan, Japanese investigators will conduct this study according to Japanese Good Post-
Marketing Surveillance Practices (GPSP) in addition to Good Clinical Practice (GCP).
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 a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The study site 
will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent document(s) used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study patient, or his or her legally acceptable 
representative (as allowed by local guideline/practice), is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
Whenever consent is obtained from patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally-impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’s assent was obtained, or waived.  If assent is obtained verbally 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative before any 

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

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

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

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

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Appendix 2. Response Evaluation Criteria in Solid Tumors Version 1.1
Adapted from E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247. 
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions 

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The short axis is used as the diameter for malignant lymph nodes, longest axis 
for all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to randomization and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large target 
lesion splits, the sum of the parts is used.
Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 

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

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of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR.
If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
Objective/Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 

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Table 9.
Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 10.
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
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest sum 
on study).  For CR and PR, the patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  CR and PR must be confirmed 
by 2 measurements at least 4 weeks apart.  In the case of SD, follow up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. 

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Appendix 3. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study Reference 
Binder for this protocol.  Alternatively, the NCI CTCAE may be reviewed online at the 
following NCI website:
http://ctep.cancer.gov/reporting/ctc.html.

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Appendix 4. Cockcroft-Gault Formula
[(140-Age) * Mass (in kg)] / [72 * Serum creatinine (in mg/dL)].
If the patient is female, multiply the above by 0.85.

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Appendix 5. Abbreviations and Definitions of Term
This is a list of abbreviations that may be used in the protocol.
18FDG PET/CT
18Fluorodeoxyglucose positron emission tomography/computed tomography
ACTH
Adrenocorticotropic hormone
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADL
Activities of daily living
AE
Adverse event
AESI
Adverse event of special interest
AIDS
Acquired immunodeficiency syndrome 
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
ANC
Absolute neutrophil count 
ANOVA
Analysis of variance
aPTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the curve
BCG
Bacille Calmette-Guérin 
BICR
Blinded Independent Central Review
BSC 
Best Supportive Care 
BUN
Blood urea nitrogen
CG
Cockcroft-Gault
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CR
Complete response
CRF
Case report form
CRP
C-reactive protein
CSA
Clinical Study Agreement
CT
Computed tomography scan
CTA
Clinical Trial Application
CTLA-4
Cytotoxic T lymphocyte-associated protein 4
CTCAE
Common Terminology Criteria for Adverse Events
cTnI
Cardiac troponin subunit I
cTnT
Cardiac troponin subunit T
DAI
Dosage and Administration Instructions
DC
Disease Control
DCR
Disease Control Rate
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DR
Duration of response
DU
Dispensable unit
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
E-DMC
External Data Monitoring Committee
EDP
Exposure During Pregnancy

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EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EOT
End of Treatment
EQ-5D-5L
EuroQol 5 dimension 5 level questionnaire
EU
European Union
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness Therapy
FBlSI
FACT-Bladder Cancer Symptom Index
FBlSI–DRS-P
NCCN-FACT FBlSI-18 Disease Related Symptoms-Physical subscale 
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin-embedded
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practices
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
GPSP
Good Post-Marketing Surveillance Practices
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed consent form
ICH
International Conference on Harmonisation
ID
Identification
IFN
Interferon
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL
Interleukin
IND
Investigational New Drug
INN
International Nonproprietary Name
INR
International normalized ratio
ir
Immune-related 
irAE
Immune-related adverse event
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation in Solid Tumors
IRT
Interactive Response Technology
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intra-uterine hormone-releasing system
IV
Intravenous
IVR
Interactive voice response
kg
Kilogram
LDH
Lactate dehydrogenase
LFT
Liver function test
LLN
Lower limit of normal
mAb
Monoclonal antibody
MedDRA
Medical dictionary for regulatory activities
MID
Minimally important difference
MHLW
Ministry of Health, Labor and Welfare
MRI
Magnetic resonance imaging 
MVAC
Methotrexate, vinblastine, doxorubicin, and cisplatin
Nab
Neutralizing antibody
NCI
National Cancer Institute

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NSAID
Nonsteroidal anti-inflammatory drug
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PD
Pharmacodynamics 
PD
Progressive disease
PD-1
Programmed death 1
PD-L1
Programmed death ligand 1
PD-L2
Programmed death ligand 2
PES
Polyether sulfone
PFS
Progression-free survival
PK
Pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency
PR
Partial response
PRO
Patient Reported Outcome
PS
Performance status
PT
Prothrombin time
Q2W
Every two weeks
QOL
Quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV2
Severe acute respiratory syndrome coronavirus 2
SD
Stable disease
SRSD
Single reference safety document
SOA
Schedule of Activities
SST
Serum separator tube
SUSAR
Serious unexpected serious adverse reaction
TEAE
Treatment emergent adverse event
TGF
Transforming growth factor
TLS
Tumor lysis syndrome
TNM
Tumor Node Metastasis
TSH
Thyroid stimulating hormone
TTD
Time to deterioration
TTR
Time to tumor response 
UC
Urothelial cancer
ULN
Upper limit of normal
US
United States
VAS
Visual analogue scale
WBC
White blood cell

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Appendix 6. Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
Use of these alternative study measures is expected to cease upon the return of business as 
usual (including the lifting of any quarantines and travel bans/advisories). 
1.1. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the Schedule of 
Activities or unscheduled visits. Telehealth visits may be used to continue to assess 
participant safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (e.g., audio, video, video-
conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit, if 
applicable as per the SOA in effect at the time of the visit:

Review and record any AEs and SAEs since the last contact. Refer to protocol 
Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing (Arm A 
only). Confirm that the participant is adhering to the contraception method(s) required 
in the protocol. Refer to Section 1.2.1 of this appendix regarding pregnancy tests.

ECOG PS 

Patient Reported Outcomes

Survival Assessment
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
1.2. Alternative Facilities for Safety Assessments
1.2.1. Laboratory Testing
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital. The 
following safety laboratory evaluations may be performed at a local laboratory:  

Required laboratory safety assessments as per protocol Section 7.1.3.

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If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible.  The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
1.3. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
Avelumab cannot be administered outside of the investigational site. If the patient cannot 
visit the site, the infusion will be omitted.
The following is recommended for the administration of avelumab for participants who have 
active confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion) SARS-CoV2 infection:

For symptomatic participants with active SARS-CoV2 infection, avelumab should be 
delayed for at least 14 days from the start of symptoms. This delay is intended to allow 
the resolution of symptoms of SARS-CoV2 infection.

Prior to restarting treatment, the participant should be afebrile for 72 hours, and SARS-
CoV2-related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 
hours.  Notify the study team when treatment is restarted.

Continue to consider potential drug-drug interactions for any concomitant medication 
administered for treatment of SARS-CoV2 infection.
1.4. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided.
Temporary discontinuation of the study intervention may be medically appropriate until the 
participant has recovered from COVID-19.
1.5. Efficacy Assessments
Survival: Collection as per SOA should continue for study patients in Follow-up.

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Tumor assessments: Tumor assessments by CT/MRI are to be performed as per protocol
requirements at the investigational site/facilities to the extent possible.

If a different imaging facility is used, please notify the site monitor and update the 
form FDA 1572 as appropriate. 

The investigational site should advise the imaging facility to obtain the images 
consistent with the study ‘Imaging Acquisition Guidelines’ and to transmit the 
resulting images to the investigational site.
Patient-Reported Outcome: In the event that study patients cannot come to the site for 
in-clinic visits, these assessments should be performed remotely (eg, via telephone).  The 
study site staff performing the remote visit are to read the instructions, questions, and 
response choices verbatim and mark the response choice selected by the study patient. 

Conduct this telephone call in a quiet, private area and ask the patient to also go to a
place where they are alone (ie, no one else around and/or able to provide input or 
influence their responses).

Please read the full text including all instructions, questions, and response options. 
Please ensure you are speaking clearly and at a comfortable pace. Also, let the study 
patient know that you can re-read the instructions, question, or response options at 
any time.

Do not interpret any part of the questionnaire for the study patient. If the study patient 
does not understand, please repeat the question and response choices verbatim and 
ask them to select the response that they feel best represents his/her experience. 

Confirm the study patient’s response selection before you record the answer (eg, you 
would like me to select “moderate pain”, is that right?).

Indicate on the paper questionnaire that it was performed via remote visit (eg, via 
telephone). Include the name of the study site staff performing the remote visit and 
confirm that the study patient was the one to answer the questions.

Add an Investigator Comment on both PRO questionnaire CRFs to indicate “Assisted 
due to COVID-19.”
1.6. Patient Discontinuation

Required in-clinic visits, including Avelumab administrations, may be missed without 
causing discontinuation from the maintenance treatment phase of the study. However, 
all study patient withdrawal criteria listed in Protocol Section 6.5 remain applicable.

For study patient discontinuation reporting in the CRF: select the most appropriate 
status for discontinuation; if the discontinuation is associated with the current 
COVID-19 pandemic, enter “COVID-19” in the “Specify Status” field.

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
It’s important to continue to enter the CRF data as quickly as possible, so we have 
access to the data for safety monitoring.  If the sponsor determines that the impact of 
COVID-19 on protocol visits and procedures and associated timeframes needs to be 
reported on a case report form (CRF), this will be requested. 

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17. SUPPLEMENT 1: CROSSOVER FROM BSC ALONE (ARM B) TO AVELUMAB 
PLUS BEST SUPPORTIVE CARE
This supplement provides details for patients in the BSC alone arm who crossover to receive 
avelumab plus BSC.  All other information in the protocol not addressed in this supplement 
still apply.   After 60 days following the final OS update or approval of Amendment 6, 
whichever is later, no additional Arm B patients will be allowed to crossover to avelumab 
plus BSC. 
ELIGIBILITY CRITERIA
Inclusion Criteria
Patients randomized to Arm B must meet all of the following inclusion criteria to be eligible 
to crossover from BSC alone to avelumab plus BSC:
1. Patients randomized to Arm B (BSC alone) ongoing in the maintentance phase 
(ie, patients must not have completed the EOT visit).
2. Patients without progressive disease while on study as per RECIST v1.1 guidelines as 
assessed by the investigator.
3. Evidence of a signed and dated informed consent document indicating that the patient 
(or a legally acceptable representative, as allowed by local guideline/practice) has 
been informed of the aspects of crossover. 
4. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 
1 (Appendix 1).
6. Adequate bone marrow function, including:
a.
Absolute neutrophil count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9 g/dL (may have been transfused).
7. Adequate renal function, defined as estimated creatinine clearance 30 mL/min as 
calculated using the Cockcroft-Gault equation (Appendix 4) or by 24-hour urine 
collection for creatinine clearance or according to the local institutional standard 
method.
8. Adequate liver function, including:
a.
Total serum bilirubin 1.5 x upper limit of normal (ULN); 

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b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
2.5 x ULN, or, for patients with documented metastatic disease to the liver, AST 
and ALT levels ≤5 × ULN. 
9. Serum pregnancy test (for females of childbearing potential) negative at screening.
2.
Exclusion Criteria
Patients with any of the following characteristics/conditions will not be eligible to crossover 
from BSC alone to avelumab plus BSC:
1. Major surgery 4 weeks or major radiation therapy 2 weeks prior to avelumab 
treatment (Cycle CR1 Day 1).  Prior palliative radiotherapy is permitted, provided it 
has been completed at least 48 hours prior to avelumab treatment (Cycle CR1 Day 1).
2. Patients with known symptomatic central nervous system (CNS) metastases requiring 
steroids.  Patients with previously diagnosed CNS metastases are eligible if they have 
completed their treatment and have recovered from the acute effects of radiation 
therapy or surgery prior to randomization, have discontinued corticosteroid treatment 
for these metastases for at least 4 weeks, and are neurologically stable.
3. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or 
hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible.
4. Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months 
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring 
medication.
5. Active infection requiring systemic therapy.
6. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3), any 
history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma 
symptom control per the Global Initiative for Asthma 2015).66
7. Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations.
8. Current or prior use of immunosuppressive medication within 7 days prior to 
avelumab treatment (Cycle CR1 Day 1), EXCEPT the following:
a.
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection);

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b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication). 
9. Diagnosis of prior immunodeficiency or organ transplant requiring 
immunosuppressive therapy.
10. Vaccination within 4 weeks of the first dose of avelumab treatment and while on trial 
is prohibited except for administration of inactivate vaccines (for example, 
inactivated influenza vaccines).
11. Breastfeeding female patients and female patients of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in 
the protocol Section 4.3.1 for the duration of the study and for at least 30 days after 
the last dose of investigational product.
12. Other severe acute or chronic medical conditions including but not limited to HIV, 
HBV, or HCV infection, colitis, inflammatory bowel disease, pneumonitis, and 
pulmonary fibrosis; 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 study treatment 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.
GENERAL TREATMENT/STUDY PLAN
Patients who crossover from BSC alone to avelumab plus BSC will receive avelumab at 
10 mg/kg on Day 1 and Day 15 of each 4-week treatment cycle after all 
procedures/assessments have been completed as described in the SOA table.  
With the exception of the detailed SOA provided below, all study treatments, concomitant 
medication restrictions, AE reporting, etc, described for patients randomized to Arm A in 
Section 5 through Section 7.1 and Section 8 of the study protocol will be followed for 
patients who crossover from Arm B to avelumab plus BSC. 

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SCHEDULE OF ACTIVITIES FOR PATIENTS WHO CROSSOVER FROM ARM B TO AVELUMAB PLUS BSC 
The SOA provides an overview of the protocol visits and procedures for patients randomized to Arm B who are eligible to crossover 
to receive avelumab plus BSC.  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.  If deemed clinically necessary, the 
investigator may schedule visits in addition to those listed in the SOA table (unplanned visits) at any time to conduct evaluations or 
assessments required to protect the well-being of the patient. Following implementation of Protocol Amendment 6 and the final OS 
update, all patients will follow the “PROTOCOL AMENDMENT 6: SCHEDULE OF ACTIVITIES FOR STUDY TREATMENT, 
END OF TREATMENT AND FOLLOW-UP PERIODS.”
CROSSOVER FROM ARM B TO AVELUMAB PLUS BSC
Visit Identifiers1
Screening
Avelumab plus BSC
(1 cycle = 4 weeks)
Within 28 Days Prior 
to Avelumab 
Cycle CR1 Day 11
CR Cycle 2 Day 1 (3 days)
Day 15 (3 days)
All CR Cycles
Clinical Assessments
Informed Consent2
X
Baseline Signs/Symptoms3
X (Cycle CR1 only)
Physical Examination4
X
X
ECOG Performance Status
X
X
Vital Signs and Weight5
X
X
X
Contraception Check6
X
X
X
Laboratory Studies
Coagulation7
X
X
X
Hematology7
X
X
X
Blood Chemistry (full and core)7,8
X
X 
X 
Thyroid Function and ACTH Tests9
X
X (at Cycles CR3, 5, 7, etc.)
Serum/Urine Pregnancy Test10
X
X 
X
Troponin11
X
X (Cycles CR1-4 and as clinically 
indicated)
X (Cycles CR1-3 and as clinically 
indicated)
Urinalysis12
X
If clinically indicated
12-Lead ECG13
X
If clinically indicated

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CROSSOVER FROM ARM B TO AVELUMAB PLUS BSC
Visit Identifiers1
Screening
Avelumab plus BSC
(1 cycle = 4 weeks)
Within 28 Days Prior 
to Avelumab 
Cycle CR1 Day 11
CR Cycle 2 Day 1 (3 days)
Day 15 (3 days)
All CR Cycles
Disease Assessments
Tumor Assessments (including scans)14
X 
Other Clinical Assessments
Adverse Events15
X
X
X
Concomitant Medications/Treatments16
X
X
X
Study Treatment
Avelumab17
X
X
Best Supportive Care (BSC)18
X (Throughout study treatment)
ACTH = adrenocorticotropic hormone; BSC = best supportive care; CR = crossover; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group 
Footnotes for SCHEDULE OF ACTIVITIES FOR SCREENING AND STUDY TREATMENT PERIOD
1.
Visit Identifiers: All assessments should be performed prior to dosing with avelumab unless otherwise indicated.  Cycle CR1 Day 1 pre-dose assessments completed 
within 7 days prior to dosing do not need to be repeated unless clinically indicated.  Acceptable time windows for performing each assessment are described in the 
column headers.  Note: laboratory tests may be performed up to 3 days prior to the scheduled clinic visit so that results will be available for review.
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure.  
3.
Baseline Signs/Symptoms: To be recorded on Cycle CR1 Day 1.  Patients will be asked about any signs and symptoms experienced within the 14 days prior to Cycle 
CR1 Day 1.
4.
Physical Examination: Includes an examination of major body systems.  
5.
Vital Signs and Weight: Vital signs to include blood pressure and pulse rate, which should be taken prior to study drug dosing (if applicable) and with the patient in the 
seated position after the patient has been sitting quietly for at least 5 minutes.  
Weight should be measured at each visit as indicated.  Weight should be measured within 3 days prior to each dose of avelumab (for determination of the avelumab dose 
[mg]).
6.
Contraception Check: Female patients who are of childbearing potential will need to affirm that they meet the criteria for correct use of the selected methods of 
contraception.  The investigator or his or her designee will discuss with the patient the need to use the selected contraception methods consistently and correctly and 
document such conversations in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if the selected 
contraception methods are discontinued, or if pregnancy is known or suspected in the patient or the male patient’s partner.  See Section 4.3.1.
7.
Coagulation, Hematology, and Blood Chemistry (full panel): Required tests are listed in Table 6.  Full chemistry panel is required at Screening, Cycle CR1 Day 1, 
Cycle CR1 Day 15, Cycle CR2 Day 1, Cycle CR3 Day 1, and Day 1 of every 2 cycles (8 weeks) thereafter.  May also be performed when clinically indicated.  If full and 
core chemistry panels are scheduled at the same visit, only the full chemistry will be performed.  
8.
Blood Chemistry (core panel): Core chemistry panel (required tests are listed in Table 6) is required at each clinic visit at which a full chemistry panel is not required. 

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9.
Thyroid Function and ACTH Tests: Free T4, TSH, and ACTH tests will be performed at screening, Cycle CR3 Day 1, and Day 1 of every 2 cycles (8 weeks) thereafter.  
Additional tests should be performed when clinically indicated.  See Table 6.
10. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on two 
occasions prior to starting avelumab: once at the start of screening and once at the Cycle CR1 Day 1 visit immediately before study treatment administration.  Additional 
pregnancy tests (serum or urine) will also be routinely repeated prior to each avelumab dose during the active treatment period, at the End of Treatment/Withdrawal visit, 
and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if 
requested by Institutional Review Board (IRB)/Ethics Committees (ECs) or if required by local regulations.  Results of the pregnancy test should be available prior to each 
dosing.  See Section 7.1.1.
11. Cardiac Troponin (cTn): Measurement of cTnT is preferred; however, cTnI may be substituted where cTnT is not available at the local laboratory.  The same subunit 
(cTnT or cTnI) measured during screening should be measured consistently throughout the study for any given patient.  During screening, clinically significant positive 
results should be further assessed as per local standard of care to rule out concurrent cardiac conditions which could make the patient ineligible for the study per the 
exclusion criteria.  During the study, clinically significant new elevations suggestive of myocarditis should be assessed as per Table 5.  Additional tests should also be 
performed when clinically indicated.  See Table 6.
12. Urinalysis: Required only at Screening and End of Treatment.  To be performed as clinically indicated at other time points.  Required tests are listed in Table 6.
13. 12-Lead Electrocardiogram (ECG): A single ECG measurement is required at screening.  Additional ECGs may be performed as clinically indicated.  Clinically 
significant new findings seen on follow-up ECGs should be recorded as adverse events.
14. Tumor Assessments: Tumor assessments will be performed according to the local standard of care and when progression is suspected, however the tumor assessment data 
will no longer be entered into the CRF nor submitted for central imaging review.
15. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the 
patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
study treatment, through and including 90 calendar days after the last administration of the study treatment.  SAEs occurring to a patient after the active reporting period 
has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable
possibility of being related to study treatment are to be reported to the sponsor.
AEs (serious and non-serious) should continue to be recorded on the Case Report Form (CRF) through and including 90 calendar days after the last administration of 
avelumab.
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 treatment, irrespective of any intervening treatment.
16. Concomitant Medications/Treatments: Concomitant medications and treatments should continue to be recorded through and up to 90 days after the last dose of avelumab.  
If a patient begins a new anti-cancer therapy, reporting of concomitant medications should end at the time the new cancer therapy is started; see Section 5.9 for additional 
details.  All concomitant medications will 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).  Concomitant medications should be reviewed at each study visit, and any 
prohibited treatments (as described in Section 5.9) should be discussed with the patient and appropriately managed. 
17. Avelumab Treatment: Avelumab (10 mg/kg) will be given as a 1-hour intravenous infusion every 2 weeks.  Patients should be weighed within 3 days prior to each dose 
of avelumab (for determination of the avelumab dose [mg]).  All safety assessments must be performed and results reviewed by the treating physician prior to avelumab 
administration.  Patients with disease progression who are continuing to derive clinical benefit from study treatment will be eligible to continue with avelumab provided 
that the treating physician has determined that the benefit/risk for doing so is favorable (See Section 5.4.1). 
18. Best supportive care (BSC): See Section 5.8.  All BSC components must comply with the permitted medications described in this protocol (see Section 5.9).

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CROSSOVER FROM ARM B TO AVELUMAB PLUS BSC: END OF TREATMENT/WITHDRAWAL AND FOLLOW-UP
Visit Identifiers1
End of 
Treatment/
Withdrawal
(±3 days)2
Follow-up3
Short-Term
Long-Term
every 3 months 
14 days)
30 days (±3 days)
After 
Last Dose 
60 days (±3 days) 
After 
Last Dose
90 days (±3 days) 
After 
Last Dose
Clinical Assessments
Physical Examination4
X
X
X
X
ECOG Performance Status
X
X
X
X
Vital Signs and Weight5
X
X
X
X
Contraception Check6
X
X
Laboratory Studies
Hematology7
X
X
X
X
Blood Chemistry (full panel)8
X
X
X
X
Coagulation7
X
X
X
X
Thyroid Function Tests and ACTH9
X
X
X
X
Serum/Urine Pregnancy Test10
X
X
Urinalysis11
X
12-lead ECG12
If clinically indicated
Disease Assessments
Tumor Assessments (including scans)13
X 
Other Clinical Assessments
Adverse Events14
X
X
X
X
Concomitant Medications/Treatments15
X
X
X
X
New Systemic Anticancer Treatment
X
X
X
X
X
Survival Assessment16
X
X
X
X
ACTH = adrenocorticotropic hormone; BSC = best supportive care; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group 
Footnotes for SCHEDULE OF ACTIVITIES FOR END OF TREATMENT/WITHDRAWAL AND FOLLOW-UP PERIODS
1.
Visit Identifiers: Acceptable time windows for performing each assessment are described in the column headers.  Per the visit time window, laboratory tests may be 
performed up to 3 days prior to the scheduled clinic visit so that results will be available for review.
2.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if performed 
within the prior 6 weeks.

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3.
Short- and Long-Term Follow-up: All patients will be followed for safety every 30 days (±3 days) through 90 days after the last dose of avelumab.  During the
post-treatment safety follow-up (beyond 30 days through 90 calendar days after last avelumab administration), AEs (serious or non-serious) that the investigator believes 
have at least a reasonable possibility of being related to study drug are to be recorded on the case report form (CRF). 
Beyond the 90 days until the end of the study (long-term follow-up), all patients will be followed every 3 months after the last study clinic visit (14 days) for survival, 
tumor assessment, and new systemic anticancer treatment; additional timepoints to collect survival information may be requested by the Sponsor in preparation for interim 
and final analyses.
4.
Physical Examination: Includes an examination of major body systems.
5.
Vital Signs and Weight: 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.  
6.
Contraception Check: Female patients who are of childbearing potential will need to affirm that they meet the criteria for correct use of the selected methods of 
contraception until at least 30 days after the last dose of avelumab.  The investigator or his or her designee will discuss with the patient the need to use the selected 
contraception methods consistently and correctly and document such conversations in the patient’s chart.  In addition, the investigator or his or her designee will instruct 
the patient to call immediately if the selected contraception methods are discontinued, or if pregnancy is known or suspected in the patient or the male patient’s partner.  
See Section 4.3.1.
7.
Hematology, Blood Chemistry, and Coagulation: Required tests are listed in Table 6.  May also be performed when clinically indicated. 
8.
Blood Chemistry: Full chemistry panel (see Table 6) is required at End of Treatment/Withdrawal and during short-term follow-up visits (Days 30 3, 60 3, 90 3 after 
last dose).   
9.
Thyroid Function Tests: Free T4, TSH, and ACTH will be performed at the End of Treatment/Withdrawal and at Follow-up visits at 30±3, 60±3, and 90 3 days after 
last dose of avelumab.  Additional tests should be performed when clinically indicated.  See Table 6.
10. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed at 
the End of Treatment/Withdrawal visit and at the 30-Day Follow-up visit, and additionally whenever one menstrual cycle is missed or when potential pregnancy is 
otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by Institutional Review Board (IRB)/Ethics Committees (ECs) or if required by local 
regulations.  See Section 7.1.1.
11. Urinalysis: Required only at the End of Treatment/Withdrawal.  To be performed as clinically indicated at other time points.  Required tests are listed in Table 6.
12. 12-Lead Electrocardiogram (ECG): When clinically-indicated.  Clinically significant new findings seen on follow-up ECGs should be recorded as adverse events.  See 
Section 7.1.5 for further details.
13. Tumor Assessments: Tumor assessments will be performed according to the local standard of care and when progression is suspected, however the tumor assessment 
data will no longer be entered into the CRF nor submitted for central imaging review.
14. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the 
patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
study treatment, through and including 90 calendar days after the last administration of the study treatment.  SAEs occurring to a patient after the active reporting period 
has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable 
possibility of being related to study treatment are to be reported to the sponsor.
AEs (serious and non-serious) should continue to be recorded on the Case Report Form (CRF) through and including 90 calendar days after the last administration of 
avelumab.
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 treatment, irrespective of any intervening treatment.

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15. Concomitant Medications/Treatments: Concomitant medications and treatments should continue to be recorded through and up to 90 days after the last dose of 
avelumab.  If a patient begins a new anti-cancer therapy, reporting of concomitant medications should end at the time the new cancer therapy is started; see Section 5.9 for 
additional details.  All concomitant medications will 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).  Concomitant medications should be reviewed at each study visit, and 
any prohibited treatments (as described in Section 5.9) should be discussed with the patient and appropriately managed.
16. Survival Assessment: All patients will be followed for survival and subsequent anticancer therapies every 3 months (±14 days) after the last study clinic visit until death, 
end of the study, or patient withdrawal of consent, whichever comes first.  These visits may be conducted in-clinic or by remote contact (eg, telephone).  Additional 
timepoints to collect survival information may be requested by the Sponsor in preparation for interim and final analyses.