A Phase 1b Study of Combination of Avelumab and Taxane Based Chemotherapy in Platinum Refractory or Ineligible Metastatic Urothelial Cancer
Phase: PHASE1
Conditions: Urothelial Carcinoma
Sponsor: Yousef Zakharia

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Protocol V3; 10/19/2020 
A phase Ib study of combination of Avelumab and Taxane based 
chemotherapy in platinum refractory or ineligible metastatic 
urothelial cancer (AVETAX study) 
 
 
Principal Investigator:  
Name: Rohan Garje, MD  
Clinical Assistant Professor  
Institution: University of Iowa 
Address: 200 Hawkins Drive, C-32 GH Iowa City, 52242 
Phone: 319-356-2075 
Fax: 319-353-8383 
Email: rohan-garje@uiowa.edu  
 
Sub Investigator: 
Yousef Zakharia, MD 
Clinical Assistant Professor  
Institution: University of Iowa 
Address: 200 Hawkins Drive, C-32 GH Iowa City, 52242 
Phone: 319-356-2075 
Fax: 319-353-8383 
Email:  yousef-zakharia@uiowa.edu 
 
 
Sub Investigator: 
Adithya Chennamadhavuni, MD 
Associate of Internal Medicine, 
University of Iowa 
 
 
Statistician:  
Timothy Ginader 
Biostatistician  
Holden Comprehensive Cancer Center 
 
Version 1 – 3/21/2018 
Version 2 – 3/19/2019 
Version 3 – 10/19/2020 
 
 
Sponsor:   University of Iowa 
Drug provided by Pfizer, Inc. 
 

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Protocol V3; 10/19/2020 
 
Summary of Changes 
Protocol Version 3 
10/19/2020 
 
Page 
Protocol Changes: 
Cover 
- Revised Version number and date 
35 
5.2 EXCLUSION CRITERIA- Prostate cancer with GS 6-7 allowed, changed from <7 
57 
6.4 CONCOMITANT THERAPY- Clarifies Long term high dose (>40 mg) glucocorticoids 
are excluded. Short course of glucocorticoids for the treatment of non-immune 
related issues such as COPD, asthma, osteoarthritis, chronic back pain etc at the 
discretion of investigator is allowed.- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol V3; 10/19/2020 
Table of Contents 
1 Protocol Summary ...................................................................................................................................................... 5 
1.1 Synopsis ............................................................................................................................................................... 5 
1.2 Schema ................................................................................................................................................................ 6 
1.3 Schedule of Activities (SoA/ Study calendar) ....................................................................................................... 7 
List of ABBREVIATIONS ................................................................................................................................................ 10 
2 Introduction .............................................................................................................................................................. 14 
2.1 Study Rationale .................................................................................................................................................. 14 
2.2 Background ........................................................................................................................................................ 16 
2.2.1 Preclinical Evidence FOR AVELUMAB ......................................................................................................... 16 
2.2.2 CLINICAL EVIDENCE for AVelumab ............................................................................................................. 19 
2.2.3 Clinical evidence for docetaxel ................................................................................................................... 23 
2.3 Risk/Benefit Assessment.................................................................................................................................... 23 
2.3.1 Known Potential Risks ................................................................................................................................. 23 
3 Objectives and Endpoints ......................................................................................................................................... 30 
4 Study Design ............................................................................................................................................................. 32 
4.1 Overall Design .................................................................................................................................................... 32 
4.2 Scientific Rationale for Study Design ................................................................................................................. 33 
4.3 Justification for Dose ......................................................................................................................................... 33 
4.3.1 Dose limiting toxicities ................................................................................................................................ 33 
4.4 End of Study Definition ...................................................................................................................................... 34 
5 Study Population ...................................................................................................................................................... 35 
5.1 Inclusion Criteria ................................................................................................................................................ 35 
5.2 Exclusion Criteria ............................................................................................................................................... 36 
5.3 Lifestyle Considerations ..................................................................................................................................... 37 
5.4 Screen Failures ................................................................................................................................................... 37 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 38 
6 Study Intervention .................................................................................................................................................... 39 
6.1 Study Intervention(s) Administration ................................................................................................................ 39 
6.1.1 Pretreatment evaluation ............................................................................................................................ 39 
6.1.2 Dosing ......................................................................................................................................................... 39 
6.1.3 Premedication for Avelumab ...................................................................................................................... 40 
6.1.4 Premedication for Docetaxel ...................................................................................................................... 40 
6.1.5 Dose Modifications and INTERRUPTION ..................................................................................................... 40 
6.1.6 Warnings and precautions for Avelumab: .................................................................................................. 50 
Immune-related Pneumonitis .................................................................................................................................. 50 
Immune-related Hepatitis ....................................................................................................................................... 51 
Immune-related Colitis ............................................................................................................................................ 51 
Immune-related Endocrinopathies .......................................................................................................................... 52 
Adrenal insufficiency ............................................................................................................................................... 52 
Type 1 Diabetes Mellitus ......................................................................................................................................... 52 
Immune-related Nephritis and Renal Dysfunction .................................................................................................. 53 
Other Immune-related adverse events ................................................................................................................... 53 
Infusion-related reactions ....................................................................................................................................... 54 
6.1.7 pregnancy, lacation and fertility issues with avelumab .............................................................................. 54 
Pregnancy ................................................................................................................................................................ 54 
Lactation .................................................................................................................................................................. 55 

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Protocol V3; 10/19/2020 
6.2 Preparation/Handling/Storage/Accountability .................................................................................................. 55 
6.2.1 Acquisition and accountability .................................................................................................................... 56 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................................... 56 
6.2.3 Product Storage and Stability ..................................................................................................................... 56 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 57 
6.4 Concomitant Therapy ........................................................................................................................................ 57 
6.4.1 Rescue Medicine ......................................................................................................................................... 58 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................. 60 
7.1 Discontinuation of Study Intervention .............................................................................................................. 60 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 60 
7.3 Lost to Follow-Up ............................................................................................................................................... 60 
8 Study Assessments and Procedures ......................................................................................................................... 62 
8.1 Efficacy Assessments ......................................................................................................................................... 62 
8.2 Safety and Other Assessments .......................................................................................................................... 66 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 66 
8.3.1 Definition of Adverse Events (AE) ............................................................................................................... 66 
8.3.2 Definition of Serious Adverse Events (SAE) ................................................................................................ 67 
8.3.3 Classification of an Adverse Event .............................................................................................................. 67 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............... Error! Bookmark not defined. 
8.3.5 Screening and baseline examination ..................................................... Error! Bookmark not defined. 
8.3.6 Treatment period ........................................................................................... Error! Bookmark not defined. 
8.3.7 End of treatment and premature withdrawal visit ........................................ Error! Bookmark not defined. 
8.3.8 Adverse Event Reporting ............................................................................................................................ 68 
8.3.9 Serious Adverse Event Reporting................................................................................................................ 69 
8.3.10 Reporting Events to Participants .............................................................................................................. 69 
8.3.11 Events of Special Interest ............................................................................ Error! Bookmark not defined. 
8.3.12 Reporting of Pregnancy ............................................................................................................................ 69 
8.4 Unanticipated Problems .................................................................................................................................... 70 
8.4.1 Definition of Unanticipated Problems (UP) ................................................................................................ 70 
8.4.2 Unanticipated Problem Reporting .............................................................................................................. 70 
8.4.3 Reporting Unanticipated Problems to Participants .................................................................................... 71 
9 Statistical Considerations ......................................................................................................................................... 72 
9.1 Statistical Hypotheses ........................................................................................................................................ 72 
9.2 Sample Size Determination................................................................................................................................ 72 
9.3 Populations for Analyses ................................................................................................................................... 74 
9.4 Statistical Analyses............................................................................................................................................. 74 
9.4.1 General Approach ....................................................................................................................................... 74 
9.4.4 Safety Analyses ........................................................................................................................................... 75 
9.4.5 Baseline Descriptive Statistics .................................................................................................................... 75 
9.4.6 Planned Interim Analyses ........................................................................................................................... 75 
9.4.7 Sub-Group Analyses .................................................................................................................................... 75 
9.4.8 Tabulation of Individual Participant Data ................................................................................................... 75 
10 Supporting Documentation and Operational Considerations ................................................................................ 77 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 77 
10.1.1 Informed Consent Process ........................................................................................................................ 77 
10.1.2 DATA Monitoring and Management......................................................................................................... 77 

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Protocol V3; 10/19/2020 
10.2 Trial-Specific Data and Safety Monitoring Plan ............................................................................................... 78 
10.2.1 Study risk-level:......................................................................................................................................... 78 
10.2.2 Reporting and Monitoring Requirements: ............................................................................................... 79 
10.2.3 Selected monitoring strategy based on risk-level:.................................................................................... 79 
10.2.4 Additional Reporting Requirements: ........................................................................................................ 79 
11 References .............................................................................................................................................................. 82 
1 Protocol Summary 
1.1 SYNOPSIS 
Title: 
A phase Ib study of combination of Avelumab and Taxane based 
chemotherapy in platinum ineligible or refractory metastatic urothelial 
cancer. (AVETAX study) 
Study Description: 
This study evaluates the safety and efficacy of the combination of 
Avelumab, (a fully human anti-programmed death ligand 1 (PD-L1) IgG1 
antibody) in combination with a taxane chemotherapy (docetaxel) in 
patients with metastatic urothelial cancer who are either ineligible to 
receive cisplatin based chemotherapy, refractory to cisplatin in first line 
setting or have disease relapse after receiving cisplatin based chemotherapy 
within a year in the neoadjuvant or adjuvant setting.  
Objectives: 
Primary Objective: To assess the safety and efficacy of the combination 
therapy 
  
Endpoints: 
Primary Endpoint:  To assess dose limiting toxicities and overall 
response rate (CR,PR) with the combination therapy in subjects with 
metastatic urothelial cancer 
 
Secondary Endpoints: To assess progression free survival and Overall 
survival  
Study Population: 
Adults, n=21, both male and female, Age ≥18, with cisplatin ineligible or 
refractory metastatic urothelial carcinoma 
Phase: 
Phase Ib 
Description of 
Sites/Facilities Enrolling 
Participants: 
University of Iowa - Holden Comprehensive Cancer Center - Iowa City, IA 
USA. 
Description of Study 
Intervention: 
After a screening phase of up to 28 days, eligible subjects will receive 
Avelumab 10 mg/kg and Taxane based chemotherapy (Docetaxel 75 
mg/m2) on Day 1 of each 3-week (Q3W) cycle for a total of 6 cycles. 
Subsequently, the subjects will receive single agent Avelumab 10 mg/kg 
every 2 weeks until documented disease progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with the trial 
treatment or procedure requirements or administrative reasons. 
Study Duration: 
We estimate that the study will require approximately 36  months from the 
time the first subject signs the informed consent until the last subject’s last 
visit 

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Protocol V3; 10/19/2020 
Participant Duration: 
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final protocol-specified contact 
(up to approximately 5 years). 
 
1.2 SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N=21 
1. 
Metastatic urothelial cancer - Cisplatin 
refractory or ineligible or relapsed 
2. 
PS 0-2 
3. 
No active auto immune disorders 
Induction phase: 
Avelumab (10 mg/kg) + Docetaxel (75 mg/m2) every 3 
weeks for 6 cycles   
 
Maintenance phase: 
Avelumab (10 mg/kg) every 2 weeks until disease 
progression or toxicity 
Screening and 
consent 

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Protocol V3; 10/19/2020 
 
 
 
1.3 SCHEDULE OF ACTIVITIES (SOA/ STUDY CALENDAR) 
 
 
 
 
Screening 
(visit 1) 
 
Treatment Cycles (Treatment cycles are 3 weeks for 
the combination therapy and 2 weeks while on 
Avelumab alone )1 
 
End of 
Treatment6 

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Protocol V3; 10/19/2020 
 
Treatment Cycle / Scheduled 
Time 
-28 to -1 
1 
2 3 4 5 6 7 8 9 10 11 12 13 14 through 
35 
Discontinuation 
Visit (30 +/- 7 
days after final 
administration of 
drug) 
Scheduling Window (Days): 
 
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (current) 
X 
X 
X X X X X X X X X X X 
X 
X 
X 
Details regarding urothelial 
cancer – Diagnosis and prior 
treatment  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures / Assessments 
 
Review Adverse Events 
X 
X X X X X X X X X X X 
X 
X 
X 
Physical Examination 
X 
X 
X X X X X X X X X X X 
X 
X 
X 
Vital Signs,Weight, Height7 
X 
X 
X X X X X X X X X X X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
X X X X X X X X X X X 
X 
X 
X 
Study Drug Administration 
Docetaxela 
X 
X X X X X 
 
Avelumab 
X 
X X X X X X X X X X X X X 
X 
 
 
Screening 
(Visit 1) 
 
Treatment Cycles (Treatment cycles are 3 weeks (21-days) for the 
combination therapy and 2 weeks while on Avelumab alone) 1 
 
 
End of 
Treatment6 
Treatment Cycle / 
Scheduled 
Time 
-28 to -1 
1 2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 
13 Subsequ
ent 
cycles 
35 
Discontinuation 
Visit (30 +/- 7 
days after final 
administration 
of drug) 
Scheduling Window 
(Days): 
 
 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
Laboratory Procedures / Assessments: 
Pregnancy Test - Urine 
or Serum β-HCG 2 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 

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Protocol V3; 10/19/2020 
 
 
  
 
  a      Premedication with dexamethasone  20 mg po once prior to infusion of Docetaxel  
1. 
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for 
each cycle unless otherwise specified. Treatment cycles are 3 weeks for the combination therapy (Avelumab and 
Docetaxel) and 2 weeks while on Avelumab alone. 
2. 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of 
trial treatment.  If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test, performed by 
the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines. Pregnancy test in woman of child bearing age will be checked every other cycle (every 6 
weeks in induction and every 4 weeks in maintenance phase) 
3. 
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving 
anticoagulant therapy. 
4. 
Brain MRI is obtained if clinically required at baseline. CT scans are performed every 3 cycles (+/- 7 days) for the first 
18 weeks during the induction phase and then every 12 weeks until treatment discontinuation. After the first 
documentation of progression (if the subject is clinically stable) or response per RECIST 1.1, repeat imaging for 
confirmation is required. Confirmatory imaging should be performed 4 to 6 weeks later. Tumor assessments will be 
adjusted accordingly to match +/-7 days from Day 1 of each even cycle.  
5. 
Thyroid function test will be checked every 8 weeks in the maintenance phase from Cycle 13. 
6. 
After the End of treatment visit, patients without disease progression will be followed every 3 months (+1 month) 
with CT scans per physician standard of care. Patients with disease progression or who have started subsequent 
therapy will move to survival only data collection (passive chart review or phone calls) every 3 months(+1 month) for 
2 years, then  every 6 months (+1 month) until death or lost-to-follow up.  
7. 
Height at screening only. 
8. 
Check PDL1 status on tumor specimen using institutional standards in any timeframe, but this is not required for 
screening or eligibility 
 
PT/INR and aPTT 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive  
Metabolic panel 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
T3, FT3, FT4 and TSH 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X5 
X 
Tumor PDL1 
Expression8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging (CT 
and/or MRI)4 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Every 12 
weeks 
X 

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Protocol V3; 10/19/2020 
LIST OF ABBREVIATIONS  
ADA  
 Anti-drug antibody 
ADCC  
 Antibody-dependent cell-mediated cytotoxicity  
ADL  
 Activities of daily living 
AE  
 Adverse event 
ALT  
 Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST  
 Aspartate aminotransferase 
AUC  
 Area under the concentration-time curve 
AUC0-t  
 Area under the concentration-time curve from 0 to last quantifiable 
concentration 
AUCtau  
 Average area under the concentration-time curve  
BOR  
 Best overall response 
bpm  
 Beats per minute 
CFR  
 Code of Federal Regulations 
CI  
 Confidence Interval 
CK  
 Creatine kinase 
Cmax  
 Maximum concentration 
Cmin  
 Minimum (trough) concentration 
CMP  
 Clinical Monitoring Plan 
CNS  
 Central nervous system 
COC  
 Certificate of Confidentiality 
CONSORT  
 Consolidated Standards of Reporting Trials 
COPD  
 Chronic obstructive pulmonary disorder 
CPK  
 Creatine phosphokinase 
CR  
 Complete response 
CRA  
 Cytokine release assays 
CRF  
 Case Report Form 
CYP  
 Cytochrome P 
DCC  
 Data Coordinating Center 
DDI  
 Drug-drug interaction 
DHHS  
 Department of Health and Human Services 
DLT  
 Dose-limiting toxicity 
DRE  
 Disease-Related Event 
DSMB  
 Data Safety Monitoring Board 
EC  
 Ethics Committee 
EC50  
 Effective concentration exerting 50% effect 
ECG  
 Electrocardiogram 

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Protocol V3; 10/19/2020 
ECOG  
 Eastern Cooperative Oncology Group 
eCRF  
 Electronic Case Report Forms 
FACS  
 Fluorescence-activated cell sorting 
Fc  
 Fragment crystalline 
FDA  
 Food and Drug Administration 
FDAAA  
 Food and Drug Administration Amendments Act of 2007 
FFR  
 Federal Financial Report 
FOLFOX  
 Combination therapy with folinic acid, 5-fluorouracil, and oxaliplatin 
GCP  
 Good Clinical Practice 
GGT  
 Gamma-glutamyl transferase 
GI  
 Gastrointestinal 
GLP  
 Good Laboratory Practice 
GM-CSF  
 Granulocyte macrophage colony-stimulating factor 
HAHA  
 Human anti-human antibody response 
HIPAA  
 Health Insurance Portability and Accountability Act 
IB  
 Investigator’s Brochure 
ICMJE  
 International Committee of Medical Journal Editors 
IFN-γ  
 Interferon-gamma 
IgE  
 Immunoglobulin E 
IgG  
 Immunoglobulin G 
IL  
 Interleukin 
IND  
 Investigational New Drug Application 
ip  
 Intraperitoneal 
irAE  
 Immune-related adverse event 
IRB  
 Institutional Review Board 
IRR  
 Infusion-related reaction 
ISM  
 Independent Safety Monitor 
ISO  
 International Organization for Standardization 
ITT  
 Intention-To-Treat 
IV  
 Intravenous 
KD  
 Dissociation constant 
KM  
 Michaelis-Menten constant (concentration at the half-maximal elimination 
rate) 
LFT  
 Liver function test 
LLN  
 Lower limit of normal 
mAb  
 Monoclonal antibody 
MBC  
 Metastatic breast cancer 
MCC  
 Merkel cell carcinoma 
MCP-1  
 Monocyte chemotactic protein-1 
MedDRA  
 Medical Dictionary for Regulatory Activities 

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Protocol V3; 10/19/2020 
MOP  
 Manual of Procedures 
MRI  
 Magnetic resonance imaging 
MSDS  
 Material Safety Data Sheet 
msec  
 Milliseconds 
MTD  
 Maximum tolerated dose 
NCI-CTCAE  
 National Cancer Institute Common Terminology Criteria for Adverse Events 
NCT  
 National Clinical Trial 
NIH  
 National Institutes of Health 
NIH IC  
 NIH Institute or Center 
NK  
 Natural killer 
NOAEL  
 No observed adverse effect level 
NSAIDs  
 Nonsteroidal anti-inflammatory drugs 
NSCLC  
 Non-small cell lung cancer 
OHRP  
 Office for Human Research Protections 
ORR  
 Objective response rate 
OS  
 Overall survival 
PBMC  
 Peripheral blood mononuclear cell 
PD  
 Pharmacodynamic(s) 
PD-1  
 Programmed death 1 
PD-L1  
 Programmed death ligand 1 
PFS  
 Progression free survival 
Ph Eur 
 European Pharmacopeia 
PHA  
 Phytohemagglutinin 
PI  
 Principal Investigator 
PK  
 Pharmacokinetic(s) 
PR  
 Partial Response 
PRES  
 Posterior reversible encephalopathy syndrome 
PT  
 Preferred term 
QA  
 Quality Assurance 
QC  
 Quality Control 
QTc  
 Corrected QC interval 
RBC  
 Red blood cell 
RECIST  
 Response Evaluation Criteria in Solid Tumors 
SAE  
 Serious adverse event 
SAP  
 Statistical Analysis Plan 
SD  
 Stable disease 
SEA  
 Staphylococcal enterotoxin A 
SMC  
 Safety Monitoring Committee 
SMC  
 Safety Monitoring Committee 
SOA  
 Schedule of Activities 

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Protocol V3; 10/19/2020 
SOC  
 System organ class 
SOP  
 Standard Operating Procedure 
StD  
 Standard deviation 
t1/2  
 Terminal half-life 
T4  
 Free thyroxine 
TCR  
 Tissue cross reactivity 
TEAE  
 Treatment-emergent adverse event 
TEM  
 T effector memory 
TGF  
 Transforming growth factor 
TNF  
 Tumor necrosis factor 
TO  
 Target occupancy 
TSH  
 Thyroid-stimulating hormone 
UC  
 Urothelial carcinoma 
ULN  
 Upper limit of normal 
UP  
 Unanticipated Problem 
US  
 United States 
USP  
 United States Pharmacopeia 
Vmax  
 Maximal elimination 
WBC  
 White blood cell 
 

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Protocol V3; 10/19/2020 
2 INTRODUCTION 
2.1 STUDY RATIONALE 
Bladder cancer is the most common malignancy of the urinary system. As per SEER database, about 
76,960 new cases of bladder cancer and an estimated 16,390 bladder cancer associated deaths were 
estimated in 2016. 
  
Platinum based chemotherapy was the only option until 2016, during which five checkpoint inhibitors 
(Nivolumab [1], Pembrolizumab [2], Avelumab [3], Atezolizumab [4] and Durvalumab) were approved 
for metastatic urothelial cancer. This new therapy has brought a paradigm shift in the treatment of 
locally advanced unresectable and metastatic urothelial cancer. Most of the patients will be able to get 
one of these agents. Also, the response rates have been in the range of 18-25%. These agents have 
broadened the options for a disease with a dismal prognosis, but eventually, most patients experience 
disease progression.  
  
In addition to the immunotherapeutic agents, there are no other standard therapeutic options. Taxane 
based chemotherapy is the most commonly utilized with low response. Single agent Docetaxel was 
studied in phase II clinical of 30 patients with metastatic urothelial cancer in a second-line setting. Four 
out of 30 patients demonstrated partial response rate of 13.3% and a median survival of 9 months. [5] In 
another phase 3 study of pembrolizumab as second line therapy for metastatic urothelial cancer, the 
comparator chemotherapy arm (Docetaxel) had median overall survival of 7.4 months with an objective 
response of 11.4%. [2] 
  
Novel and newer treatment strategies are warranted to improve the outcome of these patients further. 
The renaissance of Immunotherapy in the past decade has opened doors to explore its synergism with 
standard treatments including chemotherapy, hormonal therapy, radiation and targeted therapy, as a 
vital component of cancer treatment.  
  
Among the various strategies, one unique approach would be to combine immunotherapy with 
chemotherapy to enhance the anti-tumor activity. Avelumab is fully human anti-programmed death 
ligand 1 (PD-L1) IgG1 antibody that binds PD-L1 receptors on tumor cells and blocks the interaction 
between PD-L1 and its receptors PD-1 and B7.1 on T cells. This interaction releases the inhibitory effects 
of PD-L1 on the immune response resulting in the restoration of immune responses, including anti-
tumor immune responses. Also, Avelumab has a unique feature of antibody-dependent cell-mediated 
cytotoxicity (ADCC) in vitro [6] that segregates it from currently available immunotherapeutic agents. 
We hypothesize that combining Avelumab with chemotherapy leads to cancer cell death releasing 
neoantigens and potentiating an inflammatory response, which could enhance the anti-tumor activity.  
 

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Protocol V3; 10/19/2020 
To evaluate its safety and efficacy with chemotherapy, a phase 3 study of Avelumab in combination with 
and/or following platinum-based chemotherapy is currently on-going in ovarian malignancies 
(NCT02718417). 
  
CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of the 
combination of nivolumab and platinum based doublet in advanced non-small cell lung cancer. 
Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus 
pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus 
paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival 
rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, 
respectively. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related 
adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) 
discontinued all study therapy as a result of treatment-related AEs. Encouraging activity was observed, 
especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%. [7] 
  
Another clinical trial KEYNOTE-021 reported that the addition of pembrolizumab to chemotherapy 
(carboplatin and pemetrexed) in patients with advanced non-small cell lung cancer (NSCLC) has 
significantly improved the overall response rate (ORR) from 29% to 55% (p = 0.0016). Progression-free 
survival (PFS) was also improved (median PFS 13.0 months vs. 8.9 months), and although toxicity was 
higher in the pembrolizumab arm, it did not increase the number of treatment discontinuations or 
treatment-related deaths. [8] Overall, from the three trials in ovarian and non-small cell lung cancers, 
the combination of immunotherapy with taxane, platinum-based drugs is a relatively safe option with 
improved overall survival compared to single therapy. Also, once a particular agent is utilized, other 
agents cannot be used as the efficacy in such setting is unknown.   
 
The therapeutic armamentarium is changing in the first line therapy as well for bladder cancer. 
Immunotherapeutic agents are being tested in first-line therapy in combination with chemotherapy and 
TKIs.  There are two randomized phase 3 trials evaluating the efficacy of checkpoint inhibitors in 
combination with platinum-based chemotherapy (NCT02853305 and NCT02807636) in first line setting 
for metastatic urothelial cancer. Realistically, the elderly patients (a major proportion of metastatic 
bladder cancer) will be Cisplatin ineligible due to renal impairment.  Also, there is a concern for toxicity 
of combining cisplatin and immunotherapeutic agents (pending final results of these studies). Hence, it 
appears rationale to combine taxane based agent along with immunotherapeutic agent in second line 
that doesn’t include cisplatin. Also, a second line option of combination therapy will be unique when 
compared to utilizing single agent immunotherapeutic agent for a vast proportion of patients who did 
not receive immunotherapeutic agent previously and were treated with either cisplatin or carboplatin 
based therapy.  Hence, this study will aim to answer the unmet need in this patient population. 
  
We hypothesize the combination of Avelumab and taxane based chemotherapy (Docetaxel) would be 
safe, synergistic in patients with metastatic urothelial cancer after progressing on cisplatin-based 
chemotherapy or in patients who are ineligible for cisplatin. PD-L1 is an important biomarker but we will 
not use it to select patients for this study. PD-L1 is a non-specific marker for response in treatment of 

16 
Protocol V3; 10/19/2020 
bladder cancer. PD-L1 low tumors had lower response with pembrolizumab and atezolizumab when 
compared to platinum-based chemotherapy. However, when Avelumab was evaluated in platinum 
ineligible patients, the responses were seen in both PDL-1 high and low tumors but responses were 
slightly lower in PD-L1 low patients. Currently single agent avelumab has accelerated approval by FDA 
irrespective of PD-L1 status. 
 
2.2 BACKGROUND 
2.2.1 PRECLINICAL EVIDENCE FOR AVELUMAB 
  
Based on the known role of PD-L1 in the suppression of T cell responses and the strong correlation 
between PD-L1 expression and prognosis in cancer, the blockade of the PD-L1/PD-1 interaction is 
viewed as a highly promising strategy for cancer immunotherapy (Topalian et al 2012a). The Sponsor has 
developed a fully human IgG1 antibody (Avelumab) with neutralizing activity against PD-L1. The 
nonclinical pharmacology investigations have shown that Avelumab functionally enhances T cell 
activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors in vivo.  
 
To further characterize the immunological activity of Avelumab, and identify potential PD biomarkers, 
various immunomonitoring assays were incorporated into in vivo studies. Surface expression of PD-1 is 
upregulated on activated T cells; thereby conferring susceptibility to PD-L1 induced apoptosis. It is 
hypothesized that treatment with Avelumab effectively blocks PD-L1 induced apoptosis of activated T-
cells, which then results in a measurable accumulation of CD8+PD-1+ T cells.  Fluorescence activated 
cell-sorting (FACS) based immunophenotyping of T cells subsets consistently showed an increase in the 
percentage of CD8+PD-1+ T cells following treatment with Avelumab. In agreement with the hypothesis 
that PD-L1 neutralization acts to release anti-tumor T cells from immune suppression, the anti-tumor 
effects of Avelumab in vivo were found to be primarily mediated by CD8+ T cells, as highlighted by the 
observation that the in vivo depletion of this cell type was sufficient to completely abrogate anti-tumor 
activity. 
 
Increased frequency of CD8+ TEM phenotype was another consistent effect of Avelumab treatment. 
Anti-tumor CD8+ T cells that become activated through blockade of inhibitory PD-1 signaling are 
expected to enter an effector phase characterized by an increased cytotoxic capacity. A fraction of these 
activated T cells will further differentiate into effector memory cells. TEM are capable of mounting a 
rapid and highly effective immune response upon a repeated encounter with their cognate antigen. The 
increases in CD8+PD-1+ T cells and CD8+ TEM cells that are consistently observed in response to 
treatment with Avelumab may be leveraged as PD biomarkers with translational relevance for the 
clinical setting.  
 
Avelumab is also capable of stimulating ADCC activity against PD-L1+ tumor cells in vitro and elimination 
of ADCC potential in vivo significantly reduced anti-tumor activity. Commonly used cancer treatments, 
such as chemotherapy and radiation therapy, that were once thought to be purely immunosuppressive 

17 
Protocol V3; 10/19/2020 
in nature, are now known to exert positive immunomodulatory effects that can be exploited to enhance 
the efficacy of immunotherapy (Nowak et al 2003a, Nowak et al 2003b, Matsumara et al 2008). Of the 
combination approaches that have currently been explored for Avelumab, chemotherapy with FOLFOX 
and radiation therapy showed the better tumor growth inhibition. In particular, radiation therapy was 
found to be a highly synergistic combination capable of causing complete regression of established 
tumors with the potential to generate anti-tumor immune memory. Depletion of CD8+ T cells also 
eliminated the synergistic efficacy of Avelumab when given in combination with radiotherapy, 
suggesting that this combination synergizes through cooperative immune-enhancing mechanisms.  
  
In summary, the available preclinical data demonstrate that Avelumab is capable of inhibiting tumor 
growth in vivo when applied as a monotherapy and its efficacy can be further enhanced via combination 
with standard-of-care therapies. Avelumab has the potential to offer significant clinical benefits to 
cancer subjects through its ability to release anti-tumor CD8+ T cells from the suppressive effects of PD-
L1 in the tumor microenvironment, increase frequency of CD8+ TEM phenotype, and improve synergistic 
response to conventional chemo and radiation therapy. The enzyme-linked immunosorbent spot and 
pentamer assays used to measure T cell responses are also commonly applied in the clinic. Therefore, it 
is desirable to measure immunophenotypic changes and, whenever possible, tumor-antigen-specific 
responses in human subjects treated with Avelumab. 
  
2.2.1.1 PHARMACOKINETICS AND PRODUCT METABOLISM IN ANIMALS SUMMARY 
  
The pharmacokinetics of Avelumab and precursor molecules were evaluated in mice, the primary 
pharmacology species, and cynomolgus monkeys, the relevant species for nonclinical safety testing. 
Avelumab has similar binding affinity to programmed death ligand 1 (PD-L1) from mouse, monkey, and 
human; therefore, these species are likely to have similar target-mediated clearance. Full PK profiles 
were evaluated in mice and cynomolgus monkeys. Additional TK data were obtained during the course 
of repeated dose toxicity studies with Avelumab in mice, rats, and cynomolgus monkeys. Molecules 
MSB0010294 and MSB0010682 are precursors to the final molecule Avelumab. The anti-PD-L1 
antibodies from research batches and precursor molecules tested in single-dose 
PK studies in mice and cynomolgus monkeys demonstrated pronounced nonlinear PK characteristics in 
mice and cynomolgus monkeys in single-dose studies at doses below 20 mg/kg, suggesting a 
combination of first order catabolic clearance and saturable target-mediated clearance. Volume of 
distribution of Avelumab was in the range of the plasma volume in each species. Similar t1/2 ranging 
from 58 to 70 hours at doses between 20 and 140 mg/kg were observed in toxicity studies in mice and 
monkeys, indicating saturation of the target-mediated clearance. No significant gender-related 
differences were observed in monkeys or mice. With weekly dosing in mice and monkey, moderate 
accumulation was observed after 4 to 5 doses, with no additional accumulation after 13 doses in 
monkey. As Avelumab represents a foreign protein to the immune system of animals, anti-Avelumab 
antibodies in rodents and nonhuman primates were observed and have been considered in interpreting 
the nonclinical data. Overall, 40.5% to 100% of mice, 22.2% of rats, and 0 to 100% of monkeys treated 
with Avelumab developed detectable ADAs. In mouse and monkey studies, 

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Protocol V3; 10/19/2020 
higher doses generally resulted in lower immunogenicity incidence, potentially due to interference of 
Avelumab trough concentrations with the measurement of ADA. The potentially underreported 
incidence in higher dose cohorts did not affect exposure, and therefore did not impact the conclusions 
of the toxicity studies. In animals, the detected ADAs seem to have the potential to increase the 
clearance of the Avelumab, although the lower observed concentration may also be due either to ADA 
interference with detection of Avelumab at lower concentrations or coinciding with the clearance 
change when target-mediated disposition is no longer saturated. It should be emphasized that 
immunogenicity incidence against the human antibody Avelumab in animals is not deemed predictive 
for human subjects. For the pivotal toxicity study in cynomolgus monkeys, exposure was maintained 
through the duration of treatment. The clearance from the clinical population PK model is well predicted 
by allometric scaling from the cynomolgus monkey, confirming the suitability as the primary nonclinical 
PK species. 
  
2.2.1.2 TOXICOLOGY SUMMARY 
  
The toxicological profile of Avelumab was investigated in vivo in mice, rats, and cynomolgus monkeys. In 
addition, in vitro cytokine release assays in human and cynomolgus monkey whole blood and PBMCs as 
well as tissue cross reactivity studies in normal human and cynomolgus monkey tissues were performed. 
Additionally, data on the UV absorption of Avelumab were generated. Investigations on local tolerance 
were integrated in the repeat-dose toxicity studies as well as investigation of safety pharmacology 
relevant parameters which was included in the primate repeat-dose toxicity studies. On the basis of the 
binding affinity data, the cynomolgus monkey and the mouse were selected as relevant species for the 
nonclinical safety testing of Avelumab. However, in the repeat dose toxicity studies in CD-1 mice with 
Avelumab IV bolus injection mortality occurred mainly after the 3rd administration. The second 
mechanistic study supported the hypothesis that the mortalities were caused by an immune-mediated 
anaphylactic reaction (IgG/IgE mediated) primarily driven by IgG isotype antibodies. Due to severe post-
dose anaphylactic reactions after repeated administration in mice and the low binding affinity in rats, 
rodent species were not considered appropriate for further nonclinical safety testing of Avelumab and 
therefore, a single species approach (cynomolgus monkey) was followed and confirmed with Health 
Authorities. Accordingly, repeat-dose toxicity studies of 4 and 13 weeks duration were conducted in 
cynomolgus monkeys. Clinical signs of hypersensitivity or Avelumab-related infusion reactions were not 
observed in cynomolgus monkeys after repeated treatment with Avelumab at dose levels of 20, 60 and 
140 mg/kg. Avelumab was well tolerated systemically and accordingly, the NOAEL was established at the 
high dose of 140 mg/kg in both, the 4-week and the pivotal 13- week, repeat-dose monkey studies. This 
dose was the maximum feasible dose based on administration volume and the concentration of the DP 
formulation. With respect to local tolerance, local inflammatory reactions at the injection site were 
slightly, but not dose dependently, enhanced in monkeys of the Avelumab-treated groups, compared to 
controls, possibly as a consequence of locally infiltrated test article. Overall, in the pivotal 13-week 
repeat-dose study, injection site findings were considered nonadverse up to the high dose and the 
changes were fully resolved during the recovery period. No reproductive toxicity studies were 
conducted. However, the reproductive and developmental toxicity potentially associated with Avelumab 

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Protocol V3; 10/19/2020 
treatment is considered adequately established based on available data, from repeat-dose studies and 
public sources and in view of the pursued indications and targeted indications (life threatening cancer 
diseases, advanced-stage cancer subjects). Considering that disruption of PD-1/PD-L1 communication 
has been reported to significantly increase the risk of fetal loss during pregnancy, the potential for 
adverse outcomes on embryofetal development cannot be excluded and adequate protections must be 
in place to prevent risk of pregnancies. 
  
Systemic AUC exposures at NOAELs from monkey repeat-dose toxicity studies are well above the 
exposure measured in human subjects at therapeutic doses, providing a safety margin of at least 10-
fold. Local tolerance was evaluated in the repeat-dose toxicity studies and only mild to moderate 
reactions at the injection/infusion sites which were slightly elevated in Avelumab treated animals, 
were observed. Injection site findings were fully resolved during recovery and overall considered 
nonadverse. Initial CRA in human and cynomolgus monkey whole blood and PBMCs revealed little to no 
release of pro-inflammatory cytokines in most samples. However, a subsequent, CRA with PHA 
prestimulated PBMCs from healthy human volunteers demonstrated evidence of cytokine release 
indicating the potential for infusion-related reactions. Evaluation of UV absorption did not show any 
evidence for phototoxicity. Toxicological assessment of the chemical substances potentially leaching 
from the CCS into Avelumab DP did not identify any risk for subjects. Overall, the nonclinical safety 
profile established for Avelumab is considered adequate to support the use of Avelumab in the planned 
therapeutic indication in humans. 
2.2.2 CLINICAL EVIDENCE FOR AVELUMAB 
  
In May 2017, the U.S Food and Drug Administration (FDA)  granted accelerated approval for Avelumab 
for patients with locally advanced or metastatic bladder cancer whose disease has progressed during or 
after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant 
chemotherapy. Also, in March 2017, the FDA granted accelerated approval for Avelumab for the 
treatment of patients 12 years and older with metastatic Merkel cell carcinoma (MCC).  
  
2.2.2.1 POPULATION PHARMACOKINETICS 
  
Data from 1629 subjects from ongoing Studies EMR100070 001 (20 November 2015 cut-off date), 
EMR100070 002 (20 November 2015 cut-off date), and EMR100070 003 (03 March 2016 cut-off date) 
were used to estimate PK parameters and to evaluate the PK interindividual variability and any 
covariates that may be predictive of the variability using the NONMEM. A 2-compartment model with 
linear elimination fitted the data best. Interindividual variability on CL, V1 and V2 were modeled as a full 
variance-covariance block. Residual error was described by a combination additive and proportional 
model. Even though nonlinearity was observed at the lower doses in Studies EMR100070-001 and 
EMR100070-002 studies by NCA analyses, TMDD was not explicitly explored given the lack of evidence in 
concentration-time plots and the adequacy of the 2-compartment linear model, and the vast majority of 
concentrations in the linear range. Body weight was included a priori on CL and V1 before the start of 

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Protocol V3; 10/19/2020 
the stepwise covariate modeling process. CL in the base Pop PK model was estimated to be 0.0268 L/h, 
was dependent upon body weight and was associated with 30.3% IIV. Vss was calculated as the sum of 
V1 and V2 for each individual, and had a geometric mean of 4.72 L (44.5% CV) for subjects in the 10 
mg/kg dose group. The calculated t1/2 for subjects in the 10 mg/kg dose group was 146 hours (6.1 days) 
(91.5 % CV). Body weight, sex, albumin, tumor burden, dose level of 3 mg/kg and tumor type (namely 
mMCC, NSCLC, head and neck, and ovarian) were included in the final model as statistically significant 
covariates. However, none of them were considered as clinically meaningful and no dose adjustment is 
warranted. 
  
• 
Absorption:  
Avelumab is administered intravenously and is 100% bioavailable. 
• 
Distribution  
Molecular weight is a key determinant of the distribution of therapeutic proteins. With a 
calculated molecular weight of 143,832 Dalton, Avelumab is expected to be distributed in the 
systemic circulation and to a lesser extent in the extracellular space. In vitro studies suggested 
that Avelumab binds to human tissues that are known for PD-L1 expression: various epithelial 
cell types, endothelium, mononuclear cells (including dendritic cells, lymphocytes, monocytes, 
and macrophages), pancreatic islets, placental trophoblasts and decidual cells, smooth muscle 
cells, neural cells, and mesenchymal stem cells as shown. The volumes of the central and 
peripheral compartments were estimated in the Pop PK analysis to be 2.84 L and 1.21 L in the 
typical subject, respectively. The geometric mean Vss (calculated from individual V1 and V2 
parameter values) for a subject receiving 10 mg/kg was 4.72 L, which is consistent with 
distribution mainly restrained to the systemic circulation. 
• 
Metabolism 
Avelumab is degraded by proteolytic catabolism. CYP450 does not contribute to its metabolism. 
• 
Elimination 
As an antibody, the primary elimination mechanism of Avelumab is proteolytic degradation 
(catabolism). The geometric mean CL calculated by NCA analysis in Study EMR100070-001 was 
0.362 mL/hr/kg (0.0264 L/hr for a typical subject who has a body weight of 73 kg) for the first 10 
mg/kg dose. The corresponding value for the Japanese subjects in Study EMR100070-002 was 
calculated to be 0.471 mL/hr/kg (0.0344 L/hr for a typical subject who has a body weight of 73 
kg) at the 10 mg/kg dose. The estimate of CL obtained for the typical subject in the Pop PK 
analysis was 0.0246 L/hr. The estimates between NCA and Pop PK analyses are comparable. 
• 
Influence of Hepatic Impairment 
No dedicated clinical studies were conducted to evaluate the effect of hepatic impairment on 
the PK of Avelumab. The Pop PK analysis of data from Studies EMR100070-001, EMR100070-002 
and EMR100070-003 examined the potential influence of hepatic impairment on systemic 

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Protocol V3; 10/19/2020 
clearance. There was no influence of the composite category of hepatic impairment on 
Avelumab CL in the final Pop PK model. 
• 
Influence of Renal Impairment 
No dedicated clinical studies were conducted to evaluate the effect of renal impairment on the 
PK of Avelumab. The Pop PK analysis examined the potential influence of renal impairment by 
evaluating the influence of baseline estimated glomerular filtration rate (eGFR) on the 
parameters of the Pop PK model in a wide range of renal function including none, mild, 
moderate and severe impairment. There was no influence of eGFR on Avelumab CL in the final 
Pop PK model. Even though a limited number of subjects with severe renal impairment have 
been studied, renal impairment including mild, moderate and severe degree is not expected to 
have an effect on the PK of Avelumab because the molecular weight of Avelumab is much higher 
than the glomerular filtration cut-off. 
2.2.2.2 METASTATIC MERKEL CELL CARCINOMA 
  
The efficacy and safety of Avelumab was demonstrated in the JAVELIN Merkel 200 trial (NCT02155647), 
an open-label, single-arm, multi-center study conducted in patients with histologically confirmed 
metastatic MCC whose disease had progressed on or after chemotherapy administered for distant 
metastatic disease. The trial excluded patients with autoimmune disease; medical conditions requiring 
systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with 
anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies; CNS metastases; infection with HIV, hepatitis B or 
hepatitis C; or ECOG performance score ≥ 2. Patients received Avelumab 10 mg/kg as an intravenous 
infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients with 
radiological disease progression not associated with significant clinical deterioration, defined as no new 
or worsening symptoms, no change in performance status for greater than 2 weeks, and no need for 
salvage therapy, could continue treatment. Tumor response assessments were performed every 6 
weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central 
review committee (IRC) and IRC-assessed duration of response. The efficacy analysis was conducted 
when the last patient enrolled had completed 12 months of follow-up. A total of 88 patients were 
enrolled. Baseline patient characteristics were a median age of 73 years (range: 33 to 88), 74% of 
patients were male, 92% were White, and the ECOG performance score was 0 (56%) or 1 (44%). 
Seventy-five percent of patients were 65 years or older, 35% were 75 or older and 3% were 85 or older. 
Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic 
MCC and 35% had two or more prior therapies. Fifty-three percent of patients had visceral metastases. 
All patients had tumor samples evaluated for PD-L1 expression; of these, 66% were PD-L1-positive (≥ 1% 
of tumor cells), 18% were PD-L1 negative, and 16% had non-evaluable results by an 
investigational immunohistochemistry assay. Archival tumor samples were evaluated for Merkel cell 
polyomavirus (MCV) using an investigational assay; of the 77 patients with evaluable results, 52% had 
evidence of MCV.  Efficacy results are presented in Table 1. Responses were observed in patients 
regardless of tumor PD-L1 expression or presence of MCV. 

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Protocol V3; 10/19/2020 
  
Table 1: Efficacy Results of the JAVELIN Merkel 200 Trial 
 
  
2.2.2.3 UROTHELIAL CARCINOMA EXPANSION COHORT 
  
Trial EMR100070-001 enrolled 2 cohorts of subjects with locally advanced or metastatic UC who were 
either cisplatin ineligible or had PD after at least 1 line of platinum-based therapy. As of 19 March 2016, 
a combined 241 subjects had been treated in the 2 UC cohorts, of whom 153 had at least 6 months of 
follow-up (all 44 subjects in the secondary UC cohort and 109 of the 197 subjects in the efficacy UC 
cohort). Of the 241 subjects, 87 (36.1%) were still on treatment at the time of data cut-off. Table 2 
presents the BOR results as assessed by the Independent Endpoint Review Committee (IERC) for the 2 
UC cohorts and the pooled group of subjects with at least 6 months follow-up, together with the ORR 
according to RECIST 1.1 and duration of response. 
In the pooled group of 153 subjects with at least 6 months of follow-up, the confirmed ORR was 17.6% 
(95% CI: 12.0, 24.6), consisting of 9 subjects (5.9%) with CR and 18 subjects (11.8%) with PR. Onset of 
response was documented at the first or second tumor assessment for 21 of the 27 confirmed responses 
(77.8%), with a median time to response of 11.43 weeks (range: 5.6 to 
48 weeks). Median duration of response was not yet reached (95% CI: 42.14 weeks, not estimable [NE]); 
the Kaplan-Meier estimate of 24-week durability of response was 92.0% (95% CI: 71.6, 97.9). Of the 27 
confirmed responses, 24 (88.9%) were ongoing at the time of data cutoff, with duration of response 
ranging from 4.7 to 65.7 weeks. 
  
Table 2: Tumor Response Observed in Subjects with ≥ 6 Months Follow-up in Urothelial Carcinoma 
Cohorts in Trial EMR100070-001 

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Protocol V3; 10/19/2020 
 
2.2.3 CLINICAL EVIDENCE FOR DOCETAXEL 
 
In a phase II trial of docetaxel conducted in patients with advanced transitional-cell carcinoma (TCC) who 
had failed to respond to prior cisplatin-based therapy, 30 patients were treated with Docetaxel 100 
mg/m2 over 1 hour every 21 days. To avoid allergic reactions and capillary leak, the patients were pre-
treated with dexamethasone and diphenhydramine. Four of 30 patients (13.3%; 95% confidence interval 
[CI], 3.8% to 30.7%) demonstrated a partial response (PR), with durations of response ranging from 3 to 
8 months. The estimated median survival duration for all patients is 9 months (95% CI, 6 to 12 months) 
with a median follow-up time of 14 months (range, 1 to 27). Hematologic toxicity included anemia, 
thrombocytopenia, neutropenia, and febrile neutropenia. Nonhematologic toxicity included alopecia 
and mucositis. Fluid retention was not observed and cutaneous toxicity was mild and infrequent. Dose 
reductions were necessary for adverse events in 18 patients (60%). 
 
As per the NCCN (National Comprehensive Cancer Network) guidelines Version 5.2017, Docetaxel is a 
standard of care medication in second line therapy for local advanced or metastatic urothelial cancer.  
 
2.3 RISK/BENEFIT ASSESSMENT 
  
2.3.1 KNOWN POTENTIAL RISKS 
  
2.3.1.1 AVELUMAB: 
  
The following adverse reactions and relative frequency were noted in the clinical studies: 

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Protocol V3; 10/19/2020 
Adverse reactions: >10%: 
• 
Cardiovascular: Peripheral edema (17% to 20%), hypertension (10% to 13%) 
• 
Central nervous system: Fatigue (41% to 50%), dizziness (14%) 
• 
Dermatologic: Skin rash (15% to 22%) 
• 
Endocrine & metabolic: Weight loss (15% to 19%), hyponatremia (grades 3/4: 16%), increased 
gamma-glutamyl transferase (grades 3/4: 12%) 
• 
Gastrointestinal: Nausea (22% to 24%), diarrhea (18% to 23%), decreased appetite (20% to 
21%), abdominal pain (16% to 19%), constipation (17% to 18%), increased serum lipase (14%), 
vomiting (13% to 14%) 
• 
Genitourinary: Urinary tract infection (21%) 
• 
Hematologic & oncologic: Lymphocytopenia (49%; grades 3/4: 11% to 19%), anemia (35%; 
grades 3/4: 6% to 9%), thrombocytopenia (27%; grades 3/4: 1%) 
• 
Hepatic: Increased serum AST (34%), increased serum ALT (20%) 
• 
Neuromuscular & skeletal: Musculoskeletal pain (25% to 32%), arthralgia (16%) 
• 
Renal: Increased serum creatinine (≤16%), renal failure (≤16%) 
• 
Respiratory: Cough (14% to 18%), dyspnea (11% to 17%) 
• 
Miscellaneous: Infusion-related reaction (14% to 30%), fever (16%) 
Adverse reactions: 1% to 10%: 
  
• 
Central nervous system: Headache (10%) 
• 
Dermatologic: Pruritus (10%), cellulitis (>1%) 
• 
Endocrine & metabolic: Hyperglycemia (grades 3/4: 3% to 9%), increased amylase (8%), 
hypothyroidism (immune-mediated: 5%) 
• 
Gastrointestinal: Colitis (immune-mediated: 2%), intestinal obstruction (≥2%) 
• 
Hematologic & oncologic: Neutropenia (6%; grades 3/4: 1%) 
• 
Hepatic: Increased serum alkaline phosphatase (grades 3/4: 7%), increased serum bilirubin (6%), 
increased serum bilirubin (grades 3/4: 1%) 
• 
Immunologic: Antibody development (4%) 

25 
Protocol V3; 10/19/2020 
• 
Neuromuscular & skeletal: Weakness (>1%) 
• 
Renal: Acute renal failure (>1%) 
• 
Respiratory: Pneumonitis (immune-mediated: 1%) 
• 
Frequency not defined: Cardiovascular: Pericardial effusion 
Adverse reactions <1%, postmarketing, and/or case reports:  
• 
Adrenocortical insufficiency (immune-mediated), arthritis (immune-mediated), erythema 
multiforme (immune-mediated), exfoliative dermatitis (immune-mediated), Guillain-Barré 
syndrome (immune-mediated), hepatitis (immune-mediated), hyperthyroidism (immune-
mediated), myocarditis (immune-mediated), myositis (immune-mediated), nephritis (immune-
mediated), pemphigoid (immune-mediated), pituitary insufficiency (immune-mediated), 
psoriasis (immune-mediated), sepsis (systemic inflammatory response; immune-mediated), 
thyroiditis (immune-mediated), type 1 diabetes mellitus (immune-mediated), uveitis (immune-
mediated) 
Contraindications  
• 
There are no contraindications   
  
2.3.1.2 DOCETAXEL 
 
The percentages reported for docetaxel monotherapy; frequency may vary depending on diagnosis, 
dose, liver function, prior treatment, and premedication. 
  
Adverse Reactions >10%: 
• 
Central nervous system: Central nervous system toxicity (20% to 58%; severe: ≤6%; including 
neuropathy) 
• 
Dermatologic: Alopecia (56% to 76%), dermatological reaction (20% to 48%; severe: ≤5%), nail 
disease (11% to 41%) 
• 
Endocrine & metabolic: Fluid retention (includes edema and effusion; 13% to 60%; severe: 7% to 
9%; dose dependent) 
• 
Gastrointestinal: Stomatitis (19% to 53%; severe 1% to 8%), diarrhea (23% to 43%; severe: 5% to 
6%), nausea (34% to 42%), vomiting (22% to 23%) 
• 
Hematologic & oncologic: Neutropenia (84% to 99%; grade 4: 75% to 86%; nadir [median]: 7 
days, duration [severe neutropenia]: 7 days; dose dependent), leukopenia (84% to 99%; grade 4: 

26 
Protocol V3; 10/19/2020 
32% to 44%), anemia (65% to 97%; dose dependent; grades 3/4: 8% to 9%), thrombocytopenia 
(8% to 14%; grade 4: 1%; dose dependent), febrile neutropenia (≤14%; dose dependent) 
• 
Hepatic: Increased serum transaminases (4% to 19%) 
• 
Hypersensitivity: Hypersensitivity (1% to 21%; with premedication 15%) 
• 
Infection: Infection (1% to 34%; dose dependent) 
• 
Neuromuscular & skeletal: Weakness (53% to 66%; severe: ≤18%), myalgia (3% to 23%), 
neuromuscular reaction (16%) 
• 
Respiratory: Pulmonary reaction (41%) 
• 
Miscellaneous: Fever (31% to 35%) 
Adverse Reactions 1% to 10%: 
• 
Cardiovascular: Decreased left ventricular ejection fraction (8%), hypotension (3%) 
• 
Central nervous system: Peripheral motor neuropathy (4%; severe; mainly distal extremity 
weakness) 
• 
Gastrointestinal: Dysgeusia (6%) 
• 
Hepatic: Increased serum bilirubin (9%), increased serum alkaline phosphatase (4% to 7%) 
• 
Infection: Severe infection (6%) 
• 
Local: Infusion site reactions (4%, including hyperpigmentation, inflammation, redness, dryness, 
phlebitis, extravasation, swelling of the vein) 
• 
Neuromuscular and skeletal: Arthralgia (3% to 9%) 
Adverse Reactions<1%, postmarketing, and/or case reports:  
• 
Abdominal pain, acute hepatic failure, acute myelocytic leukemia, acute respiratory distress, 
alopecia (permanent), anaphylactic shock, anorexia, ascites, atrial fibrillation, atrial flutter, back 
pain, bronchospasm, cardiac arrhythmia, cardiac tamponade, chest pain, chest tightness, chills, 
colitis, confusion, conjunctivitis, constipation, cystoid macular edema, deep vein thrombosis, 
dehydration, disease of the lacrimal apparatus (duct obstruction), disseminated intravascular 
coagulation, drug fever, duodenal ulcer, dyspnea, ECG abnormality, epiphora (more common 
with weekly administration [Kintzel 2006]), erythema multiforme, esophagitis, flushing, 
gastrointestinal hemorrhage, gastrointestinal obstruction, gastrointestinal perforation, hearing 
loss, hemorrhagic diathesis, hepatitis, hypertension, hyponatremia, intestinal obstruction, 
interstitial pulmonary disease, ischemic colitis, lacrimation, localized erythema of the 
extremities, loss of consciousness (transient), lymphedema (peripheral), multiorgan failure, 

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Protocol V3; 10/19/2020 
myelodysplastic syndrome, myocardial infarction, neutropenic enterocolitis, ototoxicity, pain, 
palmar-plantar erythrodysesthesia, pneumonia, pneumonitis, pruritus, pulmonary edema, 
pulmonary embolism, pulmonary fibrosis, radiation pneumonitis, radiation recall phenomenon, 
renal failure, renal insufficiency, respiratory failure, skin changes (scleroderma-like), seizure, 
sepsis, sinus tachycardia, skin rash, Stevens-Johnson syndrome, subacute cutaneous lupus 
erythematosus, syncope, tachycardia, thrombophlebitis, toxic epidermal necrolysis, unstable 
angina pectoris, visual disturbance (transient) 
Contraindications  
• 
Severe hypersensitivity to docetaxel or any component of the formulation; severe 
hypersensitivity to other medications containing polysorbate 80; neutrophil count <1,500/mm3 
2.3.1.3 SPECIFIC SITUATIONS FOR DOCETAXEL: 
• Bone marrow suppression:   Patients with an absolute neutrophil count <1,500/mm3 should not 
receive docetaxel. Monitor blood counts frequently to monitor for neutropenia (which may be severe 
and result in infection). The dose-limiting toxicity is neutropenia. Platelets should recover to 
>100,000/mm3 prior to treatment. Patients with increased liver function tests experienced more 
episodes of neutropenia with a greater number of severe infections; monitor liver function tests 
frequently. Hematologic toxicity may require dose reduction or therapy discontinuation. 
 
• Cutaneous reactions: Cutaneous reactions, including erythema (with edema) and desquamation, have 
been reported; may require dose reduction. 
 
• Extravasation: Docetaxel is an irritant with vesicant-like properties; ensure proper needle or catheter 
placement prior to and during infusion; avoid extravasation. 
 
• Fluid retention: Severe fluid retention, characterized by pleural effusion (requiring immediate 
drainage), ascites with pronounced abdominal distention, peripheral edema (poorly tolerated), dyspnea 
at rest, cardiac tamponade, generalized edema, and weight gain, has been reported. Fluid retention may 
begin as lower extremity peripheral edema and become generalized with a median weight gain of 2 kg. 
In patients with breast cancer, the median cumulative dose to onset of moderate or severe fluid 
retention was 819 mg/m2; fluid retention resolves in a median of 16 weeks after discontinuation. 
Patients should be premedicated with a corticosteroid (starting 1 day prior to administration) to reduce 
the incidence and severity of fluid retention. Closely monitor patients with existing effusions. 
 
• Hypersensitivity reactions: [US Boxed Warning]: Severe hypersensitivity reactions, characterized by 
generalized rash/erythema, hypotension, bronchospasms, or rare anaphylaxis may occur (may be fatal; 
has occurred in patients receiving a 3-day corticosteroid premedication). Hypersensitivity reactions 
require immediate discontinuation of the docetaxel infusion and administration of appropriate therapy. 
Do not administer to patients with a history of severe hypersensitivity to docetaxel or polysorbate 80. 
Minor reactions including flushing or localized skin reactions may also occur. Observe for 

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Protocol V3; 10/19/2020 
hypersensitivity, especially with the first 2 infusions. Discontinue for severe reactions; do not 
rechallenge if severe. Patients should be premedicated with a corticosteroid (starting 1 day prior to 
administration) to prevent or reduce the severity of hypersensitivity reactions. 
 
• Neurosensory symptoms: Dosage adjustment is recommended with severe neurosensory symptoms 
(paresthesia, dysesthesia, pain); persistent symptoms may require discontinuation. Reversal of 
symptoms may be delayed after discontinuation. 
 
• Ocular adverse effects: Cystoid macular edema (CME) has been reported; if vision impairment occurs, 
a prompt comprehensive ophthalmic exam is recommended. If CME is diagnosed, initiate appropriate 
CME management and discontinue docetaxel (consider non-taxane treatments). In a study of patients 
receiving docetaxel for the adjuvant treatment of breast cancer, a majority of patients experienced 
tearing, which occurred in patients with and without lacrimal duct obstruction at baseline. Onset was 
generally after cycle 1, but subsided in most patients within 4 months after therapy completion (Chan 
2013). 
 
• Secondary malignancies: Treatment-related acute myeloid leukemia or myelodysplasia occurred in 
patients receiving docetaxel in combination with anthracyclines and/or cyclophosphamide. 
 
• Treatment-related mortality: [US Boxed Warning]: Patients with abnormal liver function, those 
receiving higher doses, and patients with non–small cell lung cancer and a history of prior treatment 
with platinum derivatives who receive single-agent docetaxel at a dose of 100 mg/m2 are at higher risk 
for treatment-related mortality. 
 
• Weakness: Fatigue and weakness (may be severe) have been reported; symptoms may last a few days 
up to several weeks. In patients with progressive disease, weakness may be associated with a decrease 
in performance status. 
 
Disease-related concerns: 
 
• Hepatic impairment: [US Boxed Warning]: Avoid use in patients with bilirubin exceeding upper limit of 
normal (ULN) or AST and/or ALT >1.5 times ULN in conjunction with alkaline phosphatase >2.5 times 
ULN. Patients with bilirubin elevations or abnormal transaminases (with concurrent abnormal alkaline 
phosphatase) are at increased risk for grade 4 neutropenia, neutropenic fever, infections, severe 
thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated 
transaminase elevations >1.5 times ULN also had a higher rate of grade 4 neutropenic fever, although no 
increased incidence of toxic death. Monitor bilirubin, AST or ALT, and alkaline phosphatase prior to each 
docetaxel cycle. The alcohol content of the docetaxel formulation should be taken into account when 
administering to patients with hepatic impairment. 
 
Concurrent drug therapy issues: 
 

29 
Protocol V3; 10/19/2020 
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency 
adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions 
database for more detailed information. 
 
Premedication:  
• 
Premedication with oral corticosteroids is recommended to decrease the incidence and severity 
of fluid retention and severity of hypersensitivity reactions. We will use dexamethasone 20 mg 
PO once prior to Docetaxel.  

30 
Protocol V3; 10/19/2020 
3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 Phase 1b Dose De-escalation: 
To determine the recommended phase 2 dose 
(RP2D) of combination therapy with Avelumab 
and Docetaxel in subjects with metastatic 
urothelial cancer 
  
 
 
Phase 1b Dose Expansion:  
To assess the preliminary efficacy of the 
established dose of combination therapy with 
Avelumab and Docetaxel in subjects with 
metastatic urothelial cancer 
 Phase 1b Dose De-escalation: 
Incidence of dose limiting toxicities in 
subjects with metastatic urothelial 
cancer 
  
  
 
 
Phase 1b Dose Expansion:  
Best overall response rate (ORR) 
(complete response (CR) + partial 
response (PR)) per RECIST v1.1 with 
the established dose of combination 
therapy with Avelumab and 
Docetaxel  in subjects with metastatic 
urothelial cancer 
The combination of Docetaxel 
and Avelumab was not tested 
in urothelial cancer. Hence, it 
would be prudent to establish 
the safe dose of this 
combination to study in phase 
II and III clinical trials 
  
Phase 1b Dose Expansion:  
The best overall response rate 
is a good surrogate marker 
and a suitable endpoint 
  
Secondary 
 
Phase 1b Dose Expansion:  
To evaluate the progression-free survival and 
overall survival of combination therapy 
with Avelumab and Docetaxel in subjects with 
metastatic urothelial cancer 
   
  
Phase 1b Dose Expansion:  
Radiologic progression-free survival 
(PFS) per RECIST v1.1 criteria. PFS is 
defined as the time between the first 
dose of study therapy and the earliest 
date of progression or death. Subjects 
who have neither progressed nor died 
will be censored at the last tumor 
assessment date for PFS. 
  
Overall survival defined as the time 
between the first dose of study therapy 
and death (subjects who have not died 
will be censored at the most recent 
last-known-alive date). 
  

31 
Protocol V3; 10/19/2020 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
  
  
Tertiary/Exploratory 
Biomarkers PDL-1 immunostains of the tumor 
specimen. Used for exploring its predictive and 
prognostic implications. It will not be used for 
response assessment or trial eligibility. 
  
  

32 
Protocol V3; 10/19/2020 
4 STUDY DESIGN 
4.1 OVERALL DESIGN 
The study is a single institution, phase 1b, single arm non-randomized, open label prospective clinical 
trial to evaluate the combination of Avelumab and Docetaxel in adult subjects with locally advanced or 
metastatic urothelial carcinoma with disease progression during or following platinum-containing 
chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. 
  
 The study has two phases:  
  
1)  A Phase 1b dose de-escalation of Docetaxel in combination with Avelumab, to establish the 
recommended phase 2 dose for the combination. The Dose De-escalation Phase will utilize a 3+3 design 
over 3 planned dose levels leading to the identification of a RP2D for the combination of Docetaxel and 
Avelumab. Note: Dose de-escalation is allowed only for Docetaxel and no changes will done to  standard 
dose of Avelumab (i.e, 10 mg/kg). 
  
2)  In the dose expansion phase of the study, the fixed dose of Docetaxel in combination with Avelumab 
will be evaluated. The study is powered to a primary endpoint of overall response rate (ORR) with the 
combination of Docetaxel and Avelumab. Enrollment for Part 2 will commence only after a RP2D is 
identified from phase 1. 
  
Treatment will be administered on an outpatient basis. The treatment will be given in two stages. The 
initial Induction phase of treatment will include the combination of Docetaxel and Avelumab for a total 
of 6 cycles (1 cycle = 21 days). The dose of Avelumab in combination with Docetaxel will be 10 mg/kg 
administered every 3 weeks (Q3W) to avoid dosing of avelumab during the period of maximum bone 
marrow suppression for patients receiving Q3W chemotherapy. This schedule of avelumab is predicted 
to achieve therapeutic avelumab levels based upon PK modeling and simulation, resulting in exposures 
of avelumab needed to achieve >95% PD-L1 target occupancy (Pfizer data on file). A similar dosing 
schedule is being investigated in the Arm C of Javelin ovarian 100 clinical trial (NCT02718417).  
 
 In the subsequent Maintenance phase, the subjects will receive Avelumab every 2 weeks (1 cycle = 2 
weeks) until disease progression. Reported adverse events and potential risks are described in section 
2.3. Appropriate dose modifications are described in Section 6.1.5 No other investigational or 
commercial cancer directed agents or therapies other than those described below may be administered. 
  
Safety assessment will follow the guidelines provided in the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. 
  

33 
Protocol V3; 10/19/2020 
Patients will be followed both clinically and radiographically. The timeline of these assessments are 
summarized as per the study calendar. Post-treatment scans will be compared to the baseline scan and 
responses will be assessed using RECIST v1.1. 
  
  
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
See section 9 
 
 
 
4.3 JUSTIFICATION FOR DOSE 
4.3.1 DOSE LIMITING TOXICITIES 
  
Standard safety monitoring will be employed for DLT assessment and dose de-escalation decisions. All 
toxicities (AEs) that are possibly related to the Avelumab and Docetaxel will be considered in DLT 
assessment unless an event is clearly unrelated to trial treatment. DLTs are assessed during the first 21 
days of therapy. All AEs, including DLTs, are to be graded using NCI CTCAE, Version 4.03. Attribution of 
AEs specifically to either Docetaxel or Avelumab is challenging. There are some toxicities that are clearly 
attributable to either docetaxel or avelumab as per section 2.3.1. The investigator will take the final 
decision on the attribution of AEs or DLTs if it is related to combination therapy. 
  
The following AEs will be considered DLTs:: 
  
 
 Hematologic criteria: 
• Grade 4 febrile neutropenia > 7 days 
• Grade 4 or greater thrombocytopenia > 7 days 
• Grade 3 or 4 thrombocytopenia with significant hemorrhage of any duration. 
 
  Non-hematologic criteria: 
• 
Grade ≥ 3 toxicities (non-laboratory) 
• 
Grade ≥ 3 nausea, vomiting or diarrhea despite maximal medical intervention 
• 
Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
• 
Other (non AST/ALT) non-hematologic Grade ≥ 3 laboratory value if the abnormality leads to 
overnight hospitalization. 

34 
Protocol V3; 10/19/2020 
 
Grade 3 or greater treatment-related clinical non-hematological toxicity excluding those listed below: 
• 
Grade 3-4 nausea, vomiting in the absence of maximal medical therapy that resolves in 72 
hours 
• 
Grade 3-4 laboratory abnormalities that are not clinically significant and which resolve in 72 
hours. 
• 
Grade 3 hypertension that can be controlled with medical therapy. 
• 
Grade 3 laboratory abnormalities that are responsive to oral supplementation or deemed by 
the investigator to be clinically insignificant 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) 
• 
Concurrent vitiligo or alopecia of any AE grade 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) 
that resolves within 6 hours with appropriate clinical management 
• 
Grade 3-4 neutropenia that is not associated with fever or systemic infection that improves by 
at least 1 grade within 3 days. 
• 
Grade 3 or 4 lymphopenia 
• 
Transient asymptomatic laboratory abnormalities that do not require hospitalization 
 
4.4 END OF STUDY DEFINITION 
The End-of-study date is defined as the date of the last visit of the last participant. However, the PI 
reserves the right to terminate the trial at any time. Reasons for discontinuation include but are not 
limited to: 
• 
Inability to enroll a sufficient number of patients into the trial 
• 
Good clinical practice (GCP) compliance issues that compromise the validity of the trial 
Procedures for withdrawal of individual patients can be found in Section 7.2 
 
 

35 
Protocol V3; 10/19/2020 
5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
1. Age ≥18 to 85 years 
2. Histologically or cytologically confirmed locally advanced or metastatic transitional cell 
carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, urethra). 
Additional mixed histologies such as squamous, plasmacytoid, adenocarcinoma, sarcomatoid, 
papillary, micropapillary are permitted provided the urothelial cancer is the predominant 
histological component.  
3. Eligible patients must have had either:  
o 
Progressed after treatment with at least 1 platinum-containing regimen (e.g., cisplatin 
or carboplatin plus another agent such as gemcitabine, methotrexate, vinblastine, 
doxorubicin, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or 
disease recurrence, or 
o 
Were ineligible for cisplatin-based chemotherapy, with ineligibility to cisplatin defined 
by impaired renal function (creatinine clearance <60 ml/min), a hearing loss of 25 
decibels at 2 contiguous frequencies, or grade ≥ 2 peripheral neuropathy or 
o 
Locally advanced or metastatic bladder cancer whose disease has progressed within 12 
months of neoadjuvant or adjuvant chemotherapy. 
4. Biopsy material is required (archival tissue is acceptable if patient could not provide fresh or 
recent biopsy) 
5. ECOG performance status of 0 to 1  
6. Estimated life expectancy ≥3 months 
7. At least one  measurable lesion by RECIST version 1.1 
8. Adequate hematologic function defined by white blood cell count ≥3 × 109/L with absolute 
neutrophil count ≥1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥100 × 109/L, and 
hemoglobin ≥9 g/dL (may have been transfused) 
9. Adequate hepatic function defined by a total bilirubin level ≤ the upper limit of normal range 
(ULN), an aspartate aminotransferase (AST) level ≤1.5 × ULN, and an alanine aminotransferase 
(ALT) level ≤1.5 × ULN. 

36 
Protocol V3; 10/19/2020 
10. Adequate renal function defined by an calculated creatinine clearance > 30 mL/min according to 
the Cockcroft-Gault formula 
11. Both male and female subjects must be willing to use highly effective contraception (that is, 
methods with a failure rate of less than 1% per year) throughout the study and for at least 30 
days after last avelumab treatment administration if the risk of conception exists (see section 
6.1.7). [NOTE: The effects of the study treatment on the developing human fetus are unknown; 
thus, women of childbearing potential and men must agree to use highly effective 
contraception, as stipulated in national or local guidelines. Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, the treating 
physician should be informed immediately. 
12. Signed written informed consent 
 
 
5.2 EXCLUSION CRITERIA 
• 
Concurrent treatment with an anticancer treatment  
• 
Prior therapy with any drug targeting T cell coregulatory proteins 
• 
Major surgery for any reason within 4 weeks or if the patient had not fully recovered within 4 
weeks 
• 
Concurrent systemic therapy with corticosteroids or other immunosuppressive agents, or use of 
any investigational drug within 28 days before starting trial drug; short-term administration of 
systemic steroids (that is, for allergic reactions or the management of immune-mediated 
adverse events while on study is allowed 
• 
Patients with active central nervous metastases will be excluded. Appropriately treated CNS 
metastases with either surgery or radiation therapy are permitted to participate in the study 
• 
Previous malignant disease (other than urothelial carcinoma) within the last 5 years, with the 
exclusion of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ and 
prostate adenocarcinoma with Gleason score 6-7, pT2b.  
• 
Prior organ transplantation, including allogenic stem-cell transplantation 
• 
Known history of testing positive for HIV/AIDS, HBV, or HCV (including acute and chronic 
infection) 
• 
Active or history of any autoimmune disease or immune-deficiencies (patients with type 1 
diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive 
treatment are eligible) 

37 
Protocol V3; 10/19/2020 
• 
Known monoclonal antibody hypersensitivity, history of anaphylaxis, or uncontrolled asthma 
• 
Persisting toxicity related to prior therapy that was > grade 1 according to NCI-CTCAE v4.0; grade 
≤2 sensory neuropathy is allowed 
• 
Pregnancy or lactation 
• 
Clinically significant (i.e., 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 All other significant diseases, which in the 
investigator’s opinion may influence the patient’s tolerance of trial treatment. Other severe 
acute or chronic medical conditions including  immune colitis, inflammatory bowel disease,  
immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the 
past year) or active suicidal ideation or behavior; or laboratory abnormalities 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 
• 
Patients with symptomatic severe COPD with continuous oxygen requirement will be excluded. 
• 
Legal incapacity or limited legal capacity, including any psychiatric condition that would prohibit 
the understanding or rendering of informed consent 
• 
Vaccination within 4 weeks of the first dose of Avelumab and while on study was prohibited 
except for administration of inactivated vaccines (e.g., inactivated influenza vaccines) 
 
 
5.3 LIFESTYLE CONSIDERATIONS 
No specific restrictions 
 
 
5.4 SCREEN FAILURES 
The reason for screen failure will be documented clearly. If the reason for screen failure is reversible, 
then the patient can be considered for the re-screening if >1 month has been passed from the time of 
initial screening, after discussion with primary investigator and the trial sponsor. 
 
 

38 
Protocol V3; 10/19/2020 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
Potential research subjects will be identified by a member of the patient’s treatment team, the protocol 
investigator, or research team at the Holden Comprehensive Cancer Center, of the University of Iowa 
Hospitals and Clinics. If the investigator is a member of the treatment team, s/he will screen their 
patient’s medical records for suitable research study participants and discuss the study and their 
potential for enrolling in the research study. Potential subjects contacted by their treating physician will 
be referred to the investigator/research staff of the study. The principal investigator may also screen the 
medical records of patients with whom they do not have a treatment relationship for the limited 
purpose of identifying patients who would be eligible to enroll in the study and to record appropriate 
contact information in order to approach these patients regarding the possibility of enrolling in the 
study. 
  
During the initial conversation between the investigator/research staff and the patient, the patient may 
be asked to provide certain health information that is necessary to the recruitment and enrollment 
process. The investigator/research staff may also review portions of their medical records at HCCC/UIHC 
in order to further assess eligibility. They will use the information provided by the patient and/or 
medical record to confirm that the patient is eligible and to contact the patient regarding study 
enrollment. If the patient turns out to be ineligible for the research study, the research staff will destroy 
all information collected on the patient during the initial conversation and medical records review, 
except for any information that must be maintained for screening log purposes. In most cases, the initial 
contact with the prospective subject will be conducted either by the treatment team, investigator or the 
research staff working in consultation with the treatment team. The recruitment process outlined 
presents no more than minimal risk to the privacy of the patients who are screened and minimal PHI will 
be maintained as part of a screening log. For these reasons, we seek a (partial) limited waiver of 
authorization for the purposes of (1) reviewing medical records to identify potential research subjects 
and obtain information relevant to the enrollment process; (2) conversing with patients regarding 
possible enrollment; (3) handling of PHI contained within those records and provided by the potential 
subjects; and (4) maintaining information in a screening log of patients approached (if applicable). 
 
 

39 
Protocol V3; 10/19/2020 
6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 SCREENING AND BASELINE EVALUATION 
  
The screening examination must start with the Informed Consent procedure. The investigator is obliged 
to give the patient thorough information about the study and the study related assessments, and the 
patient should be given ample time to consider his/her participation. The investigator must not start any 
study related procedure before ICF is signed and dated by both patient (and impartial witness, if 
applicable) and investigator. 
Screening includes obtaining written informed consent, a physical exam, demography, medical 
history/current medical conditions, current concomitant medications/therapies, disease history and 
extent of disease, and prior anticancer therapies. 
• 
The following patient demographic and baseline characteristics will be collected: 
· General demography 
· Medical history/current medical conditions (including prior and concomitant 
medications) 
· History and current disease status (including staging, diagnosis information, , and sites of 
disease). 
· Additionally, the following assessments will be performed: 
· Physical examination, weight and height 
· Vital signs including sitting blood pressure/pulse and heart rate, respiratory rate and 
temperature 
· ECOG performance status 
• 
· ECG 
• 
· Safety laboratory assessments: biochemistry,  INR, PT, TSH,T3, FT3, FT4, hematology and 
urinalysis 
· Pregnancy test (if applicable) 
· Chest, abdomen and pelvis CT-scan. Consider MRI if CT scan not feasible 
· Brain MRI (if clinically indicated for assessment of neurological symptoms). 
Patients will be asked to visit the clinic as per the study calendar in section 1.3 
• 
 
6.1.2 DOSING 
  
Both the study drugs will be administered in the infusion center at Holden Comprehensive Cancer 
Center. In the initial induction phase, Avelumab is administered 10 mg/kg as an intravenous infusion 
over 60 minutes every 3 weeks followed by Docetaxel (dose level depends on the study cohort). 
Docetaxel is administered as per institutional guidelines, the first 2 doses over 90 minutes to decrease 
the risk of infusion reaction and then subsequently it can be infused over 1 hour through non-absorbing 

40 
Protocol V3; 10/19/2020 
polyethylene lined (non-DEHP) tubing. After 6 cycles of combination therapy, Avelumab will be 
continued at 10 mg/kg every 2 weeks.   
  
6.1.3 PREMEDICATION FOR AVELUMAB 
  
Premedicate patients with an antihistamine and with paracetamol (acetaminophen) prior to the first 4 
infusions of Avelumab. Premedication should be administered for subsequent Avelumab doses based 
upon clinical judgment and presence/severity of prior infusion reactions. 
  
6.1.4 PREMEDICATION FOR DOCETAXEL 
Premedication with dexamethasone 20 mg PO once prior to docetaxel administration is recommended 
to reduce the incidence and severity of hypersensitivity reactions and fluid retention.  
6.1.5 DOSE MODIFICATIONS AND INTERRUPTION 
  
Subjects will be monitored for AEs from the Cycle 1 Day 1 of infusion of combination therapy until Day 
30 post investigational treatment. Subjects will be instructed to notify their physician immediately for 
any occurring AE. Causality assessment of AEs should include at minimum confounding factors such as 
disease and concomitant medications. Adverse event severity will be graded by the investigator 
according to CTCAE v. 4.03. Dose escalation or reduction is not recommended for Avelumab.   
  
The following should be taken into consideration in decisions regarding dose modifications: (reductions 
or interruption): 
• 
As a general approach, all AEs should be managed with supportive care at the earliest signs of 
toxicity considered related to study treatment. Should this be ineffective, dose reductions or 
interruptions should be considered to prevent worsening of toxicity. 
• 
If the etiology of AEs is unclear the first dose reduction must be made to Docetaxel. 
• 
Dose reductions and/or interruptions should be implemented for unacceptable toxicity. Doses 
may be modified at any time while on study. 
• 
Dose reductions or interruptions may also occur in the setting of lower grade toxicity than 
defined in Table below, if the investigator feels it is in the interest of a subject’s safety and will 
optimize drug tolerability. 
• 
Interruption of Docetaxel or Avelumab treatment for AEs may occur at any time per investigator 
discretion. If treatment is interrupted due to AEs for more than 6 weeks, Docetaxel should be 
discontinued unless the investigator deems there to previous or ongoing clinical benefit. 

41 
Protocol V3; 10/19/2020 
• 
Dose interruptions for reason(s) other than AEs (e.g., surgical procedures) can be longer than 6 
weeks. The acceptable length of interruption will be determined by PI. 
• 
Dose interruption prior to the initiation of a new cycle: If the investigator decides on day 1 of a 
new cycle that dose interruption should occur, that cycle may be delayed. When the investigator 
decides that dosing should resume, the day that the patient restarts drug will be day 1 of that 
new cycle. Tumor assessments will be adjusted accordingly to match +/-7 days from Day 1 of 
each even cycle 
• 
Re-escalation to any previous dose may be allowed at the discretion of the investigator no 
sooner than 2 weeks beyond resolution of AEs that led to the dose reduction. Dose re-escalation 
is not allowed for a previous dose reduction triggered by Grade 4 hematologic toxicities or by 
Grade 4 AEs affecting major organs (e.g., central nervous system, cardiac, hepatic, renal). 
 
Table 4: Dose Modifications of Docetaxel for Treatment Related AEs 
CTCAE v4.1 
Recommended Guideline for Management 
Grade 1 AEs 
Supportive care as indicated. Continue docetaxel 
at the current dose level if AE is manageable and 
tolerable. 
Grade 2 AEs which are tolerable and are easily 
managed 
  
  
Grade 2 AEs which are intolerable and cannot be 
adequately managed 
Continue combination therapy at the current dose 
level with supportive care. 
  
At the discretion of the investigator, Docetaxel 
should be dose reduced or interrupted. 
Note: It is recommended that dose holds be as 
brief as possible. 
Grade 3 AEs (except clinically non-relevant 
laboratory abnormalities) 
Docetaxel should be interrupted unless the toxicity 
can be easily managed with a dose reduction and 
optimal medical care. 
  
Note: It is recommended that dose holds be as 
brief as possible 
Grade 4 AEs (except clinically non-relevant 
laboratory abnormalities) 
Subjects should have Docetaxel interrupted 
immediately. 
Discontinue Docetaxel unless the following criteria 
are met: 
• 
Subject is deriving clear clinical benefit as 
determined by the investigator. 
• 
Toxicity can be managed with a dose 
reduction following recovery to Grade 1 
(or baseline) and optimal medical care. 
  

42 
Protocol V3; 10/19/2020 
  
Management of Avelumab for Immune-Related Adverse Events (IRAEs): 
  
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment of irAEs is mainly 
dependent upon severity (NCI-CTCAE grade): 
  
• 
Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent monitoring 
• 
Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) 
• 
Grade 3 to 4: treat with high dose corticosteroids 
  
Management of specific IRAEs: 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab 
therapy 
Symptomatic treatment 
(e.g. loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day 
over Baseline; IV fluids 
indicated < 24 hours; not 
interfering with ADL 
Colitis: abdominal pain; blood 
in stool  
 
Withhold avelumab 
therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If  persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 h; 
interfering with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
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 
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: 

43 
Protocol V3; 10/19/2020 
peritoneal signs 
Grade 4: life-threatening, 
perforation 
equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections  
Consider lower 
endoscopy  
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Continue avelumab 
therapy Symptomatic 
therapy (for example, 
antihistamines, topical 
steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone 
or equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and resume 
avelumab therapy following steroids 
taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering >  
30% body surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
for Grade 4 or recurrent 
Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 

44 
Protocol V3; 10/19/2020 
Grade 1 
Radiographic changes only  
Consider withholding 
avelumab therapy  
Monitor for symptoms 
every 2 to 3 days  
Consider Pulmonary and 
Infectious Disease 
consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new 
symptoms  
Withhold avelumab 
therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections  
Consider bronchoscopy, 
lung biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, 
taper steroids over at least 1 month, 
and then resume avelumab  therapy 
following steroids taper  
If not improving after 2 weeks or 
worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day  
prednisone or equivalent  
Add prophylactic 
antibiotics for 
opportunistic infections  
Consider bronchoscopy, 
lung biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or 
worsening:  
Add additional immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV immunoglobulin, 
or mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 
x ULN and/or Total bilirubin > 
Continue avelumab 
therapy 
Continue liver function monitoring  
If worsens:  
 Treat as Grade 2 or 3 to 4.  

45 
Protocol V3; 10/19/2020 
ULN to 1.5 x ULN  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 
3 x ULN  
Withhold avelumab 
therapy 
Increase frequency of 
monitoring to every 3 
days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
avelumab therapy. 
If elevation persists > 5 to 7 days or 
worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or 
total bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections  
Consult 
gastroenterologist/ 
hepatologist 
Consider obtaining 
MRI/CT scan of liver and 
liver biopsy if clinically 
warranted  
If returns to Grade ≤ 1:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, 
worsens or rebounds:  
Add mycophenolate mofetil 1 gram (g) 
twice daily  
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants per local 
guidelines. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 
1.5 x ULN 
Continue avelumab therapy 
Continue renal function 
monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 
6 x ULN 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of  monitoring 
to every 3 days 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
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. 

46 
Protocol V3; 10/19/2020 
 
Consider renal biopsy 
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 (e.g. troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis.  
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
arrhythmia management. 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
Guideline based supportive 
treatment as per cardiology 
consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start avelumab 
therapy. 
 
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis Permanently discontinue avelumab. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids 
over at least 1 month. 
 
If no improvement or 
worsening, consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 

47 
Protocol V3; 10/19/2020 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for Type I 
diabetes mellitus) as appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for type I 
diabetes mellitus) as appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Resume avelumab once 
symptoms and/or laboratory 
tests improve to Grade ≤ 1 
(with or without hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is confirmed 
(i.e. subnormal serum FT4 with 
inappropriately low TSH and/or 
low serum cortisol with 
Resume avelumab once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone 
replacement). 

48 
Protocol V3; 10/19/2020 
inappropriately low ACTH) : 
• 
Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women)  
• 
Hormone 
replacement/suppressive 
therapy as appropriate  
• 
Perform pituitary MRI and 
visual field examination 
as indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during 
at least 1 month. 
• 
Add prophylactic antibiotics 
for opportunistic infections. 
 
In addition, for hypophysitis 
with abnormal MRI, resume 
avelumab only once shrinkage 
of the pituitary gland on 
MRI/CT scan is documented.  
 
Continue hormone 
replacement/suppression 
therapy as appropriate. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential irAE 
Withhold avelumab therapy 
pending clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-
starting avelumab therapy 
If irAE is confirmed, treat as 

49 
Protocol V3; 10/19/2020 
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 
 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal. 
Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.03 (NCI-CTCAE v4.0). 
  
 
  
Management of infusion - Related reactions: 
In order to mitigate infusion-related reactions, subjects have to be premedicated with an antihistamine 
and with paracetamol (acetaminophen) prior to the first 4 infusions of Avelumab. Premedication should 

50 
Protocol V3; 10/19/2020 
be administered for subsequent Avelumab doses based upon clinical judgment and presence/severity of 
prior infusion reactions. 
 
  
Treatment Modification for Symptoms of Infusion-Related Reactions Caused by Avelumab: 
 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 1 – mild 
·   Mild transient reaction; infusion interruption 
not indicated; intervention not indicated 
  
·   Decrease the Avelumab infusion rate by 50% 
and monitor closely for any worsening 
Grade 2 – moderate 
·   Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for £ 
24h 
  
·   Temporarily discontinue Avelumab infusion 
·   Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening 
Grade 3 or Grade 4 – severe or life-threatening 
·   Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
·   Grade 4: Life-threatening consequences; urgent 
intervention indicated 
  
·   Stop the Avelumab infusion immediately and 
disconnect infusion tubing from the subject 
·   Subjects have to be withdrawn immediately 
from Avelumab treatment and must not receive 
any further Avelumab treatment 
 
IV: intravenous; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
  
6.1.6 WARNINGS AND PRECAUTIONS FOR AVELUMAB: 
  
IMMUNE-RELATED PNEUMONITIS 
  
Avelumab can cause immune-related pneumonitis, including fatal cases. Monitor patients for signs and 
symptoms of pneumonitis and evaluate patients with suspected pneumonitis with radiographic imaging. 
Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a 
corticosteroid taper) for Grade 2 or greater pneumonitis. Withhold Avelumab for moderate (Grade 2) 
pneumonitis, and permanently discontinue for severe (Grade 3), life-threatening (Grade 4) or recurrent 
moderate (Grade 2) pneumonitis. 
  
Pneumonitis occurred in 1.2% (21/1738) of patients receiving Avelumab including one (0.1%) patient 
with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3 pneumonitis. Immune-related 

51 
Protocol V3; 10/19/2020 
pneumonitis led to permanent discontinuation of Avelumab in 0.3% (6/1738) of patients. Among the 21 
patients with immune-related pneumonitis, the median time to onset was 
2.5 months (range: 3 days to 11 months) and the median duration of pneumonitis was 7 weeks (range: 4 
days to 4+ months).  All 21 patients were treated with systemic corticosteroids; 17 (81%) of the 21 
patients received high-dose corticosteroids for a median of 8 days (range: 1 day to 2.3 months). 
Resolution of pneumonitis occurred in 12 (57%) of the 21 patients at the time of data cut-off. 
  
  
IMMUNE-RELATED HEPATITIS 
  
Avelumab can cause immune-related hepatitis including fatal cases. Monitor patients for abnormal liver 
tests prior to and periodically during treatment. Administer corticosteroids (initial dose of 1 to 2 
mg/kg/day prednisone or equivalent, followed by a corticosteroid taper) for Grade 2 or greater 
hepatitis. Withhold Avelumab for moderate (Grade 2) immune-related hepatitis until resolution and 
permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-related hepatitis. 
  
Immune-related hepatitis occurred in 0.9% (16/1738) of patients receiving Avelumab including two 
(0.1%) patients with Grade 5 and 11 (0.6 %) patients with Grade 3 immune-related hepatitis. Immune-
related hepatitis led to permanent discontinuation of Avelumab in 0.5% (9/1738) of patients. Among the 
16 patients with immune-related hepatitis, the median time to onset was 
3.2 months (range: 1 week to 15 months), and the median duration of hepatitis was 2.5 months (range: 
1 day to 7.4+ months). All 16 patients were treated with corticosteroids; 15 (94%) of the 16 
patients  received  high-dose  corticosteroids  for  a  median  of  14 days  (range:  1 day  to 
2.5 months). Resolution of hepatitis occurred in 9 (56%) of the 16 patients at the time of data cut-off. 
  
IMMUNE-RELATED COLITIS 
  
Avelumab can cause immune-related colitis. Monitor patients for signs and symptoms of colitis. 
Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a 
corticosteroid taper) for Grade 2 or greater colitis. Withhold Avelumab for moderate or severe (Grade 2 
or 3) colitis until resolution. Permanently discontinue Avelumab for life-threatening (Grade 4) or for 
recurrent (Grade 3) colitis upon re-initiation of Avelumab. 
  
Immune-related colitis occurred in 1.5% (26/1738) of patients receiving Avelumab including seven 
(0.4%) patients with Grade 3 colitis. Immune-related colitis led to permanent discontinuation of 
Avelumab in 0.5% (9/1738) of patients. Among the 26 patients with immune-related colitis, the median 
time to onset was 2.1 months (range: 2 days to 11 months) and the median duration of colitis was 6 
weeks (range: 1 day to 14+ months). All 26 patients were treated with corticosteroids; 15 (58%) of the 

52 
Protocol V3; 10/19/2020 
26 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months). 
Resolution of colitis occurred in 18 (70%) of the patients at the time of data cut-off. 
 
 
  
IMMUNE-RELATED ENDOCRINOPATHIES 
  
Thyroid disorders (Hypothyroidism/Hyperthyroidism) 
  
Avelumab can cause immune-related thyroid disorders. Thyroid disorders can occur at any time during 
treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone-
replacement therapy. Initiate medical management for control of hyperthyroidism. Withhold Avelumab 
for severe (Grade 3) or life threatening (Grade 4) thyroid disorders. 
  
Immune-related thyroid disorders occurred in 6% (98/1738) of patients receiving Avelumab including 3 
(0.2%) Grade 3 immune-related thyroid disorders. Immune-related thyroid disorders led to 
discontinuation of Avelumab in 0.1% (2/1738) of patients. Hypothyroidism occurred in 90 (5%) patients, 
hyperthyroidism in seven (0.4%), and thyroiditis in four (0.2%) patients treated with Avelumab. Among 
the 98 patients with immune-related thyroid disorders, the median time to onset was 2.8 months 
(range: 2 weeks to 13 months) and the median duration was not estimable (range: 6 days to more than 
26 months). Immune-related thyroid disorders resolved in seven (7%) of the 98 patients. 
  
ADRENAL INSUFFICIENCY 
  
Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment. Administer 
corticosteroids as appropriate for adrenal insufficiency. Withhold Avelumab for severe (Grade 3) or life 
threatening (Grade 4) adrenal insufficiency. 
  
Adrenal insufficiency occurred in 0.5% (8/1738) of patients receiving Avelumab including one patient 
(0.1%) with Grade 3 adrenal insufficiency. Immune-related adrenal insufficiency led to permanent 
discontinuation of Avelumab in 0.1% (2/1738) of patients. Among the 8 patients with immune-related 
adrenal insufficiency, the median time to onset was 2.5 months (range: 1 day to 8 months). All eight 
patients were treated with corticosteroids; four (50%) of the eight patients received high-dose 
corticosteroids for a median of 1 day (range: 1 day to 24 days). 
  
TYPE 1 DIABETES MELLITUS 
  

53 
Protocol V3; 10/19/2020 
Avelumab can cause type 1 diabetes mellitus, including diabetic ketoacidosis. Monitor patients for 
hyperglycemia or other signs and symptoms of diabetes. Withhold Avelumab and administer anti-
hyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia. Resume 
treatment with Avelumab when metabolic control is achieved on insulin replacement or anti-
hyperglycemics. 
  
Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients and led to 
permanent discontinuation of Avelumab. 
  
IMMUNE-RELATED NEPHRITIS AND RENAL DYSFUNCTION 
  
Avelumab can cause immune-related nephritis. Monitor patients for elevated serum creatinine prior to 
and periodically during treatment.  Administer corticosteroids (initial dose of 1 to 2 mg/kg/day 
prednisone or equivalent followed by a corticosteroid taper) for Grade 2 or greater nephritis. Withhold 
Avelumab for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to ≤ Grade 1. 
Permanently discontinue Avelumab for life-threatening (Grade 4) nephritis. 
  
Immune-related nephritis occurred in 0.1% (1/1738) of patients receiving Avelumab; Avelumab was 
permanently discontinued in this patient. 
  
OTHER IMMUNE-RELATED ADVERSE EVENTS 
  
Avelumab can result in severe and fatal immune-related adverse reactions. These immune-related 
reactions may involve any organ system. Most immune-related reactions initially manifest during 
Avelumab treatment; however, immune-related adverse reactions can occur after discontinuation of 
Avelumab. 
  
For suspected immune-related adverse reactions, evaluate to confirm or rule out an immune- related 
adverse reaction and to exclude other causes. Depending upon the severity of the adverse reaction, 
withhold or permanently discontinue Avelumab, administer high dose corticosteroids, and if 
appropriate, initiate hormone replacement therapy. Upon improvement to Grade 1 or less, initiate 
corticosteroid taper. Resume Avelumab when the immune-related adverse reaction remains at Grade 1 
or less following corticosteroid taper. Permanently discontinue Avelumab for any severe (Grade 3) 
immune-related adverse reaction that recurs and for any life-threatening immune-related adverse 
reaction. 
  
The following clinically significant, immune-related adverse reactions occurred at an incidence of less 
than 1% of 1738 patients treated with Avelumab for each of the following adverse reactions: immune-

54 
Protocol V3; 10/19/2020 
related myocarditis including fatal events, immune-related myositis, hypopituitarism, uveitis, and 
Guillain-Barré syndrome. 
  
 
 
INFUSION-RELATED REACTIONS 
  
Avelumab can cause severe or life-threatening infusion-related reactions. Premedicate with 
antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms 
of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back 
pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-
related reactions. Stop the infusion and permanently discontinue Avelumab for severe (Grade 3) or life-
threatening (Grade 4) infusion-related reactions. 
  
Infusion-related reactions occurred in 25% (439/1738) of patients treated with Avelumab including 
three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Ninety-three percent 
(1615/1738) of patients received premedication with antihistamine and acetaminophen. Eleven (92%) of 
the 12 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. 
  
6.1.7 PREGNANCY, LACATION AND FERTILITY ISSUES WITH AVELUMAB 
PREGNANCY 
  
Based on its mechanism of action, Avelumab can cause fetal harm when administered to a pregnant 
woman. 
  
In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy 
through induction of maternal immune tolerance to fetal tissue. 
  
Human IgG1 immunoglobulins are known to cross the placenta. Therefore, Avelumab has the potential 
to be transmitted from the mother to the developing fetus. 
  
Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the 
foetus and to result in an increase in fetal loss. Therefore, potential risks of administering Avelumab 
during pregnancy include increased rates of abortion or stillbirth. 
  
Advise females of reproductive potential to use effective contraception during treatment with Avelumab 
and for at least one month after the last dose of Avelumab. Highly effective methods of contraception 

55 
Protocol V3; 10/19/2020 
are those that, alone or in combination, result in afailure rate of less than 1% per year when used 
consistently and correctly (ie, perfect use) and include the following: 
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the patient plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label). 
6. Female patients of non-childbearing potential must meet at least one of the following 
criteria: 
• 
Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
• 
Have medically confirmed ovarian failure; or 
• 
Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 
consecutive months with no alternative pathological or physiological cause; status may be 
confirmed by having a serum FSH level within the laboratory’s reference range for 
postmenopausal women. 
 
All other female patients (including females with tubal ligations) will be considered to be of childbearing 
potential. 
 
 
  
LACTATION 
  
There is no information regarding the presence of Avelumab in human milk, the effects on the breastfed 
infant, or the effects on milk production. Since many drugs including antibodies are excreted in human 
milk, advise a lactating woman not to breastfeed during treatment and for at least one month after the 
last dose of Avelumab due to the potential for serious adverse reactions in breastfed infants. 
  
 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
  

56 
Protocol V3; 10/19/2020 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
  
Drug accountability and subject compliance will be assessed with drug dispensing and return records. 
  
Study Drug Accountability: The investigator will maintain accurate records of receipt of all Avelumab, 
including dates of receipt. In addition, accurate records will be kept regarding when and how much 
study treatment is dispensed and used by each subject in the study. Reasons for deviation from the 
expected dispensing regimen must also be recorded. At completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all unused Avelumab will be reconciled and destroyed in 
accordance with applicable state and federal regulations. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
  
DOSAGE FORMS AND STRENGTHS 
Injection: 200 mg/10 mL (20 mg/mL), clear, colorless to slightly yellow solution in a single-dose vial. 
  
6.2.3 PRODUCT STORAGE AND STABILITY 
  
All study medications will be stored and inventoried in accordance with applicable state and federal 
regulations. 
  
Avelumab Injection is a sterile, preservative-free, and clear, colorless to slightly yellow solution for 
intravenous infusion supplied as a single-dose vial of 200 mg/10 mL (20 mg/mL), individually packed into 
a carton (NDC 44087-3535-1). Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to 
protect from light. Do not freeze or shake the vial. The vial stopper is not made with natural rubber 
latex. 
  
Preparation of Avelumab: 
• Visually inspect vial for particulate matter and discoloration. Avelumab is a clear, colorless to slightly 
yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate matter. 
• Withdraw the required volume of Avelumab from the vial(s) and inject it into a 250-mL infusion bag 
containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection. 
• Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing. 
• Inspect the solution to ensure it is clear, colorless, and free of visible particles. 
• Discard any partially used or empty vials. 
 
Storage of diluted Avelumab solution: 
Protect from light 
Store diluted Avelumab solution: 
• At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution.  
Or 

57 
Protocol V3; 10/19/2020 
• Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If 
refrigerated, allow the diluted solution to come to room temperature prior to  
administration. Do not freeze or shake diluted solution. 
  
• 
Administration of Avelumab: 
• Administer the diluted solution over 60 minutes through an intravenous line containing 
a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron). 
• Do not co-administer other drugs through the same intravenous line. 
• 
Setting: 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 
• 
Observation period:  Following avelumab infusions, patients must be observed for 30 minutes 
post-infusion for potential infusion-related reactions. 
 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
The study is non-randomized and open label.  
 
6.4 CONCOMITANT THERAPY 
  
All treatments that the investigator considers necessary for a subject’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care. All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, over-
the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date will also be included on the CRF. 
  
Palliative and supportive care is permitted during the course of the trial for underlying medical 
conditions and management of symptoms. Palliative surgery (for eg: TURBT) is allowed for symptom 
control (eg: bleeding or intractable pain). Procedures such as thoracentesis, paracentesis, pericardial 
fluid drainage etc, are also allowed for symptom management. Palliative radiotherapy is permitted to a 
single lesion if considered medically necessary by the treating physician as long as the lesion is NOT a 
RECIST 1.1 defined target lesion.. Trial therapy should be held during the course of palliative 
radiotherapy and should be resumed no earlier than the next scheduled administration of trial therapy. 
The specifics of the radiation treatment, including the location, will be recorded. All concomitant 
medications received within 30 days before the first dose of trial treatment through the Safety Follow-
up Visit should be recorded. 
  

58 
Protocol V3; 10/19/2020 
Prohibited Concomitant Medications and/or Treatments: 
Subjects are prohibited from receiving the following therapies during the Screening, Treatment Phases 
of this trial. 
• 
Immunotherapy not specified in this protocol. 
• 
Chemotherapy not specified in this protocol. 
• 
Investigational agents other than Avelumab and Docetaxel 
• 
Radiation therapy for tumor control 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, seasonal flu (that contain a live virus), H1N1 flu, 
rabies, BCG, and typhoid vaccine. 
• 
Long term use of high dose glucocorticoids (>40mg) for any purpose other than to modulate 
symptoms from an event of clinical interest, use as a pre-medication for chemotherapeutic 
agents specified in the protocol, or for use as a pre medication in subjects with a known history 
of an IV contrast allergy administered as part of CT radiography. Replacement doses of steroids 
(for example, prednisone 5-10 mg daily) are permitted while on study. Short course of 
glucocorticoids for the treatment of non-immune related issues such as COPD, asthma, 
osteoarthritis, chronic back pain etc at the discretion of investigator is allowed. 
• 
Bisphosphonates and/or RANKL inhibitor therapies cannot be initiated after informed consent 
has been signed. These therapies may be continued IF treatment with an agent from one of 
these two classes was initiated PRIOR to signing informed consent 
  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically necessary. 
6.4.1 RESCUE MEDICINE 
  
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator including but not limited to the items outlined below. 
  
Diarrhea: Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus). In symptomatic subjects, infectious etiologies should be ruled out, and if 
symptoms are persistent and/or severe, endoscopic evaluation should be considered. All subjects who 
experience diarrhea should be advised to drink liberal quantities of clear fluids. If sufficient oral fluid 
intake is not feasible, fluid and electrolytes should be substituted via IV infusion. 

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Protocol V3; 10/19/2020 
  
Nausea/vomiting: Administration of prophylaxis for nausea and vomiting should be administered per 
institutional guidelines and local standard practices for the standard of care chemotherapies.For 
Avelumab, the therapy is considered to be of low to moderate emetogenic potential. Consideration for 
chemo induced nausea and vomiting prophylaxis should be given in subsequent cycles of the 
administration according to standard institutional practice and should not be routinely administered 
prior to the initial trial treatment of Avelumab. Subjects should be strongly encouraged to maintain 
liberal oral fluid intake 
  
Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated for the treatment of 
anemia, but should be clearly noted as concurrent medications. Consider a potential immunologic 
etiology. 
  
Neutropenia: Use of colony-stimulating factors including Granulocyte Colony-Stimulating Factor (G-CSF), 
pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating Factor GM CSF is allowed in 
accordance to institutional standards or as deemed appropriate by study investigator.  
  
Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. ITP should be ruled out 
before initiation of platelet transfusion. 
  
Anti-infectives: Subjects 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. 
  
Events of Clinical Interest with a potential immunologic etiology (ECI): Please see the separate 
guidance document in the administrative binder regarding identification, evaluation and management of 
adverse experiences of a potential immunologic etiology. Depending on the type and severity of an ECI, 
oral or intravenous treatment with a corticosteroid should be considered, in addition to appropriate 
symptomatic treatment of a given condition. 

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Protocol V3; 10/19/2020 
7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Treatment with Docetaxel and Avelumab may continue until one of the following events occurs: 
• 
Documented disease progression after confirmation with a scan as per the criteria described in 
section 8  
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse experiences. 
• 
Patient withdraws consent 
• 
If in the opinion of the Investigator, a change or temporal or permanent discontinuation of 
therapy would be in the best interest of the patient.   
• 
Patient is lost to follow-up 
• 
Pregnancy in patient 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Patients may withdraw from the study at any time. Patients who discontinue early should return within 
30 days (+/- 7 days) of the last dose of the study drugs for a follow-up evaluation. Any assessments listed 
for the final visit in the Schedule of Activities will be performed at that time. 
   
 
 
If a subject withdraws consent to participate in the study, the reason for withdrawal will be 
documented, no further study procedures or assessments will be performed, and no further study data 
will be collected for this subject, other than the determination of survival status from public records 
such as government vital statistics or obituaries. 
 
 
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits and is 
unable to be contacted by the study site staff. 
  

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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The trial coordinator will attempt to contact the participant and reschedule the missed visit, at 
the earliest available appoint and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
• 
Before a participant is deemed lost to follow-up, the investigator and trial coordinator will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record or 
study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
7.4 END OF TREATMENT AND PREMATURE WITHDRAWAL VISIT 
• 
An end of treatment visit will occur 30 days(+/- 7days) after last dose of study treatment.  
 After the End of Treatment visit, patients without disease progression will be followed every 3 
months (+1 month) with CT scans per physician standard of care. Patients with disease 
progression or who have started subsequent therapy will move to survival only data collection 
(passive chart review or phone calls) every 3 months (+1 month) for 2 years, then every 6 
months (+ 1 month) until death or lost-to-follow up. 
• 
 

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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
  
Conventional response criteria may not adequately assess the activity of immunotherapy because 
progressive disease (by initial radiographic assessment) does not necessarily reflect therapeutic failure. 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy as:  
• 
Response to immunotherapy may be delayed 
• 
Response to immunotherapy may occur after disease progression as defined by conventional 
criteria (because of potential for pseudo progression/tumor-immune infiltration) 
• 
The appearance of new lesions may not represent PD with immunotherapy 
 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti-cancer 
medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anti-cancer 
compounds, the study will implement the following in addition to standard RECIST 1.1 criteria: 
 
• 
Patients progressing by RECIST 1.1 criteria will be allowed to remain on study treatment 
(provided they have no significant clinical deterioration) until disease progression is confirmed 
in follow up scans obtained in 6 weeks. If the patients have confirmed disease progression in the 
follow-up scan when compared to the first assessment scan, then they will be taken off study. 
On the other hand, if the patients have partial response or stable disease when compared to the 
first assessment scan, they will continue with the study therapy. 
• 
The study treatment will be discontinued if significant clinical deterioration occurs at any time 
due to disease progression. Some examples of significant clinical deterioration include – new 
CNS metastases, organ failure, cord compression etc.  
 
 
EFFICACY ASSESSMENT SCHEDULE: 
 
• 
The intention of the study design is to closely monitor patients with safety follow-up and disease 
assessments in the absence of study discontinuation criteria. 
• 
For the purposes of this study, patients should be re-evaluated after Cycles 3 and 6 and then 
every 12 weeks during maintenance treatment. In addition to a baseline scan, confirmatory 
scans will also be obtained in 6 weeks following initial documentation of an objective response 
(CR, PR) or progressive disease (PD). 
• 
 
The tumor assessment (TA) performed during screening will be used as a baseline for efficacy 
assessments. CT/MRI imaging of the chest, abdomen and pelvis is required at screening and at each TA, 

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regardless of the location of known metastases. In addition, CT/MRI scans must be obtained of anatomic 
regions not covered by the chest,  abdomen and pelvis scans in subjects where there is clinical suspicion 
of deep soft tissue metastases (e.g., lesions in the thigh). Such additional CT/MRIs will be required at 
Screening when deep soft tissue disease is known/suspected and must be consistently repeated at all 
TAs if a deep soft tissue lesion is identified during screening. The same imaging modality must be used 
for all TAs, unless contraindicated. Imaging-based evaluation is preferred to clinical examination. IV 
contrast should be used for all CT scans; if IV contrast is contraindicated, oral contrast maybe used. If 
contrast cannot be used then non-contrast scans are allowed as determined by investigator.Sections 
should be contiguous, similarly sized and consistent from visit-to-visit. Section thickness must be based 
on institutional standards (e.g., from 5 to 8 mm, 10 mm cuts are not recommended). Chest x-rays and 
ultrasound are not acceptable methods to measure disease. Response and progression of disease must 
be documented by CT or MRI similar to the methods used at Screening. 
  
\ 
  
Definition of Measurable and Non-measurable Lesions: 
 
• 
Disease measurements:  
 
We will use RECIST 1.1 to define measurable and non-measurable lesions. 
 
 
Measurable Lymph nodes:  Lymph nodes ≥15 mm in short axis can be considered for selection as target 
lesions. Lymph nodes measuring 10 mm to <15 mm are considered non-measurable. Lymph nodes 
smaller than 10 mm in short axis at baseline, regardless of the slice thickness, are normal and not 
considered indicative of disease. 
 
  
Measurable disease: (non-nodal): 
Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam.   
Target lesions: 
 
At screening (baseline), when more than one measurable lesion is present all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
 
 
 
Non-Target lesions: 

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All other lesions (or sites of disease) including pathological lymph nodes, malignant effusions should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. In 
addition, it is possible to record multiple nontarget lesions involving the same organ as a single item on 
the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver/lung metastases’). 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the measurable dimension 
of the disease.  
 
Note: Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, that can 
be evaluated by CT/MRI, can be considered as measurable lesions, if the soft tissue component meets 
the definition of measurability. 
 
EVALUATION OF TARGET LESIONS 
 
Complete 
Response (CR) 
Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial Response 
(PR) 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study).  In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one 
or more new lesions is also considered progressions). 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study 
 
Evaluation of Non-target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response. 

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Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the investigator 
should prevail in such circumstances, and the progression status should be confirmed by scans in 6 
weeks. 
 
EVALUATION 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 PD the smallest measurements recorded since the 
treatment started). In general, the subject's best response assignment will depend on the achievement 
of both measurement and confirmation criteria.  
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”.  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When the 
evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 

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Protocol V3; 10/19/2020 
 
DEFINITIONS FOR RESPONSE EVALUATION:  
• 
Objective response rate (ORR) defined as the proportion of all treated subjects whose best 
response at any time during the study following initiation of therapy is confirmed CR or 
confirmed PR. This will be assessed according to the RECIST v1.1 
 
• 
Progression free survival (PFS) defined as the time between the first dose of study therapy and 
the earliest date of confirmed progression or death. Subjects who have neither progressed nor 
died will be censored at the last tumor assessment date for PFS.  
  
• 
Disease control rate (DCR) defined as the percentage of patients achieving CR + PR + SD at any 
time during the study following initiation of therapy. This will be assessed according to RECIST 
v1.1 criteria.  
  
• 
Overall survival (OS) defined as the time between the first dose of study therapy and death 
(subjects who have not died will be censored at the most recent last-known-alive date), will also 
be analyzed. 
  
 
 
8.2 SAFETY ASSESSMENTS 
• 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.03.  
• 
Any adverse event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets.  
• 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.   
As the study treatment is combination regimen, the investigator may attribute each adverse 
event causality to the combination regimen or to a single agent of the combination. In general, 
causality attribution should be assigned to the combination regimen (i.e., to all agents in the 
regimen). However, causality attribution may be assigned to a single agent if in the 
investigator’s opinion, there is sufficient data to support full attribution of the adverse 
experience to the single agent.  
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
  
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  

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Protocol V3; 10/19/2020 
An adverse event can therefore be any unfavorable and unintended sign, symptoms, clinically significant 
laboratory abnormality,, temporally associated with the use of a medicinal product or protocol-specified 
procedure, whether or not considered related to the medicinal product or protocol-specified procedure. 
Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a 
preexisting condition that is temporally associated with the use of the Sponsor's product, is also an 
adverse event. 
  
  
Progression of the cancer under study is not considered an adverse event unless it is considered to be 
drug related by the investigator. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
  
A serious adverse event is any adverse event occurring at any dose or during any use 
of Investigation product/s that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Is another important medical event 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE criteria; the 
event itself may be of relatively minor medical significance (such as severe headache without 
any further findings). Severity and seriousness need to be independently assessed for each 
adverse event recorded on the CRF. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
  
8.3.3.1 SEVERITY OF EVENT 
  
An investigator who is a qualified physician will evaluate all adverse events as to: 
CTCAE V 4.03 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic 

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observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
  
The determination of the likelihood that the study treatment caused the adverse event will be provided 
by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. 
  
   
8.3.3.3 Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding the event, and 
an evaluation of any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the study treatment. 
 
AEs will be categorized according to the likelihood that they are related to the study drug(s). Specifically, 
they will be categorized using the following terms:  
 
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
  
8.3.8 ADVERSE EVENT REPORTING 
 
For non-serious Adverse Events, documentation must begin from the time the informed consent 
document is signed through the 30 day follow-up period after study drug is discontinued. 
 
Collected information should be recorded in the electronic/Case Report Forms (eCRF/CRF) for that 
subject. A description of the event, its severity or toxicity grade (according to NCI’s Common Toxicity 
Criteria (CTCAE)v.4.03), onset and resolved dates (if applicable), and the relationship to the study drug 

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Protocol V3; 10/19/2020 
should be included. Documentation should occur in real time. The principal investigator has final 
responsibility for determining the attribution of the event as it is related to the study drug. 
8.3.9 SERIOUS ADVERSE EVENT REPORTING 
  
For any experience or condition that meets the definition of a serious adverse event (SAE), recording of 
the event must begin after signing of the informed consent and continue through the 30 day follow-up 
period after treatment is discontinued.  
Given the potential risk for delayed immune-related toxicities, SAE’s that are at least possibly related to 
study drug will be captured  for 90 days after the last dose of study drug administration. 
 
Investigators must report to the DSMC any serious adverse events (SAE), whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64). SAEs must be reported 
via an OnCore SAE Report within 24 hours of learning of the event.  
 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
 
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization OR prolongation of existing 
hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
 
The extended safety follow-up beyond 30 days after last avelumab administration may be performed 
either via a site visit or via a telephone call with subsequent site visit requested in case any concerns 
noted during the telephone call. 
8.3.10 REPORTING EVENTS TO PARTICIPANTS 
  
All grade 4 adverse events noted among other patients in this study, or other studies with this 
combination will be notified to other patients enrolled in the study.   
  
8.3.11 REPORTING OF PREGNANCY 
  
  

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Protocol V3; 10/19/2020 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial or within 120 days of completing the trial or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All 
subjects who become pregnant must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must 
also be reported. Such events must be reported within 24 hours to the Sponsor either by electronic 
media or paper. 
 
 
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
  
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the principal investigator. The UP report will include the following information: 
  
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 

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Protocol V3; 10/19/2020 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
  
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
  
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 10 working days of the investigator becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 10 working days 
of the investigator becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 10 working days of the IRB’s receipt of the report of 
the problem from the investigator. 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
  
Not applicable 

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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
The combination of Avelumab and Docetaxel was not tested in urothelial cancer. Hence, it would be 
prudent to establish the safe dose of this combination to study in phase II and III clinical trials. We 
hypothesize the combination of Avelumab and Docetaxel is safe and efficacious in patients with 
metastatic urothelial cancer.  
Primary Endpoints: 
Phase 1b Dose De-escalation: Incidence of dose limiting toxicities (DLTs) with combination of Avelumab 
and Docetaxel in subjects with metastatic urothelial cancer 
Phase 1b Dose Expansion:  Overall response rate (ORR) (complete response (CR) + partial response (PR)) 
per RECIST v1.1 with the established dose of combination therapy with Avelumab and Docetaxel in 
subjects with metastatic urothelial cancer 
Secondary Endpoints: 
Phase 1b Dose Expansion:  
• 
Radiologic progression-free survival (PFS) per RECIST v1.1. PFS is defined as the time between 
the first dose of study therapy and the earliest date of confirmed progression or death. Subjects 
who have neither progressed nor died will be censored at the last tumor assessment date for 
PFS. Efficacy assessments as per section 8. 
• 
Overall survival (OS) defined as the time between the first dose of study therapy and death 
(subjects who have not died will be censored at the most recent last-known-alive date). 
9.2 SAMPLE SIZE DETERMINATION 
 
Phase Ib De-escalation phase: 
The primary objectives of the Phase 1b portion of this study are to assess the safety of and determine 
the recommended dose of a combination treatment of avelumab (10 mg/kg) and docetaxel for 
metastatic bladder cancer. This study will utilize a standard 3+3 dose de-escalation design. The dose 
levels to which patients will be assigned in sequential cohorts are listed below.  
 
Avelumab 
Docetaxel 
Level 0 
10 mg/kg 
75 mg/m2 
Level -1 
10 mg/kg 
60 mg/m2 
Level -2 
10 mg/kg 
45 mg/m2 
 
 
 
An initial cohort of three patients will be treated at dose level 0.  Decision of when and how to de-
escalate are described below. 

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Protocol V3; 10/19/2020 
 
Number of patients with DLT 
at a given dose level 
Decision Rule 
0 out of 3 
Enter 3 additional patients at the same dose level 
• 
If 1 or fewer of these three patients experience DLT, this dose level will be 
declared the maximally administered dose. 
• 
If 2 or more experience a DLT, de-escalate to next dose level. 
1 out of 3 
Enter up to 3 additional patients at the same dose level.  
• 
If 0 of these 3 patients experience DLT, this dose level will be declared the 
maximally administered dose. 
• 
If 1 or more of these 3 patients experience DLT, de-escalate to the next dose 
level. 
≥2 out of 3 
De-escalate the next dose level. 
 
 
 
Up to 6 patients will be treated at each dose level. If DLT meets the stopping boundaries set by the 
above dose algorithm at dose level 0 (for example, more than 1 out of 3 or more than 1 out of 6 
patients), the next set of 3 patients will be entered at the dose level of -1. If dose level -1 meets the 
stopping boundaries, the next set of 3 patients will be entered at dose level -2. If dose level -2 meets the 
stopping boundaries, the trial will be stopped. The recommended Phase Ib dose for the expansion 
cohort will be defined as the highest dose level for which at most 1 out of 6 patients experience a DLT. 
  
Phase Ib Expansion 
The primary objective of the expansion cohort is to evaluate initial tumor response to a combination 
treatment of avelumab (10 mg/kg) and docetaxel at the recommended dose for metastatic bladder 
cancer. The overall response rate for avelumab alone in second line is approximately 18% [3].  For the 
combination treatment, a response rate of 33% or more is considered clinically important, whereas 18% 
or below is considered uninteresting. A response is defined as a complete or partial response.  To obtain 
preliminary information regarding the response rate and evaluate futility, sample size requirements are 
based on the probability of stopping early for futility under the two response rates.  If the true response 
rate is 33%, we want to probability of stopping for futility to be less than 15% and if the true response 
rate is 18% we want the probability of stopping for futility to be at least 65%.  The table below shows 
the probability of stopping for futility under the two response rates when R or fewer of the N patients 
has a response. 
 
 
Number of 
Patients (N) 
Rejection 
number (R) 
Probability of stopping under response 
rate of 33% 
Probability of stopping under 
response rate of 18% 
20 
4 
15.9% 
71.5% 
20 
5 
30.8% 
86.4% 
21 
3 
4.9% 
46.2% 
21 
4 
12.8% 
67.7% 

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21 
5 
25.9% 
83.8% 
22 
3 
3.8% 
42.2% 
22 
4 
10.2% 
63.8% 
 
The bolded line in the table is the preferred combination of patients and responses.  Twenty one (21) 
patients will be enrolled. If 4 or fewer patients have a response the trial will stop for futility.  If 5 or more 
patients have a response, the treatment will be deemed worthy of further investigation in a Phase II 
Trial. 
 
Sample Size/Accrual Rate 
The Phase Ib portion of this study is expected to require a minimum of 6 and a maximum of 18 evaluable 
patients (if de-escalation to dose levels -1 and -2 is warranted). Patients treated in Phase Ib at the 
recommend dose will also be included in the Phase Ib expansion portion. Additional evaluable patients 
will be accrued for a total of 21 patients treated at the recommended dose. The anticipated accrual rate 
is 1-2 patients per month who would meet inclusion criteria.  
 
9.3 POPULATIONS FOR ANALYSES 
The safety population will include all enrolled patients who receive at least 1 dose of both Avelumab and 
Docetaxel.  The primary analysis population for the study will include the safety population with 
separate analyses for Phase 1 dose escalation and Phase 1b dose expansion cohort. The efficacy 
population will comprise all patients who receive at least 1 dose of both Avelumab and Docetaxel and 
who have baseline and at least 1 post-baseline imaging assessment. 
9.4 STATISTICAL ANALYSES 
This section outlines the statistical analysis strategy and procedures for the trial. If, after the trial has 
begun, changes are made to primary or exploratory objectives and/or hypotheses, or to the statistical 
methods related to those objectives and/or hypotheses, then those changes, along with an explanation 
as to when and why they occurred, will be listed in the Clinical Study Report (CSR) for the trial. Post hoc 
exploratory analyses will be clearly identified in the CSR. No imputations will be made for missing data. 
Additional details of the statistical analyses to be performed will be provided in the trial Statistical 
Analysis Plan. 
9.4.1 GENERAL APPROACH 
  
Descriptive statistics will be employed to evaluate the endpoint and analyze the data. Summary 
statistics for continuous variables will include mean, standard deviation, median and range. 
  
Categorical variables will be presented as frequency counts and percentages; and time-to-event 
variables will be summarized by Kaplan-Meier medians and survival plots. Data listings will be created to 
support tables and present data. The preliminary efficacy analysis will be conducted on the efficacy 
evaluable population and safety analysis will be performed on the safety population. SAS 9.2 or higher 

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will be used for data analysis. The data will be tabulated and analyzed with respect to patient 
enrollment and disposition, demographic and baseline 
9.4.4 SAFETY ANALYSES 
  
All safety data will be analyzed descriptively. Absolute and relative frequencies will be used to describe 
the incidence of all injection-site reactions, AEs, SAEs, deaths, and laboratory values. DLTs occurring in 
Phase 1 will be summarized by dose level received and presented in both tables and listings 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
  
Demographic and baseline characteristics will be listed by patient and summarized using the all-treated 
population. Descriptive summary statistics (sample size, mean, median, SD, and range, when 
appropriate) will be provided for the continuous variables such as age, weight, and height. Count and 
percentage will be reported for categorical variables such as sex, race, and ethnicity. 
9.4.6 PLANNED INTERIM ANALYSES 
  
No interim efficacy analysis is planned.  
9.4.7 SUB-GROUP ANALYSES 
  
No sub-group analysis is planned. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
  
The investigator must maintain detailed records of all trial participants who are enrolled in the trial or 
who undergo screening. Source documents include, but are not limited to, patient medical records and 
investigator’s patient trial files, as well as all test results. 
 
The following minimum information should be entered into the enrolled patient’s source documents: 
 
• The date the patient entered the trial and the patient number 
• The trial protocol number  
• The date that informed consent was signed 
• Evidence that the patient meets trial eligibility requirements (e.g., medical history, trial procedures, 
evaluations) 
• The dates of all trial-related patient visits 
• Evidence that trial-required procedures and/or evaluations were completed 
• Use of any concurrent medications 
• Documentation of trial medication accountability 
• Occurrence and status of any AEs 

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• The date the patient exited the trial, and a notation as to whether the patient completed the trial or 
was discontinued early, including the reason for discontinuation 
• Any deviations from the protocol 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
  
Potential subjects will be recruited from patients seen at the Holden Comprehensive Cancer Center at 
University of Iowa Hospitals and Clinics who appear to be eligible for the study.  A member of the 
research team will meet with the patient to go over the informed consent document and answer any 
questions they may have.  Other potential treatment options, whether investigational or standard of 
care, will be discussed with the patient.  The patient will be given the time they need to make their 
decision; they are encouraged to discuss it with their family and/or friends.  If the patient decides to 
participate, they will need to sign the consent form during one of their clinic visits.  No study-specific 
procedures will be performed before the informed consent document is signed. 
  
To avoid coercion, potential patients will be informed that they are free to refuse to participate in the 
trial, and that refusing to participate will not affect the availability of future medical care at UIHC.  A 
copy of the signed informed consent document will be given to the patient.  
  
10.1.2 DATA MONITORING AND MANAGEMENT  
 
All studies that undergo PRMC review and/or utilize HCCC Clinical Research Services (CRS) resources are 
required to register subjects in OnCore. Each subject registration includes the following: 
• 
The subject’s IRB approved (version date) consent form and the date of their consent.  
• 
Date of eligibility and eligibility status (eligible, not eligible) 
• 
On study date and subject’s disease site (and histology if applicable) 
• 
On treatment date (if applicable)  
 
All subject registration information is expected to be entered into OnCore within 2 (two) business days 
after the subject’s study visit.  
 
10.1.2.1 SUBJECT DATA 
 
For HCCC investigator initiated trials, research staff are responsible for entering subject study data (data 
collection) into OnCore electronic case report forms (eCRFs). These eCRFs must be approved by the PI 
and statistician prior to study activation to ensure sufficient and necessary data acquisition. All 
information entered into eCRFs will be traceable to the source documents which are generally 
maintained in the subject’s file.  
 

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eCRF data entry needs to be timely and should be entered into OnCore as soon as possible but no later 
than 14 (fourteen) business days after the subject’s visit, including adverse events, tumor 
measurements, administration of study medication, concomitant medications, labs, and vitals. Physical 
exam assessments must be entered no later than 14 (fourteen) business days following completion of 
the physician’s clinic note in the medical record.  
 
Timely data entry facilitates remote monitoring of data, allows the data to progress appropriately 
through the data cleaning process, and helps prevent a backlog of data queries. 
 
10.1.2.2 FORMS MONITORING 
 
OnCore eCRF data are monitored on a routine basis (dependent on accrual) to ensure all data are 
entered completely, accurately, and within time requirements outlined above. The assigned DSMC 
monitor will coordinate and complete the data monitoring review. When the time comes to monitor a 
study (based on patient accrual and assigned risk level of trial) the monitor arranges for a selection of 
cases to be reviewed from among the subjects registered in OnCore.  As part of the forms monitoring 
process, the assigned monitor will issue queries via OnCore (linked to the eCRF) to resolve missing, 
incomplete, and/or incorrect information. A member of the research team is expected to respond to 
these monitoring queries within 14 (fourteen) business days.  
 
The monitoring process can often identify misunderstandings or deficiencies in the written, research 
protocol requirements earlier in the study process and thereby improve data quality and reduce rework.  
 
10.1.2.3 FINAL REPORTS 
 
A summary of each subject’s data record is continually available to the PI, research staff, and DSMC from 
OnCore’s Biostat Console. The availability of this information is a valuable tool for the preparation of 
final reports and manuscripts as well as ongoing deficiency reports. 
 
10.2 TRIAL-SPECIFIC DATA AND SAFETY MONITORING PLAN 
10.2.1 STUDY RISK-LEVEL: 
 
 Level 1—low risk of morbidity or death, * <1% of death or any adverse event  
 Level 2—risk of death* <1% or any adverse event 1% – 5%  
 Level 3—risk of death* 1% – 5% or grade 4 – 5 ADvers 1% – 5%  
                       Level 4—risk of death* >5% or grade 4 – 5 SAE >5%  
 Drugs being used on a “compassionate” basis  
 
* Risk of death” refers specifically to 100-day treatment-related mortality 

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10.2.2 REPORTING AND MONITORING REQUIREMENTS: 
All institutional investigator initiated trials (IITs), regardless of assigned risk level are subject to routine 
DSMC monitoring activities which may include but are not limited to review of signed consent 
documents, eligibility and adverse event reporting. 
  
All institutional IITs have the following reporting requirements as part of their DSMP: 
• 
Register all subjects in HCCC’s Clinical Trial Management System, OnCore 
• 
Document Adverse Events  
• 
Document protocol deviations  
• 
Provide an annual progress report to the DSMC via OnCore data export 
  
10.2.3 SELECTED MONITORING STRATEGY BASED ON RISK-LEVEL: 
 
10.2.3.1 RISK LEVEL 4 
Interventional treatment trials involving investigational agents or devices with a risk of death* (>5% or 
grade 4 – 5 SAE >5%), e.g. all investigator initiated INDs, most Phase I/II trials, gene therapy, gene 
manipulation or viral vector systems high-risk clinical procedures if performed solely for research 
purposes.  The use of a new chemical or drug for which there is limited or no available safety data in 
humans. 
 
10.2.3.2 STUDY SAFETY REVIEW 
An independent study monitor and/or the DSMC Chair (or designee), will review study data (provided by 
the PI/available in OnCore) and communicate with the PI at least biannually.  A copy of this 
communication will be forwarded to the DSMC and PRMC Chairs.  
 
10.2.4 ADDITIONAL REPORTING REQUIREMENTS: 
• 
A scanned copy of the completed eligibility checklist, with screening information and PI 
signature, will be attached in OnCore for ongoing review by DSMC staff. 
• 
Serious adverse events will be entered directly into an OnCore SAE report by the research team. 
OnCore will send an automatic notification to the DSMC Chair/acting Chair and staff for review. 
• 
The DSMC utilizes a risk-based monitoring approach. The trial's research records will be 
monitored at minimum twice per year.  Monitoring may be done more frequently depending on 
the protocol, risks to subjects, reported serious/adverse events, patient population and accrual 
rate.   Records for a minimum of 25% of subjects will be monitored for the entire study.   
Monitoring will involve the following: 

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Protocol V3; 10/19/2020 
• 
review eligibility of patients accrued to the study, 
• 
check for the presence of a signed informed consent, 
• 
determine compliance with protocol’s study plan, 
• 
determine whether SAEs are being appropriately reported to internal and external regulatory 
agencies, 
• 
compare accuracy of data in the research record with the primary source documents, 
• 
review investigational drug processing and documentation, 
• 
Assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
FDA Reporting Requirements (for Sponsor-Investigators)  
It is the responsibility of the IND sponsor-investigator to comply with IND safety reporting as set forth 
in the Code of Federal Regulations, Section 312.32. This responsibility includes providing an annual IND 
report to the FDA.  
All IND safety reports must be submitted on Form 3500A  and be accompanied by Form 1571. The type 
of report (initial or follow-up) should be checked in the respective boxes on Forms 3500A and 1571. See 
Instructions for completing Form 3500A.  Please note all instance of UIHC, location, and faculty / staff 
should be redacted from supporting documentation and the 3500A. 
The submission must be identified as: 
• 
“IND safety report” for 15-day reports, or 
• 
“7-day IND safety report” for unexpected fatal or life-threatening suspected adverse reaction 
reports, or 
• 
“Follow-up IND safety report” for follow-up information. 
For detailed explanation of the above definitions, requirements, and procedures related to IND 
application safety reports and the responsibilities of IND applications sponsors with regard to such 
reporting, refer to Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and 
BA/BE Studies (PDF - 227KB) 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome, if known (grading the event per CTCAE) 
• 
Supportive laboratory results and diagnostics 

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• 
Sponsor-Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
 
 
 
 
 

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11 REFERENCES 
1. Sharma, P., et al., Nivolumab monotherapy in recurrent metastatic urothelial carcinoma 
(CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol, 
2016. 17(11): p. 1590-1598. 
2. Bellmunt, J., et al., Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. 
New England Journal of Medicine, 2017. 376(11): p. 1015-1026. 
3. Apolo, A.B., et al., Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With 
Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin 
Oncol, 2017. 35(19): p. 2117-2124. 
4. Rosenberg, J.E., et al., Atezolizumab in patients with locally advanced and metastatic urothelial 
carcinoma who have progressed following treatment with platinum-based chemotherapy: a 
single-arm, multicentre, phase 2 trial. Lancet, 2016. 387(10031): p. 1909-20. 
5. Sengelov, L., et al., Docetaxel and cisplatin in metastatic urothelial cancer: a phase II study. J Clin 
Oncol, 1998. 16(10): p. 3392-7. 
6. Boyerinas, B., et al., Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 
Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Cancer Immunol Res, 2015. 3(10): 
p. 1148-57. 
7. Rizvi, N.A., et al., Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for 
First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol, 2016. 34(25): p. 
2969-79. 
8. Langer, C.J., et al., Carboplatin and pemetrexed with or without pembrolizumab for advanced, 
non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label 
KEYNOTE-021 study. Lancet Oncol, 2016. 17(11): p. 1497-1508.