Conditions: Bladder Cancer Metastatic Bladder Cancer Invasive Bladder Cancer
Keywords: muscle invasive bladder cancer non-muscle invasive bladder cancer radical cystectomy monoclonal antibodies Avelumab Invasive Resectable disease MIBC NMIBC neoadjuvant chemotherapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is a pilot study of avelumab in patients with non-metastatic, muscle invasive bladder cancer who are eligible for radical cystectomy (RC), but are ineligible for cisplatin based neoadjuvant therapy. The target recruitment is 10 evaluable patients for this window of opportunity study. Pre- and post-treatment tumor samples from transurethral resection of the bladder tumor and RC will be used for study endpoints.

Detailed description:
Avelumab is a fully human monoclonal PD-L1 antibody of the immunoglobulin G1 (IgG1) subclass. It works by binding to PD-L1 on tumor cells, immune cells and/or stromal cells. This prevents PD-L1 from interacting with PD-1. Inhibition of this interaction increases activation/survival of antitumor lymphocytes. It also increases innate immunity by resulting in decreased PD-1 suppression of NK cell function and bolsters antibody production by B cells due to less PD-L1 binding of PD-1 on B-cells. Additionally, avelumab has been suggested to have another mechanism involving antibody dependent cellular cytotoxicity (ADCC). ADCC in these cases involves NK cell recognition and lysis of tumor cells that have antibody bound to PD-L1. By blocking PD-L1, avelumab leads to less CD80 binding by PD-L1 and more CD80-CD28 binding in response to antigen presentation to T-cells. This results in increased costimulatory signaling and is another mechanism by which avelumab may enhance T-cell activation.

Avelumab has been shown to be efficacious across multiple metastatic tumor types, including urothelial cancer. The phase Ib study has reported survival and safety outcomes with \>12 months followup using pooled data on 249 patients with metastatic UC (Apolo et al, ESMO Sept 2017). Patients had been treated with a median of 2 prior therapies in the metastatic setting and 13 patients who were cisplatin-ineligible were evaluated for safety alone. PD-L1 expression was not a criterion for enrollment. The confirmed objective response rate (ORR) was 16.1%, with 5% complete responses and 11.2% partial responses. The 6-month progression-free survival was 27%. The ORR was better than or comparable to chemotherapy in historical controls. Among responders, 70.3% were maintained \> 12 months. Treatment-related adverse events (AE) occurred in 70%, with 10.7% of the total with AE's of grade \>3. Immune-mediated AE's occurred in 18.5%, of which 4% were grade \>3. There is currently a phase III clinical trial ongoing comparing avelumab to standard of care chemotherapy in the second line setting or beyond for metastatic UC. Two other checkpoint inhibitors have been approved in the last 2 years for first line treatment of patients with metastatic UC who are ineligible for cisplatin-based therapy.

Arms:
arm 1: Avelumab 10 mg/kg intravenously, over 60 minutes every 2 weeks for 3 cycles or 42 days.

Interventions: intervention 1: Avelumab
Intervention descriptions: intervention 1: avelumab 10 mg/kg intravenously every 2 weeks for 3 cycles or 42 days.

Protocol document:
Prot_000.pdf: 
Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 1  
Investigational 
Drug 
Substance(s) 
Avelumab 
Study Number 
Version Number 2 
Date 
December 11, 2017 
A Window of Opportunity Trial: Avelumab in Non-metastatic Muscle 
Invasive Bladder Cancer (BL-AIR: Bladder cancer-Avelumab for 
Invasive Resectable disease) 
Sponsor: Martha Mims, MD, PhD, Baylor College of Medicine  
 
 
 
IND:  138429 
 
NCT Number:  (need NCT number, once registered with ct.gov) 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 2  
PERSONNEL 
Principal Investigator                                       
Jennifer M. Taylor, MD MPH 
Baylor College of Medicine, Department of Urology 
Dan L Duncan Comprehensive Cancer Center (DLDCCC)   
Michael E. DeBakey VA Medical Center        
Academic Office: 713-798-7670 
Email: Jennifer.Taylor@bcm.edu 
 
Senior Investigator 
Martha P. Mims, MD PhD 
Baylor College of Medicine 
Department of Medicine 
Division of Hematology and Oncology   
DLDCCC 
Office: 713-798-7535                                   
Email: mmims@bcm.edu                            
Co-Investigator 
Keith Chan, PhD 
Baylor College of Medicine 
Department of Molecular and Cell Biology 
Office: 713-798-5485 
Email: kc1@bcm.edu 
 
 
 
Co-Investigator                                           
Susan Hilsenbeck, PhD                                
Baylor College of Medicine                          
Lester and Sue Smith Breast Center           
Dan L. Duncan Comprehensive Cancer 
Center         
Office: 713-798-1627                                   
Email: sgh@bcm.edu  
Co-Investigator 
Eunji Jo, MS 
Baylor College of Medicine 
Department of Biostatistics 
DLDCCC 
Office: 713-798-4923 
Email: ejo@bcm.edu 
 
 
Co-Investigator 
Seth P. Lerner, MD 
Baylor College of Medicine 
Department of Urology 
DLDCCC 
Office: 713-798-4001 
Email: slerner@bcm.edu 
Co-Investigator 
Guilherme Godoy, MD 
Baylor College of Medicine 
Department of Urology 
DLDCCC 
Office: 713-798-4001 
Email: godoy@bcm.edu 
 
Co-Investigator 
Aihua Edward Yen, MD  
Baylor College of Medicine 
Department of Medicine 
Division of Hematology and Oncology   
DLDCCC 
Michael E. DeBakey VA Medical Center   
Office: 713-798-3750 
Email: ay044661@bcm.edu 
Co-Investigator 
Anita Sabichi, MD 
Baylor College of Medicine 
Department of Medicine 
Division of Hematology and Oncology   
DLDCCC 
Michael E. DeBakey VA Medical Center   
Office: 713-798-3750 
Email: sabichi@bcm.edu 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 3  
TABLE OF CONTENTS 
 
 
1. 
INTRODUCTION ................................................................................................................ 7 
1.1 Role of Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer ........................... 7 
1.2 Overview of Immune Checkpoint Inhibition and Implications in Bladder Cancer 
Carcinogenesis .......................................................................................................................... 8 
1.3 Treatment with Immune Checkpoint Inhibitors in Bladder Cancer .....................................10 
1.4 Cyclooxygenase Levels In Tumor Tissue ..........................................................................11 
1.5 Antitumor and Tumor Promoting Factors ..........................................................................12 
1.6 Avelumab Background ......................................................................................................12 
1.6.1 Structure, Mechanism and Identifiers .........................................................................12 
1.6.2 Summary of non-clinical experience ...........................................................................13 
1.6.3 Summary of clinical experience ..................................................................................13 
1.7 Research Hypotheses ......................................................................................................15 
1.8 Rationale for Conducting this Study ..................................................................................15 
1.9 Benefit/risk and Ethical Assessment .................................................................................15 
1.9.1 Risks associated with avelumab……........……………………………...…………………. 16 
2. 
STUDY OBJECTIVES........................................................................................................17 
2.1 Primary objective(s) ..........................................................................................................17 
2.2 Secondary objective(s) .....................................................................................................17 
2.3 Translational endpoints .....................................................................................................17 
3. 
STUDY DESIGN ................................................................................................................17 
3.1 Overview of Study Design .................................................................................................17 
3.2 Study Schema ..................................................................................................................18 
3.3 Study Oversight for Safety Evaluation...............................................................................18 
3.4 Evaluability and Patient Replacement ...............................................................................18 
4. 
SUBJECT SELECTION: ....................................................................................................19 
4.1 Inclusion Criteria ...............................................................................................................19 
4.2 Exclusion Criteria ..............................................................................................................20 
4.3 Withdrawal of Subjects from Study Treatment and/or Study .............................................22 
5. 
TREATMENT PLAN ...........................................................................................................23 
5.1 Premedication ...................................................................................................................23 
5.2 Dosage and Administration of Avelumab ..........................................................................23 
5.3 Radical Cystectomy (RC) ..................................................................................................23 
5.4 Supportive Care ................................................................................................................23 
5.5 Table 5: Adverse Drug Reactions Requiring Avelumab Discontinuation or Modification ...23 
5.6 Table 6: Treatment Modification for Symptoms of Infusion-Related Reactions ..................24 
5.7 Table 7: Management of Immune-Related Adverse Reactions .........................................25 
6. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENTS ................31 
6.1 Restrictions during the study .............................................................................................31 
6.2 Excluded concomitant medications or therapies ...............................................................32 
7. 
STUDY PROCEDURES .....................................................................................................33 
7.1 Study Calendar .................................................................................................................33 
7.2 Study Procedures .............................................................................................................35 
7.3 Biological Sampling Procedures .......................................................................................36 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Page 4  
8. 
DRUG INFORMATION .......................................................................................................37 
9. 
ASSESSMENT OF SAFETY ..............................................................................................38 
9.1 Definition of an adverse event ..........................................................................................38 
9.2 Definition of serious adverse events .................................................................................38 
9.3 Definition of adverse events of special interest .................................................................38 
9.4 Infusion related reactions and serious allergic reactions ...................................................38 
9.5 Select immune mediated adverse events .........................................................................39 
9.6 Incidence of select adverse events with immune checkpoint inhibitors .............................40 
9.7 Attribution/recording of adverse events and serious adverse events .................................41 
9.8 Study recording period and follow-up for adverse events ..................................................41 
9.9 Follow-up of unresolved events ........................................................................................42 
9.10 Post-study events ...........................................................................................................42 
9.11 Reporting of adverse events ...........................................................................................43 
9.12 Reporting of Deaths ........................................................................................................43 
9.13 Overdose ........................................................................................................................44 
9.14 Pregnancy.......................................................................................................................44 
10. 
STATISTICAL METHODS ................................................................................................45 
10.1 Study design and sample size .........................................................................................45 
10.2 Statistical analysis ...........................................................................................................45 
11. 
ETHICAL AND REGULATORY REQUIREMENTS ...........................................................45 
11.1 Ethical conduct of the study ............................................................................................45 
11.2 Ethics and regulatory review ...........................................................................................45 
11.3 Informed consent ............................................................................................................45 
11.4 Changes to the protocol and informed consent form .......................................................45 
11.5 Audits and inspections ....................................................................................................45 
12. 
STUDY MANAGEMENT ..................................................................................................46 
12.1 Training of study site personnel ......................................................................................46 
12.2 Monitoring of the study ....................................................................................................46 
12.3 Study timetable and end of study ....................................................................................46 
13. 
DATA MANAGEMENT .....................................................................................................46 
14. 
DATA AND SAFETY MONITORING AND QUALITY ASSURANCE .................................46 
15. 
REFERENCES .................................................................................................................47 
 
 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 5  
 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
1. A2AR = adenosine A2a receptor  
2. ADCC = antibody dependent cellular cytotoxicity  
3. Adeno = adenocarcinoma 
4. AEs = adverse events 
5. AESIs = adverse events of special interest 
6. BC = bladder cancer 
7. BCM = Baylor College of Medicine 
8. BSC = best supportive care 
9. BTLA4 = B and T lymphocyte attenuator  
10. C = Cycle 
11. CBP = child bearing potential 
12. CCL = C-C motif chemokine ligand 
13. CD = cluster of differentiation 
14. Chemo = chemotherapy 
15. CMV = cisplatin + methotrexate + vinblastine 
16. CT =computed tomography 
17. CTCAE = common terminology criteria for adverse events 
18. CTLA-4 = cytotoxic T-lymphocyte protein 4 
19. CXCL = C-X-C motif chemokine ligand 
20. D = day 
21. DAMP = damage-associated molecular pattern 
22. DFS = disease free survival 
23. DLDCCC = Dan L Duncan Comprehensive Cancer Center 
24. DSS = disease specific survival 
25. ELISA = enzyme-linked immunosorbent assay 
26. EPO = erythropoietin 
27. FDA = federal drug administration 
28. FFPE = formalin fixed paraffin embedded  
29. FOXP3 = forkhead box P3 
30. F/U = follow-up 
31. GC = gemcitabine + cisplatin  
32. G-CSF = granulocyte macrophage colony stimulating factor 
33. GE = gastroesophageal 
34. GM-CSF = granulocyte macrophage colony stimulating factor 
35. ICI = immune checkpoint inhibitors 
36. IDO = indoleamine 2-3  dioxygenase 
37. IFN-γ = interferon gamma 
38. IHC = immunohistochemistry 
39. IRB = institutional review board 
40. KIR = killer immunoglobulin receptor  
41. LAG3 = lymphocyte activation gene 3  
42. ICH = International Conference on Harmonization  
43. ICOS = inducible T-cell costimulatory 
44. IgG1 = immunoglobulin G1  


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 6  
45. IRB = institutional review board 
46. iNOS = inducible nitric oxide synthase 
47. IL = interleukin 
48. m = months 
49. mABs = monoclonal antibodies 
50. M-CSFR = macrophage colony stimulating factor receptor 
51. MDSCs = myeloid derived suppressor cells 
52. MHC = major histocompatibility 
53. MIBC = muscle invasive bladder cancer  
54. MRI = magnetic resonance imaging 
55. MVAC = methotrexate + vinblastine + adriamycin + cisplatin 
56. NA = neoadjuvant 
57. N/A = not available 
58. NAC = neoadjuvant chemotherapy 
59. NMIBC = non-muscle invasive bladder cancer 
60. NSCLC = non-small cell lung cancer 
61. NK = natural killer 
62. ORR = overall response rate 
63. OS = overall survival  
64. PD-1 = programmed death 1 
65. PD-L1 = programmed death ligand 1 
66. PD-L2 = programmed death ligand 2 
67. PGE2 = prostaglandin E2 
68. PLND = pelvic lymph node dissection 
69. PFS = progression free survival 
70. pT0 = pathologic complete response 
71. RC = radical cystectomy 
72. RCT = randomized controlled trial 
73. RECISTv1.1 = response evaluation criteria in solid tumors version 1.1 
74. RNA = ribonucleic acid 
75. SAE = serious adverse event 
76. SC = squamous cell carcinoma 
77. SITC = society for immunotherapy in cancer 
78. T-bet = t box protein in B cells 
79. TGF-β = transforming growth factor β 
80. TIM3 = T-cell membrane protein 3  
81. TNBC = triple negative breast cancer 
82. TNF = tumor necrosis factor 
83. TPO = thrombopoetin 
84. TTP = time to progression 
85. TURBT = transurethral resection of the bladder tumor 
86. UCB = urothelial cancer of the bladder 
87. UCC = urothelial cell carcinoma 
88. ULN = upper limit normal 
89. VEGF = vascular endothelial growth factor 
90. wks = weeks 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 7  
1. INTRODUCTION 
1.1 Role of Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer 
Multiple clinical trials have shown improvements in overall survival (OS) and disease free 
survival (DFS) for patients with muscle invasive bladder cancer (MIBC) administered cisplatin 
containing neoadjuvant chemotherapy (NAC) when compared to radical cystectomy (RC) alone.  
(Table 1) (1-11) In these studies improved survival has been associated with lack of residual 
disease at the time of RC. (2-10) Additionally, multiple meta-analyses have shown significant 
benefits for cisplatin containing NAC when compared to RC alone.  One of these meta-analyses 
consisted of 3005 patients across 11 trials; it showed 5 year absolute improvements for OS of 
5% and DFS of 9%. (12)  
 
Traditionally the NAC of choice was standard dose methotrexate + vinblastine + adriamycin + 
cisplatin (MVAC), but recently studies have suggested equivalency of gemcitabine + cisplatin 
(GC) and dose-dense MVAC.  (Table 1) The three cisplatin containing NAC regimens 
recommended by the National Comprehensive Cancer Network include 1) dose-dense MVAC 
for 3-4 cycles, 2) GC for 4 cycles or 3) cisplatin + methotrexate + vinblastine (CMV) for 3-4 
cycles. (13) The regimen we generally use neoadjuvantly for MIBC at Baylor affiliates is GC.  
These regimens and the data in Table 1 are for those with predominantly urothelial cell 
carcinoma (UCC), which is the majority of the patients seen in clinical practice and those that 
will be included in our trial.  Perioperative recommendations for other histologies (e.g., 
squamous cell and adenocarcinoma) are different and are not discussed here since those 
patients without predominant UCC histology are excluded from participation in our trial.   
 
 
Table 1: Studies of Cisplatin Containing Neoadjuvant Chemotherapy in Muscle Invasive 
Bladder Cancer 
Study 
Study Type 
Patient 
Number 
NAC 
Treatment 
pT0 Rate 
OS  
Grossman HB 
et al. 
Phase III RCT 
317 
3 cycles 
standard 
dose MVAC 
a) NAC – 
38%, p 
< 0.001 
b) No 
NAC – 
15% 
c) NAC – 
median 
77m, p = 
0.05 
d) No NAC 
– median 
46m 
BA06 30894 
trial 
 
Phase III RCT 
976 
3 cycles of 
CMV 
a) NAC – 
32.5% 
b) No 
NAC – 
12.3% 
c) NAC – 
10 year  
36%, HR 
0.84, p = 
0.037 
d) No NAC 
– 10 year 
30% 
Pilmack ER et 
al. 
Phase II 
40 
3 cycles of 
dose-dense 
MVAC 
38% 
N/A 
Herchenhorn  
D et al. 
Phase II 
22 
3 cycles of 
GC 
26.7% 
Median 36m 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 8  
Fairey AS et al.  Retrospective  
116 
4 cycles of 
GC (n = 58) 
or 4 cycles of 
standard 
dose MVAC 
(n = 58) 
a) GC – 
21% 
b) MVAC 
– 10% 
a) GC – 
Median 
24.8m 
b) MVAC – 
Median 
26.4m, p 
= 0.634 
Galsky MD et 
al. 
Retrospective 
212 
3 cycles GC 
(n = 146) or 3 
cycles MVAC 
(77% dose-
dense) (n = 
66) 
a) GC – 
31%, p 
= 0.77 
b) MVAC 
– 29% 
a) GC – 
Median 
26.8m 
b) MVAC – 
Median 
35.5m, p 
= 0.17 
Van de Putte 
EE et al. 
Retrospective 
80 
4 cycles 
dose-dense 
MVAC 
29% 
N/A 
Yeshchina O et 
al. 
Retrospective  
114 
MVAC (n = 
77) or GC(n = 
37) 
a) MVAC 
– 31%, 
p = 
0.645 
b) GC – 
25% 
a) MVAC – 
5 year 
47%, p = 
0.346 
b) GC – 5 
year 
35% 
Yuh BE et al.   
Meta-analysis 
164 
GC 
25.6% 
N/A 
NAC = neoadjuvant chemotherapy, pT0 = pathologic complete response, OS = overall survival, RCT = randomized 
controlled trial, MVAC = methotrexate + vinblastine + adriamycin + cisplatin, m = months, CMV = cisplatin + 
methotrexate + vinblastine, N/A = not available, GC = gemcitabine + cisplatin 
 
NAC regimens containing carboplatin instead of cisplatin have not been demonstrated 
equivalent to cisplatin based NAC. (13) Limited data in the advanced, unresectable setting has 
suggested substituting carboplatin for cisplatin in combination regimens may actually be inferior. 
(14) Because of lack of data it is not recommended to use carboplatin in the NAC setting. (13) 
Investigations are currently ongoing to see if carboplatin based NAC regimens could provide a 
benefit in patients whom are not candidates for cisplatin; however, carboplatin use in the NAC 
setting is not currently part of standard of care.  For those unable or unwilling to receive cisplatin 
containing NAC the standard of care is to proceed directly to RC, as there is no alternative 
systemic regimen accepted in the NA setting.   
 
 
1.2 Overview of Immune Checkpoint Inhibition and Implications in Bladder Cancer 
Carcinogenesis 
Immune checkpoints regulate the ability of T-cells to act against tissues or cells expressing 
specific antigens.  This has benefit in that inhibitory checkpoints help limit T-cell effector 
functions against self-tissues.  However, some tumors can take advantage of this mechanism 
and over-express inhibitory proteins in the immune checkpoint pathway (both on tumor cells 
themselves and in the tumor microenvironment) leading to tumor evasion of the immune system 
and lack of effector T-cell attack against tumors. (15) 
 
CD8+ T-cells are involved in the cell-mediated component of antigen recognition and CD4+ T-
cells have roles in both cell-mediated/humoral immune responses.  New anti-cancer drugs 
targeting inhibitory immune checkpoints are revolutionizing cancer therapy.  These drugs do not 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 9  
target tumors directly, rather they target lymphocyte receptors or their ligands to enhance 
endogenous anti-tumor immunity. (15) While there are multiple immune checkpoints, the two 
most well-known pathways include the programmed death 1 (PD-1) pathway (CD279) and the 
cytotoxic T-lymphocyte protein 4 (CTLA4) pathway (CD152). CTLA4 is a receptor on T-cells that 
when bound by its activating ligands (CD80 and CD86) inhibits the effector function of T-cells 
and prevents proper costimulatory signaling via CD28, resulting in decreased effector T-cell 
function.  (15) Ipilimumab is a Federal Drug Administration (FDA) approved drug that is an 
inhibitor of CTLA4.  This drug has demonstrated improved OS when compared to standard 
chemotherapy in advanced melanoma; however, it has increased rates of high grade adverse 
events and immune-mediated adverse events when compared to antibodies against PD-1 or 
PD-L1. (16-17) 
 
Immune checkpoint inhibitors (ICIs) targeting the PD-1 pathway are more widely utilized and 
more effective than those targeting CTLA4.  Additionally, PD-1 pathway inhibition appears to 
have less side effects than that of CTLA4 inhibition.  Activation of PD-1 is much more specific 
than CTLA4 with regards to inhibiting T-cell effector functions against a particular stimulus.  PD-
1 is a cell surface receptor located on T-cells, B-cells and natural killer (NK) cells. Thus, PD-1 
inhibition can also enhance lytic activity of NK cells against tumors and antibody production by 
B-cells.  The two ligands for this receptor are programmed death ligand 1 (PD-L1 or CD274) 
and programmed death ligand 2 (PD-L2 or CD273). PD-L1 is the more studied of these ligands. 
(15)  
 
PD-L1 expression on tumor cells and other cells within the tumor microenvironment may be 
induced by interferon-γ (IFN-γ) or result from genetic changes within tumor cells themselves.  
IFN-γ is secreted by effector T-cells targeting the tumor and this is why some have 
hypothesized that increased PD-L1 staining may be reflective of a stronger antitumor immune 
response waiting to be unleashed by ICIs. (18-19) Several studies have suggested increased 
response rates in tumors where the cancer cells and the immune infiltrates express higher 
amounts of this ligand, and some have even suggested improved survival with increased 
staining of PD-L1. (20-22) There are currently inhibitory antibody drugs against both PD-1 and 
PD-L1.     
 
Other immune checkpoints include lymphocyte activation gene 3 (LAG3), T-cell membrane 
protein 3 (TIM3), adenosine A2a receptor (A2AR), killer immunoglobulin receptor (KIR) and B 
and T lymphocyte attenuator (BTLA). (15) There are drugs in early clinical development against 
LAG3 and in certain tumor types this checkpoint has been suggested to be involved in 
dampening the antitumor response that is elicited by agents blocking the PD-1 pathway. (23-24) 
LAG3 has also been shown to be overexpressed in some bladder cancers. (25) Thus, because 
of these aforementioned points we plan to examine LAG3 in our study.   
 
In contrast to traditional chemotherapies, ICIs may have a longer time to response and in rare 
cases it may appear as if lesions are enlarging due to the immune cells infiltrating the tumor. 
Thus, some have proposed different response criteria to evaluate their effectiveness. (15) The 
most exciting thing about these checkpoint inhibitor drugs is the prolonged anti-tumor responses 
they produce and the potential to transform some cases of metastatic cancer into chronic 
diseases.    
 
Both the PD-1 pathway and CTLA-4 pathway have been suggested to be involved in the 
transition from non-muscle invasive bladder cancer (NMIBC) to muscle invasive bladder cancer 
(MIBC).  In MIBC PD-1 expression is 59.5%, versus 22.5% in NMIBC and 6.7% in normal 
bladder tissue.  PD-L1 expression in MIBC is 60.7% versus 4.2% in NMIBC and 0% in normal 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 10  
bladder.  Similarly, CTLA4 was overexpressed in 84.5% of MIBC versus 20% of normal bladder 
tissue.  One of the ligands for CTLA4, CD80, is overexpressed in 92.9% of MIBC versus 46.5% 
of NMIBC and 6.7% of normal bladder tissue. (26)  
 
1.3 Treatment with Immune Checkpoint Inhibitors in Bladder Cancer 
Only one ICI has been evaluated previously in the NA setting for MIBC.  This ICI was 
ipilimumab, which is an inhibitory antibody to CTLA-4.  12 patients were evaluated.  Some of 
these patients were chemotherapy candidates and received adjuvant platinum based therapy.  
While no long-term survival data were reported, the combination was found to be safe and 
tolerable.  The use of pre- and post-treatment biopsies allowed for analysis of antitumor immune 
responses to ICIs and correlation with outcome parameters. They found that the infiltrating cells 
seen in response to ipilimumab treatment consisted predominately of CD4+ and CD8+ T-cells, 
with very few B cells or NK cells. They also found that greater levels of CD4+ T-cells with high 
expression of inducible T-cell costimulatory (ICOS) receptor in tumor tissue and systemic 
circulation correlated with improved outcomes when compared to levels of CD4+ T-cells with 
lower expression of ICOS. (27) 
 
Recent data suggests that ICIs targeting PD-L1 or PD-1 (e.g., avelumab, atezolizumab, 
durvalumab, nivolumab and pembrolizumab) may provide good responses and survival 
outcomes in metastatic BC after progression on cisplatin-based chemotherapy. (22, 28-32) The 
two agents that are approved for this patient population are atezolizumab and nivolumab.  
Atezolizumab was the first such agent approved.  It was evaluated in a phase II trial consisting 
of 310 patients with metastatic UCC progressing during or after a cisplatin based regimen.  The 
ORR was 15%.  The median PFS was 2.1 months and the median OS was 7.9 months for the 
whole study population.  The median OS in those with PD-L1 staining by immunohistochemistry 
(IHC) of ≥ 5% on immune cells was 11.4 months.  The vast majority of responses were still 
ongoing at data cutoff.  These outcomes were felt to be comparable or better to second line 
chemotherapy with less toxicity. (22) A subsequent randomized phase III study demonstrated 
improved OS for pembrolizumab when compared to single agent chemotherapy for patients with 
advanced UCC after progression on platinum based chemotherapy. (33) Data for the trials of 
other ICI drugs in this patient population can be found in Table 2. (28-32) 
 
 
 
TABLE 2: Immune Checkpoint Inhibitor Trials in Advanced Urothelial Cancer Patients 
Progressing During or After Prior Platinum Based Chemotherapy 
Drug  
Targe
t 
Patient
s 
Follow-
up (m) 
Phas
e  
ORR by 
RECIST 
PFS 
OS 
High 
Grade 
AEs 
Avelumab      
(PD-L1+ ≥ 5% 
on tumor cells) 
PD-L1 
44 
13 
Ib 
18.2% 
(50% in 
PD-L1+ 
and 
4.3% in 
PD-L1-) 
24 
weeks: 
58.3% 
in PD-
L1+, 
16.6% 
PD-L1- 
1 year 
50.9% 
11.3% 
Durvalumab   
(PD-L1+ ≥ 25% 
on tumor cells or 
immune cells) 
PD-L1 
103 
7.3 
I/II 
20.4% 
(29.5% 
in PD-
L1+ and 
7.7% in 
PD-L1-) 
N/A 
  6 
month 
OS 
60.3% 
(PD-
L1+ 
5.2% 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 11  
68.4%, 
PD-L1- 
44.7%) 
Pembrolizumab 
(PD-L1+ ≥ 1% 
on tumor cells or 
immune cells) 
PD-1 
33 
13 
Ib 
25% 
(38% in 
PD-L1+) 
1 year  
19% 
  N/A 
15% 
Nivolumab    
(PD-L1+ ≥ 1% 
on tumor cells) 
PD-1 
78 
15.2 
I/II 
24.4% 
(24% 
PD-
L1+and 
26% 
PD-L1-) 
Median 
2.8 m, 
(PD-
L1+  
5.5m, 
PD-L1- 
2.8 m), 
1 year 
PFS 
21%  
Median 
9.7 m, 
(PD-
L1+ 
16.2m, 
PD-L1- 
9.9 m), 
1 year 
OS 
46%   
 
22% 
m = months, ORR = overall response rate, PFS = progression free survival, OS = overall survival, AEs = adverse 
events, PD-1 = programmed death 1, PD-L1 = programmed death ligand 1, N/A = not available.  High grade AEs are 
defined as ≥ 3 on the CTCAE grading scale.   
 
 
Atezolizumab has data reported from the first-line setting for a cohort of patients with metastatic 
UCC who were ineligible for cisplatin-based combination chemotherapy.  When results of this 
cohort were reported, the ORR was 23% and the median OS was 15.9 months.  This OS was 
much higher than historical controls receiving carboplatin based regimens or single agent 
regimens, which has been reported at 9-10 months. (34)  
 
ICI combinations have also been evaluated in metastatic UCC.  While the full manuscript has 
not been published, the data has been presented in abstract form at the 2016 Society for 
Immunotherapy in Cancer (SITC) Annual Meeting.  The combination of ipilimumab 3 mg/kg + 
nivolumab 1 mg/kg q 3 weeks x 4 cycles followed by nivolumab maintenance at 3 mg/kg q 2 
weeks suggested an improved ORR compared to nivolumab monotherapy (38% vs 24%). (35) 
 
The above studies which involve ICIs after progression despite platinum based chemotherapy 
have shown comparable if not better outcomes than historical controls given single agent 
chemotherapy (which the vast majority of patients receive) or combination therapy (only 
received by a select few).  (36-38) 
 
1.4 Cyclooxygenase Levels in Tumor Tissue 
Prostaglandin E2 (PGE2) has been shown to increase production of tumor promoting factors (IL-
6, IL-8 and Cxcl1) and decrease production of anti-tumor factors (IFN-y, IL-12, TNF, Cxcl9, 
Cxcl10, Cxcl11, CD8, CD40, CD86, antigen presenting dendritic cells and interferon response 
genes).  Decreased PGE2 production via cyclooxygenase-1 and -2 (COX-1 and -2) inhibition has 
been shown to have an anti-tumor effect that is dependent on anti-tumor lymphocytes/dendritic 
cells.  COX-1 and -2 inhibition lead to decreased tumor growth in mouse models of melanoma, 
colorectal and breast cancer with over-activation of the RAS/RAF/MEK pathway.  The beneficial 
effect of COX-1 and -2 inhibition was lost when mice were depleted of dendritic cells and T/B 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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cells.  Interestingly, the combination of aspirin (an irreversible COX-1 and -2 inhibitor) in 
combination with PD-1 inhibition led to significantly more suppression of tumor growth when 
compared to either monotherapy alone.  There was no benefit of this combination in mice depleted 
of T and B cells. (39)   
 
BC is a tumor type that may overexpress COX-1 and -2 enzymes. (40) COX-2 dependent 
production of PGE2 has a multifaceted role in mediating immunosuppression through induction 
of T regulatory cells and MDSCs, suppressing the accumulation of antigen-presenting dendritic 
cells, and most recently, as an inhibitory DAMP. (39, 41-43) Thus, we plan to examine mRNA 
levels COX-1 and COX-2 in pre-treatment biopsy specimens to determine if their levels may 
correlate with response or lack thereof to PD-L1 blockade.   
1.5  Antitumor and Tumor Promoting Factors 
 
Table 3: Mediators of an Effective Antitumor Immune Response 
Tumor Promoting 
Chemokines/Cytokines 
and Enzymes 
Growth 
Factors or 
Their 
Receptors 
that May 
Inhibit the 
Antitumor 
Immune 
Response 
Cell Types that 
May Inhibit the 
Antitumor 
Immune 
Response 
Anti-tumor 
Chemokines/Cytokines 
Arginase-1, CCL2, 
CXCL8, CXCL12, IL-1, 
IL-6, , IDO, iNOS 
M-CSFR, TGF-
β, VEGF 
MDSCs, T-
regulatory cells 
(FOXP3+), M2 
macrophages 
CXCL9, CXCL10, IFN-γ, 
IL-2, IL-10*, IL-12  
CCL = C-C motif chemokine ligand, CXCL = C-X-C motif chemokine ligand, IL = interleukin, IDO = indoleamine 2-3 
dioxygenase, iNOS = inducible nitric oxide synthase, M-CSFR = macrophage colony stimulating factor receptor, TGF-
β = transforming growth factor β, VEGF = vascular endothelial growth factor, MDSCs = myeloid derived suppressor 
cells, FOXP3 = forkhead box P3 and IFN-γ = interferon γ.  *IL-10 was previously felt to be associated with inhibiting 
antitumor immunity; however, recent evidence suggests that it may induce an antitumor immune response in some 
tumors. (39, 44-47) 
 
1.6 Avelumab Background  
 
1.6.1 Structure, Mechanism and Identifiers 
Avelumab is a fully human monoclonal PD-L1 antibody of the immunoglobulin G1 (IgG1) 
subclass.  It works by binding to PD-L1 on tumor cells, immune cells and/or stromal cells.  This 
prevents PD-L1 from interacting with PD-1.  Inhibition of this interaction increases 
activation/survival of antitumor lymphocytes. It also increases innate immunity by resulting in 
decreased PD-1 suppression of NK cell function and bolsters antibody production by B cells due 
to less PD-L1 binding of PD-1 on B-cells.  Additionally, avelumab has been suggested to have 
another mechanism involving antibody depemetandent cellular cytotoxicity (ADCC).  ADCC in 
these cases involves NK cell recognition and lysis of tumor cells that have antibody bound to 
PD-L1. (48) By blocking PD-L1, avelumab leads to less CD80 binding by PD-L1 and more 
CD80-CD28 binding in response to antigen presentation to T-cells.  This results in increased 
costimulatory signaling and is another mechanism by which avelumab may enhance T-cell 
activation. (49)  


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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CAS Number: 1537032-82-8 
UNII: KXG2PJ551I 
 
1.6.2 Summary of non-clinical experience 
The PD-1 pathway has been shown to be involved in inhibiting over activation of the immune 
system.  This was supported by data in PD-1 deficient mice that showed development of 
delayed onset autoimmunity that was organ specific and had incomplete penetrance.  After 
approximately 6 months C57BL/6 mice deficient in PD-1 developed a lupus like syndrome 
characterized by glomerulonephritis and arthritis.  PD-1 deficient BALB/c mice developed an 
autoimmune dilated cardiomyopathy caused by antibodies to troponin-I.  Selective deficiency of 
PD-L1 in mice may also result in autoimmune adverse events. (49) 
 
Blockade of PD-1 or PD-L1 in mice did not have significant immune mediated adverse events in 
preclinical studies.  However, these studies did suggest that such blockade may exacerbate 
pre-existing autoimmune pathology (e.g., significantly worsening autoimmune attack on the 
pancreas in a mouse with type I diabetes mellitus). (49) 
 
PD-1 has been found to be highly expressed on T-cells in states of chronic viral infection. 
Blockade of PD-L1 on virally infected cells enhanced T-cell control of viruses.  However, lack of 
expression of PD-L1 in mice resulted in fatal autoimmune pathology in the setting of chronic 
viral infection.  Because of this there is uncertainty about the safety of blocking the PD-1 
pathway in organisms with chronic viral infection. (49) 
 
The epitope on PD-L1 that binds avelumab overlaps with the same epitope region that binds 
PD-1.  This supports the mechanism of avelumab functioning by inhibiting interaction between 
PD-L1 and PD-1. (50) The other mechanism through which avelumab functions is by stimulating 
ADCC.  This mechanism has been shown to be effective across multiple tumor types. (48, 51) 
PD-L1 inhibition by avelumab may also increase the availability of the co-stimulatory molecule 
CD80, allowing for enhanced activation of T-cells, through increased CD80-CD28 binding when 
antigens are presented by major histocompatibility (MHC) molecules to the T-cell receptor. (49) 
In vitro analysis of virus stimulated mononuclear cells from healthy patients have suggested that 
the mechanisms of avelumab lead to increased antigen specific CD8+ T-cells, reduced 
proliferation of  CD4+ T-cells and a shift in the cytokine profile from an tumor promoting Th2 
phenotype to a antitumor Th1 phenotype. (52)  
 
The role of PD-L1 in impairing antitumor immunity has been supported in a variety of tumor 
models.  PD-L1 expression on mastocytoma tumors was shown in vitro to promote immune 
evasion and enhance tumor growth.  Blockade of PD-L1 on these same tumors promoted 
immune mediated rejection.  Additionally, PD-L1 blockade on myeloma, melanoma and breast 
tumors has been shown to promote immune mediated tumor rejection. (49)  
 
Avelumab has been examined in an orthotopic mouse model of NMIBC.  In this model, 
avelumab had significant antitumor effects that appeared more mediated by CD4+ T-cells than 
CD8+ T-cells. (53)    
 
1.6.3 Summary of Clinical Experience 
Avelumab has been shown to be efficacious across multiple metastatic tumor types (Table 4).  
(54-59) One of these tumor types was UCC.  There was a phase Ib study reported at the 
American Society of Clinical Oncology meeting in 2016 where data were presented on the 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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safety and efficacy of avelumab in the second line setting for metastatic UCC.  Patients had 
been treated with a median of 2 prior therapies in the metastatic setting.  High grade adverse 
events were 11.2%.  The ORR was 18.2% and the 1 year OS was 50.9%.  The ORR was better 
or comparable to chemotherapy in historical controls and the OS was improved compared to 
most other trials of second line or greater chemotherapy for such patients.  There is currently a 
phase III clinical trial ongoing comparing avelumab to standard of care chemotherapy in the 
second line setting or beyond for metastatic UC. (28)   
 
Table 4: Studies of Avelumab in Advanced Solid Tumors 
Tumor Type 
Phase 
ORR by RECIST v1.1 
PFS 
(median) 
OS 
(median) 
High 
Grade 
AEs 
NSCLC after 
progression on 
platinum based chemo 
(n = 184) 
Ib 
Adeno – 11.4% 
SC – 13.2% 
Other – 29.4% 
(15% PD-L1+, PD-L1- 
10%) 
11.6 wks 
(12 wks PD-
L1+, 5.9 wks 
PD-L1-) 
8.4 m 
(8.9 m PD-
L1+, 4.6m 
PD-L1-) 
12.5% 
Urothelial cell 
carcinoma after 
progression on 
platinum based chemo 
(n = 44) 
Ib 
18.2% 
(50% in PD-L1+ and 
4.3% in PD-L1-) 
24 wks: 
58.3% in PD-
L1+, 16.6% 
PD-L1- 
1 year 
50.9% 
11.3% 
Breast Cancer 
unselected by subtype 
progressing on 
standard of care 
therapy 
(n = 168) 
Ib 
4.5% (33.3% PD-L1+, 
2.4% PD-L1-, 8.8% 
TNBC) 
N/A 
N/A 
14.3% 
Merkel cell that was 
chemo refractory 
(n = 88) 
II 
31.8% (34.5% PD-
L1+, 18.8% PD-L1-) 
2.7 m, 40% 
was 6 m PFS 
11.3 m, 
69% was 6 
m OS 
5% 
Ovarian cancer that 
was recurrent or 
refractory 
(n = 124) 
Ib 
9.7% (12.3% PD-L1+, 
5.9% PD-L1-) 
11.3 wks 
10.8 m 
6.5% 
Mesothelioma 
progressing after a 
platinum-pemetrexed 
regimen (n = 53) 
Ib 
9.4% (14.3% PD-L1+, 
8.0% PD-L1-) 
17.1 wks 
(17.1 wks in 
PD-L1+, 7.4 
wks in PD-L1-
) 
38.4% was 24 
wk PFS 
N/A 
7.5% 
Gastric or GE junction 
cancer as 
maintenance after first 
line therapy or as 
second line treatment 
(n = 151) 
Ib 
Maintenance – 9.0% 
(10% PD-L1+, 3.1% 
PD-L1-) 
Second line – 9.7% 
(18.2% PD-L1+, PD-
L1- 9.1%) 
Maintenance 
– 12 wks 
(17.6 wks  
PD-L1+, 11.6 
wks PD-L1-) 
Second line – 
6 wks (6.3 
wks PD-L1+, 
10.4 wks PD-
L1-) 
N/A 
9.9% 
ORR=overall response rate, RECISTv1.1 = response evaluation criteria in solid tumors version 1.1, PFS = 
progression free survival, OS = overall survival, AEs = adverse events, NSCLC = non-small cell lung cancer, chemo 


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= chemotherapy, Adeno = adenocarcinoma, SC = squamous cell carcinoma, PD-L1 = programmed death ligand 1, 
wks = weeks, m = months, TNBC = triple negative breast cancer, N/A = not available, GE = gastroesophageal 
 
1.7 Research Hypotheses 
 
• 
Primary Hypothesis: Avelumab treatment will result in an increase in CD3+CD4+ T-cell and 
CD3+CD8+ T-cell infiltrates.   
 
• 
Secondary Hypotheses:  
o Pathological response rate will be comparable to historical controls receiving NA 
cisplatin based chemotherapy.  
o 2 year disease free survival (DFS) will be better than historical controls not receiving 
NAC and comparable to historical controls receiving cisplatin based NAC.  
o Avelumab will be safe and tolerable in our patient population.   
o Infiltration of regulatory B-cells will increase with avelumab treatment and increased 
levels will be associated with less response to treatment.   
o Increased COX-1 and COX-2 levels on transurethral resection of the bladder tumor 
(TURBT) tissue will be associated with decreased response to avelumab.   
 
1.8 Rationale for Conducting this Study 
Up to 50% of patients are unable or unwilling to receive cisplatin-based NAC and their median 
DFS ranges from 12 to 48 months, compared to 48 months to > 5 years for those who receive 
cisplatin-based NAC. (60) Patients who are unable to receive cisplatin-based NAC go straight to 
RC.  There is no approved NA systemic therapy for this population and survival outcomes are 
significantly inferior to those who receive cisplatin-based NAC.  ICIs have been observed to be 
superior to non-cisplatin based chemotherapy in the first line setting for metastatic UCC and 
have shown significant efficacy after progression on platinum based chemotherapy in metastatic 
UCC. (28-34) Thus, there is rationale that ICIs may be of benefit in the NA treatment of MIBC 
patients who are not candidates for cisplatin-based NAC.  We plan to examine this as one of our 
secondary endpoints in this window of opportunity trial.   
 
1.9 Benefit/risk and Ethical Assessment   
High grade (grade 3-4) AEs with PD-1 or PD-L1 inhibitors in metastatic UCC range from 5-22%, 
with such events being slightly lower in those who received PD-L1 as opposed to PD-1 
inhibitory antibodies. (28-33) Our inclusion and exclusion criteria are in agreement with these 
previous studies and thus we expect to see a similar incidence of AEs.  This estimated 
occurrence of high grade AEs is significantly less than the 50-80% seen with cisplatin-based 
NAC or with cisplatin-based chemotherapy in the metastatic setting.  (11, 61-62)  
 
We know that cisplatin-based NAC provides a significant survival benefit for non-metastatic 
MIBC and that ICIs are suggested to have similar or better efficacy than systemic chemotherapy 
in metastatic BC.  Thus, the potential benefit to administering avelumab in the NA setting is 
significant.  The benefit to risk ratio of this trial is judged to be acceptable.   
 
 
1.9.1 Risks Associated with Avelumab 
Three types of risks are associated with avelumab: general signs and symptoms, reactions that 
occur during or following the infusion, and immune side effects.  
 
The following side effects have been observed among 1,738 patients treated with avelumab 
according to the results from two oncology clinical studies in patients with various solid tumors.  


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Side effects observed in 10% or more of patients: 
 
• 
General signs or symptoms: Tiredness; Nausea; Loose or watery stools (diarrhea); 
Constipation; Reduced appetite; Decrease in weight; Vomiting; Low number of red blood 
cells (anemia); Belly pain; Cough; Fever; Shortness of breath; Swelling of feet and legs; 
Back pain; Joint pain. 
• 
Reactions that occur during or following the infusion: may include chills or shaking, 
fever, flushing, back pain, belly pain, shortness of breath or wheezing, decrease in blood 
pressure, hives.  These infusion reactions are mostly mild or moderate and generally resolve 
with a slowdown or discontinuation of the infusion and administration of medications such as 
anti-allergic and pain-killer drugs.  In some cases these reactions may be severe or life-
threatening (in less than 1% of patients) and can require intensive medical care. 
 
Immune side effects 
Immune side effects result from an increased activity of the immune system.  Most of these side 
effects are reversible, which means they will stop once treatment with avelumab is discontinued. 
However, in some cases these reactions may be severe (approximately 2% of patients) and 
may lead to death in rare cases.  The reactions that are more severe require treatment with 
drugs that decrease the immune system function, also called immunosuppressant drugs (like 
corticosteroids or more potent drugs). No immune side effects were observed in 10% or more of 
patients. 
 
Immune side effects observed in 5% to less than 10% of patients: 
 
• 
Abnormal function of the thyroid gland (could include low or high function or 
inflammation of the thyroid gland): may include rapid heartbeat; increased sweating; 
extreme tiredness; weight gain or weight loss; hair loss; changes in mood or behavior such 
as irritability or forgetfulness; feeling cold; constipation; voice gets deeper. 
• 
Inflammation of the skin (rash): may include skin rash, itchy skin, skin redness, skin 
blisters, or peeling. 
 
Immune side effects observed in 1% to less than 5% of patients: 
 
• 
Inflammation of the large intestine (colitis): may include diarrhea (loose stools) or more 
frequent bowel movements than usual; blood in stools or dark, tarry, sticky stools; severe 
stomach area (abdomen) pain or tenderness. 
• 
Inflammation of the lungs (pneumonitis): may include new or worsening cough, 
shortness of breath, chest pain. 
 
Immune side observed in less than 1% of patients: 
 
• 
Inflammation of the liver (hepatitis): may include yellowing of skin or of the whites of 
eyes; severe nausea or vomiting; pain on the right side of stomach area (abdomen); 
drowsiness; dark urine (tea colored); bleeding or bruising more easily than normal; feeling 
less hungry than usual. 
• 
Inflammation of the kidneys (nephritis): may include urinating less than usual; blood in 
urine; swelling in ankles; loss of appetite. 


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• 
Low function of the adrenal glands (glands on top of the kidneys), which may be due 
to the reduced function of the pituitary gland (a gland in the head): may include very 
low blood pressure; extreme tiredness. 
• 
Increase in blood sugar (diabetes): may include urinating more often than usual; feeling 
more hungry or thirsty than usual, nausea or vomiting, stomach area (abdomen) pain. 
• 
Inflammation of the eyes (uveitis): may include changes in eyesight. 
• 
Inflammation of the muscles (myositis): may include severe or persistent muscle or joint 
pain; severe muscle weakness. 
• 
Inflammation of the heart (myocarditis): may include chest pain or tightness; tiredness; 
changes in heartbeat, such as beating fast, or seeming to skip a beat, or pounding 
sensation; swelling of feet and legs; trouble breathing.  
• 
Inflammation of the nerves (Guillain-Barre syndrome): may include "pins and needles" 
sensations in arms and legs; weakness in legs that spreads to the upper body and may lead 
to temporary paralysis.  
 
2. STUDY OBJECTIVES 
2.1 Primary objective(s) 
• 
To evaluate change in T cell subpopulations (CD8, CD4 and/or CD3) in tumor samples 
collected pre- and post-treatment with avelumab.  
 
2.2  Secondary objective(s) 
• 
To evaluate pathologic partial response (downstaging to < pT2) and complete 
response 
• 
To evaluate 2 year DFS 
• 
To evaluate safety of drug in the NA setting 
• 
To evaluate correlation of translational studies with response parameters 
 
2.3 Translational endpoints 
• 
To evaluate PD-L1 by IHC and COX-1/COX-2 expression by mRNA in pre- treatment 
cancer tissues (focusing on epithelial cell expression and immune cell expression).   
• 
To evaluate infiltrating CD3+, CD4+ and CD3+, CD8+ T cells in pre- and post- PD-L1 
antibody treated patient cancer tissues by IHC.   
• 
To evaluate change in regulatory B-cell populations with treatment as identified by IHC 
for CD1d, CD5, CD19 and CD24.   
• 
To evaluate mRNA levels of the following chemokines/cytokines and immune 
checkpoints on formalin fixed paraffin embedded (FFPE) tissue from pre- and post-
treatment specimens: IFN-γ, TNF-α, TNF-β, T-box protein in B-cells (T-bet), IL-2, IL-
10, IL-35, FOXP-3, CTLA-4, LAG-3, PD-L1, Granzyme-A and Perforin-1.  
3. STUDY DESIGN 
3.1 Overview of Study Design 
This is a pilot study of avelumab in patients with non-metastatic, MIBC who are eligible for RC, 
but refuse or are ineligible for cisplatin based NAC.  The target recruitment is 10 evaluable 
patients for this window of opportunity study.  Pre- and post-treatment tumor samples from 
TURBT and RC will be used for study endpoints. 
 


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Patients will be recruited from sites within the academic system of Baylor College of Medicine.  
Recruitment will be over one year and patients will undergo systemic treatment followed by 
surgery as per protocol.  They will be followed for 2 years for survival, recurrence, and safety 
monitoring.  
 
3.2 Study Schema 
 
 
 
 
3.3 Study Oversight for Safety Evaluation 
 
In metastatic UCC, the high grade treatment related adverse event rate with avelumab is 
approximately 10% and the rate of serious adverse events (SAEs) is 5-10%.  (54-59) 
 
Treatment may be put on hold, and pending full review of the data, the study may be stopped if 
any of the following criteria are met:  
• 
Two (2) avelumab-related SAEs are reported 
• 
At least 2 subjects experience a similar unanticipated avelumab-related AE 
 
 
3.4 Evaluability and Patient Replacement 
 
 
Patients will continue to be enrolled on study until we have enrolled/treated 10 patients who are 
evaluable for the primary endpoint. Patients will be replaced after enrollment if they are later 
determined not to be evaluable for the primary endpoint.   
 
Evaluable patients 
• 
For primary endpoint 
o Receive ≥ 1 dose of avelumab, undergo RC within 5 weeks of last dose of 
avelumab, and are not started on systemic steroids at a dose of > 10 mg/d of 
prednisone or equivalent, while taking avelumab.   
• 
For safety endpoint 
o Receive ≥ 1 dose of avelumab  
• 
For pathologic complete response/partial response 
o Receive ≥ 1 dose of avelumab and undergo RC < 42 days from last avelumab 
dose 
• 
For 2 year disease free survival 
o Meet evaluability criteria for complete response/partial response, participate in 90 
day on study follow-up after RC and participate in off study follow-up as part of 
regular care up to 2 years post RC.   
Inevaluable patients 
• 
Patients who receive < 1 dose of avelumab after study enrollment for any reason. 
 
 
Non-metastatic muscle 
invasive bladder cancer 
 
Avelumab 10 mg/kg IV 
q 2 weeks x 3 cycles 
 
 
Radical Cystectomy 
within 5 weeks after 
finishing avelumab 


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4. SUBJECT SELECTION:  PATIENT INITIALS:  ______________ 
4.1 Inclusion Criteria 
____ a) Have undergone TURBT showing newly diagnosed muscle invasive UCB (mixed 
histology is allowed if the predominant histology is UCC) within 6 weeks prior to 
cycle 1, day 1 of treatment. 
____ b) No prior systemic treatment for muscle invasive UCB 
____ c) Clinical T2-T4a disease 
____ d) No evidence of clinically positive lymph nodes or distant metastasis on computed 
tomography (CT) scans of chest and CT or magnetic resonance imaging (MRI) 
studies of the abdomen/pelvis. Imaging must be within 90 days of registration.  
____ e) Male or female subjects aged ≥ 18 years old.   
____ f) Must have adequate kidney, liver, and bone marrow function within 30 days of 
registration, as follows: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. platelet count ≥ 100 × 109/L 
c. hemoglobin ≥ 9 g/dL (may have been transfused)   
d. Total bilirubin level ≤ 1.5 × ULN 
e. AST and ALT  levels ≤ 2.5 × ULN 
f. Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault 
formula 
____ g) Negative serum or urine pregnancy test at screening for women of childbearing 
potential (WOCBP), within 30 days of registration. 
____ h) Both male and female subjects must agree to use highly effective contraception 
(see Section 6.1 Table 8) while receiving avelumab and for at least 60 days after 
last avelumab treatment if the risk of conception exists.   
Female patients must agree to inform study coordinator or investigator immediately 
if they think they have become pregnant during the study. 
____ i) Must have FFPE tissue available from the TURBT, and patient must consent to the 
use of tissue specimens from TURBT and RC for the study. 
____ j) Patients must have refused or have been determined to be ineligible for cisplatin-
based NAC. Ineligibility criteria include: creatinine clearance < 60 ml/min by 
Cockcroft-Gault formula, CTCAE grade ≥ 2 hearing loss, CTCAE grade ≥ 2 
neuropathy, and at discretion of medical oncologist. 
If a patient is eligible for cisplatin-based NAC but has refused it, the reason for 
refusal must be documented in the patient record. 
____ k) Must be eligible for RC in the opinion of the treating investigator, and willing to 
undergo this procedure. 
____ l) ECOG performance status (PS) score of 0-2 
____ m) Signed informed consent form. 


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4.2 Exclusion Criteria  
Patients must not have any of the following:  
____ a) IMMUNOSUPRESSANTS:  Current use of immunosuppressive medication or 
within 4 weeks of C1D1, EXCEPT for the following: a. intranasal, inhaled, topical 
steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic 
corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
____ b) AUTOIMMUNE DISEASE:  Active autoimmune disease that might deteriorate 
when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, 
psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive 
treatment are eligible. Patients with type I diabetes or hypo- or hyperthyroidism 
should be on stable doses of medications for participation. 
____ c) ORGAN TRANSPLANTATION:  Prior organ transplantation including allogenic 
stem-cell transplantation. 
____ d) INFECTIONS: Active infection requiring systemic therapy.  
____ e) HIV/AIDS: Known history of testing positive for HIV or known acquired 
immunodeficiency syndrome. 
____ f) HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at 
screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody 
screening test positive) 
____ g) VACCINATION: Vaccinate within 4 weeks of the first dose of avelumab and while 
on study drug is prohibited except for administration of inactivated vaccines 
____ h) HYPERSENSITIIVTY TO STUDY DRUG:  Known prior severe hypersensitivity to 
investigational product or any component in its formulations, including known 
severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 
Grade ≥ 3) 
____ i) CARDIOVASCULAR DISEASE:  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. 
____ j) Other severe acute or chronic medical conditions including colitis, inflammatory 
bowel disease, 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. 
____ k) Relapsed MIBC (all patients participating in the study should be newly diagnosed) 
____ l) Concomitant UCC outside the bladder (e.g., ureter, urethra or renal pelvis) 
____ m) Underlying immune disorder (e.g., combined variable immunodeficiency syndrome) 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Page 21  
____ n) Erythropoietin receptor agonists within 30 days prior to enrollment.    
____ o) G-CSF, GM-CSF or TPO mimetics during the study period or within 3 weeks prior 
to study enrollment  
____ p) Malignancies other than UCB within 5 years prior to Cycle 1, Day 1, with the 
exception of those with low risk of metastasis or death treated with expected 
curative outcome (such as, but not limited to, adequately treated carcinoma in situ 
of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated 
with curative intent and absence of PSA relapse, or ductal carcinoma in situ of the 
breast treated surgically with curative intent) or incidental prostate cancer (T1a, 
Gleason score ≤ 6 and PSA < 0.5 ng/ml) 
____ q) Prior immunotherapy with T-cell co-stimulation or checkpoint targeted agents (e.g., 
CTLA-4 inhibitors, anti-PD1 antibodies or anti-PD-L1 antibodies) 
____ r) Intravesical chemotherapy or biologic therapy within 6 weeks of Cycle 1, Day 1 
____ s) Current participation in another clinical trial for MIBC 
____ t) Nursing or pregnant woman 
____ u) Uncontrolled cystitis, significant bladder pain or spasms, or gross hematuria that in 
the opinion of the principal investigator will preclude study participation 
____ v) Major surgical procedures within 4 weeks of registration (other than for diagnosis) 
or anticipation that such a procedure will be needed during the study (other than 
RC) 
 
Treating Investigator Name:  ____________________ 
 
Treating Investigator Signature:  _____________________ 
 
Date:  ______________________ 
 
 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 22  
4.3 Withdrawal of Subjects from Study Treatment and/or Study 
 
An individual subject will not receive any further investigational product if any of the following 
occur after enrollment on study: 
 
o Withdrawal of consent by subject 
o Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute 
a safety risk 
o Pregnancy or intent to become pregnant 
o Any criteria that necessitates discontinuation of study treatment as outlined in 
sections 5.5-5.7 
o Subject noncompliance that in the opinion of the investigator or sponsor warrants 
withdrawal; e.g., refusal to adhere to scheduled visits 
o Initiation of alternative anticancer therapy including another investigational agent 
o Subject has > 2 week delay in the administration of avelumab.  Such patients will 
still receive surgery and laboratory/clinical follow-up to complete the 90 day 
safety monitoring after RC.  Some of these patients may be evaluable for primary 
and/or secondary outcomes.   
 
Subjects who are permanently discontinued from further receipt of avelumab, regardless of 
the reason, will be identified as having permanently discontinued treatment.  
 
• 
Withdrawal of consent 
Patients are free to withdraw their consent to further participation in this trial  
without prejudice. If consent is withdrawn, the subject will not receive any further  
investigational product.    
 
• 
Withdrawal from study 
Patients determined to be inevaluable will be removed from study.  Such patients will 
receive standard of care and follow-up.  Such patients will be followed off study for 
recurrence and/or survival as part of routine care.   
 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 23  
5. TREATMENT PLAN 
5.1 Premedication 
The following will be administered 30-60 minutes prior to avelumab  
• 
Diphenhydramine: 25 mg IV, or 25-50 mg PO  
• 
Paracetamol (acetaminophen): 500 to 650 mg PO 
 
 
5.2 Dosage and Administration of Avelumab 
• 
Avelumab will be given at a dose of 10 mg/kg IV over 60 minutes every 2 weeks (Days 1, 
15, and 29), for 3 cycles. Each cycle is 14 days.   
 
• 
Drug will be given in outpatient infusion centers, all of which have immediate access to 
emergency services or critical care.  The following medications or equivalents will be 
immediately available in the case of a severe allergic reaction: 10 mg dexamethasone, 
epinephrine (1:1000 dilution), IV anti-histamines, bronchodilators and oxygen.   
 
• 
Patients will be observed for 2 hours post-infusion to monitor for infusion reactions. 
 
     
5.3 Radical Cystectomy (RC) 
• 
Patients will undergo RC within five weeks after the 3rd dose of avelumab.   
• 
Cystectomy will be done per standard clinical care.  
 
5.4 Supportive Care 
• 
Patients will receive supportive care for acute or chronic toxicity, including blood 
components or antibiotics, and other intervention as appropriate 
 
 
5.5 Table 5: Adverse Drug Reactions Requiring Avelumab Discontinuation or 
Modification 
 
Any Grade 4 ADR requires treatment discontinuation with avelumab, except for single 
laboratory values out of normal range that are unlikely related to study treatment as assessed 
by the Investigator, do not have any clinical correlate, and resolve within 7 days with adequate 
medical management. 
 
Any Grade 3 ADR requires treatment discontinuation with avelumab except for any of 
the following:  
• Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
• Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to 
Grade ≤ 1  
• Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test increase) that 
are unlikely related to study treatment according to the Investigator, do not have any clinical 
correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management 
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 24  
• Change in ECOG PS to ≥ 3 that resolves to ≤ 2 within 14 days (infusions should not be given on 
the following cycle, if the ECOG PS is ≥ 3 on the day of study drug administration) 
 
Any Grade 2 ADR should be managed as follows: 
• If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may continue. 
• If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions should 
not be given on the following cycle.  If at the end of the following cycle the event has not resolved 
to Grade 1, the subject should permanently discontinue treatment with avelumab ADR (except for 
hormone insufficiencies that can be managed by replacement therapy.   
• Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies that 
can be managed by replacement therapy) in the same subject, treatment with avelumab has to be 
permanently discontinued. 
 
 
5.6 Table 6: Treatment Modification for Symptoms of Infusion-Related Reactions  
NCI-CTCAE Grade  
Modification of Study Drug 
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Decrease the study drug infusion rate 
by 50% and monitor closely for any 
worsening. 
The total infusion time for study drug 
should not exceed 120 minutes. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 h. 
Hold the study drug infusion. 
Resume infusion at 50% of previous 
rate once infusion-related reaction has 
resolved or decreased to < 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 study drug infusion 
immediately and disconnect infusion 
tubing from the subject. 
Subjects have to be withdrawn 
immediately from study drug treatment 
and must not receive any further study 
drug treatment. 
- Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions. 
- If the subject has a second infusion-related reaction Grade ≥ 2 on the slower infusion rate, 
the infusion should be stopped and the subject should be removed from study treatment. 
- If hypersensitivity reaction occurs, the subject must be treated according to the best 
available medical practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 25  
5.7 Table 7: Management of Immune-Related Adverse Reactions 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (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 
 
Treatment of gastrointestinal, dermatological, pulmonary, hepatic, endocrine and cardiac 
irAEs should follow guidelines set forth in the table below. 
 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over 
baseline 
Colitis: asymptomatic  
Continue avelumab 
therapy 
 
Symptomatic treatment 
(for example, loperamide) 
Close monitoring for 
worsening symptoms 
Educate subject to report 
worsening immediately 
If worsens: 
Treat as Grade 2 or 3/4  
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  
Delay avelumab therapy 
unless systemic steroids 
needed.  If systemic 
steroids are needed, 
discontinue avelumab.  
 
Symptomatic treatment 
If improves to Grade 1:  
Resume avelumab therapy 
 
If persists > 5 to 7 days or 
recurs: 
0.5 to 1.0 mg/kg/day 
methylprednisolone or 
equivalent; when 
symptoms improve to 
Grade 1, taper steroids 
over at least 1 month, 
consider prophylactic 
antibiotics for opportunistic 
infections and remove 
patient from study 
treatment. 
 
If worsens or persists > 3 to 
5 days with oral steroids: 
Treat as Grade 3 to 4  
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over baseline; 
incontinence; IV fluids ≥ 24 
hrs.; interfering with ADL 
Discontinue avelumab 
therapy per protocol 
 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
equivalent 
 
If improves:  
Continue steroids until 
Grade 1, then taper over at 
least 1 month 
 
If persists > 3 to 5 days, or 
recurs after improvement: 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 26  
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs 
Grade 4:  life-threatening, 
perforation 
Add prophylactic 
antibiotics for opportunistic 
infections  
 
Consider lower endoscopy  
Add infliximab 5 mg/kg (if 
no contraindication), Note: 
Infliximab should not be 
used in cases of perforation 
or sepsis  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
 
Continue avelumab 
therapy unless systemic 
steroids are needed.  If 
systemic steroids are 
needed, discontinue 
avelumab.   
If persists > 1 to 2 weeks or 
recurs:  
Consider skin biopsy  
Delay avelumab therapy 
Consider 0.5 to 1.0 
mg/kg/day 
methylprednisolone IV or 
oral equivalent. Once 
improving, taper steroids 
over at least 1 month, 
consider prophylactic 
antibiotics for opportunistic 
infections, and if systemic 
steroids used discontinue 
study treatment.   
 
If worsens:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Covering > 30% body surface 
area; life threatening 
consequences  
Discontinue avelumab 
therapy 
 
Consider skin biopsy  
 
Dermatology consult  
 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent  
If improves to Grade 1:  
Taper steroids over at least 
1 month and add 
prophylactic antibiotics for 
opportunistic infections  
 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Consider delay of 
avelumab therapy  
 
Re-image at least every 3 
weeks 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 27  
Monitor for symptoms 
every 2 to 3 days  
 
Consider Pulmonary and 
Infectious Disease 
consults  
If worsens:  
Treat as Grade 2 or Grade 
3 to 4  
Grade 2 
Mild to moderate new 
symptoms  
Discontinue avelumab 
therapy 
 
Pulmonary and Infectious 
Disease consults 
 
Monitor symptoms daily, 
consider hospitalization  
 
1.0 mg/kg/day methyl-
prednisolone IV or oral 
equivalent  
 
Consider bronchoscopy, 
lung biopsy  
 
 
 
Re-image every 1 to 3 days  
 
If improves:  
When symptoms return to 
near baseline, taper 
steroids over at least 1 
month and consider 
prophylactic antibiotics. 
 
If not improving after 2 
weeks or worsening:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Severe new symptoms; New / 
worsening hypoxia; life-
threatening  
Discontinue avelumab 
therapy 
 
Hospitalize  
 
Pulmonary and Infectious 
Disease consults 
 
2 to 4 mg/kg/day 
methylprednisolone IV or 
IV equivalent  
 
Add prophylactic 
antibiotics for opportunistic 
infections  
 
Consider bronchoscopy, 
lung biopsy  
If improves to baseline:  
Taper steroids over at least 
6 weeks  
 
If not improving after 48 
hours or worsening:  
Add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil)  


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 28  
Hepatic irAEs 
Grade of Liver Test 
Elevation 
(NCI-CTCAE v4) 
Management 
Follow-up 
Grade 1 
AST or ALT > ULN to 3.0 x 
ULN and / or total bilirubin > 
ULN to 1.5 x ULN  
Continue avelumab 
therapy 
Continue liver function 
monitoring  
 
If worsens:  
Treat as Grade 2 or 3 to 4  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and / or total bilirubin > 
1.5 to ≤ 3 x ULN  
Delay avelumab therapy.   
 
If systemic steroids are 
required, avelumab 
therapy will be 
discontinued.   
 
Increase frequency of 
monitoring to every 3 days  
If returns to Baseline:  
Resume routine monitoring, 
resume avelumab therapy 
 
If elevations persist > 5 to 7 
days or worsens:  
0.5 to 1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT 
returns to grade 1 or 
baseline, taper steroids 
over at least 1 month, 
consider prophylactic 
antibiotics for opportunistic 
infections, and discontinue 
avelumab therapy 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 29  
Grade 3 to 4 
AST or ALT > 5 x ULN and / 
or total bilirubin > 3 x ULN  
Discontinue avelumab 
therapy  
 
Increase frequency of 
monitoring to every 1 to 
2 days  
 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
 
Add prophylactic 
antibiotics for opportunistic 
infections  
 
Consult gastroenterologist 
 
Consider obtaining 
MRI/CT scan of liver and 
liver biopsy if clinically 
warranted  
 
 
 
If returns to Grade 2:  
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  
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH 
abnormality  
Continue avelumab therapy   
 
 If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently 
out of range in 2 subsequent measurements: include T4 
at subsequent cycles as clinically indicated; consider 
endocrinology consult  
Symptomatic endocrinopathy  
Evaluate endocrine 
function  
 
Consider pituitary scan  
 
Symptomatic with 
abnormal lab / pituitary 
scan:  
Discontinue avelumab 
therapy 
1 to 2 mg/kg/day 
methylprednisolone IV or 
by mouth equivalent (with 
the exception of diabetes 
mellitus) 
If improves (with or without 
hormone replacement):  
Taper steroids over at least 
1 month and consider 
prophylactic antibiotics for 
opportunistic infections  
 
Subjects with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid 
component  


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 30  
Initiate appropriate 
hormone therapy  
 
No abnormal lab / pituitary 
MRI scan but symptoms 
persist:  
Repeat labs in 1 to 3 
weeks / MRI in 1 month  
Suspicion of adrenal crisis (for 
example, severe dehydration, 
hypotension, shock out of 
proportion to current illness)  
Delay or discontinue avelumab therapy  
 
Rule out sepsis  
 
Stress dose of IV steroids with mineralocorticoid activity  
 
IV fluids  
 
Consult endocrinologist  
 
If adrenal crisis ruled out, then treat as above for 
symptomatic endocrinopathy.   
Cardiac irAEs 
Myocarditis 
Management 
Follow-up 
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 appropriate 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 per 
cardiology consult.* 
Once improving, taper 
steroids over at least 1 
month and add 
prophylactic antibiotics 
for opportunistic 
infections. 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 31  
Methylprednisolone 1-2 
mg/kg/day.  
If no improvement or 
worsening, consider 
additional 
immunosuppression 
(e.g. azathioprine, 
cyclosporine A) 
ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = 
computed tomography; irAE = immune-related adverse event; IV=intravenous; LFT = liver function test; 
LLN = lower limit of normal; MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer Institute-
Common Terminology Criteria for Adverse Event; T4 = free thyroxine; TSH = thyroid-stimulating hormone; 
ULN = upper limit of normal.  *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=100
1 
 
6. RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENTS 
6.1  Restrictions during the study 
 
Contraception 
Women of childbearing potential (WOCBP) who are sexually active with a non-sterilized male 
partner must use at least one highly effective method of contraception (Table 8) from the time of 
screening and must agree to continue using such precautions for 60 days after the last dose of 
avelumab. The male partner of a female subject must also use male condom plus spermicide 
throughout this period. Cessation of birth control after this point should be discussed with a 
responsible physician. Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Female patients should refrain from breastfeeding and egg cell 
donation throughout this period. 
• Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal 
(defined as 12 months with no menses without an alternative medical cause). 
• Effective methods (including highly effective methods) of contraception are described in Table 
8. A highly effective method of contraception is defined as one that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly. Note that not all methods in 
Table 8 are considered highly effective.  
• Non-sterilized male subjects who are sexually active with a female partner of childbearing 
potential must use male condom plus spermicide  (see Table 8) from screening through 60 
days after the last dose of avelumab. Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.  Male patients should refrain from sperm donation 
throughout this period. Female partners of a male subject must use an effective method of 
contraception throughout this period. 
 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 32  
 
Table 8: Effective Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• Male or female condom with or without spermicide a,b,c 
• Female cap, diaphragm or sponge with spermicide a,b,c   
• Copper T intrauterine device e 
• Levonorgesterel-releasing intrauterine system (eg, 
Mirena®) d,e 
• Implantse 
• Hormone shot or 
injectione  
• Combined pille 
• Minipillb 
• Patche 
a 
Female partners of male subjects must use an effective method of birth control 
b 
Not highly effective (i.e. failure rate of >1% per year)  
c 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are also considered acceptable, but not highly effective, birth control methods  
d 
This is also considered a hormonal method 
e 
Highly effective (i.e. failure rate of <1% per year)    
 
 
Blood donation 
Subjects should not donate blood while participating in this study, and for at least 60 days 
following the last infusion of avelumab. 
 
6.2 Excluded concomitant medications or therapies  
 
 
The following medications are considered exclusionary during the study.  
• 
Any investigational anticancer therapy other than avelumab. 
• 
Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal 
therapy for cancer treatment. 
• 
Growth factors (including G-CSF, GM-CSF, EPO agonists or TPO mimetics) 
• 
Systemic administration of immunosuppressive medications will not be allowed except 
for those detailed in section 4.2 and those used to manage adverse events as detailed in 
sections 5.5-5.7 of the protocol.  
• 
Live vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited. Inactivated vaccines are allowed to be administered.   
 
 
 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 33  
 
7. STUDY PROCEDURES 
7.1 Study Calendar 
 
Time Points 
Pre-
study 
C1 
C2 
C3 
Pre-
surgeryb 
Surgery 
Follow-up 
End of 
Study 
visit 
Follow-up 
30 days 
before 
D1 
D1 
D15 
D29 
D40-50 
D41-64 
2-3 
weeks 
post-op 
30 
days 
post-
op 
60 
days 
post-
op 
90 days 
post-
opc 
To 2 years 
post-op 
Study Assessment  
 
 
 
 
 
 
 
 
 
 
 
Signed Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Cancer Staging 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam with ECOG 
Performance Status (PS) 
Xa 
 
X 
X 
Xb 
 
X 
X 
X 
Xc 
 
Medical History/Smoking 
History/Occupation Hazard 
X 
 
 
 
 
 
 
 
 
 
 
FFPE Tissue for 
Translational Endpointsd 
X 
 
 
 
 
 
X 
 
 
 
 
Laboratory Analysis 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff and CMP 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
UPT (if female of CBP) 
X 
 
 
X 
X 
 
 
 
 
 
 
Hepatitis B surface 
antigen, Hepatitis C 
antibody and HIV 1/2 
ELISA 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis C RNA (if 
hepatitis C antibody 
positive) 
X 
 
 
 
 
 
 
 
 
 
 
ACTH, Hemoglobin A1C, 
and TSH 
X 
 
 
 
X 
 
 
X 
 
X 
 
Free T4 (if TSH abnormal 
as indicated in Table 7) 
X 
 
 
 
     X 
 
 
X 
 
X 
 
Imaging 
 
 
 
 
 
 
 
 
 
 
 
CT cheste 
X 
 
 
 
X 
 
 
 
 
X 
 
CT or MRI 
abdomen/pelvisf 
X 
 
 
 
X 
 
 
 
 
X 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
Avelumab  
 
X 
X 
X 
 
 
 
 
 
 
 
Adverse events and their 
management noted 
 
 
X 
X 
X 
 
X 
X 
X 
Xg 
 
Radical Cystectomy 
 
 
 
 
 
X 
 
 
 
 
 
Pathology Assessment 
 
 
 
 
 
 
X 
 
 
 
 
DFS Follow-up post-
study 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 34  
Footnotes:  
a. Enrollment history and physical. 
b. End of treatment visit. 
c. End of study visit to be performed no earlier than Day 90 after RC.   
d. FFPE tissue from the pre-study time point refers to tissue from the TURBT. FFPE tissue from the 2-
3 week post-op time point refers to FFPE tissue from the RC.   
e. Contrast will be used as long as not precluded by creatinine clearance.  If a patient is allergic to CT 
contrast they will be appropriately pre-medicated with steroids +/- antihistamines unless they have a 
history of anaphylaxis.  CT of the chest to be completed in +/- 14 days. 
f. 
CT with contrast is preferable.  However, MRI with contrast or non-contrast CT may be done based 
on creatinine clearance, allergies, and ability to tolerate contrast.  If a patient is allergic to CT 
contrast, they will be appropriately pre-medicated with steroids +/- antihistamines unless they have 
a history of anaphylaxis.  CT of the abdomen/pelvis to be completed in +/- 14 days. 
g. To be performed at the end of study visit.   
 
Allowable Windows: 
1. TURBT should be done within 6 weeks of registration.   
2. Avelumab administration should be within +/- 3 days of listed days. 
3. Laboratory analysis on day 15 and day 29 may be performed on the day of infusion if results are 
received prior to avelumab administration.  Alternatively, these laboratory analysis may be 
performed the day prior to avelumab administration.   
4. The end of treatment visit (post-treatment pre-surgery) should be performed between days 40 
and 50.   
5. The end of study visit should be 90 days after surgery +/- 10 days. 
6. On-treatment visits with history and physical exam should be <3 days before a scheduled dose of 
avelumab.   
7. RC may be done any time after the pre-surgery evaluation is completed, but no later than day 64.  
8. History and physical exams performed after RC (with the exception of the end of study visit) have a 
time window of +/- 7 days.    
9. Post-operative labs up to day 60 after RC have a time window of +/- 7 days.   
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
Version: 2       Date: December 11, 2017 
 
Page 35  
7.2 Study Procedures 
 
7.2.1 Medical history and physical exam 
The following needs to be documented: 
• 
For enrollment history and physical exam:  
o complete history of present illness 
o past medical history 
o social history (including smoking history) 
o family history 
o allergy list 
o medication list including dosages and frequency of administration 
o full twelve point review of systems 
o vital signs 
o 10 system physical exam including ECOG PS 
o laboratory data and imaging 
o TURBT pathology specimen report 
o assessment/plan.   
• 
For routine history and physical exam:  
o ECOG PS 
o presence or absence of adverse effects for visits after treatment has started 
(including management of such events) 
o full twelve point review of systems 
o vital signs 
o 10 system physical exam 
o list of medications including dosages and frequency of administration 
o dose and rate of avelumab being given 
o laboratory data and imaging 
o assessment and plan.   
• 
End of treatment visit must include all the components of a routine history and physical.   
• 
End of study visit must include all the components of a routine history and physical (minus 
dosage/rate of avelumab) and pathology results from RC.     
 
7.2.2 Radical cystectomy 
Radical cystectomy procedure is to be done per standard clinic practice.  
In men this procedure involves removal of the bladder and prostate.  In women it involves 
removal of the bladder and oftentimes a hysterectomy as well.  In both sexes the procedure is 
followed by formation of a urinary diversion.  The forms of urinary diversion include formation of 
an ileal conduit (where the ureters empty into the ileum) or formation of an internal reservoir, 
such as neobladder or continent cutaneous diversion. Relative contraindications to these 
internal drainage procedures include Tis in the prostatic ducts or a positive urethral margin. (63) 
 
Bilateral pelvic lymph node dissection (LND) is considered standard of care and will be pursued 
in all patients with no set criteria for dissection template or number of LNs.  Unusual 
circumstances, such as prior LND for another malignancy, significant scarring or inflammation, 
may preclude a full LND in some patients and will not qualify as a protocol deviation. 
 
7.2.3 Radiographic imaging 
• 
CT and/or MRI imaging will be used to determine suitability for study, adequately stage 
patients and determine presence or absence of progression.  


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7.2.4 Clinical laboratory tests 
• 
CBC with diff – will be used to evaluate for autoimmune cytopenias.   
• 
CMP – will be used to evaluate for electrolyte abnormalities, autoimmune nephritis or 
autoimmune hepatitis.    
• 
UPT – will be performed as indicated in the study calendar for females of CBP. 
• 
Free T4 – to evaluate for autoimmune hypothyroidism or hyperthyroidism. 
• 
TSH – to evaluate for signs of hypophysitis, autoimmune hypothyroidism or 
hyperthyroidism 
• 
ACTH – this may be used to evaluate for signs of hypophysitis and/or adrenal insufficiency.  
• 
Hepatitis B surface antigen/hepatitis C antibody/hepatitis C RNA panel/HIV – patients with 
chronic viral infections must be excluded from the administration of immune checkpoint 
inhibitors (e.g., avelumab) due to lack of published safety data. 
• 
Hemoglobin A1C – to evaluate for worsening of glycemic control, new onset autoimmune 
diabetes mellitus or worsening of preexisting type I diabetes mellitus.  
 
7.2.5 Follow-up schedule 
• 
Any patient receiving ≥ 1 dose of avelumab will be followed up to 90 days after RC (or 
end of last cycle of avelumab for those not receiving RC) to evaluate for safety.  The 
indicated follow-up is outlined in the study calendar.     
• 
Those patients evaluable for secondary endpoints will be followed up on study to day 90 
after RC as outlined in the study calendar.     
• 
After the safety monitoring period of 90 days post RC those patients who are evaluable 
for secondary endpoints will be followed off study for recurrence and survival for up to 2 
years after RC.  This may be done by physician visits/imaging performed approximately 
every 3 months for those undergoing surveillance at Baylor affiliates or by phone 
conversations approximately every 3 months for those undergoing surveillance at 
practices outside of Baylor affiliates.   
 
7.3  Biological Sampling Procedures 
Tumor and/or bladder tissue will be collected at two primary time points during the study: 
at time of TURBT and at time of RC.  Peripheral blood will be collected at the time points 
and for the tests indicated in the study calendar.      
 
7.3.1 Biomarker evaluation methods 
Immunohistochemistry: 
Concentrations of PD-L1 protein expression on tumor cells or other cell types (e.g. 
immune cells) will be measured by IHC analysis of FFPE tissues from the TURBT and 
RC specimens.  PD-L1 expression will be assessed using one of the following anti-
human-PD-L1 antibodies, depending on initial studies of the relative staining patterns on 
serial sections: SP142 (Spring Bioscience) (64), SP263 (Ventana Medical Systems), or 
E1L3N (Cell Signaling Technologies). (65)  PD-L1 levels will be evaluated according to 
the percentage of positively stained cells based on a score ranging from 0 to 3: 0 = <1%; 
1 = 1 to <5%; 2 = 5 to <10%; 3 = >10% of cells positive. (66) 
FFPE tissue from TURBT and RC specimens will also be stained with primary antibodies 
for lymphocytic markers CD1d, CD3, CD4, CD5, CD8, CD19 and CD24.  This will be 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Page 37  
followed by staining with a secondary antibody for horseradish peroxidase and then DAB 
or blue chromogranin.  The results of these lymphocyte IHC stains will be appraised 
using a semiquantitative scale scored according to the percentage of positively stained 
cells in tumor or stroma as follows: 0=none, 1 = up to 33% cells in tumor were positive, 2 
= 33-66% positive cells and 3=more than 66% cells positive. (67) Tissue sections will be 
scored by at least two independent staff pathologists.     
RNA Extraction from FFPE Tissue: 
We have compared three different methodologies head-to-head for extraction of high 
quality RNA from FFPE tissues, namely ThermoFisher (PureLink™ FFPE RNA Isolation 
Kit), Clontech (NucleoSpin® totalRNA FFPE) and Covaris (truXTRAC FFPE RNA Kit).  
Covaris FFPE RNA extraction resulted in the highest quality RNA, sufficient for 
downstream qPCR and even RNA seq analysis.  The main advantages of the Covaris 
protocol includes its efficiency to completely deparaffinize without using high-
temperature enzymatic degradation (which also degrades RNA) and the overall shorter 
time required to complete the overall protocol.  Thus we will extract RNA from FFPE 
tissue using the protocol for the Covaris truXTRAC FFPE RNA Kit.     
qRT-PCR: 
RNA will be reverse transcribed according to the manufacturer’s instructions with 
Superscript III First-Strand Synthesis (Invitrogen) to form cDNA. (68) Tagman probes or 
specific primers will be designed to detect the following genes IFN-γ, TNF-α, TNF-β, T-
box protein in B-cells (T-bet), IL-2, IL-10, IL-35, FOXP-3, CTLA-4, LAG-3, PD-L1, 
Granzyme-A and Perforin-1. 
 
7.3.2 Withdrawal of informed consent for use of biological samples 
If a subject withdraws consent to the use of biological samples, the samples will be 
disposed of and destroyed, and the action documented.  
 
The Principal Investigator: 
• 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented  
• 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site 
• 
Ensures that the subject is informed about the sample disposal. 
 
8. DRUG INFORMATION 
Pfizer, Inc. manufactures Avelumab.  Specific storage, preparation, and other information is 
contained within the Investigational Product Manual for Active and Placebo MSB0010718C, 
Avelumab (v.3). 
Drug supply will be ordered from Pfizer via the Drug Supply Form. 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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9. SAFETY ASSESSMENT 
9.1 Definition of an adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject following use of avelumab.  There does NOT need to be a 
causal relationship between the event and the Pfizer product.   
 
9.2 Definition of serious adverse events 
• 
Results in death;  
• 
Is life-threatening (i.e., causes an immediate risk of death);  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization;  
• 
Results in a persistent or significant disability/incapacity (i.e., substantial disruption in the 
ability to conduct normal life functions); or  
• 
Considered to be an important medical event 
 
Serious adverse events (SAEs) during pregnancy are defined as follows: 
• 
Spontaneous abortion (includes miscarriage and missed abortion) 
• 
Stillbirth 
• 
Congenital anomaly (including in an aborted fetus, a stillborn infant, or neonate that dies 
shortly after birth) 
• 
Neonatal death within 1 month of birth 
• 
Infant death that is considered possibly related to intrauterine exposure to avelumab 
 
9.3 Definition of adverse events of special interest 
Adverse events of special interest (AESIs) are events specific to the further understanding of 
the safety profile of avelumab and require close monitoring and rapid communication by the 
investigator to the sponsor. Avelumab AESIs may be serious or non-serious.  
 
AESIs include immune-mediated reactions such as enterocolitis, dermatitis, hepatotoxicity or 
hepatitis, endocrinopathy, neuropathy, nephritis and pneumonitis, as well as infusion related 
reactions, serious allergic reactions and anaphylaxis.  
 
9.4 Infusion related reactions and serious allergic reactions 
The frequency of high grade infusion reactions in clinical trials with ICIs is rare. (16, 22, 69-80) A 
high frequency of mild infusion reactions, was observed with anti-PD-L1 and anti-PD-1 therapy 
(81).  
 
As with the administration of any foreign protein and/or other biologic agents, reactions following 
the infusion of MAbs can be caused by various mechanisms, including acute anaphylactic (IgE-
mediated) and anaphylactoid reactions against the MAb, and serum sickness. Hypersensitivity 
reactions as well as infusion-related reactions have been reported with anti-PD-L1 and anti-PD-
1 therapy (71).  
 
Acute allergic reactions may occur, may be severe, and may result in death. Acute allergic 
reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritis, 
angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, 
headache, hypertension, myalgia, vomiting and unresponsiveness.  The incidence of high grade 
(grade ≥ 3) allergic reactions (e.g., anaphylaxis) have an incidence of ≤ 1%. (16, 22, 69-80). The 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Page 39  
typical onset is within 30 minutes to two hours after the initiation of drug infusion, although 
symptoms may be delayed for up to 24 hours. The majority of reactions occur after the first or 
second exposure to the agent, but between 10 and 30 percent occur during subsequent 
treatments (82). 
 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in Section 5.2 and Table 6 (section 5.6). 
 
9.5 Select immune mediated adverse events  
• 
Immune mediated pneumonitis  
o Signs and symptoms of pneumonitis include dyspnea (53%), new or worsening 
cough (35%), chest pain (7%), and radiographic changes.  Up to 33% of patients 
may be asymptomatic at the onset of pneumonitis.  Fatal cases of pneumonitis 
have occurred in less than 0.5% of cases in clinical trials of PD-1/PD-L1 inhibitor 
monotherapy. A case series from Memorial Sloan Kettering and the Melanoma 
Institute of Australia reported a pneumonitis incidence of 3% in patients treated 
with PD-1 or PD-L1 inhibitor monotherapy, with only 2% of cases being fatal.  
Most cases are grade 1 to 2 and improve with instituting the recommended 
therapies (88%). The median time to onset is approximately 2.8 months. (72, 83)  
• 
Immune mediated colitis 
o Signs and symptoms include diarrhea (loose stools) or bowel movements more 
than usual, blood in stool or dark/tarry/sticky stool or severe abdominal 
pain/tenderness. (72)  
• 
Immune mediated hepatitis 
o Signs and symptoms include transaminase elevations, elevations in total bilirubin, 
yellowing of the skin or the whites of the nails, severe nausea or vomiting, right 
sided abdominal pain, drowsiness, dark or tea colored urine, bleeding or bruising 
more easily than normal, and feeling less hungry than usual. (72) 
• 
Immune mediated endocrinopathy 
o Signs and symptoms – headaches that will not go away or unusual headaches, 
extreme tiredness, weight gain and/or weight loss, dizziness or fainting, changes 
in mood or behavior (e.g., decreased sex drive, irritability or forgetfulness), hair 
loss, feeling cold, constipation, voice gets deeper, increased thirst, or change in 
frequency of urination. (72)  
• 
Adrenal crisis 
o Signs and symptoms may include – severe dehydration, hypotension or shock out 
of proportion to current illness. (72) 
• 
Immune mediated nephritis 
o Signs and symptoms – increase in serum creatinine, decrease in the amount of 
urine output, blood in the urine, swelling of the ankles, or loss of appetite. (72)  
• 
Immune mediated rash 
o Signs and symptoms – rash, itchiness of the skin, skin blisters, and ulcers in the 
mouth or other mucous membranes.  Signs and symptoms of dermatitis should be 
considered immune-mediated when on avelumab unless another etiology has 
been found. (72) 
• 
Immune mediated encephalitis and other immune mediated neurological syndromes 
o Signs and symptoms – headache, fever, tiredness or weakness, confusion or 
memory problems, sleepiness, hallucinations, seizures or stiff neck.  (72) 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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• 
Immune mediated myocarditis  
o Signs and symptoms include chest pain, dyspnea, fatigue, myositis with elevated 
creatinine kinase and cardiac conduction abnormalities. (84) Severe immune 
mediated myocarditis is a rare event with PD-1 pathway inhibitors, reported in less 
than 0.10% of treated patients.  Review of a large safety database by Bristol Myers 
Squib that included 20,594 patients treated with nivolumab (a PD-1 inhibitory 
antibody) or nivolumab + ipilimumab (a CTLA4 inhibitory antibody) found a 0.09% 
incidence of severe drug related immune mediated myocarditis.  This event rate 
was lower for nivolumab monotherapy at 0.06%. (85)   
 
 
9.6 Incidence of select adverse events with immune checkpoint inhibitors 
 
Table 10: Incidence of Adverse Events with Immune Checkpoint Inhibitors 
Adverse events 
CTLA-4 inhibitors 
PD-1 or PD-L1 inhibitors 
Any high grade (≥ 3) event 
20-55% 
10-43% 
Anemia 
8% grade 1-2 
3% grade 3-4 
0-8% grade 1-2 
0-17% grade 3-4 
Common adverse events 
(almost always grade 1-2) 
include: arthralgia, asthenia, 
back pain, constipation, 
decreased appetite, fatigue, 
fever, musculoskeletal pain, 
nausea and vomiting. 
3-42% 
0-34% 
Endocrinopathies (e.g, 
disorders affecting the 
adrenal, gonadal, pancreas, 
pituitary or thyroid glands) 
Unclear incidence due 
to variable reporting 
across trials 
Unclear incidence due to variable 
reporting across trials 
Infusion reactions 
< 1% grade ≥ 3 
< 1% grade ≥ 3 
High grade diarrhea and 
colitis 
5-17% (intestinal 
perforation had an 
incidence of 1% across 
studies and death was 
0.8%) 
0-5% 
Myocarditis  
N/A 
0.06% grade ≥ 3 
Nephritis 
Rare 
0-3% grade ≥ 3 
Neutropenia 
Rare 
Rare 
Pneumonitis (usually mild) 
5% grade 1-2 
0-3% grade ≥ 3 
1-5% grade 1-2 
0-3% grade ≥ 3 
Rash (usually mild) 
18-40% grade 1-2 
0-26% grade 1-2 
Severe dermatologic 
reactions (including bullous 
pemphigoid, full thickness 
ulceration, hemorrhagic or 
2.5% 
Rare 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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necrotic rash, Steven 
Johnson syndrome and 
toxic epidermal necrolysis) 
Other rare events (including 
duodenitis, gastritis, 
hematologic events, 
hypercalcemia, neurologic 
events, pancreatitis, pleural 
effusion, pneumonia, 
polymyalgia rheumatica, 
sarcoidosis, systemic 
inflammatory response 
syndrome, uveitis and 
vasculitis) 
Rare 
Rare 
Thrombocytopenia 
Rare 
0-17% grade 1-2 
Transaminitis (usually mild) 
1-10% grade ≥ 3 
0-5% grade ≥3 
Grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening and grade 5 = death.  Rare adverse 
events are limited to case reports and are generally < 1% across studies.  Neurologic adverse events include things 
such as (e.g., abducens or facial nerve palsy, autoimmune neuropathy, encephalitis, Guillain-Barre Syndrome, motor 
dysfunction, myasthenia gravis or transverse myelitis). (16, 22, 69-80, 84-85) 
 
 
9.7 Attribution/recording of adverse events and serious adverse events 
All adverse events, regardless of relatedness, will be reported on the appropriate case report 
forms. Adverse events will be described by nature of the event, the duration (start and stop 
dates and times), grade, treatment, relation to study drug, or if unrelated then the cause will be 
reported, the clinical course of the patient and the final outcome of the event.  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 will be utilized for all toxicity reporting. A copy of the CTCAE 
version 4.03 can be downloaded from the CTEP website. 
 
Each event should be evaluated for its relatedness to participation in the research:  
• 
Definite: The AE is clearly related to the study treatment.  
• 
Probable: The AE is likely related to the study treatment.  
• 
Possible: The AE may be related to the study treatment.  
• 
Unlikely: The AE is doubtfully related to the study treatment.  
• 
Unrelated: The AE is clearly NOT related to the study treatment.  
 
9.8 Study recording period and follow-up for adverse events 
AEs and SAEs will be recorded from the time of first treatment with Avelumab, throughout the 
treatment period and including the follow-up period (90 days after RC).  During the course of the 
study all AEs and SAEs will be proactively followed up for each subject. Every effort will be 
made to obtain a resolution for all events, even if the events continue after discontinuation/study 
completion. 
 
If a subject discontinues treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until 


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the patient is considered to have confirmed PD and will have no further tumor assessments.  
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
 
9.9 Follow-up of unresolved events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the adverse event 
log. After 90 days post-RC, only subjects with ongoing investigational product-related SAEs will 
continue to be followed for safety. 
 
Pfizer retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
 
9.10 
Post-study events 
After the subject has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AEs or SAEs occurring in former study 
subjects after the 90-day post-RC safety follow-up period for patients treated with avelumab. 
However, if the investigator learns of any SAEs, including death, at any time after the subject 
has been permanently withdrawn from study, and he/she considers there is a reasonable 
possibility that the event is related to study treatment, the investigator will notify Pfizer 
immediately. 
 


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9.11 
Reporting of Adverse Events 
The investigator primary responsibilities in the safety reporting are to identify and follow-
up on SAEs experienced by participants in the study and to forward the information to the 
local regulatory authorities and Pfizer, as required by local regulations (for regulatory 
reporting) and IIR agreement (for reporting to Pfizer). 
 
The following reportable events must be submitted to Pfizer within 24 hours of knowledge 
of the event (or immediately for death or life-threatening events) using the 
provided Investigator-Initiated Research Serious Adverse Event Form (IIR SAE) with 
the Pfizer Reportable Events Fax Cover Sheet with each SAE submission. 
 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an 
adverse event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases):  These events are considered 
important medical events and should be reported as SAEs. 
Detailed guidance on the safety reporting is provided in the Safety Reporting Reference 
Manual. 
Contact information for submission of reportable events to Pfizer: 
 
• 
Fax:  Pfizer U.S. Clinical Trial Department, Fax 1-866-997-8322.  
 
or 
 
• 
E-mail: USA.AEReporting@pfizer.com, specifying: 
- 
PROTOCOL:        
- 
SUBJECT:              
- 
SITE/PI:                 
- 
SAE/ONSET:        
Serious adverse events are to be reported to the Baylor College of Medicine (BCM) Institutional 
Review Board (IRB) according to the board’s reporting requirements and required time frame.   
 
Any event that is reportable to the BCM IRB must also be reported to the Dan L Duncan 
Comprehensive Cancer Center (DLDCCC) Data Review Committee (DRC) via the Patient Safety 
Officer at dldcc-pso@bcm.edu. 
 
 
9.12 
Reporting of Deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-RC safety 
follow-up period must be reported as follows: 
• 
Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported as a SAE within 24 hours.  The 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Page 44  
report should contain a comment regarding the co-involvement of progression of 
disease, if appropriate, and should assign main and contributory causes of death.   
• 
Deaths with an unknown cause should always be reported as a SAE.   
 
              Deaths that occur following the protocol-defined 90-day post-RC safety follow-up 
period will        
              be documented as events for survival analysis, but will not be reported as a SAE. 
 
9.13 
Overdose 
An overdose is defined as a subject receiving a dose of avelumab in excess of that specified in 
the protocol. 
 
Any overdose of a study subject with avelumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to Pfizer using the contact for 
SAE reporting.  If the overdose results in an AE, the AE must be recorded as an AE. Overdose 
does not automatically make an AE serious, but if the consequences of the overdose are 
serious, for example death or hospitalization, the event is serious and must be recorded and 
reported as a SAE. There is currently no specific treatment in the event of an overdose of 
avelumab.  The investigator will use clinical judgment to treat any overdose of avelumab. 
 
9.14 
Pregnancy 
Pregnancy itself, or pregnancy of a subject’s partner, is not regarded as an AE unless there is a 
suspicion that the investigational product under study may have interfered with the effectiveness 
of contraception.  Elective abortions without complications should not be handled as AEs. The 
outcome of any conception occurring from the date of the first dose until 90 days after the last 
dose (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should be followed up/documented even if the subject was withdrawn 
from study.  
 
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to the sponsor and Pfizer Patient Safety 
or designee using the designated safety contact provided under the SAE reporting section. 
 
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be followed 
for outcome of the mother and child (including any premature terminations) and should be 
reported to Pfizer Patient Safety or designee after outcome. 
 
Males should refrain from fathering a child or donating sperm during study and for 90 days 
following the last dose of avelumab.   
 
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to Pfizer Patient Safety or designee using the safety contact provided 
under the SAE reporting section. The sponsor will endeavor to collect follow-up information on 
such pregnancies provided the partner of the study subject provides consent. 
 
The full details of reporting for any pregnancy that occurs while exposed to avelumab is 
described in the Pfizer Safety Reporting Reference Manuel.   


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10. STATISTICAL METHODS 
10.1 
 Study design and sample size 
This is a single arm, non-randomized window of opportunity study to see the change in T cell 
subpopulations (CD8, CD4 and/or CD3) in tumor samples collected pre- and post-treatment with 
avelumab. Assuming that pre- and post-treatment values within patients are moderately 
correlated (r≥0.5), then 10 patients with paired pre- and post-treatment samples will provide ~80% 
power to detect a 1 standard deviation change in T cell populations (alpha=5% two-tailed). 
 
10.2 
Statistical analysis 
To see the change in T cells pre- and post-treatment, paired t-test or nonparametric Wilcoxon 
signed rank test will be used after checking its normality.  
Pathological response rate will be estimated along with 95% confidence interval. Two year 
disease free survival will be calculated using Kaplan-Meier survival curves with estimates of 
median and 95% confidence interval. Patients who are decided not to be evaluable for the 
primary outcome will be considered evaluable for the safety analysis and secondary outcomes, 
such patients will be summarized descriptively. The correlation of translational studies with 
response parameters will be summarized descriptively.  Changes from pre- and post- treatment 
will be assessed using paired tests. SAS software will be used for all statistical analyses. 
 
11. ETHICAL AND REGULATORY REQUIREMENTS 
11.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the International Conference on Harmonization 
(ICH) /Good Clinical Practice, and applicable regulatory requirements for subject data 
protection. 
 
11.2 
Ethics and regulatory review 
Avelumab is an investigational drug not approved for clinical use in patients with bladder cancer.  
Our study will undergo review by the BCM Institutional Review Board (IRB). Investigational New 
Drug applications will also be filed with the FDA. 
 
11.3 
Informed consent 
Informed consent shall be documented by the use of a written consent form approved by the 
IRB and the sponsor.  This consent form shall be signed and dated by the subject or the 
subject's legally authorized representative at the time of consent. A copy shall be given to the 
person signing the form. 
 
11.4 
Changes to the protocol and informed consent form 
Any changes to the protocol or informed consent form will be reviewed by the sponsor and the 
local IRB prior to implementation. Any changes to the informed consent form that impact 
currently enrolled subjects (e.g., changes in procedures, changes in the benefit/risk profile) will 
require that subjects are re-consented with the new consent form.  
 
11.5 
Audits and inspections 
All records and documents pertaining to the study will be maintained in appropriate permanent 
files as per the ICH guidelines for Essential Documents for the Conduct of a Clinical Trial and 21 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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CFR 11, and will be available for inspection by the Sponsor, Sponsor designee, the FDA, or any 
other designated review body at any time. 
12. STUDY MANAGEMENT 
The principal investigator assumes all oversight and reporting of the study, including the training 
of study site personnel and monitoring of the study.   
 
12.1 
Training of study site personnel 
The PI of this study will train the study coordinator in the procedures necessary to identify and 
accrue appropriate individuals to the study. The PI of the study will also train the staff scientist in 
the lab on appropriate tissue collection and storage procedures. The PI will train infusion center 
staff on appropriate administration of study drugs. 
 
12.2 
Monitoring of the study 
Subjects will be monitored closely throughout the course of the study via regular visits with the 
study PI and direct access to the PI throughout the duration of the study. The PI is directly 
responsible for the study subjects, and the study staff will be instructed to contact the PI 
immediately with any concerns regarding patient safety or other matters.  
 
12.3 
Study timetable and end of study 
The end of the study will be defined as the time point 90 days after RC. The recruitment period 
is estimated to take place over a period of approximately 12 months. 
 
13. DATA MANAGEMENT 
The database that will be utilized for data collection and storage will be OnCore. The PI and 
study staff will adhere to the reporting requirements of the data to the institutional IRB. 
14. DATA AND SAFETY MONITORING AND QUALITY ASSURANCE 
This study will be monitored regularly by the Data Review Committee (DRC) of the Dan L. 
Duncan Comprehensive Cancer Center, at a frequency of at least once per year, in accordance 
with the DLDCCC Data and Safety Monitoring Plan.  The DRC will monitor the study for 
progress and enrollment, toxicities, adverse events, and soundness of data. 
 
This study will be monitored by the DLDCCC Quality Assurance program for study conduct and 
quality of data. 
 
 


Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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15. REFERENCES 
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Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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Study H-41207 (BL-AIR)                                                             Investigation Drug: Avelumab 
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SAP_001.pdf: 
Document Date: 02-23-18 
 
ID: H-41207 
 
Title: A Window of Opportunity Trial: Avelumab in Non-metastatic Muscle Invasive 
Bladder Cancer 
 
NCT03498196 
 
Statistical analysis  
To see the change in T cells pre- and post-treatment, paired t-test or nonparametric 
Wilcoxon signed rank test will be used after checking its normality. Pathological 
response rate will be estimated along with 95% confidence interval. Two year disease 
free survival will be calculated using Kaplan-Meier survival curves with estimates of 
median and 95% confidence interval. Patients who are decided not to be evaluable for 
the primary outcome will be considered evaluable for the safety analysis and secondary 
outcomes, such patients will be summarized descriptively. The correlation of 
translational studies with response parameters will be summarized descriptively. 
Changes from pre- and post- treatment will be assessed using paired tests. SAS 
software will be used for all statistical analyses.