A Phase 2 Study of Avelumab in Combination With Bladder-Directed Radiation in Cisplatin-Ineligible Patients With Muscle-Invasive Urothelial Carcinoma of the Bladder
Phase: PHASE2
Conditions: Bladder Cancer, Muscle Invasive Bladder Cancer
Sponsor: Dana-Farber Cancer Institute

1
DF/HCC Protocol #: 18-464
TITLE: A Phase 2 Study of Avelumab in Combination with Bladder-Directed Radiation in Cisplatin-
Ineligible Patients with Muscle-Invasive Urothelial Carcinoma of the Bladder
Coordinating Center:
       Dana-Farber Cancer Institute
Principal Investigator (PI):
Kent Mouw, MD, PhD
Department of Radiation Oncology
Brigham and Women’s Hospital/Dana-Farber Cancer Institute
kent_mouw@dfci.harvard.edu 
Other Investigators:
Ali Baghian, MD
Beth Israel Deaconess Medical Center 
abaghian@bidmc.harvard.edu 
Mark Preston, MD
Brigham & Women’s Hospital
mpreston@bwh.harvard.edu 
Joaquim Bellmunt, MD
Dana Farber Cancer Institute 
Joaquim_Bellmunt@dfci.harvard.edu 
Responsible Research Nurses:
Beverly Spicer, RN
Eileen Mann, RN
Dana-Farber Cancer Institute
bspicer@bwh.harvard.edu
emann@bwh.harvard.edu

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NCI-Supplied Agent(s): N/A
EMD Serono to supply:
Study drug, Avelumab (EMD Serono), as well as funding for this study.
IND #:  141049 
IND Sponsor: Kent Mouw, MD, PhD
Protocol Type / Version # / Version Date: Original / v.10 / 9.18.2024

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SCHEMA
Muscle-invasive (T2-T4a) 
urothelial bladder carcinoma 
patient not eligible for 
cisplatin-based chemotherapy
Begin radiation within 2 
weeks (during cycle 1 of 
avelumab)
Following completion of radiation, 
continue avelumab until a total of 6 
cycles have been completed
Begin cycle 1 of 
avelumab q 2 weeks 
(1 cycle is 14 days)
Concurrent avelumab (q 2 weeks) and 
radiation (4-7 weeks  of daily 
treatments)
Registration 
Post treatment subjects will be 
followed for a minimum of 2 
years

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TABLE OF CONTENTS
SCHEMA ...........................................................................................................................................3
1.
OBJECTIVES......................................................................................................................6
1.1
Study Design............................................................................................................6
1.2
Primary Objective....................................................................................................6
1.3
Secondary Objectives...............................................................................................6
2.
BACKGROUND .................................................................................................................6
2.1
Study Disease...........................................................................................................6
2.2
IND Agent................................................................................................................7
2.3
Other Agent(s) .........................................................................................................7
2.4
Rationale ..................................................................................................................7
2.5
Correlative Studies Background ..............................................................................9
3.
PARTICIPANT SELECTION...........................................................................................10
3.1
Inclusion Criteria ...................................................................................................10
3.2
Exclusion Criteria ..................................................................................................11
3.3
Inclusion of Women and Minorities ......................................................................13
4.
REGISTRATION PROCEDURES ...................................................................................13
4.1
General Guidelines for DF/HCC Institutions ........................................................13
4.2
Registration Process for DF/HCC Institutions.......................................................13
5.
TREATMENT PLAN........................................................................................................13
5.1
Treatment Regimen................................................................................................13
5.2
Agent Administration.............................................................................................16
5.3
General Concomitant Medication and Supportive Care Guidelines......................18
5.4
Criteria for Taking a Participant Off Protocol Therapy.........................................19
5.5
Duration of Follow Up...........................................................................................20
5.6
Criteria for Taking a Participant Off Study ...........................................................22
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................22
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................28
7.1
Expected Toxicities................................................................................................29
7.2
Adverse Event Characteristics...............................................................................30
7.3
Expedited Adverse Event Reporting......................................................................32
7.4
Reporting to the Food and Drug Administration (FDA) .......................................33
7.5
Routine Adverse Event Reporting .........................................................................34
8.
PHARMACEUTICAL INFORMATION..........................................................................34
8.1
Avelumab (MSB0010718C)..................................................................................34
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................36
9.1
Biomarker Studies..................................................................................................38

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9.1
Laboratory Correlative Studies..............................................................................39
10.
STUDY CALENDAR .......................................................................................................41
11.
MEASUREMENT OF EFFECT .......................................................................................43
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................47
12.1
Data Reporting.......................................................................................................48
12.2
Data Safety Monitoring..........................................................................................48
12.3
Collaborative Agreements Language.....................................................................48
13.
STATISTICAL CONSIDERATIONS...............................................................................48
13.1
Study Design/Endpoints ........................................................................................49
13.2
Sample Size, Accrual Rate and Study Duration ....................................................51
13.3
Stratification Factors..............................................................................................51
13.4
Interim Monitoring Plan ........................................................................................51
13.5
Analysis of Primary Endpoints..............................................................................52
13.6
Analysis of Secondary Endpoints..........................................................................52
13.7
Reporting and Exclusions ......................................................................................52
14.
PUBLICATION PLAN .....................................................................................................53
APPENDIX A: PERFORMANCE STATUS CRITERIA.............................................................57

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1.
OBJECTIVES
1.1 Study Design
This study will investigate the safety and efficacy of the combination of the anti-PD-L1 agent 
avelumab and bladder-directed radiation in patients with muscle-invasive urothelial carcinoma of 
the bladder.
1.2 Primary Objective
To assess efficacy of the combination of avelumab and radiation in cisplatin-ineligible muscle-
invasive bladder patients as measured by the complete clinical response rate at 3 months 
following completion of radiation.
1.3 Secondary Objectives
1. To assess locoregional control, progression-free survival, and overall survival
2. To assess patient-reported quality-of-life using QLQ-C30 and FACT-Bladder instruments 
at the following timepoints: baseline, end of radiation, and at each follow-up visit
3. To explore the association of tumor PD-L1 expression, immune cell subsets, T cell 
receptor diversity, mutational status, immune-related gene expression signatures, 
circulating immune cell subsets, and plasma/urine cell-free DNA with treatment response
2.
BACKGROUND
2.1 Study Disease
Nearly 70,000 new cases of urothelial bladder cancer are diagnosed each year in the US.[1]  
Although the majority of cases are non-invasive and can be managed with tumor removal and 
close surveillance, approximately one in four patients will present with muscle-invasive (T2-T4) 
bladder cancer (MIBC).  Historically, the most common curative-intent treatment for MIBC in 
the United States has been radical cystectomy with or without neoadjuvant or adjuvant cisplatin-
based chemotherapy.[2] 
An alternative to cystectomy-based treatment is a bladder-sparing treatment approach involving 
trimodality therapy (TMT).  TMT consists of maximal transurethral resection of the bladder 
tumor (TURBT) followed by concurrent chemotherapy and bladder-directed radiation.[3]  
Randomized data comparing cystectomy-based treatment to bladder-sparing TMT are lacking, 
but long-term outcomes of patients managed with high-quality TMT compares favorably with 
cystectomy-treated patients.[4, 5]  
Several studies have demonstrated that the addition of concurrent chemotherapy to radiation 
improves disease outcomes in MIBC patients undergoing TMT.[4-7]  Cisplatin-based 
chemotherapy is often favored in this context; however, a significant fraction of MIBC patients 
are not eligible for cisplatin-based concurrent chemotherapy due to comorbidities such as renal 

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dysfunction, hearing loss, or peripheral neuropathy.  Non-cisplatin based regimens can also be 
used, but can also be associated with significant toxicity.[8, 9]
A significant percentage of MIBC patients develop recurrent or metastatic disease despite 
aggressive therapy.  Metastatic bladder cancer remains a lethal disease, and little progress has 
been made in the past several decades in improving outcomes for patients with metastatic 
bladder cancer.  The recent discovery and clinical implementation of immunotherapy has 
transformed the management of metastatic bladder cancer, and five immune checkpoint 
inhibitors are now approved for use in the first-line and/or cisplatin-refractory metastatic 
setting.[10]  However, the role of immune checkpoint blockade in the curative management of 
non-metastatic bladder cancer – alone or in combination with other agents such as chemotherapy 
and/or radiation – is unknown.  
  
2.2 IND Agent
Avelumab
Avelumab is a fully human IgG1 monoclonal antibody directed against programmed death-
ligand 1 (PD-L1), a transmembrane receptor expressed on tumor and immune cells.  PD-L1 
binds to programmed death 1 (PD-1) on activated T cells and acts as a negative regulator of the 
host immune response.
Avelumab is FDA-approved for the treatment of metastatic Merkel cell carcinoma (mMCC) and 
platinum-refractory metastatic urothelial carcinoma.[11]  Clinical trials in other disease settings 
are on-going.[12, 13]  The approved dose is 10 mg/kg as an intravenous infusion over 60 minutes 
every two weeks.[11]
2.3 Other Agent(s)
Radiation
Therapeutic radiation is a mainstay of cancer treatment, and it is estimated that nearly two-thirds 
of cancer patients will receive radiation at some point during their disease course.[14]  Advances 
in imaging and dosimetry allow for precise delivery of higher radiation doses to the target while 
minimizing radiation to the surrounding normal tissues. 
Radiation is used in both the curative and palliative treatment of bladder cancer.[2]  For patients 
with non-metastatic MIBC, radiation is a critical component of trimodality therapy (TMT), as 
outlined in Section 2.1.[4, 5]  In this setting, radiation is typically delivered to the bladder and 
adjacent lymph nodes, with the bladder tumor bed receiving a total dose of 55-65 Gray (Gy).
2.4 Rationale
Optimal treatment for MIBC involves either cisplatin-based neoadjuvant chemotherapy followed 
by cystectomy or bladder-sparing TMT with concurrent cisplatin-based chemoradiotherapy.[3]  
However, a significant percentage of MIBC patients are ineligible for cisplatin-based 

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chemotherapy due to poor renal function or other medical comorbidities.
For MIBC patients who are not candidates for cisplatin-based chemotherapy, treatment options 
include cystectomy followed by investigational non-cisplatin-based chemotherapy or 
immunotherapy.  However, many patients who are not candidates for cisplatin-based 
chemotherapy are also poor candidates for cystectomy (or refuse cystectomy).  
An alternative treatment option for cisplatin-ineligible MIBC patients is bladder-sparing 
trimodality therapy involving bladder-directed radiation with or without concurrent non-
cisplatin-based chemotherapy such as 5-fluorouracil/mitomycin C (5FU/MMC), gemcitabine, or 
carboplatin/paclitaxel.  The addition of 5FU/MMC to bladder-directed radiation has been shown 
in a randomized setting to improve locoregional disease-free survival, but did not improve 
overall survival.[7] Non-randomized studies investigating other non-cisplatin regimens such as 
single-agent gemcitabine or paclitaxel have been reported, and significant chemotherapy-related 
toxicity can occur.[6, 9] 
Avelumab is a PD-L1 inhibitor shown to be effective in advanced solid tumors, including 
bladder cancer.[11]  Although avelumab has been shown to be active in the metastatic setting, 
the impact of PD-L1 blockade in the treatment of non-metastatic disease is not known.  In 
cisplatin-ineligible MIBC patients, the use of checkpoint inhibitors such as avelumab is of great 
interest because PD-L1 blockers may be better tolerated than conventional (cytotoxic) 
chemotherapy.  
Combining radiation with PD-L1 blockade in MIBC is an attractive therapeutic strategy because 
an increasing body of pre-clinical evidence suggests that PD-L1 blockade can synergize with 
radiation to improve both local (in the radiation field) and distant (outside the radiation field) 
disease control.  Radiation has been shown to have numerous immunostimulatory effects on the 
tumor and microenvironment, including a dose-dependent upregulation of MHC class I and co-
stimulatory molecules such as CD70 and CD86 on dendritic cells.  In addition, radiation 
activates chemokine release, promotes cross-presentation of tumor antigens, and attracts tumor-
infiltrating lymphocytes.[15] Numerous cases of systemic disease response following focal 
radiation (the so-called ‘abscopal effect’) in patients receiving an immune checkpoint inhibitor 
have been reported.[16]  Additionally, PD-L1 inhibitors have an excellent therapeutic index 
compared to chemotherapy, which is desirable when treating this population with comorbidities 
and suboptimal performance status.
Importantly, radiation has been shown to increase PD-L1 expression on tumor cells, and this 
inhibitory effect can be overcome with immune checkpoint blockade.[17, 18] Radiation and 
immune checkpoint blockade activate the immune system in non-redundant mechanisms[19], 
suggesting that combining radiation with PD-1/PD-L1 blockade represents a promising 
therapeutic strategy.
Despite compelling pre-clinical evidence, clinical experience with combining radiation and PD-
L1 blockade is limited.  The non-cisplatin-eligible MIBC clinical setting is particularly well-
suited for investigating the safety and efficacy of combining radiation and PD-L1 blockade.  A 
significant fraction of newly-diagnosed MIBC patients are not eligible for cisplatin-based 

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therapy, and there is no randomized evidence demonstrating an overall survival advantage with 
addition of any systemic agent to bladder-directed radiation in this population.  Currently, these 
patients are treated with radiation alone or with radiation and concurrent cytotoxic chemotherapy 
(which can be associated with significant toxicity).  Therefore, combining radiation with PD-L1 
blockade may provide this patient population with an alternative treatment option that is safe and 
effective.  
We hypothesize that avelumab in combination with standard radiation for non-metastatic MIBC 
is both safe and effective.  This trial is designed to test this hypothesis, with the primary goal of 
assessing the rate of complete clinical response at 3 months following completion of radiation.
2.5 Correlative Studies Background
Planned correlative studies are aimed at elucidating the cellular effects of combined immune 
checkpoint blockade and radiation as well as identifying biomarkers of therapy response and 
resistance.
Correlative studies performed on tumor tissue (pre-treatment tumor biopsy obtained at the time 
of diagnosis from all patients as well as biopsy of residual/recurrent muscle-invasive bladder 
tumor obtained during standard of care follow-up for patients who fail treatment):
1. Evaluation of PD-L1 expression by immunohistochemistry (IHC).  PD-L1 staining has 
been associated with response to immune checkpoint blockade in several disease 
settings.[20]
2. IHC analysis of immunologic markers for T-cell subsets (CD3, CD4, CD8, PD-1, 
FoxP3), B cells, myeloid cells, and other targetable checkpoint receptors and ligands 
including PD-L2, Tim-3, and Lag-3. The presence of specific T cells including CD4+ and 
CD8+ cells has been correlated with improved response to immune checkpoint blockade, 
whereas other receptors such as FoxP3 (a marker of Tregs) are associated with immune 
suppression.[21]
3. Sequencing analysis of T cell receptor (TCR) diversity. TCR clonality has been 
associated with anti-PD-L1 response.[22]
4. Whole exome sequencing (WES).
5. Immune-related gene expression signatures (RNAseq and/or NanoString).
Correlative studies performed on plasma (P) and/or urine (U):
1. Whole exome sequencing of peripheral mononuclear cells for germline analysis (P)
2. Evaluation of circulating immune cells including T-cell subsets, B cells, and myeloid 
cells by flow cytometry (P)
3. T cell receptor (TCR) diversity (P)
4. Ultra-low pass whole genome sequencing (ULP-WGS) of tumor cell-free DNA (P, U)
The overall principal investigator may allow the specimens collected at DFCI to be sent to other 
facilities for future analysis. Investigators, including investigators from collaborating institutions, 
can request this data and samples for new research. 

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3.
PARTICIPANT SELECTION
3.1 Inclusion Criteria
Subjects must meet all of the following applicable inclusion criteria to participate in the study.  
Baseline clinical and laboratory evaluations are to be conducted within 28 days prior to 
registration.  If these screening assessments occur within 3 days before start of study treatment, 
then they may serve as the baseline C1D1 values.  Scans must be done within 28 days prior to 
start of therapy
1. Histologically confirmed transitional cell (urothelial) carcinoma of the bladder that is 
invasive into the muscularis propria (T2 disease) within 6 months of enrollment date. 
The presence of variant histologies (squamous, adenocarcinoma, micropapillary, etc.) is 
allowed.  Note:  A prior diagnosis of non-muscle-invasive bladder cancer (≤T1) managed 
with transurethral resection with or without intravesicular therapy (now with muscle 
invasion) is allowed
2. Male or female subjects aged 18 years
Value: ________
3. ECOG performance status ≤2 or Karnofsky score ≥60% (see Appendix A)
Value: ________
4. Life expectancy of greater than 1 year
5. Demonstrate normal organ and marrow function as defined in the table below. 
System
Laboratory Value 
Requirement
Patient Value
Hematological:
Hemoglobin
>9 g/dL
Platelet count 
>100,000 per mm3
Leukocyte count
>3,000 per mm3
Absolute neutrophil 
count (ANC)
>1,500 per mm3
Hepatic:
Total bilirubin*
<1.5 x ULN
Aspartate aminotrasferase 
(AST)
<2.5 x ULN
Alanine aminotransferase 
(ALT)
<2.5 x ULN
*For patients with Gilbert’s syndrome, if total bilirubin is >1.5 x ULN, direct bilirubin 
must be <1.5 x ULN
6. Estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula.
Value: ________

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7. Inability to receive cisplatin-based chemotherapy, as defined by creatinine clearance <60 
ml/min, ECOG PS ≤2, grade 2 or higher hearing loss, NYHA class 3 or higher, 
neuropathy (grade 2 or higher), or patient refusal to receive cisplatin-based 
chemotherapy.
8. Women of child-bearing age must have a negative serum pregnancy test at screening.
9. Women of child-bearing potential and men must agree to use a highly effective method 
of contraception (hormonal or barrier method of birth control, or abstinence) beginning 
prior to study entry, for the duration of study participation, and for at least 30 days after 
last avelumab treatment administration if the risk of conception exists
10. Ability to start study treatment (first cycle of Avelumab) within 1-8 weeks of the most 
recent pre-study TURBT.
11. Ability to understand and willingness to sign a written informed consent document
3.2 Exclusion Criteria
Indicate that the subject follows the criteria by checking the boxes below.
12. Prior intravenous therapy for treatment of bladder cancer 
13. Prior pelvic radiation 
14. Any component of small cell histology in the bladder biopsy
15. Evidence of lymph node involvement or metastatic disease on CT of the chest, abdomen, 
and pelvis. To be considered positive, a lymph node must measured >15 mm in short 
axis. Bone scan is recommended in patients with bone pain or elevated alkaline 
phosphatase. PET/CT can be considered in patients with renal dysfunction who are 
unable to receive IV contrast
16. Clinically significant (i.e. active) cardiovascular disease: symptomatic congestive heart 
failure (≥ New York Heart Association Classification Class II), unstable angina pectoris, 
serious cardiac arrhythmia requiring medication, or CVA/stroke/MI (< 6 months prior to 
enrollment)
17. Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE Grade ≥ 3)
18. Breast feeding women who are unwilling to stop breastfeeding during treatment and for 
at least one month after the duration of treatment
19. Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment
20. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, 
inhaled, topical steroid, 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) are 
allowed.
21. Active autoimmune disease requiring systemic immunosuppressive treatment. Patients 
with controlled autoimmune disease not requiring systemic immunosuppressive treatment 
including diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid are eligible.
22. History of another malignancy within 5 years prior to randomization except for: non-
muscle-invasive bladder cancer (i.e., ≤T1), completed resected basal cell or squamous 
cell skin cancer, completed resected carcinoma in situ of any site, or localized prostate 

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cancer managed curatively with a non-radiation based approach
23. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited 
except for administration of inactivated vaccines
24. Major surgery within the last 30 days (with the exception of TURBT).
25. Active and/or uncontrolled infection. The following exceptions apply:
a.
Participants with HIV infection are eligible if they are on effective antiretroviral 
therapy with undetectable viral load within 6 months, provided there is no 
expected drug-drug interaction.
b. Participants with evidence of chronic HBV infection are eligible if the HBV viral 
load is undetectable on suppressive therapy (if indicated), and if they have ALT, 
AST, and total bilirubin levels < ULN, and provided there is no expected drug-
drug interaction.
c.
Participants with a history of HCV infection are eligible if they have been treated 
and cured. For participants with HCV infection who are currently on treatment, 
they are eligible if they have an undetectable HCV viral load, and if they have 
ALT, AST, and total bilirubin levels < ULN.”
26. Prior organ transplantation including allogenic stem-cell transplantation 
27. Patient is unwilling to stop (or wishes to start) taking herbal and natural remedies that 
may have immune-modulating effects during the study period 
28. Persisting toxicity related to prior therapy (NCI CTCAE Grade > 1); however, alopecia, 
sensory neuropathy Grade  ≤ 2, or other Grade  ≤ 2 not constituting a safety risk based on 
investigator’s judgment are acceptable
29. Other severe acute or chronic medical conditions including  immune colitis, 
inflammatory bowel disease,  immune pneumonitis, pulmonary fibrosis or psychiatric 
conditions including recent (within the past year) or active suicidal ideation or behavior; 
or laboratory abnormalities that may increase the risk associated with study participation 
or study treatment administration or may interfere with the interpretation of study results 
and, in the judgment of the investigator, would make the patient inappropriate for entry 
into this study.
30. Pregnant women are excluded from this study. Based on its mechanism of action. 
Avelumab can cause fetal harm when administered to a pregnant woman. In animal 
models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy 
through induction of maternal immune tolerance to foetal tissue. Human IgG1 
immunoglobulins are known to cross the placenta. Therefore, Avelumab has the potential 
to be transmitted from the mother to the developing foetus. Blockade of PD-L1 signaling 
has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to 
result in an increase in foetal loss. Therefore, potential risks of administering Avelumab 
during pregnancy include increased rates of abortion or stillbirth. Advise females of 
reproductive potential to use effective contraception during treatment with Avelumab and 
for at least one month after the last dose of avelumab.
The Overall PI should be alerted if the participant is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes.  See section 5.3 for more details.

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3.3 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial. Pregnant women 
are excluded from the trial due to known harms of avelumab to a fetus.
4.
REGISTRATION PROCEDURES
4.1 General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the DF/HCC Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy 
or intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following DF/HCC registration, participants may begin protocol-specific therapy. Issues that 
would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If 
the subject does not receive protocol therapy within one month after registration, the subject 
must be taken off-study in the CTMS (OnCore) with an appropriate date and reason entered.  
4.2 Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (REGIST-101) must be followed.  
5.
TREATMENT PLAN
5.1 Treatment Regimen
Patients will be enrolled in two stages. In the first stage, 12 patients will be accrued. If there are 5 
or fewer responses measured by the 3 month complete clinical response rate in these 12 
evaluable patients, the study will be stopped. Otherwise, 12 additional patients will be accrued 
for a total of 24 patients. See Section 13 for more details.
5.1.1
Surgery
All patients should undergo maximal safe transurethral tumor resection of the bladder tumor 
(TURBT) performed by a urologist.  TURBT can be performed before or after trial enrollment.  
A second TURBT by the same or a different urologist prior to initiation of avelumab is 
encouraged but not required.
5.1.2
Avelumab
The first cycle of avelumab will begin within 1-8 weeks of the final TURBT.

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Avelumab will be administered every 2 weeks, with 14 consecutive days defined as a treatment 
cycle.  Treatment will be administered on an outpatient basis. Safety will be assessed at each 
biweekly trial visit and will include assessment of performance status, physical examination, 
clinical laboratory tests (complete blood count, serum chemistry, hepatic panels, and free T4 and 
TSH), and documentation of concurrent medications and adverse events. At these visits, labs 
must be reviewed by study staff prior to treatment to ensure that lab values meet criteria as 
described below. Other labs (e.g. TSH) which may take longer to obtain results are not required 
to be reviewed prior to dosing.
The criteria to treat at the beginning of each cycle are:
 
-
Hemoglobin ≥9.0 g/dL (Note: Transfusion to achieve this is allowed)
-
Absolute neutrophil count (ANC) 1.5 x 109/L (> 1500 per mm3)
-
Platelet count ≥100) x 109/L)
-
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN)
-
AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal 
If labs were obtained within 72 hours prior to cycles 1-6, they do not need to be repeated on Day 
1 of the respective cycle. 
Appropriate dose modifications are described in Section 6.  Reported adverse events and 
potential risks are described in Section 7. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy.
5.1.3
Radiation
The radiation planning and treatment process will proceed as follows:
5.1.3.1 Timing:  
The radiation mapping CT should take place after the final TURBT has been performed and 
prior to the first avelumab infusion.
5.1.3.2 Preparation:  
Patients should be encouraged to initiate daily Miralax one week prior to the CT and perform a 
Fleet’s enema on the evening before and morning of the CT to facilitate rectal emptying.  
Patients should drink at least 8 ounces of oral contrast agent one hour prior to the radiation 
mapping CT.  Patients should attempt to empty their bladder immediately prior to the radiation 
mapping CT. 
5.1.3.3 Immobilization:  
Patients will be positioned in a stable and comfortable supine position with arms rested on the 
chest. 
5.1.3.4 Radiation CT simulation: 
The treatment planning process will include CT based simulation with axial imaging (slice 

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thickness of 1.25-2.5 mm).  The superior border of the CT should be no lower than the L4 
vertebral body and the inferior border should be below the ischial tuberosities.  Use of 
intravenous (i.v.) contrast during the CT is optional.
5.1.3.5 Contours: 
The GTV (gross tumor volume) includes any remaining gross bladder tumor, the tumor bed (i.e., 
the portion of the bladder wall initially involved with tumor).  Information available from 
physical examination, cystoscopic bladder mapping, intraoperative reports, and radiographic 
studies should be used to delineate these structures.  Close cooperation with the treating urologist 
is essential.  Cystoscopically placed fiducial markers may be used. 
The CTV_tumor includes the GTV plus a 1.0 cm uniform expansion.  
The CTV_bladder includes the entire bladder volume (including the bladder wall thickness) plus 
a 1.0 cm uniform expansion and should be inclusive of the entire CTV tumor.  
The CTV_pelvis will include the CTV_bladder, the prostate and prostatic urethra (in men), and 
the regional lymph nodes.  The regional lymph nodes include the perivesciular, internal iliac, 
external iliac, and obturator lymph nodes from the level of the anterior aspect of the S2-S3 
junction superiorly to the lower pole of the obturator foramen inferiorly.
A 5 mm planning tumor volume (PTV) margin will be uniformly added to all CTVs to account 
for set-up variation.
Conventional or IMRT treatment planning is allowed.
5.1.3.6 Prescription: 
Two dose schemes are allowed at the discretion of the treating radiation oncologist:  

Scheme #1 (preferred):  65 Gy in 35 fractions over 7 weeks.  PTV_pelvis, PTV_bladder, 
and PTV_tumor will first receive 45 Gy in 25 fractions.  PTV_bladder and PTV tumor 
will then receive an additional 8 Gy in 4 fractions (for a total PTV_bladder dose of 53 
Gy), and then the PTV_tumor will receive an additional 12 Gy in 6 fractions (for a total 
PTV_tumor dose of 65 Gy).

Scheme #2 (allowed):  55 Gy in 20 fractions over 4 weeks. PTV_bladder will receive 55 
Gy in 20 fractions.
5.1.3.7 Daily Target Localization:  
Isocenter or reference point port localization images should be obtained on the treatment unit 
immediately before each treatment to ensure proper alignment of the geometric center (i.e., 
isocenter) of the simulated fields. These IGRT images can be obtained with planar kV imaging 
devices or cone-beam CT equipment.
5.1.3.8 Timing of Radiation Treatment:  
Daily radiation treatments will commence within 14 days of C1D1 of avelumab. On the days of 

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avelumab administration that fall within the 4-7 weeks of daily radiation, participants will 
receive both radiation treatment and avelumab infusion. Avelumab or radiation may be delivered 
first, and there is no additional wait time required between administration of avelumab and 
radiation treatment on those days. Radiation treatments will be delivered daily with the exception 
of weekends (Saturdays and Sundays) and departmental holidays.  Every effort should be made 
to complete at least four radiation treatments in each seven day consecutive period.
5.1.3.9 Dosimetry:
The minimum dose to each PTV should be no less than 95% of the prescribed PTV dose.  At 
least 99% of each PTV should receive 100% of the prescribed PTV dose.  The maximum dose to 
any PTV should be less than 110% of the prescribed PTV dose.
5.1.3.10
Organs at Risk:
The rectum volume is defined on CT from the anus (at the level of the ischial tuberosities) for a 
length of 15 cm or to the rectosigmoid flexure. The femoral head volumes include the femurs 
from their superior extent to the level of the lesser trochanters.  The following DVH criteria 
should be achieved. 
Rectum:  No more than 50% of the volume above 55 Gy 
Femoral heads:  No more than 10% of the volume above 50 Gy 
5.1.3.11
Planning Priorities:
1. Respect dose limits to organs at risk
2. Achieve PTV coverage
5.1.3.12
Technical Factors:
Conventional linear accelerators or specialized linear accelerators with image guidance (e.g., 
TrueBeam, Agility, Novalis, Trilogy, Synergy, Artiste) and photon energies of at least 6MV are 
allowed. These units can be used with 3D-conformal dose delivery or IMRT.
5.2 Agent Administration
5.2.1
Avelumab
Avelumab is administered as a 60 minute (±5 minutes) IV infusion, diluted with 0.9% saline 
solution; alternatively a 0.45% saline solution can be used if needed. Administration completion 
in under 55 minutes is considered a deviation. 
Patients will receive 10 mg/kg avelumab via IV infusion every 2 weeks for 6 doses unless there 
is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
In order to mitigate infusion-related reactions, subjects must be premedicated with an
antihistamine and with paracetamol (acetaminophen) prior to the first 4 infusions of avelumab.

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Premedication should be administered for subsequent avelumab doses if the patient has any 
Grade 1 or 2 infusion-related reaction as described in Table 2 below or if deemed necessary 
based upon clinical judgment of the provider. 
In the event of infusion-related reactions, treatment should be modified as outlined below:
Table 2. Treatment Modification for Symptoms of Infusion-Related Reactions 
NCI-CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for  
24 h.
Temporarily discontinue avelumab infusion..
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop avelumab 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.
 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs.
Patients will be monitored before, during and after the infusion with assessment of vital signs. 
Patients are monitored (pulse rate, blood pressure) approximately prior to the start of infusion 
(±5 minutes), 30 minutes from infusion start (±5 minutes), and post infusion completion (±5 
minutes) for infusion-related reactions. When infusion rate is slowed or temporarily stopped, or 
in the event that it is anticipated that administration will take longer than 89 minutes, patients 
will be monitored at every 30 minute interval (±5 minutes). Following the first avelumab 
infusion, patients must be observed for 30 minutes post-infusion for potential infusion-related 
reactions. If no infusion-related reactions are noted in this 30 minute post-infusion period, post-
infusion monitoring is not required following subsequent infusions.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered and document if the line 
was not flushed.

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It is important to note for administration that the expiry time of final IP is 24 hours from the time 
the vials were removed from the refrigerator and allowed to reach room temperature: 24 hours 
under refrigerated conditions (2-80 C, 36-46F) with no more than 8 of those hours at room 
temperature (15-25C, 59-77F), including infusion time.
If either the preparation time or the infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Avelumab does not contain preservatives, and any unused portion must 
be discarded.
Avelumab should be administered in a setting that allows for immediate access to an intensive 
care unit or equivalent environment and administration of therapy for anaphylaxis, such as the 
ability to implement immediate resuscitation measures.  Steroids (dexamethasone 10 mg), 
epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or 
equivalents, and oxygen should be available for immediate access.
See Section 6.0 for dosing delays/dose modifications.
5.2.2
Radiation
See section 5.1 for radiation planning details.  Daily radiation treatments will commence within 
14 days of C1D1 of avelumab (i.e., during cycle 1 of avelumab).  On days when both an 
avelumab infusion and radiation are planned (such as C2D1 and C3D1), either avelumab or 
radiation can be administered first.
5.3 General Concomitant Medication and Supportive Care Guidelines
Because there is a potential for interaction of avelumab with other concomitantly administered 
drugs through the cytochrome P450 system, data capture must include the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies.  The Overall PI should be 
alerted if the participant is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes.  
Table 1. Permitted concomitant medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care. 
To be administered as prescribed by the 
Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [excluding palliative radiotherapy])
Should be used, when necessary, for all 
patients
Inactivated viruses, such as those in the influenza 
vaccine
Permitted

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Table 2. Excluded concomitant medications
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly with the study 
treatment
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly with the study 
treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study
Should not be given concomitantly with the study 
treatment. (Concurrent use of hormones for non-
cancer-related conditions [e.g., insulin for diabetes 
and hormone replacement therapy] is acceptable. 
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions:
-
Use of immunosuppressive medications for 
the management of treatment-related AEs.
-
Use in patients with contrast allergies.
-
In addition, use of inhaled, topical and 
intranasal corticosteroids is permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related 
events experienced by the patient (e.g., chronic 
obstructive pulmonary disease, radiation, nausea, 
etc).
Live attenuated vaccines
Should not be given through 30 days after the last 
dose of avelumab 
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the Principal Investigator
5.4 Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression, and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment will continue 
until the prescribed radiation has been delivered and the patient has received 6 cycles of 
avelumab, or until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s) possibly, probably, or definitely related to the study drug, 
defined as:

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o
Grade ≥3 adverse reaction 
o
Persistent Grade ≥ 2 treatment-related adverse reaction that does not recover to 
Grade 1 or resolve within 30 days after last dose
o
Uveitis grade ≥2
o
For immunologic adverse events that require treatment with corticosteroids: 
Inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 6 weeks

Participant demonstrates an inability or unwillingness to comply with the treatment 
regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Avelumab dosing delay of >6 weeks 

Interruption to radiation for any reason that results in ≥5 successive treatments missed
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
5.5 Duration of Follow Up
Participants will be followed for a minimum of two years after removal from protocol therapy or 
until death, whichever occurs first.  Participants removed from protocol therapy for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event.  Follow-
up by telephone is allowed.  If patient wishes to transfer care back to local urologist following 
completion of trial therapy, records will be obtained from the outside urologist if possible.
If a participant is found to have disease progression, the patient will be treated at the discretion of 
their clinicians and followed via electronic medical record. If protocol assessments are no longer 
clinically indicated following progression and thus do not occur, they will not result in a 
deviation or violation.
The following assessments will be performed 10-14 weeks following completion of the 
radiotherapy:  cystoscopy, urine cytology, bladder biopsy of any suspicious areas per standard of 
care, CT scan (abdominal/pelvic and chest).  
Additional follow-up will be performed as per standard of care and should include:

Post-treatment years 1-2: 
o
History/physical every 3 months
o
Laboratory studies (including CBC and CMP) every 3-6 months
o
Cystoscopy and urine cytology every 3 months as clinically indicated

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o
CT of abdomen and pelvis (including visualization of the upper tracts) and chest 
CT (or chest xray) every 3-6 months
o
Adverse event and concomitant medication assessment 

Post-treatment years 3-5:
o
Cystoscopy and urine cytology every 6 months, as clinically indicated
o
CT of abdomen and pelvis (including visualization of the upper tracts) and chest 
CT (or chest xray) every 12 months, as clinically indicated 
o
Laboratory studies as clinically indicated 
o
Adverse event and concomitant medication assessment
o
History/Physical exam 

Post-treatment years 6-10:
o
Cystoscopy annually, as clinically indicated
o
Laboratory or imaging studies as clinically indicated
o
Adverse event and concomitant medication assessment 
o
History/Physical exam

Post-treatment years >10:
o
All studies as clinically indicated
o
Adverse event and concomitant medication assessment 
o
History/Physical exam
Additional follow-up unique to this study will include:

Urodynamic evaluation (cystometrogram + uroflow, pressure flow study, or 
fluorourodynamics study) and AUA symptom score are recommended in the third post-
treatment year for patients who still have a native bladder. This will incorporate measures 
of average and peak urinary flow rate, bladder functional capacity, compliance, and leak 
pressures (continence). 

The following patient-reported QOL assessments will be administered at enrollment 
(prior to initiation of avelumab and radiation), near completion of radiation (+/- 7 days of 
the final radiation treatment), and at each follow-up visit, except the 30 day post 
treatment follow-up and, 30 day post-treatment safety follow-up after the end of 
radiation):
o
European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire (QLQ-C30)[28]
o
FACT-Bladder instruments[29]
5.6 Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

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
Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101.
6.
DOSING DELAYS/DOSE MODIFICATIONS
Guidelines for infusion-related reactions are in Section 5.2, Agent Administration.
There are no modifications allowed to the dose of avelumab. However, adjustments to rate of 
administration are allowed (see Section 5.2). 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an irAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related.
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Table 3.  Management of Immune-mediated Adverse Reactions
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Diarrhea: Increase of <4 stools per 
day over baseline; mild increase in 
ostomy output compared to baseline 
Colitis: asymptomatic
Continue avelumab therapy
Symptomatic treatment (e.g. 
loperamide)
Close monitoring for worsening symptoms
Educate subject to report worsening 
immediately
If worsens:
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: Increase of 4 - 6 stools per 
day over baseline; moderate 
increase in ostomy output compared 
to baseline; limiting instrumental 
ADL 
Colitis: abdominal pain; mucus or 
blood in stool
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤ 1: 
Resume avelumab therapy
If  persists > 5-7 days or recurs:
Treat as Grade 3 or 4.

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Grade 3 to 4
Diarrhea (Grade 3): Increase of >=7 
stools per day over baseline; 
hospitalization indicated; severe 
increase in ostomy output compared 
to baseline; limiting self care ADL 
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Diarrhea (Grade 4): Life-threatening 
consequences; urgent intervention 
indicated 
Colitis (Grade 4): Life-threatening 
consequences; urgent intervention 
indicated
Withhold avelumab for 
Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3.
1 to 2 mg/kg/day 
methylprednisolone IV or 
equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider lower endoscopy 
If improves: 
Continue steroids until Grade ≤ 1, then taper 
over at least 1 month; resume avelumab 
therapy following steroids taper (for initial 
Grade 3). 
If worsens, persists > 3 to 5 days, or recurs 
after improvement:
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab should 
not be used in cases of perforation or sepsis. 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤ 30% body surface area
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
If persists > 1 to 2 weeks or recurs: 
Withhold avelumab therapy 
Consider skin biopsy 
Consider 0.5-1 mg/kg/day 
methylprednisolone or equivalent. Once 
improving, taper steroids over at least 1 
month, consider prophylactic antibiotics for 
opportunistic infections, and resume 
avelumab therapy following steroids taper.
If worsens: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Covering > 30% body 
surface area;
Grade 4: Life threatening 
consequences 
Withhold avelumab for 
Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy 
Dermatology consult 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month; resume 
avelumab therapy following steroids taper 
(for initial Grade 3).

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1 to 2 mg/kg/day 
methylprednisolone or 
equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated
Consider withholding 
avelumab therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
Grade 2
Symptomatic; medical intervention 
indicated; limiting instrumental 
ADL 
Withhold avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily; 
consider hospitalization 
1 to 2 mg/kg/day 
methylprednisolone or 
equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then 
resume avelumab  therapy following steroids 
taper 
If not improving after 2 weeks or worsening: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe symptoms; limiting 
self care ADL; oxygen indicated 
Grade 4: Life-threatening 
respiratory compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
Permanently discontinue 
avelumab therapy.
Hospitalize.
Pulmonary and Infectious 
Disease consults.
1 to 2 mg/kg/day  
methylprednisolone or 
equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
If not improving after 48 hours or worsening: 
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1:
AST or ALT > ULN to 3.0 x ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 

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and/or Total bilirubin > ULN to 1.5 
x ULN
 Treat as Grade 2 or 3 to 4. 
Grade 2:
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN
Withhold avelumab therapy
Increase frequency of 
monitoring to every 3 days.
If returns to Grade ≤ 1:
Resume routine monitoring; resume 
avelumab therapy.
If elevation persists > 5 to 7 days or worsens: 
Treat as Grade 3 to 4.
Grade 3 to 4
Grade 3 to 4: AST or ALT > 5 x 
ULN and/or total bilirubin > 3 x 
ULN
Permanently discontinue 
avelumab therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1 to 2 mg/kg/day 
methylprednisolone or 
equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consult gastroenterologist/ 
hepatologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted 
If returns to Grade ≤ 1: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, worsens 
or rebounds: 
Add mycophenolate mofetil 1 gram (g) twice 
daily 
If no response within an additional 3 to 5 
days, consider other immunosuppressants per 
local guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 x 
ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2
Creatinine increased 
>1.5 - 3.0 x baseline; >1.5 - 3.0 x 
ULN 
Withhold avelumab therapy 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤ 1: 
Taper steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper. 
If worsens: 
Treat as Grade 3 
Grade  3
Creatinine increased  
>3.0 x baseline; >3.0 - 6.0 x ULN 
Withhold avelumab therapy
Increase frequency of  monitoring to 
every 3 days
1 to 2 mg/kg/day methylprednisolone 
or equivalent.
If returns to  Grade ≤1:
Taper steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper.
If worsens: 
Treat as Grade 4.

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Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Permanently discontinue avelumab 
therapy upon 3rd Grade 3 event (2nd 
recurrence).
Grade 4
Creatinine increased > 6.0 x ULN
Permanently discontinue avelumab 
therapy
Monitor creatinine daily
1 to 2 mg/kg/day methylprednisolone 
or equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade ≤1:
Taper steroids over at least 1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive 
of myocarditis. 
Withhold avelumab therapy.
Hospitalize.
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management.
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis. 
Guideline based supportive treatment as 
per cardiology consult.*
Consider myocardial biopsy if 
recommended per cardiology consult.
If symptoms improve and 
immune-mediated etiology is ruled 
out, re-start avelumab therapy.
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-mediated 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis.
Immune-mediated myocarditis
Permanently discontinue avelumab.
Guideline based supportive treatment as 
appropriate as per cardiology consult.*
1 to 2 mg/kg/day methylprednisolone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections.
Once improving, taper steroids 
over at least 1 month.
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A).

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*Local guidelines, or eg. ESC or AHA guidelines 
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website:
professional.heart.org/en/guidelines-statements 
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Hyperthyrodism: 
(Grade 1): Asymptomatic; clinical 
or diagnostic observations only; 
intervention not indicated 
(Grade 2): Symptomatic; thyroid 
suppression therapy indicated; 
limiting instrumental ADL 
Hypothyroidism:
(Grade 1): Asymptomatic; clinical 
or diagnostic observations only; 
intervention not indicated 
(Grade 2): Symptomatic; thyroid 
replacement indicated; limiting 
instrumental ADL 
Adrenal insufficiency 
(Grade 1): Asymptomatic; clinical 
or diagnostic observations only; 
intervention not indicated 
(Grade 2): Moderate symptoms; 
medical intervention indicated 
Continue avelumab therapy
Endocrinology consult if needed
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.  
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Hyperthyrodism: 
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤ 1 (with or without 
hormone replacement/suppression).

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(Grade 3): Severe symptoms; 
limiting self care ADL; 
hospitalization indicated 
(Grade 4): Life-threatening 
consequences; urgent intervention 
indicated 
Hypothyroidism:
(Grade 3): Severe symptoms; 
limiting self care ADL; 
hospitalization indicated  
(Grade 4): Life-threatening 
consequences; urgent intervention 
indicated 
Adrenal insufficiency: 
(Grade 3): Severe symptoms; 
hospitalization indicated  
(Grade 4): Life-threatening 
consequences; urgent intervention 
indicated 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.  
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH) :

Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women) 

Hormone 
replacement/suppressive therapy 
as appropriate 

Perform pituitary MRI and visual 
field examination as indicated
If hypophysitis confirmed:

Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month

Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
methylprednisolone or equivalent) 
followed by corticosteroids taper 
during at least 1 month.
Resume avelumab once symptoms 
and hormone tests improve to 
Grade ≤ 1 (with or without 
hormone replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented. 
Continue hormone 
replacement/suppression therapy as 
appropriate.
Permanently discontinue avelumab 
therapy for recurrent ≥ Grade 3 
hypophysitis.

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
Add prophylactic antibiotics for 
opportunistic infections.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold avelumab therapy pending 
clinical investigation
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy
If irAE is confirmed, treat as Grade 
2 or 3 irAE.
Grade 2 irAE  or first occurrence 
of Grade 3 irAE
Withhold avelumab therapy
1 to 2 mg/kg/day methylprednisolone  
or equivalent  
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
and resume avelumab therapy 
following steroids taper.
Recurrence of same Grade 3 
irAEs
Permanently discontinue avelumab 
therapy
1 to 2 mg/kg/day
methylprednisolone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month.
Grade 4 
Permanently discontinue avelumab 
therapy
1 to 2 mg/kg/day
prednisone or equivalent and/or other 
immunosuppressant as needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult.
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
Requirement for 10 mg per day 
or greater methylprednisolone  
or equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Permanently discontinue avelumab 
therapy
Specialty consult
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB;  CT= computed 
tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; 
irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; 
NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.

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7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
7.1 Expected Toxicities
7.1.1
Adverse Event List for Radiation
 Immediate Reactions 
Long-Term Reactions 
Common: 
Common: 
• Tiredness 
• Bladder spasms (mild to moderate) 
• Burning on urination (mild to moderate) 
• More frequent bowel movements 
• Decreased blood count
• Chronic mildly increased need to empty bladder more often that 
prior to radiotherapy 
• Occasional bladder spasm 
• Males: Sterility 
• Females: Sterility
• Menopause, if premenopausal, decreased vaginal secretions 
Uncommon: 
Uncommon: 
• Bowel cramping 
• Diarrhea 
• Feel the need to empty bowels with nothing 
to pass 
• Dehydration requiring I.V. fluids 
• Incontinence due to urgency 
• Need for a bladder catheter 
• Significant bladder spasm 
• Significant burning on urination 
• Hospitalization to control symptoms 
• Occasional blood in urine 
Rare: 
Rare: 
• Skin reddening and irritation 
• Chronic blood in urine requiring treatment 
• Bothersome need to empty bladder often 
• Incontinence (usually in patients with prior history of TURBT’s) 
• Rectal or urinary bleeding requiring transfusion 
Extremely Rare: 
Extremely Rare: 
• Bladder problems requiring surgery 
• Bowel problems requiring surgery 
• Cancers caused by radiation
7.1.2
Adverse Event List for Avelumab
Refer to the current version of the Investigator’s Brochure for detailed avelumab safety and 
toxicity information.
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the potential 
for adverse effects on other tissues.

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Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory mechanism and which may require more frequent 
monitoring and/or unique interventions such as immunosuppressants and/or endocrine 
replacement therapy. 
Important identified risks for avelumab are immune-mediated adverse reactions and infusion 
related reactions.
Immune-mediated adverse reactions:
immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies [thyroid disorders, adrenal 
insufficiency, type 1 diabetes mellitus], nephritis and renal dysfunction, and other immune-
mediated adverse reactions [myocarditis, pancreatitis, myositis, hypopituitarism, uveitis, 
myasthenia gravis/myasthenic syndrome, Guillain-Barré syndrome, sclerosing cholangitis, 
arthritis, polymyalgia rheumatica and Sjogren’s syndrome].
Patients with pre-existing autoimmune disease (AID) 
In patients with pre-existing AID, data from observational studies suggest that the risk of 
immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be 
increased compared to the risk in patients without pre-existing AID. In addition, flares of the 
underlying AID were frequent, but the majority were mild and manageable.
Infusion-related Reactions
Possible IRRs are defined based on the following Preferred Terms (PTs) and temporal 
relationship criteria. Events are divided into reactions versus signs and symptoms:

Reactions include the PTs infusion-related reaction, drug-hypersensitivity, 
hypersensitivity, type-1-hypersensitivity and anaphylactic reaction. These PTs should be 
considered when the onset is on the day of study drug infusion (during or after the 
infusion) or within 1 day thereafter.

Signs and symptoms of IRRs include the PTs pyrexia, chills, flushing, hypotension, 
dyspnea, wheezing, back pain, abdominal pain and urticaria. These PTs should be 
considered, if the onset occurs on the day of study drug infusion (during or after the 
infusion) and resolves within 2 days after onset.
7.2 Adverse Event Characteristics
An adverse event (AE) is any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 

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abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product (definition per 
International Conference on Harmonisation (ICH).  
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AE’s will be categorized according to the likelihood that they are related to the study drug (s). 
Specifically, they will be categorized using the following terms:

Attribution of the AE:
-
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.
AEs and SAEs will be recorded from the date of randomization until 90 days after the last dose 
of study treatment due to the potential risk for delayed immune-related toxicities with avelumab. 
The extended safety follow-up beyond 30 days after last avelumab administration may be 
performed either via a site visit or via a telephone call with subsequent site visit requested in case 
any concerns noted during the telephone call. Reporting of Serious Adverse events will be per 
DFCI Reporting Policy.
Special Considerations: 

Use of a medicinal product during pregnancy or breastfeeding: reports where embryo, 
fetus or child may have been exposed to medicinal products (either through maternal 
exposure or transmission of a medicinal product via semen following paternal 
exposure),

Reports of medication errors, uses outside what is foreseen in the protocol, including 
misuse and abuse of the product,

Occupational exposure (even if not associated with an adverse event)

Overdose

Potential drug induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs. 

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Serious Adverse Event (“SAE” or “SAEs”): 
A SAE is any AE as defined above, which also fulfills at least one of the seriousness criteria 
below:

results in death,

is life-threatening1),

requires in-patient hospitalization or prolongation of existing hospitalization,

results in persistent or significant disability/ incapacity,

is a congenital anomaly/ birth defect, or

is otherwise considered as medically important2).
1) Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
2) Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the patient 
or might require intervention to prevent one of the other outcomes listed above. Examples of 
such events are intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization or development of 
dependency or abuse. 
Adverse Events of Special Interest (“AESI”):
An AESI is an AE of scientific and medical concern specific to EMD Serono’s Investigational 
Product or program, for which ongoing monitoring and rapid communication by Principal 
Investigator to EMD Serono can be appropriate.
Safety Issues/Concerns:
A safety issue/concern is defined as an important identified risk, important potential risk or 
important missing information. Safety issues/concerns are events which may occur during the 
Study, not falling under the definition of SUSARs and consequently not being subject of the 
reporting requirements for SUSARs. Examples are events related to the conduct of the Study or 
the development of an investigational medicinal product likely to affect the safety of subjects, 
such as (but not limited to):

a major safety finding from a newly completed animal study (such as 
carcinogenicity),

recommendations of the Safety Data Monitoring Committee (SMC/DMC), if any, 
where relevant for the safety of subjects,

in the case of advanced therapy investigational medicinal products, relevant safety 
information regarding the procurement or the donor.
Events Not to be considered AEs:
Medical conditions present in a patient and documented at the time of Study enrollment, and that 

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do not worsen in severity or frequency during the Study, are defined as baseline medical 
conditions, and are NOT to be considered AE.
7.3 Expedited Adverse Event Reporting 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 90 days of the last dose of treatment 
on the local institutional SAE Form.
It is the responsibility of each participating investigator to report serious adverse events within 
24 hours of knowledge to the Overall PI, Dr. Kent Mouw (at the contact given below), or 
representative personnel; and submit to DFCI IRB within 10 working days.
Kent Mouw, MD, PhD
617-732-7948
kent_mouw@dfci.harvard.edu
Recording and Transmission of Safety Events: 
SAEs (related and non-related), AESIs (if there are any for EMD Serono’s Product), Special 
Considerations and Safety Issues/Concerns shall be sent to EMD Serono in English language for 
recording in EMD Serono’s safety database.
In addition to the participating site submitting the SAE to the Overall PI and local institution via 
the local institutional SAE form, the information shall be sent to EMD Serono by the DFCI study 
team via email or facsimile listed below within one (1) business day or three (3) calendar days, 
whatever comes first, after becoming aware of the event. SAE reporting to EMD Serono should 
be via the applicable EMD Serono report form for clinical studies (either the serious adverse 
event and overdose report form, parent-child/fetus adverse event report form, or pregnancy 
report form depending on the nature of the adverse event). Only the DFCI study team will submit 
SAE reports directly to EMD Serono.
Fax No.: 781-681-2961
Email address: usdrugsafety@emdserono.com
Please specify in the cover letter:

Protocol Number and/or Title

Study Identifier

Subject Number

Principal Investigator Name

Sponsor Name

(S)AE/Onset Date
7.3.1
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 

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Research Studies (OHRS) per the DFCI IRB reporting policy. 
7.4 Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.5 Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. In the event of an 
unanticipated problem or life-threatening complications treating investigators must immediately 
notify the Overall PI.
8.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1.
8.1 Avelumab (MSB0010718C)
8.1.1
Description
Avelumab (MSB0010718C) (Bavencio®)  is a fully human monoclonal antibody directed 
against PD-L1 and has been approved for treatment of metastatic urothelial cancer.
8.1.2
Form
Avelumab (MSB0010718C) drug product is a sterile, clear, and colorless concentrate for solution 
intended for intravenous (IV) infusion. The drug is presented at a concentration of 20 mg/mL in 
single-use glass vial containing 200 mg of avelumab (MSB0010718C).
8.1.3
Storage and Stability

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Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Avelumab (MSB0010718C) must be used within the individually assigned expiry date on the 
label.
8.1.4
Compatibility
The solution supplied will be diluted with 0.9% (w/v) saline or 5% (w/v) dextrose for 
intravenous (IV) administration.
8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
immunotherapeutic agent in a self-contained and protective environment. 
8.1.6
Availability
EMD Serono will supply avelumab (MSB0010718C) to the investigator as a 20 mg/ml solution 
for infusion after dilution.
8.1.7
Preparation
The dose of avelumab (MSB0010718C) for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique. 
Prior to the preparation of the dilution for infusion of avelumab (MSB0010718C), allow each 
vial to equilibrate to room temperature. Use a disposable syringe equipped with a needle of 
suitable size to remove a volume of sodium chloride solution to be replaced by avelumab from 
the infusion bag and discard the removed solution. Use a new disposable syringe equipped with a 
needle of suitable size to inject a volume of avelumab drug product identical to the discarded 
volume of sodium chloride solution into the infusion bag. Gently invert the mixture 10 times. 
Infusion bags must not be shaken, in order to avoid foaming or excessive shearing of the protein 
solution. The preparation must be carefully inspected as it should result in a homogeneous 
looking clear solution, free of visible particles.
The expiry time of final IP is 24 hours from the time the vials were removed from the 
refrigerator and allowed to reach room temperature: 24 hours under refrigerated conditions (2-80 
C, 36-46F) with no more than 8 of those hours at room temperature (15-25C, 59-77F), 
including infusion time.
Weight-based dosing (10 mg/kg) will be administered using an IV bag containing commercially 
available 0.9% (w/v) saline or 5% (w/v) dextrose, with a final avelumab (MSB0010718C) 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set with 
a 0.2- or 0.22-μm in-line filter. DFCI standard of practice for weight based dosing and BSA 
calculation may be used.

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Calculate the dose volume of avelumab (MSB0010718C) needed for the patient to achieve the 
accurate weight-based dose. To prepare the IV bag remove a volume of diluent equal to the 
calculated volume of avelumab (MSB0010718C) to be added to the IV bag. The calculated 
volume of avelumab (MSB0010718C) is then added to an appropriately-sized IV bag such that 
the final concentration is within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
8.1.8
Ordering
The study site will order the avelumab (MSB0010718C) from EMD Serono. EMD Serono’s 
internal identifier for this research study is MS100070_0217.
8.1.9
Accountability
The Principal Investigator, or a responsible party designated by the Principal Investigator, should 
maintain a careful record of the inventory and disposition of avelumab (MSB0010718C) using 
the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability 
form. Certificates of delivery must be signed. The date, quantity and batch or code number of 
avelumab (MSB0010718C), and the identification of patients to whom study drug has been 
dispensed by patient number and initials will be included.
8.1.10 Destruction and Return
The Principal Investigator shall not make avelumab (MSB0010718C) available to any 
individuals other than to qualified study patients. Furthermore, the Principal Investigator will not 
allow avelumab (MSB0010718C) to be used in any manner other than that specified in this 
protocol. Any unused portion of avelumab (MSB0010718C) left in a vial may be destroyed as 
per institutional standard of practice (SOP). 
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Rationale 
Because determinants of response to immune checkpoint blockade and radiation are poorly 
understood, we plan to perform comprehensive immunogenomic analyses of patient blood, 
tumor, and urine samples in an effort to identify predictive biomarkers. All planned biomarker 
and laboratory-based correlative studies are ancillary/exploratory.
Correlative studies are planned for the following specimens:
  
- pre-treatment muscle-invasive tumor biopsy
- post-treatment residual or recurrent muscle-invasive tumor (when available)
- blood (including peripheral blood mononuclear cells and plasma) 
- urine
All specimens for biomarker and correlative studies will be stored in the Gelb Center at DFCI. 
Specimens collected at Beth Israel Deaconess Medical Center will be transferred, processed by 

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and stored in the Gelb Center at DFCI. Documentation of specimen transfer will be recorded for 
each sample on an IRB-approved transfer log.
Pre-treatment/post-treatment tumor
All analyses will be performed on biopsy specimens that are collected during routine clinical 
care.  No additional biopsy procedures will be performed for the planned translational biomarker 
studies, and no additional tissue will be harvested beyond what is collected as part of routine 
clinical care. The timing of the collection and use of biopsy specimens will be at the discretion of 
the overall PI.
Formalin-fixed paraffin-embedded (FFPE) tissue from the pre-treatment muscle-invasive tumor 
biopsy will be collected for all patients.  For patients who have an incomplete response to 
avelumab plus radiation or who experience a tumor recurrence at any time following treatment, 
FFPE tumor and normal tissue from the residual/recurrent muscle-invasive tumor biopsy (and/or 
cystectomy specimen) will also be collected for analysis.
We will use immunohistochemistry to analyze PD-L1 expression as well as immune cell subsets 
including CD3+, CD4+, CD8+ T-cells.  PD-L1 expression and immune cell infiltration have 
been identified as potential predictors of response to immune checkpoint blockade in other 
clinical contexts[23]; however, these associations have not been characterized in the context of 
combined immune checkpoint blockade and radiation for muscle-invasive bladder cancer.
Whole exome sequencing (WES) will be performed on all available tumor specimens to 
determine mutational burden, neoantigen profile, and mutational status of known bladder cancer 
genes.[24]  For each FFPE tumor sample, genomic DNA will isolated in the Mouw laboratory 
using a commercially available kit.  WES will be performed at the Broad Institute.
Whole transcriptome RNA sequencing (RNAseq) will be performed to evaluate transcriptional 
profiles of tumor and infiltrating immune cells.  RNA will be isolated using a commercially 
available kit.  RNA sequencing will be performed at the Broad Institute.  For cases in which 
RNAseq is not feasible, Nanostring cancer and immune gene expression analysis will be 
performed at DFCI or BWH.
Other tumor immunogenomic studies as deemed feasible and informative by the principal 
investigators may also be performed.
Peripheral blood 
Pre-treatment peripheral blood samples will be collected for all patients.  In addition, a blood 
sample will be collected near the end of radiation (+/-5 days from the date of last radiation 
treatment), and at the End of radiation follow-up visit follow-up visit. 
At each blood collection time point 2 purple tops, 2 red tops, and 1 PBMC tube will be collected.  
All samples will be de-identified and labeled with the participant’s initials, participant’s study ID 

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number, date of collection, and time point (“pre-treatment”, “on-treatment”, “3 mo post-
treatment”).  Unless otherwise specified, samples will be processed and stored in the Gelb Center 
at DFCI.
From the pre-treatment blood sample, genomic DNA for WES will be isolated from peripheral 
mononuclear cells using a commercially available kit.
Ultra-low pass whole genome sequencing (ULP-WGS) and/or deep targeted sequencing of cell-
free DNA (cfDNA) will be performed on pre-treatment, end-of-treatment, and 3 month post-
treatment blood specimens.  If tumor cfDNA is detectable at sufficient levels, WES of cfDNA 
will be performed. 
Cytokine profiling using Luminex technology will be performed using plasma samples from pre-
treatment, end-of-treatment, and 3 month post-treatment blood specimens.
T cell receptor (TCR) sequencing will be performed on pre-treatment, end-of-treatment, and 3 
month post-treatment blood specimens.
Other blood-based studies as deemed feasible and informative by the principal investigator may 
also be performed.
Urine
A pre-treatment urine sample will be collected for all patients.  In addition, a urine sample will 
be collected near the end of radiation (+/-5 days from the date of last radiation treatment), and at 
the end of radiation follow-up visit.
Urine samples will be processed as follows:
1. Collect >50 ml urine sample in 100 ml container
2. Divide half of sample into 4-8 ml aliquots
3. Transfer other half into a 50 ml tube and spin the tube at 2500 rpm for 10 min then 
aliquot supernatant as above
4. Re-suspend the pellet in 2 ml 1xPBS, split into two 1.5 ml Eppendorf tubes, and 
centrifuge at >10,000g for 5 minutes, then remove the supernatant.
5. All urine specimens will be stored in a -80C freezer in the Gelb Center at DFCI.
Ultra-low pass whole genome sequencing and/or deep targeted sequencing of cell-free DNA 
(cfDNA) will be performed at Fox Chase Cancer Center for all pre-treatment, on-treatment, and 
3 month post-treatment urine samples.  If tumor cfDNA is detectable at sufficient levels, whole 
exome sequencing from cfDNA will be performed. 
Other urine-based studies as deemed feasible and informative by the principal investigators may 
also be performed.
9.1 Biomarker Studies

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Immunohistochemistry/Immunofluorescence
Immunohistochemical (IHC) analysis will be performed on unstained FFPE slides from all 
available primary and residual/recurrent tumor specimens to determine intratumoral and stromal 
PD-L1 (CD274), expression and infiltration of CD3+/CD8+ and CD3+/CD4+ T-cells.  In 
addition, multiplex immunofluorescence (IF) will be used to score the tumor microenvironment 
for integrated expression of PD-1, PDL1, PD-L2, CD3, CD4, and CD8.  For these IHC and IF 
studies, up to 10 unstained FFPE slides may be requested.
These planned IHC and IF studies are designed to evaluate the immunomodulatory effects of 
radiotherapy in combination with anti-PD-L1 therapy. Tumor PD-L1 expression has been linked 
to response rates of PD-1 checkpoint blockade.[25] Pre-clinical data suggests that radiotherapy 
may upregulate intratumoral PD-L1 expression, and that this upregulation can be overcome with 
anti-PD-L1 therapy.[18] However, little is known about how the pattern of expression (i.e. tumor 
cells vs. infiltrating immune cells) impacts response, particularly in bladder cancer. 
The purpose of these studies is to investigate if PD-L1 expression as a biomarker of response in 
patients treated with radiotherapy plus avelumab and to evaluate the effects of radiotherapy plus 
avelumab on PD-L1 expression. We hypothesize that patients with detectable PD-L1 expression 
will be more likely to respond to therapy. We further hypothesize that PD-L1 expression will 
increase in patients who fail to have a complete clinical response to radiation plus avelumab at 3 
months following completion of radiotherapy. Exclusion of T-cells in the tumor 
microenvironment has also been linked with lack of response to checkpoint inhibition the 
planned studies will examine the density and subtype of tumor-infiltrating lymphocytes using 
markers such as CD3, CD4, and CD8. 
As described above, based on prior preliminary studies conducted in patients across several 
disease types, PD-L1 expression and greater numbers of infiltrating lymphocytes may predict 
response to PD-1 / PD-L1 inhibitors in certain settings.[22] However, the biologic activity of 
PD-1 / PD-L1 inhibitors suggest that expression of PD-1 on tumor-infiltrating lymphocytes and 
PD-L2 on tumor-infiltrating lymphocytes and tumor immune cells could also be valuable 
predictive biomarkers.[25] Additionally, spatial resolution may be of importance; co-localization 
of multiple protein biomarkers on the surface of tumor cells or tumor-infiltrating lymphocytes 
could add extra diagnostic and predictive value, especially when the amount of tissue available 
for analysis is limited. 
9.1
Laboratory Correlative Studies
Consented subjects processing and collection of tissue will be collected under the GELB 
protocol (DFCI Protocol #15-349). Urine and blood will be collected under either the GELB 
protocol OR this research protocol. 
 
DNA sequencing
Whole exome sequencing (WES) will be performed for all available primary and 
residual/recurrent tumor samples.  WES of germline DNA will also be performed from 

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peripheral blood mononuclear cells (PBMCs).  For urine and plasma samples with detectable 
cfDNA, WES will be performed.  
In addition to determining the mutational status of known bladder cancer genes, WES will also 
allow us to calculate tumor mutational burden and neoantigen load, which have been associated 
with response to checkpoint blockade.[26]  
T cell receptor (TCR) sequencing will be performed from each pre-treatment tumor, from 
residual tumor and adjacent lymph nodes (when available from patients with residual/recurrent 
disease following protocol therapy), and pre-treatment, on-treatment, and post-treatment blood 
samples.
RNA sequencing
Whole transcriptome RNA sequencing (RNAseq) will be performed from available tumor 
samples to determine the transcriptional features of the tumor as well as peri-tumoral immune 
cells.  Genes examined will include known bladder cancer drive genes as well as cytokines, 
chemokines, markers of T-cell exhaustion, and canonical pathways of immune activation or 
suppression.[27] RNAseq will be used to identify infiltrating immune cell populations using 
deconvolution techniques and also confirm expression of predicted neoantigens. 
Flow cytometry 
Flow cytometry will be performed from available PBMCs to provide a detailed examination of 
immune cell subsets and functionality.

42
10. STUDY CALENDAR
 
Screening (28 
day period 
prior to 
Registration)
Cycle 
1 Day 
12,**
Cycle 
2 Day 
1 (± 2 
days)
Cycle 
3 Day 
1 (± 2 
days)
Cycle 4 
Day 1 
(± 2 
days)
End of 
Radiati
on (± 7 
days)
Cycle 5 
Day 1 
(± 2 
days)
Cycle 6 
(± 2 
days) 
30 day 
post-
treatment 
safety 
follow-up 
(+/- 7 days)
End of 
radiation 
follow up  
(70-96 
days post 
RT))7 
Follow 
up14  7
Follow 
up15 
Follow 
up16 =
Post-
treatme
nt years 
>106
Sign Informed 
Consent 
x
 
 
 
 
 
 
 
 
 
 
 
History/Physical 
Exam
x
x
x
x
x
 
x
x
x
x
x
x
x
x
Performance 
status
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
Medications 
x
x
x
x
x
 
x
x
x
x
x
x
x
x
Adverse event 
reporting 
 
x
x
x
x
 
x
x
x
x
x
x
x
x
Avelumab 
 
x
x
x
x
 
x
x
 
 
 
 
Serum pregnancy 
test
x
x
x
x
Radiation1
 
x
x
x
x
 
 
 
 
 
 
 
CBC w/ diff
x
x
x
x
x
 
x
x
x
x
x4
x6
x6
x
Complete 
Metabolic Panel
x
x
x
x
x
 
x
x
x
x
x4
x6
x6
x
HBV, HCV
x
Creatinine 
clearance
x
Free T4 and TSH
x
x
x
x
x
Research Blood 
Collection
x12 
 
 
 
x3
 
 
x13
 
 
 
Urine Sample
x12 
 
 
 
x3
 
 
x13
 
 
 
QLQ-C30
x12 
 
 
 
 x
 
 
x
x
x
x
FACT-Bladder
x12 
 
 
 
 x
 
 
x
x
x
x
AUA Symptom 
Score
x12
x8

DF/HCC Protocol #: 18-464
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Urodynamic 
Evaluation
 
 
 
 
 
 
 
 
 
x8
 
 
Cystoscopy and 
Urine Cytology
 
 
 
 
 
 
 
 
x
x6
x6
x6
x6
 CT of the 
Abdomen 
/Chest/Pelvis9
x
x
x4
x5
x6
x6
Chest X-Ray 
 
 
 
 
 
 
 
x10
x10
x6 10
x6 10
TURBT 
x11 
 
 
 
 
 
 
 
x6
x6
x6
x6
x6
Biopsy
x6
x6
x6
x6
x6
1 Radiation to commence within 14 days of C1D1. On days when both an avelumab infusion and radiation are planned (such as C2D1 and C3D1), either 
avelumab or radiation can be administered first 
2 The first cycle of avelumab will begin within 1-8 weeks of the final TURBT
3 Collected +/- 5 days from the last day of radiation for correlative studies. See section 9.
4 Every 3-6 months
5 Every 12 months 
6 Assessments only done as clinically indicated
7 If the appointment windows for End of Radiation follow up and the 1st post treatment follow up align, appointments can be combined as one. 
8 Urodynamic evaluation (cystometrogram + uroflow, pressure flow study, or fluorourodynamics study) and AUA symptom score are recommended in the 
third post-treatment year for patients who still have a native bladder 
9 A PET/CT that includes the chest, abdomen, and pelvis can also be used, a urogram/chest CT should be performed if feasible, but is not required. 
10 Can be used in place of Chest CT, otherwise not required
11 Can be performed before or after trial enrollment
12 Must be obtained prior to infusion, can happen any time between consent and first infusion.
13 Blood and urine research specimens collected at the End of Radiation Follow Up 
14 Years 1-2 (Every 3 Months (± 14 days)
15 Years 3-5 (Every 6 Months (± 28 days)
16 Years 6-10 (Every Year (± 28 days)
** Labs 3 days before start of treatment do not need to be repeated.

44
11. MEASUREMENT OF EFFECT
11.1.1 Definitions
Complete Response (CR):  Patients will be considered as having a clinical complete response 
when all biopsies are negative for tumor.  A urine cytology specimen that is not positive for 
malignant cells is also required.  Patients with borderline enlarged pelvic lymph nodes that do 
not meet RECIST criteria (i.e., >1 cm in short axis but <1.5 cm in short axis) must have 
shrinkage of the node to <1 cm in short axis).  In this trial, pelvic lymph nodes are defined as 
those included in the radiation treatment field (see Section 5.1.3.5).
Partial Response (PR):  A PR requires all response criteria for a CR with the exception of either a 
urine cytology that is positive for malignant cells or Ta/Tis tumor present in a bladder biopsy 
specimen. 
No Response (NR):  NR is defined as the presence of the tumor (≥T1) in the tumor-site biopsy 
specimen. 
Progressive Disease (PD):  PD is defined as an increase of 50% or more in the largest diameter 
of the endoscopically appreciable tumor in the tumor-site biopsy specimen, the development of 
new bladder tumors (≥T1), or the development of metastatic disease.
Distant metastasis (DM): The first appearance of disease in a lymph node, solid organ, or bone. 
This may be identified on routine follow-up imaging or on a study performed to evaluate a 
specific patient complaint. Additional radiographic studies or biopsies may be performed at the 
discretion of the treating physician in equivocal cases but are not required. Radiographic 
evidence of metastasis is sufficient for evaluation of this endpoint. Time to development of 
distant metastasis will be defined as the time from the start of protocol therapy to the first 
appearance of distant metastasis.
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions in the bladder are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) by a urologist.  
Measurable non-bladder lesions are those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) and are ≥20 mm by chest x-ray or ≥10 mm on CT 
scan, MRI, or with calipers on clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 

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diameter <10 mm or lymph nodes with ≥10 to <15 mm short axis), are considered non-
measurable disease.  
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be optimized for 
the evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST guidelines 
to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with breath-hold 

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scanning techniques, if possible.
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD.
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if it 
can be documented that the CT performed as part of a PET-CT is of identical diagnostic quality 
to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used 
for RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.  
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later data and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure from CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological response 

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when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases.
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
11.1.4 Response Criteria
11.1.4.1
Evaluation of Bladder Tumor and Pelvic Lymph Nodes
Complete Response (CR):  Patients will be considered as having a clinical complete response 
when all biopsies are negative for tumor.  A urine cytology specimen that is not positive for 
malignant cells is also required.  Patients with borderline enlarged pelvic lymph nodes that do 
not meet RECIST criteria (i.e., >1 cm in short axis but <1.5 cm in short axis) must have 
shrinkage of the node to <1 cm in short axis).  In this trial, pelvic lymph nodes are defined as 
those included in the radiation treatment field (see Section 5.1.3.5).
Incomplete response:  Any response other than a CR.  See sections 11.1.1 and 11.1.2 for 
additional definitions.
11.1.4.2
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e., not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor; for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical location that was not scanned 
at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of small 
size, etc.), follow-up evaluation will clarify if it truly represents new disease and, if PD is 
confirmed, progression should be declared using the date of the initial scan on which the lesion 
was discovered.
11.1.5 Duration of Response
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is 
objectively documented, or death due to any cause.  Participants without progressive disease or 
death are censored at the last disease evaluation.
11.1.6 Local Control

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Local control is defined as lack of biopsy-proven invasive (T1) recurrence in the bladder.  Non-
invasive bladder recurrences (Ta/Tis) are not considered local failure and can be managed 
conservatively with transurethral resection with or without intravesicular therapy.
11.1.7 Locoregional Control
Locoregional control is defined as lack of biopsy-proven invasive (T1) recurrence in the 
bladder and lack of imaging evidence of a pathologically enlarged lymph node within the 
radiation field (see Section 5.1.3.5 for anatomic boundaries of pelvic radiation field).
11.1.8 Metastasis-free survival
Metastasis-free survival is defined as the time from start of protocol therapy to the date of 
development of disease outside of radiation field (bladder or radiated portion of the pelvis; see 
Section 5.1.3.5 for anatomic boundaries of pelvic radiation field), such as disease in a non-
radiated lymph node, a solid organ, or bone. This may be identified on routine follow-up imaging 
or on a study performed to work-up a specific patient complaint. Additional radiographic studies 
or biopsies may be performed but are not required. Radiographic evidence of metastasis is 
sufficient for evaluation of this endpoint. Participants without events reported are censored at the 
last disease evaluation.
11.1.9 Cystectomy-free Survival
Cystectomy-free survival is defined as the time from start of protocol therapy to the date of 
cystectomy for any reason (progressive disease, toxicity, etc).  Participants without events 
reported are censored at the last disease evaluation.
11.1.10
 Progression-Free Survival
Progression-free survival is defined as the time from start of protocol therapy to the date of 
disease recurrence, defined as biopsy-confirmed invasive (T1) disease in the bladder, or 
radiographic and/or pathologic evidence of disease in a lymph node or a metastatic site, or death, 
whichever comes first.  Participants without events reported are censored at the last disease 
evaluation.
11.1.11
 Overall Survival
Overall survival is defined as the time from start of protocol therapy to the time of death from 
any cause.  Participants without events reported are censored at the date last known to be alive.
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).

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12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request. 
12.3
Collaborative Agreements Language
N/A
13. STATISTICAL CONSIDERATIONS
Bladder-preserving trimodality therapy (TMT) consisting of maximal transurethral resection of 
the bladder tumor (TURBT) followed by concurrent chemoradiotherapy is an acceptable 
alternative to radical cystectomy-based therapy for muscle-invasive bladder cancer (MIBC).[2]  
The addition of cisplatin-based chemotherapy to radiation improves disease outcomes compared 
to radiation alone; however, a subset of MIBC patients are not eligible for cisplatin-based 
chemotherapy.[4]  Non-cisplatin based concurrent chemotherapy regimens are also available, but 
these regimens can be associated with significant toxicity and none have been shown to improve 
overall survival compared to radiation alone.[8, 9]  
In RTOG 0524, a recently published multi-institutional study of non-cisplatin based TMT for 
cystectomy-ineligible MIBC patients, 70% of patients completed the planned course of 

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chemoradiotherapy.[9]  Among the patients who completed chemoradiotherapy, the 3 month 
complete clinical response rate was 60%.  
Immune checkpoint inhibitors (anti-PD1 and anti-PD-L1 agents) are active in cisplatin-ineligible 
patients with metastatic bladder cancer[30]; however, the role of immune checkpoint inhibitors 
in non-metastatic bladder cancer is unknown.  
13.1
Study Design/Endpoints
13.1.1 Primary Endpoint
The primary endpoint in this study is the 3-month complete clinical response rate.  This 
evaluation is performed at 3 months (10-14 weeks) from the date of the last radiation treatment.  
A complete response requires that all biopsies are negative for tumor and that a urine cytology 
specimen is not positive for malignant cells. See Section 11.1.1 for definition. 
.
The historical 3-month complete response rate is based on published data from RTOG 0524, a 
recently reported multi-institutional study of TMT for cystectomy-ineligible MIBC patients.  
Although cystectomy-ineligibility is not required for this current trial, the characteristics of 
patients who are cystectomy-ineligible and those who are cisplatin-ineligible are often closely 
correlated (i.e., many cisplatin-ineligible patients are often also poor cystectomy candidates).  In 
contrast, many TMT trials that use concurrent cisplatin-based chemotherapy enroll patients who 
are likely to be significantly healthier than the patients who are likely to enroll on this trial.
Across the two arms of RTOG 0524 (paclitaxel plus radiation or paclitaxel/traztuzumab plus 
radiation), 70% of patients completed the planned radiation course.  Of these patients, 62% had a 
complete response at 3 months.  Therefore, the complete response rate among all enrolled 
patients was 0.7 x 0.62 = 0.43, or 43%.  
We hypothesize that the combination of avelumab and radiation will result in an improvement in 
the 3-month complete response rate following completion of radiotherapy. 
13.1.2 Secondary endpoints
13.1.2.1
Overall survival: Overall survival is defined as the time from start of 
protocol therapy to the time of death from any cause.  Participants without a 
death event reported are censored at the date last known to be alive.  
Participants without a death event or who are lost to follow up will be 
censored at the last date of known follow-up.
13.1.2.2
 Progression-free survival: Progression-free survival is defined as the time 
from start of protocol therapy to the date of disease recurrence, defined as 
                     biopsy-confirmed invasive (T1) disease in the bladder, or radiographic and/or 
                     pathologic evidence of disease in a lymph node or a metastatic site, or death, 
                     whichever comes first.  Participants without PFS events reported are censored at 

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   the last disease evaluation.
13.1.2.3
Metastases-free survival:  Metastasis-free survival is defined as the time 
from start of protocol therapy to the date of development of radiographic 
and/or pathologic evidence of disease outside the radiation field, or death, 
whichever comes first. Participants with MFS events reported are censored at  
the last disease evaluation.
13.1.2.4
Locoregional control:  Locoregional control is defined as lack of biopsy 
proven invasive (T1) recurrence in the bladder and lack of imaging evidence 
of a pathologically enlarged lymph node within the radiation field.
13.1.2.5
Quality-of-life (QOL):  Patient-reported quality of life (QOL) data will be 
collected longitudinally using two validated QOL instruments (QLQ-C30 and   
FACT-Bladder questionnaires).  
13.1.3  Exploratory Endpoints
13.1.3.1
Genomic alterations:  Whole exome sequencing of tumor and matched 
germline DNA will be performed.  Copy number and mutational events will 
be identified and genomic features will be correlated with clinical data.
13.1.3.2
Gene expression:  Whole transcriptome RNAseq will be performed and 
gene expression-based subtying and gene set enrichment analysis will be 
performed.  
13.1.3.3
Immune features:  Tumor immune features will be characterized by 
immune-based IHC and TCR sequencing, and results will be correlated with 
clinical data.
13.1.3.4
Urine-based biomarkers:  Pre-treatment and post-treatment urine samplese 
will be collected and urine cell-free DNA analysis will be performed.  Results 
will be correlated with clinical data.
13.1.4 Study Design
Simon's two-stage minimax design will be applied.[31] The null hypothesis that the true 
response rate is 0.43 will be tested against a one-sided alternative. In the first stage, 12 patients 
will be accrued. If there are 5 or fewer responses measured by the 3 month complete clinical 
response rate following completion of radiotherapy in these 12 evaluable patients, the study will 
be stopped. Otherwise, 12 additional patients will be accrued for a total of 24. The null 
hypothesis will be rejected if 15 or more responses are observed in 24 patients. This design 
assumes a type I error rate of 0.05 and power of 80% when the true response rate is 0.68. The 
probability of early stopping is 0.56. All patients with intent-to-treat are evaluable patients.

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Accrual pause period: As the complete clinical response rate is evaluated at 3 months from the 
date of last radiation treatment, there will be a “accrual pause period” of  maximum 4 months (3 
month for the maturity of the last patient enrolled in first stage plus maximum of 1 month for 
data evaluation period) after the 12th patient (the last patient) in the first stage completes 
radiation, and a decision will be made whether accrual will be continued to second stage or not 
based on the decision rule described above.
13.2
Sample Size, Accrual Rate and Study Duration
The total sample size will be 24 (12 patients in the first stage and 12 patients in the second stage 
if continued) as described above.  The expected accrual rate is one patient per month.  The trial 
will be conducted over 32 months.
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
2
+
4
=
6
Not Hispanic or Latino
5
+
13
=
18
Ethnic Category: Total of all subjects
7
(A1)
+
17
(B1) =
24
(C1)
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian
0
+
1
=
1
Black or African American
1
+
2
=
3
Native Hawaiian or other Pacific 
Islander
0
+
1
=
1
White
6
+
13
=
19
Racial Category: Total of all subjects
7
(A2)
+
17(B
2)
=
24(C2
)
(A1 = A2)
(B1 = B2)
(C1 = C2)
We target the accrual of the trial to match the ethnic breakdown of the state of Massachusetts, 
which was estimated by the US Census Bureau in 2013 to be 75.1% non-Hispanic White, 10.5% 
Hispanic, 8.1% Black, 6.0% Asian, 0.5% Native American, 2.1% with two or more races, and 
0.1% other.
13.3
Stratification Factors
Patients will not be stratified.  
13.4
Interim Monitoring Plan
No interim monitoring will be performed.

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13.5
Analysis of Primary Endpoints
The primary analysis will be an evaluation of 3-month complete clinical response rate for all 
patients (intent-to-treat population) that started treatment. No replacement will be performed for 
any patients who were removed from the trial after initiating treatment. Exact proportions and 
95% confidence intervals for 3-month complete clinical response rate will be provided. 
13.6
Analysis of Secondary Endpoints 
13.6.1 Overall survival
Overall survival is defined as the time from start of protocol therapy to the time of death from 
any cause. Overall survival (OS) will be evaluated with Kaplan-Meier curves methods and Cox 
regression Patients without a death event will be censored at the date last known to be alive. See 
section 11.1.11 for definition.
13.6.2 Progression-free survival
Progression-free survival (PFS) will be evaluated with Kaplan-Meier curve methods and Cox 
regression. PFS  is defined as the time from the start of protocol treatment to progression or 
death due to any cause. Patients without a PFS event will be censored at the date of last disease 
evaluation for progression. 
13.6.3 Locoregional control
Locoregional control will be calculated as the percentage of evaluable patients with lack of 
biopsy-proven invasive (T1) recurrence in the bladder and lack of imaging evidence of 
pathologically enlarged lymph node within the radiation field at the time of the first post-
treatment assessment (10-14 weeks following completing of radiation).
13.6.4 Quality-of-life
Patient-reported quality of life (QOL) data will be collected longitudinally using two validated 
QOL instruments (QLQ-C30 and FACT-Bladder questionnaires).  QOL data will be analyzed 
using linear models for repeated measures data. 
13.7
Reporting and Exclusions
13.7.1 Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first treatment.
13.7.2 Evaluation of the Primary Efficacy Endpoint

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The primary endpoint will be analyzed on an intent-to-treat basis.  
14. PUBLICATION PLAN
The results will be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes will be made public no later than three (3) 
years after the end of the study. 

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APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.