Conditions: Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall Stage II Bladder Cancer AJCC v8 Stage II Renal Pelvis Cancer AJCC v8 Stage II Ureter Cancer AJCC v8 Stage II Urethral Cancer AJCC v8 Stage III Bladder Cancer AJCC v8 Stage III Renal Pelvis Cancer AJCC v8 Stage III Ureter Cancer AJCC v8 Stage III Urethral Cancer AJCC v8 Stage IIIA Bladder Cancer AJCC v8 Stage IIIB Bladder Cancer AJCC v8 Urethral Urothelial Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects of avelumab and how well it works in combination with fluorouracil and mitomycin or cisplatin and radiation therapy in treating participants with muscle-invasive bladder cancer. Monoclonal antibodies, such as avelumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as fluorouracil, mitomycin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving avelumab with chemotherapy and radiotherapy may work better in treating participants with muscle-invasive bladder cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the complete response rate of concurrent chemotherapy radiation treatment combined with avelumab for patients with muscle invasive bladder cancer.

SECONDARY OBJECTIVES:

I. To evaluate the safety and toxicity (adverse event profile) of concurrent chemotherapy radiation treatment combined with avelumab.

II. To evaluate quality of life (QoL) at 1 year of concurrent chemotherapy radiation treatment combined with avelumab.

III. To evaluate progression-free survival and relapse-free survival at 1 year with concurrent chemotherapy radiation treatment combined with avelumab.

CORRELATIVE OBJECTIVES:

I. To explore biomarkers that may predict response to avelumab in the muscle invasive population.

II. To evaluate the association of tumor mutational burden with response to concurrent chemo- radiation and immunotherapy.

III. To evaluate whether concurrent chemoradiation and immunotherapy after maximal transurethral resection of bladder tumor (TURBT) is associated with a decrease in circulating Bim+CD11a\^high PD-1+CD8+ T-cells and myeloid-derived suppressor cells (MDSCs).

OUTLINE:

Participants receive avelumab intravenously (IV) over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during radiation therapy (RT) and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, 6, 9, and 12 months.

Arms:
arm 1: Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Avelumab intervention 2: Cisplatin intervention 3: Fluorouracil intervention 4: Mitomycin intervention 5: Quality-of-Life Assessment intervention 6: Radiation Therapy
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Ancillary studies intervention 6: Undergo RT

Protocol document:
Prot_SAP_000.pdf: 




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Table of Contents 
Phase II study evaluating combination chemotherapy + Radiotherapy (RT) with avelumab in 
muscle invasive bladder cancer. ................................................................................................................ 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ........................................................................................................................................... 12 
3.0 
Registration Patient Eligibility .................................................................................................... 13 
4.0 
Test Schedule .............................................................................................................................. 16 
5.0 
Grouping Factor: ......................................................................................................................... 19 
6.0 
Registration Procedures .............................................................................................................. 19 
7.0 
Protocol Treatment ...................................................................................................................... 22 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 27 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 37 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 43 
11.0 
Treatment Evaluation .................................................................................................................. 52 
12.0 
Descriptive Factors: .................................................................................................................... 53 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 53 
14.0 
Body Fluid Biospecimens ........................................................................................................... 55 
15.0 
Drug Information ........................................................................................................................ 55 
16.0  
Statistical Considerations and Methodology ............................................................................... 64 
17.0  
Pathology Considerations/Tissue Biospecimens ......................................................................... 70 
18.0 
Records and Data Collection Procedures .................................................................................... 72 
19.0 
Budget Considerations ................................................................................................................ 72 
20.0 
References ................................................................................................................................... 73 
Appendix I 
ECOG Performance Status ............................................................................................... 75 
Appendix II 
EORTC QLQ-C30 ............................................................................................................ 76 
Appendix III 
EORTC QLQ-BLM30 ...................................................................................................... 78 
Appendix IV 
Patient Information Sheet ................................................................................................. 81 
 
 
 
 
 
 
 
 
 
 


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Schema 
 
 
For the run-in portion only, prior to discussing protocol entry with the patient, call the MCCC 
Registration Office (
) to insure that a place on the protocol is open to the patient.  
 
 
Registration  
 
 
↓ 
 
 
Concurrent chemo RT + (Avelumab 
x10 cycles)  
 
 
↓ 
 
 
End of Treatment (30 days after last 
avelumab dose) 
 
 
↓ 
 
 
Events at any time: 
Disease Progression 
Intolerable adverse effects 
Pregnancy 
Patient refusal 
 
 
↓ 
 
 
Clinical Follow-up (CFU) 6 month, 
9 month, 12 month after registration 
 
 
Cycle = 14 days 
NOTE: All cycles will be based on avelumab given once every 14 days. 
Chemo therapy may be given as clinically indicated and any delays are per healthcare provider’s 
discretion. Radiation therapy to be given as clinically indicated per section 7.2. Options for concurrent 
chemotherapy (Providers choice) listed below. They do not affect the cycle length. (See Section 7.1) 
 
 
Generic name: avelumab 
Brand name(s): Bavencio 
Mayo Abbreviation: AVELUMAB 
Availability: Drug company providing to Mayo 
Clinic Pharmacy 
Generic name: 5-fluorouracil 
Brand name(s): Adrucil  
Mayo Abbreviation:  5FU 
Availability: Commercial 
Generic name: mitomycin 
Brand name(s): Mutamycin 
Mayo Abbreviation: MITOC 
Availability: Commercial 
Generic name: cisplatin 
Brand name(s): Platinol 
Mayo Abbreviation:  CDDP 
Availability: Commercial 


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1.0 
Background  
1.1 
Defining clinical unmet need 
In the US alone over 75,000 new patients are diagnosed every year with bladder cancer 
and the median age is 73 years. Treatment patterns in the community consistently 
demonstrate that despite potential lethal outcomes, many patients with bladder cancer do 
not receive appropriate aggressive and potentially curative therapy. Analysis of over 
28,000 patients with T2-T4a bladder cancer in National cancer database showed that only 
52% patients received aggressive therapy for their bladder cancer and over 25% patients 
received observation only. [1]  As our population is aging, the predominant proportion of 
the newly diagnosed patients are elderly and they are even at higher risk of not receiving 
appropriate care. A recent NCDB analysis evaluated over 9000 patients diagnosed with 
bladder cancer with age greater than 80. [2] They observed that only 4.2 percent of the 
patients received standard of care chemotherapy followed by radical cystectomy, while 
44% underwent TURBT alone. A study looking at data from the SEER database 
demonstrated that only 21% of patients received radical cystectomy for stage II or higher 
bladder cancer. At the same time radical cystectomy can potentially be a life changing 
event for many patients. Even in experienced specialized centers, radical cystectomy 
entails a high risk of morbidity(up to 60%) and mortality of up to (2.5%)[3] A number of 
patients may not be fit for or refuse radical cystectomy . These data clearly indicate the 
need to improve access to definitive therapy and to test strategies to improve the 
outcomes with CRT.  
 
Combined analysis of RTOG/NRG patients enrolled on concurrent CRT trials has shown 
a complete response rate of 69% with five-year overall survival of 57% and disease-
specific survival of 71%.[4, 5] In a propensity-matched retrospective analysis the group 
from Princess Margaret Hospital in Toronto reported no differences in 5-year disease-
specific survival between trimodality therapy and radical cystectomy (RC) (76.6% vs. 
73.2%, p=0.49).[6]  In a recent 2017 guideline paper from collaborative panel   of experts 
from American Urological Association, American Society of Clinical Oncology, 
American Society of Radiation Oncology and Society of Urologic Oncology 
recommended that bladder preservation therapy is the preferred treatment for patients 
desiring bladder preservation and understand the unique risks associated with this 
approach and/or those who are medically unfit for surgery.[19] 
1.2 
Development of concurrent CRT in bladder cancer 
Cisplatin as single agent or in combination with 5-FU had traditionally been the drug of 
choice for radio- sensitization. Earlier trials investigated the role of neoadjuvant 
chemotherapy prior to radiation alone and demonstrated 6% absolute survival advantage 
at 10 years.[8]. Subsequent trials investigated the role of neoadjuvant chemotherapy 
followed by CRT. In one of these trials, RTOG  89-03, patients were randomized to 
concurrent CRT with or without neoadjuvant chemotherapy. The trial was prematurely 
closed when an increased incidence of neutropenic complications was observed.  The 
analysis of enrolled patients showed no significant benefit of neoadjuvant 
chemotherapy.[9] In the large phase III trial BC2001, where neoadjuvant chemotherapy 
was allowed but not mandated, one third of patients received neoadjuvant chemotherapy. 
The primary endpoint of loco-regional disease control was not different in the group 
receiving neoadjuvant chemotherapy as compared to the one without chemotherapy.  
BC2001 also demonstrated that an alternative chemotherapy regimen, 5- fluorouracil and 
mitomycin, can be used effectively, including in patients with poor renal function who 




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BC2001
[10] 
55-64 Gy 
5FU500 + MMC12 (5d 
CI) 
36
0 
NR 
89% 
(2yr) 
82% 
(2yr) 
48% 
Table 1: CRT  Clinical Trial Results [9, 10, 13-19] 
(N = number of patients, CR = complete response rate, yr = year, LRFS = local relapse free survival, OS 
= overall survival, Gy = gray, C = cisplatin, NAC = neoadjuvant chemotherapy, M = methotrexate, V = 
vinblastine, BID = twice daily, fxns = fractions, 5FU = 5-fluorouracil, d = days, wkly = weekly, P = 
paclitaxel, G = gemcitabine, Adj = adjuvant chemotherapy, NR = not reported, TROG = Tazmanian 
radiation oncology group, DSS = disease specific survival, MMC = mitomycin C, CI = continuous 
infusion) 
1.3 
Rationale for combining immune checkpoint inhibition and concurrent chemo 
radiation  
In recent years checkpoint inhibitor therapy (CPI) has been approved for multiple cancer 
types including bladder cancer. These drugs have shown significant activity in patients 
who are cisplatin ineligible and those that have progressed following treatment with first 
line platinum based chemotherapy[11, 20-23].    These drugs are known for their 
durability of response and excellent tolerability but limited overall response rate.  
Both chemotherapy and radiotherapy have pleiotropic effects on the immune system that 
can potentially trigger an antitumor response. It has been shown in pre-clinical and 
clinical settings that checkpoint inhibition in combination with either modality of therapy 
can augment and sustain this antitumor activity. For example, Apetoh et al. demonstrated 
the emission of a danger signal known as high mobility box binding protein-1 (HMGB1) 
from dying tumor cells in response to either chemotherapy or radiotherapy.[24]    Tumor 
HMGB1 expression in combination with toll-like receptor-4 (TLR4) expression on 
dendritic cells was shown to be prerequisites for effective tumor antigen presentation. 
Another example is demonstrated with anthracyclines, which are used in the treatment of 
both NMIBC and MIBC. Anthracyclines induce rapid production of type I interferons, 
which in turn induce chemokine ligand 10 (CXCL10) release which is intricately 
involved in tumor cell death. [25]    Wu et al. demonstrated in cell lines that radiation can 
induce PD-L1 expression in tumor cells and addition of a PD-L1 inhibitor to radiation 
decreased cell proliferation and augmented cell death. [26]  The same group investigated 
PD-L1 expression in pre-treatment biopsies in patients who had received concurrent  
CRT  for bladder cancer. They observed that high PD-L1 expression was significantly 
associated with lower complete response rates after CRT. Recently published studies in 
non-small cell lung cancer demonstrated superior efficacy and safety of combining 
checkpoint inhibitors and chemotherapy vs. chemotherapy alone leading to a change in 
treatment paradigm[27] In a retrospective series of lung cancer patients who had received 
prior radiation, either- concurrent with or following checkpoint inhibition therapy, the 
authors observed a modest increased risk of severe side effects especially in the group 
receiving radiation after immunotherapy.[28] Multiple groups have published their 
experience in melanoma and lung cancer with combining radiation and checkpoint 
inhibitors reporting abscopal effects raising the possibility of not only improving local 
control but also of reducing systemic recurrences.[29, 30].  
Data from these studies is hypothesis generating and suggest that a combinatorial strategy 
of CRT and checkpoint inhibition could improve outcome in localized muscle invasive 
bladder cancer. There is potential for an increase in local GI, GU and systemic immune- 
related side effects that would need to be balanced with the potential benefit of 


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combination therapy. There is clearly an unmet need to optimize the integration of these 
therapies in order to lower the impact of potential antagonistic interactions and also 
assess additive toxicity.  
In this study we are testing the efficacy of avelumab in combination with concurrent 
CRT. Avelumab,   (MSB0010718C) is an investigational fully human anti–PD-L1 IgG1 
antibody that inhibits PD-1/PD-L1 interactions while leaving the PD-1/PD-L2 pathway 
intact. This enhances immune activation against tumor cells. Unlike other anti–PD-
L1/PD-1 antibodies that are approved or in advanced clinical development, avelumab 
induces lysis of tumor cells via antibody-dependent cell-mediated cytotoxicity in vitro, 
suggesting an additional mechanism of action.  Importantly, avelumab has not shown 
antibody-dependent cell-mediated cytotoxicity against immune cell subsets in humans.  
In a large phase Ib study evaluating range of tumor types, avelumab showed activity in a 
44 patient cohort of patients with metastatic urothelial carcinoma refractory to 
chemotherapy. Subsequent study including two hundred and forty two patients with 
locally advanced or metastatic urothelial carcinoma with disease progression on or after 
platinum containing chemotherapy.  The confirmed overall response rate was 13 % at 13 
week follow up. Toxicities were consistent with this class of drugs with 5.5% of patients 
having grade 3-4 treatment related toxicity.   Based on this study it received approval for 
use in patients with urothelial carcinoma who have progressed on platinum containing 
chemotherapy.    The proposed study will be a phase II single arm trial evaluating 
combination of chemoradiation with avelumab in patients with T2-T4a N0M0 bladder 
cancer. The trial has built in safety run in of 6 patients and accrual will be stopped to 
evaluate toxicity after 6 patients are enrolled.  
1.4 
Safety data from combination of immunotherapy and radiation or chemotherapy. 
Safety of immunecheckpoint inhibitors in combination with chemoradiation for bladder is 
not established.  However there is data from other tumor types which shed light on 
activity and potential adverse events. Pembrolizumab was recently   approved in 
combination with chemotherapy in lung cancer. This approval was based on a phase III 
trial as mentioned above. The most common immune-mediated adverse events of any 
grade in avelumab plus chemotherapy groups were hypothyroidism(15%), 
hyperthyroidism(8%) and pneumonitis (5%).Overall no significant increase in toxicity as 
compared to chemotherapy alone arm.  Interestingly, in a previous trial evaluating 
avelumab alone vs  physician choice chemotherapy  in lung cancer,  hypothyroidism was 
observed in (9%) of patients, hyperthyroidism (7.8%) and pneumonitis (5.8%). Another 
phase III study evaluating durvalumab consolidation after definitive chemoradiotherapy 
in lung cancer observed 3.4% grade 3-4 immune related side effects vs 2.6% in the 
placebo arm. [31] This lead to recent apporval of durvalumab in lung cancer for 
maintainence therapy after concurrent chemoradiation. 
There is ongoing phase I/II trial of gemcitabine with radiation and pembrolizumab for 
muscle invasive bladder cancer at New York University hospital. Among 6 patients 
enrolled by December 2017  one patient had dose limiting toxicity of diarrhea which 
responded to steroids.(personal communication with Arjun Balar, MD) another similar 
trial opened through Australian and New Zealand Urogenital and Prostate cancer trials 
group is  evaluating pembrolizumab with cisplatin and radiation for localized muscle 
invasive bladder cancer. The trial has enrolled 4 patients who all have finished their 
concurrent chemoradiation and are currently on adjuvant avelumab by December 2017( 
personal communication Andrew Weickhardt, MD ) . None of the patients had any grade 
3-4 toxicity which would require treatment delays.   


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No published  safety data exist with avelumab  or any other checkpoint inhibitor therapies 
in patients receiving definitive pelvic radiation doses of up to 64.8 Gy as is standard in 
MIBC. IMpower132 is evaluating atezolizumab in combination with cisplatin and 
pemetrexed   in lung cancer   and safety analysis is expected in first quarter of 2018.  
Atezolizumab is also being investigated in a phase II trial in combination with concurrent 
chemotherapy and radiation in lung cancer at MD Anderson cancer center. In personal 
communication with the Stephen Li(PI) 25 patients have been enrolled on to the study. 
Fifteen patients have finished their protocol assigned treatment with only one patient 
having immune related pneumonitis. This patient was taken off atezolizumab and 
responded to steroids and recovered completely.  No excess toxicity was observed and all 
patients completed the protocol assigned concurrent chemoradiation therapy. 
While the safety data of avelumab is impressive thus far, MIBC patients represent a 
patient population in which the goal of therapy in not only cure  of bladder cancer but 
also reduce morbidity associated with the treatment. This proposal will give us insights 
into the safety of combining immune check point inhibitor with concurrent 
chemoradiation.  Therefore this trial has been designed to evaluate both early signals of 
safety and maintain close monitoring throughout the trial for any excessive toxicity. The 
translational work associated with the clinical trial will help prepare for preliminary data 
for similar proposal that we will prepare for the phase III clinical trial which PI is 
preparing for NCI.       
1.5 
Correlative Research 
It is becoming increasingly recognized that cancers can thrive upon evading the immune 
system.  Malignancies such as urothelial carcinoma, melanoma and   renal cell carcinoma 
are known to exploit the programmed death 1 (PD-1) pathway in order to evade the 
immune system through adaptive immune resistance. [1-3] Monoclonal antibodies 
targeting PD-1 have recently been introduced, and have been shown to improve survival 
when used in patients with advanced  bladder cancer  who have previously failed  prior 
cisplatin based chemotherapy or are ineligible for chemotherapy.[1, 4-6]   
The success of PD-1 blockade therapy in treatment of solid cancers is dependent on the 
presence of pre-existing tumor-reactive CD8+ T lymphocytes[3, 7]. Sharma et al had 
shown previously that patients with advanced urothelial carcinoma have higher numbers 
of CD8+ TILs within the tumor. They also observed positive correlation of advanced 
stage and better disease free survival and overall survival with higher number of CD+8 
cells.  [7]We and others have established that PD-1 and CD11a can be used to identify 
tumor-reactive CD8+ cytotoxic T lymphocytes in the peripheral blood or in tumor tissues 
[8-10].   We observed that patients with advanced cancers have high levels of 
CD11ahighPD-1+ CD8+ T cells in peripheral blood [8].  
Bim (BCL-2-interacting mediator of cell death) is a downstream pro-apoptotic signaling 
molecule of PD-1 in antigen-primed CD8+ T-cells [11]. Interaction of PD-L1 (the ligand 
expressed on tumor cells) with PD-1 (on the cell surface of T-cells), leads to the 
upregulation of Bim in tumor-reactive (PD-1+ CD11a high) CD8+ T-cells [2]. Given that 
Bim is a pro-apoptotic mediator, this upregulation essentially leads to the removal of 
tumor-reactive effector CD8+ T-cells from the memory pool, which leads to tumor 
resistance to the immune system.[2]  Interestingly, in patients with metastatic melanoma 
who did not receive anti-PD-1 therapy, high levels of Bim in circulating PD-1+ CD11a 
high CD8+ T-cells predicted poor survival, while it was predictive of clinical benefit with 
treatment using anti-PD-1 therapy. Furthermore, the frequency of Bim+ PD-1+ CD11a+ 
CD8+ T-cells decreased in responders to anti-PD-1 therapy, but not in non-responders. 


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[2]  All this data and common theme in response to immune therapy among various solid 
tumors begs investigation in bladder cancer which is a solid tumor in which 
immunotherapy appears to be very effective in select group of patients. It remains to be 
evaluated whether high levels of Bim in circulating PD-1+ CD11a high CD8+ T-cells are 
associated with more aggressive disease in bladder cancer and it’s eventual impact on 
outcomes with concurrent chemoradiation and immunotherapy.    
On the other hand, we recently identified that CX3CR1 defined a PD-1 therapy-
responsive CD8+ T cells with effector memory phenotype and function. In responders to 
PD-1 therapy or combined (chemotherapy), CX3CR1 identified an increased CD8 T cell 
population with effector function and endure cytotoxic chemotherapy drugs. Thus, 
measurement of CX3CR1+ among CD11a high CD8 T  cells will give us a full coverage 
of therapy-responsive T cell population for understanding the potential cellular 
mechanism underlying clinical outcomes in patients following immunotherapy or 
combined therapy.  
Myeloid-derived suppressor cells (MDSCs)  which  comprise of heterogenous population 
of cells consisting of myeloid progenitor cells and immature myeloid cells have been 
associated with cancer progression and tumor – induced immune dysfunction in variety 
of solid and hematologic malignancies including bladder cancer.  MDSCs cells observed 
in bladder cancer expressed CD11b+CD33lowHLA-DR−CD3− .  
CD11b+CD33lowHLA-DR−CD3−  cells were significantly higher peripheral blood  in 
bladder cancer patients as compared to healthy donors and correlated with advanced stage 
( Ta/T1 vs T2-4).  In a Mayo study of prostate cancer patients undergoing salvage 
lymphadenectomy, we evaluated compared CD14+ monocytic and CD14- granulocytic 
MDSCs, and found that the latter exhibited immunosuppressive activity with high 
expression of PD-L1 (Sharma, Dong and Karnes; unpublished). Given the presence of a 
systemic immune dysfunction in BC, this warrants further study in patients with BC. 
Specifically, it is unclear whether higher MDSC levels (and the relative proportions of 
the granulocytic and monocytic subtypes) in the peripheral blood are associated with 
adverse  clinical outcomes after concurrent chemoradiation and immunotherapy. 
Clinical response to chemoradiotherapy (CRT) combined with immunotherapy (CIRT) 
may be predicted by both genomic and immune-based markers (1, 2).    It is anticipated 
that the addition of immunotherapy to CRT will improve the immune response to 
bladder-directed CRT by global alteration of T-cell function. Augmented response to 
combination CRT and immunotherapy (CIRT) may occur by several mechanisms 
including 1) increased numbers of neoantigens, 2) induction of tumor antigen-specific 
immune response after CRT resulting in cross presentation of released tumor antigens by 
dendritic cells in draining lymph nodes and 3) reversal of T-cell exhaustion by immune 
checkpoint inhibitors leading to improved clinical response compared to CRT alone (3).  
A large single arm phase II trial (IMvigor210) with two large independent parallel 
bladder cancer cohorts (310 and 119 patients) showed that higher TMB was very strongly 
associated with higher response rate and longer overall survival with atezolizumab (P < 
0.0001; Rosenberg et al. Lancet 2016; Balar et al. Lancet 2016). In the confirmatory large 
IMvigor 211 phase III clinical trial, 931 bladder cancer patients were randomized to 
atezolizumab or chemotherapy. In patients with higher TMB (N=274), overall survival 
was longer with atezolizumab vs. chemotherapy (median 11.3 months [95%CI 8.7–13.2] 
vs 8.3 months [7.2–10.4]; HR 0.68, 95%CI 0.51–0.90), while in patients with low TMB 
(N=270), survival was similar in treatment arms (median 8.3 months [6.4–9.8] vs 8.1 
months [6.2–10.4]; 1.00, 0.75–1.32 (Powles T et al. Lancet 2017). Moreover, higher 
TMB correlated with better response to immunotherapy in a variety of tumor types 


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(Goodman AM et al. Mol Cancer Ther. 2017;16(11):2598-2608). In addition, recent data 
support that the large proportion of mutant neoantigens in mismatch repair-deficient 
tumors, as well as those with DNA damage response gene mutations, render them 
sensitive to immune checkpoint blockade in several solid tumors, including bladder 
cancer (Le DT et al. Science. 2017;357(6349):409-13; Teo et al. 2017 ASCO Meeting; 
Iyer et al. 2017 ASCO Meeting). Therefore, a critical goal is to assess predictors of 
response to local and systemic immune activity. 
The predicted somatic neoantigenic load is a product of the somatic TMB. Somatic 
mutations result in the formation of altered peptides recognized as ‘‘non-self’’ by the 
immune system . These 9- to 11-amino acid peptides termed nonamers are subsequently 
presented in the major histocompatibility complex (MHC)- class I context and recognized 
by cytotoxic T cells . This suggests that a high mutational burden would evoke a more 
robust antitumor immune response that could be reinvigorated by ICIs. Several studies 
show the correlation between mutational load and response to ICIs in advanced UC13 
and other cancers . In primary muscle-invasive bladder UC, patients with fewer 
neoantigens have shorter RFS compared to those with a high neoantigenic load.. 
The predicted neoantigenic burden was previously reported as a favorable prognostic 
indicator of increased patient survival in six major cancer types (colorectal, ovary, breast, 
brain, kidney, and lung). Inferring the MHC haplotypes from the sequence of germline 
DNA and combining this information with somatic mutational data can help predict 
mutant nonamers that can bind to patients’ specific MHC complexes.  
PD-L1 expression was previously thought of a possible predictor of response to IO 
therapy. Multiple studies published in bladder cancer failed to make that correlation. 
Keynote 045 , Phase III randomized trial evaluating pembrolizumab vs chemotherapy in 
secondline setting in patients who had previous platin based therapy  had co primary end 
points among all patients and among patients who had a tumor PD-L1 ligand combined 
positive score  of 10% or more. The results showed no significant difference in duration 
of OS and PFS among total population and the group who had PD-L1 CPS of 10% or 
more. (p=0.24)  Similar study ImVigor 211 evaluating atezolimab vs chemotherapy in 
second line setting in patients with advanced urothelial carcinoma showed no difference 
in outcomes in overall survival among two treatment arms clearly indicating that may be 
PD-L1 is not a good predictive but a prognostic marker. In our study we will evaluate 
PD-L1 expression on the immune and tumor cells using panel of antibodies available at 
Mayo and assess its correlation to response with chemoradiation. 
 
Hypothesis: 
1. Concurrent chemo-immuno- radiotherapy is safe and efficacious for patients with 
bladder cancer opting for bladder salvage.  
 
 


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2.0 
Goals  
2.1 
Primary Goal 
2.11 
To evaluate the complete response rate of concurrent chemotherapy radiation 
treatment combined with avelumab for patients with muscle invasive bladder 
cancer. 
2.2 
Secondary Goals 
2.21 
To evaluate the safety and toxicity (adverse event profile) of concurrent 
chemotherapy radiation treatment combined with avelumab.  
2.22 
To evaluate quality of life (QoL) at 1 year of concurrent chemotherapy radiation 
treatment combined with avelumab.  
2.23 
To evaluate progression-free survival and relapse-free survival at 1 year with 
concurrent chemotherapy radiation treatment combined with avelumab. 
2.3  
Correlative Research  
2.31  
To explore biomarkers that may predict response to avelumab in the muscle 
invasive population. The following markers will be tested: 
• Expression of PD-L1 and CD8 by immunohistochemistry (IHC) 
• Expression of immune signatures by RNA-sequencing (RNA-seq). 
• To evaluate the association of tumor mutational burden with response to 
concurrent chemo- radiation and immunotherapy 
• To evaluate whether concurrent chemoradiation and immunotherapy after 
maximal TURBT  is associated with a decrease in circulating Bim+CD11ahighPD-
1+CD8+ T-cells and MDSCs. 
 


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3.0 
Registration Patient Eligibility 
For the run-in portion only, prior to discussing protocol entry with the patient, call the 
MCCC Registration Office 
 to insure that a place on the protocol is open to 
the patient.  
3.1 
Registration – Inclusion Criteria 
3.11 
Age ≥18 years. 
3.12 
Histologic proof of T2-T4a N0M0 (AJCC 8th edition ) with predominant 
urothelial carcinoma. Mixed histologies are acceptable provided urothelial 
carcinoma is the predominant histology. Small cell urothelial carcinoma is 
excluded.  
3.13 
Cystoscopy with maximal TURBT performed < 70 days of study registration. 
NOTE: Both completely resectable or partially resectable tumors are eligible as 
long as the treating urologist attempted complete resection. Exam under 
anesthesia needs to be performed and documented. 
3.14 
The following laboratory values obtained ≤ 28 days prior to registration.  
• 
ANC ≥ 1500/mm3 
• 
PLT ≥ 100,000/mm3 
• 
Total bilirubin ≤  1.5 upper limit of normal (ULN) 
• 
Aspartate transaminase (AST) ≤ 2.5 x ULN (≤5 x ULN for patients with liver 
involvement) 
• 
Alanine Aminotransferase (ALT) ≤ 2.5 x ULN (≤5 x ULN for patients with 
liver involvement) 
• 
Hgb > 9 gm/dl 
• 
Calculated creatinine clearance must be ≥ 30 ml/min using the Cockcroft-
Gault formula below: 
Cockcroft-Gault Equation: 
Creatinine clearance for males =  
(140 - age)(weight in kg) 
 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females =  
(140 - age)(weight in kg)(0.85) 
 
(72)(serum creatinine in mg/dL) 
3.15 
ECOG Performance Status (PS 0, 1, 2) (Appendix I). 
3.16 
Ability to provide informed written consent. 
3.17 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.18 
Life expectancy ≥ 6 months.  
3.19 
Negative serum pregnancy test done ≤ 14 days prior to registration, for women of 
childbearing potential only. 
3.2 
Registration - Exclusion criteria 
3.21 
Patients with locally advanced unresectable (T4b) or metastatic urothelial 
carcinoma (N1M0-1) as assessed on baseline radiographic imaging obtained < 70 
days prior to study registration.  The required radiographic imaging includes: 


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• 
Abdomen/Pelvis CT or MRI scan 
• 
Chest x-ray or CT scan 
 
3.22 
Patients with concurrent urothelial carcinoma and/or related variants anywhere 
outside bladder 
NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelial 
carcinoma that has been definitively treated with at least one post-treatment 
disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no 
evidence of residual disease are eligible.  
3.23 
A prior or concurrent malignancy of any other site or histology unless the patient 
has been disease-free for > 2 years prior to registration except for: 
• 
non-melanoma skin cancer and/or  localized  prostate cancer( T2 a or b , 
Gleason <3+4) or carcinoma in situ of the uterine cervix which has been 
adequately treated ≤2 years prior to registration 
• 
or undergoing active surveillance per standard-of-care management (e.g., 
chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason 
score ≤ 3+4, and prostate-specific antigen [PSA] ≤ 10 mg/mL, etc.) 
3.24 
Patients who have received the last administration of an anti-cancer therapy 
including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks 
prior to registration, or who have not recovered from the side effects of such 
therapy.  
EXCEPTION: Except single dose intravesical chemotherapy administered after 
TURBT. 
3.25 
Patients who have received prior therapy with immune checkpoint inhibitors (e.g. 
anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4, anti-TIM3) or immune 
costimulatory molecules (e.g. anti-CD137, anti-OX40, anti-GITR) directed 
agents. 
3.26 
Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal 
or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to 
registration, or who have not recovered from side effects of such procedure or 
injury prior to registration.  
NOTE: Patients who have had minor procedures (i.e. TURBT) or percutaneous 
biopsies prior to registration are eligible. 
3.27 
Patients with history of cirrhosis, alcoholic or non-alcoholic steatohepatitis 
(NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis. 
3.28 
Patient with history of prior solid organ or allogeneic bone marrow transplant. 
3.29 
Clinically significant cardiac diseases, including any of the following: 
• 
History or presence of serious uncontrolled ventricular arrhythmias 
• 
Clinically significant resting bradycardia 
• 
Any of the following < 3 months prior to registration: myocardial infarction 
(MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), 
Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), 
Transient Ischemic Attack (TIA), Pulmonary Embolism (PE) 


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• 
Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 
100 mm Hg, with or without anti-hypertensive medication(s) 
3.29a 
History of untreated HIV 
NOTE: There is no requirement to screen patients for HIV. Patient with history 
of HIV infection are allowed if on effective HAART therapy and CD4 count 
more than 250.  
3.29b  History of active hepatitis B infection  
 
NOTE: There is no requirement to screen patients for hepatitis B 
3.29c  History  of active hepatitis C infection  
 
NOTE: There is no requirement to screen patients for hepatitis C 
3.29d Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant, 
rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, 
etc.) that requires chronic immunosuppressive therapy.   
NOTE: Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the 
treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of 
gout are permitted.  For questions, please consult the study chair. 
3.29e 
Other concurrent severe and/or uncontrolled concomitant medical conditions 
(e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause 
unacceptable safety risks or compromise compliance with the protocol 
3.29f 
Pregnant or breast-feeding women 
3.29g Women of child-bearing potential, who are biologically able to conceive, and not 
employing two forms of highly effective contraception. Highly effective 
contraception must be used throughout the trial and up to 8 weeks after the last 
dose of study drug (e.g. male condom with spermicidal; diaphragm with 
spermicide; intra-uterine device).  Women of child-bearing potential, defined as 
sexually mature women who have not undergone a hysterectomy or who have not 
been naturally postmenopausal for at least 12 consecutive months (i.e., who has 
had menses any time in the preceding 12 consecutive months), must have a 
negative serum pregnancy test ≤ 14 days prior to registration. 
3.29h Fertile males not willing to use contraception, as stated above 
3.29i 
Patients unwilling or unable to comply with the protocol 
3.29j 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
3.29k Known prior severe hypersensitivity to investigational product or any component 
in its formulations, including known severe hypersensitivity reactions to 
monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3) 
 


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Protocol Version Date: 21JUN2018 
4.0 
Test Schedule 
 
 
Active Monitoring Phase 
Tests and 
procedures 
≤70 
days 
prior 
to reg 
Screening 
(≤28 days  
prior to 
reg) 
C1 
(D1) 
C2 
(D15) 
C3 
(D29) 
C4-C10 
(D43, D57, 
D71, D85, 
D99, D113, 
D127) 
End of 
Treatment 
(30 days 
after last 
dose) 
6 Mo after 
registratio
n 
(Clinical 
Follow-up) 
9 Mo after 
registration 
(Clinical 
Follow-up) 
EOS 
(12 Mo after 
registration) 
(Clinical 
Follow-up) 
Window 
 
 
 
±3 days 
±3 days 
±3 days 
±3 days 
±14 days 
±14 days 
±14 days 
Maximal 
TURBT/EU
A 
X 
 
 
 
 
 
 
 
 
 
History and 
Physical 
Exam 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 Vital Signs, 
Weight and 
ECOG PS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
(serum) 
 
X1 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine)1 
 
 
 
X 
X 
X 
 
 
 
 
Adverse event 
assessment/ 
Toxicity 
notation4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmeds 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease 
assessment: 
CT/MRI 
abdomen/ 
pelvis8 
X 
  
 
 
 
X3 
 
X 
X 
X 
Chest CT8 
X 
 
 
 
 
X3 
 
X 
X 
X 
ECG R 
X 
  
 
 
 
 
 
 
 
 
Hematology2 
 
X 
 
X 
X 
X 
X 
X 
X 
X 


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Protocol Version Date: 21JUN2018 
 
 
Active Monitoring Phase 
Tests and 
procedures 
≤70 
days 
prior 
to reg 
Screening 
(≤28 days  
prior to 
reg) 
C1 
(D1) 
C2 
(D15) 
C3 
(D29) 
C4-C10 
(D43, D57, 
D71, D85, 
D99, D113, 
D127) 
End of 
Treatment 
(30 days 
after last 
dose) 
6 Mo after 
registratio
n 
(Clinical 
Follow-up) 
9 Mo after 
registration 
(Clinical 
Follow-up) 
EOS 
(12 Mo after 
registration) 
(Clinical 
Follow-up) 
Window 
 
 
 
±3 days 
±3 days 
±3 days 
±3 days 
±14 days 
±14 days 
±14 days 
Blood-
chemistries6 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Free T4 and 
TSH 
 
 
X 
 
 
 
 
X7 
 
X7 
 
 
 
X7 
Urine cytology 
 
X 
 
 
 
 
 
X 
X 
X 
Urodynamic 
study    
X5 
   
 
 
 
 
 
 
 
X R 
Bladder Biopsy 
X 
 
 
 
 
 
 
X 
 
 
Cystoscopy 
X 
 
 
 
 
 
 
X 
X 
X 
QOL forms11 
 
X 
 
 
 
 
X 
 
 
X 
Optional 
Research 
specimens 
per IRB 16-
0052609 
 
 
 
 
 
 
 
 
 
 
Optional 
Archived 
research 
tissue 
specimens  
10,R 
 
 
 
 
 
 
 
 
 
 
Cycle = 14 days All tests and procedures are clinically indicated, unless noted with an R to indicate funding by research 
1. For women of childbearing potential only.  Serum must be performed ≤14 days prior to registration 
2. CBC with differential 
3. Abdomen, pelvis, chest CT/MRI to be done at C7(Day 85) +/- 7 days 
4. Adverse event/Toxicity notation to be done WEEKLY during radiation treatment 
5. Uroflow/post void residual; not required to be done prior to registration; however, if done then data will be collected. .  
6. Blood chemistries: Comprehensive Metabolic Panel (CMP) {Albumin, Bilirubin(total), Calcium, Carbon dioxide 


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Protocol Version Date: 21JUN2018 
(bicarbonate), Chloride, Creatinine, Glucose, Phosphatase alkaline, Potassium, Protein (total), Sodium, Transferase aspartate 
amino(AST) (SGOT), Transferese alanine amino (ALT) (SGPT), Urea nitrogen (BUN} and Mg prior to each avelumab dose, 
at end of study visit, and 30 days post-treatment safety follow-up 
7. Free T4 and TSH at least every 8 weeks during treatment (Collect at same time as treatment related labs). Also collect at end 
of study or 30 days post-treatment safety follow-up (if not performed in the previous 8 weeks) 
8. With contrast preferred; however if treating Provider determines that contrast is contraindicated then contrast can be omitted. 
9. NOTE: Participants sign a separate consent for IRB 16-005260  
10. Archived tissue per section 17.0  
11. EORTC QLQ-C30 (Appendix II) and EORTC QLQ-BLM30 (Appendix III). Booklets are to be used for this study. 
R   Research funded (see Section 19.0) 
4.1 
Survival Follow-up 
This study does not involve survival follow-up. Patients are considered off study 12 months after registration.  
 


5.0 
Grouping Factor:  
Study Stage: 
1=Safety Run-in vs 2=Expansion portion 
 
6.0 
Registration Procedures 
6.1 
Safety Run-In 
Prior to discussing protocol entry with the patient, call the MCCC Registration Office 
 to insure that a place on the protocol is open to the patient. 
 
To register a patient, fax (
) a completed eligibility checklist to the Mayo Clinic 
Cancer Center (MCCC) Registration Office between 8 a.m. and 4:30 p.m. central time Monday 
through Friday. 
6.2 
Registration, following the completion of run-in portion:  
6.21 
Registering a patient 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/ randomization application is 
available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the website. If unable to access the website, call the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page 
) and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol treatment, 
this process must be completed in its entirety and an MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent. Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
. If the patient was fully 
registered, the MCCC Registration Office staff can access the information from 
the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.3 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health information  
6.4 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an investigator 
may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval documentation 
must be on file (no less than annually) at the Registration Office (fax: 
). If the 
necessary documentation is not submitted in advance of attempting patient registration, the 
registration will not be accepted and the patient may not be enrolled in the protocol until the 
situation is resolved. 


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Protocol Version Date: 21JUN2018 
When the study has been permanently closed to patient enrollment, submission of annual IRB 
approvals to the Registration Office is no longer necessary. 
6.5 
Correlative Research 
6.42 
Optional 
An optional correlative research component is part of this study, there will be an option to 
select if the patient is to be registered onto this component (see Section 17.0). 
• 
Patient has/has not given permission to give his/her tissue sample for research testing.  
6.6 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a medical 
oncologist or radiation oncologist 
6.7 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤7 days after registration. 
6.8 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines specified 
on the test schedule. 
6.9a 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.9b 
A radiation oncologist has seen the patient and confirms the patient is a suitable candidate 
for this study.  
6.9c 
Study drug 
Study drug is available on site.  
6.9d 
Patient questionnaire booklets 
Patient questionnaire booklets are available on site. Copies are not acceptable for these 
submissions. Booklets should be ordered using the Patient Questionnaire Order Form 
 
 


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Protocol Version Date: 21JUN2018 
6.9e 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 56), 
guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with general ethical 
principles outlined in the Declaration of Helsinki; informed consent will be obtained from all 
participating patients; the protocol and any amendments will be subject to approval by the 
designated IRB prior to implementation, in accordance with 21 CFR 56.103(a); and subject 
records will be stored in a secure location and subject confidentiality will be maintained. The 
investigator will be thoroughly familiar with the appropriate use of the study drug as described in 
the protocol and Investigator’s Brochure. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Master files should be 
established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations. 
 
 


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Protocol Version Date: 21JUN2018 
7.0 
Protocol Treatment 
Safety Run-in  
The first 6 patients enrolled will be included in the safety run-in portion following the treatment schedule 
included below (section 7.1).  Patients will be treated for the first two cycles with avelumab only. 
Chemoradiation will begin at cycle 3 (Day 29). This will be performed to determine whether or not the 
proposed concurrent chemotherapy radiation treatment combined with avelumab is a safe regimen.   
ACCRUAL WILL BE TEMPORARILY HALTED between the safety run-in and expansion portion  in 
order to evaluate the concurrent radiation therapy adverse event data.  This data will be reviewed by the 
Study Chair and Study Statistician. 
7.1 
Treatment Schedule 
7.11 
Drug Treatment schedule - Use actual weight or estimated dry weight if fluid retention. 
Chemotherapy choice is based on treating provider’s discretion.  
7.12 
For both cohorts: Avelumab 10mg/kg  doses prior to initiation of concurrent chemo- 
radiation therapy. The treatment will continue for 10 total doses.  
7.13 
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 10mg), epinephrine (1:1,000 dilution), allergy medications (IV 
antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access. 
Patients must be observed for 30 mins post avelumab infusion for potential related 
reactions 
7.14 
Premedication 
Premedicate patients with an antihistamine and with acetaminophen 
(acetaminophen 650 mg ) PO and diphenhydramine 25-50 mg PO x 1 prior to the first 4 
infusions of avelumab. Premedication 
should be administered for subsequent avelumab doses based upon clinical judgement 
and presence/severity of prior infusion reactions.  
 
 




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Protocol Version Date: 21JUN2018 
Avelumab dosing: 
To account for drug quantities supplied within each vial and to minimize wasted unused 
investigational drug, pharmacy may adjust the calculated drug dose +/- 10% for each patient.  All 
patients dosed within these parameters will be considered dosed at full dose. 
Definition of an Overdose for Avelumab used in this protocol: 
Patients dosed > 10% above their calculated drug dose will be considered over-dosed. 
7.2 
Radiation Therapy 
NOTE: Protocol defined radiation treatment is planned to begin at C3D1 (D29 of 
overall study) (+/- 7 days) 
NOTE: Protocol radiation simulation can begin before or after registration in 
anticipation to start radiation C3D1 (D29 of overall study) (+/- 7 days) 
7.21 
Radiation Dose 
7.211 Doses throughout will be prescribed in Gy for the IMRT. Total dose will be 64 
Gy (in 2 Gy; or 55 Gy in 2.75Gy(RBE)/Gy, for 5 fractions per week. The D95% 
of the PTV1 should receive the prescription dose. The minimum dose to the 
OTV1 or PTV1 should be 90% of the prescription dose.  
7.212 For prescription purposes D95% of the PTV2 shall receive ≥80% of the 
prescription. Minimum dose to the PTV2 or OTV 2 will be >70% of the 
prescription. 
7.213 Prescription dose to the PTV shall be according to the following schema 
delivered in 2 Gy per fraction or 2.75 Gy per fraction. in consecutive fractions 
Monday-Friday for a total of 20 treatments or 32 treatments based on the 
radiation regimen chosen by the physician. 
 
7.215 Volumes: 
 
• 
CTV 1= GTV including intra-vesical or extra-vesical tumor + tumor 
bed resection area. 
• 
PTV 1= CTV1+8mm 
• 
CTV 2 = CTV 1 + bladder + bladder neck 
• 
PTV 2= CTV 2 +8mm 
7.22 
Equipment and Physical Factors 
Radiation will be delivered using the available x-ray equipment  
 
 


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Protocol Version Date: 21JUN2018 
7.23 
Localization and Imaging Requirements 
• 
Localization: Proper localization of the appropriate target volumes requires 
reproducible immobilization and correlation of imaging studies. Planning CT 
scans will be performed using a high-resolution scanner with ≤ 2 mm cuts 
through the region of interest (bladder), and at least 5mm elsewhere in the pelvis. 
MRI will also be considered appropriate for structures’ definition. 
MRI of the pelvis and bladder can be used for treatment planning volume delineation. T2 
sequence 3D with ≤ 2mm spacing is recommended.  
If PET scan was done prior to the TURBT it can be used to help define the CTV1. 
• 
Immobilization: Patients will be immobilized for the treatment in a 
supine or prone position, using an appropriately customized 
immobilization device.  
• 
Treatment: Patients will be encouraged to undergo treatment with an 
empty bladder and an empty bowel. Close fitting devices as used for 
simulation will be used for daily treatments. 
Daily position verification: Patients will be setup with lasers in a custom fitting device. 
Patient orientation will be verified based on skin marks. Daily bladder position will then 
be verified based on volumetric guidance employing the techniques described below. 
7.24 
On-line Daily Correction 
We do realize that for an individual patient bladder movement and set up error may be 
non-parametric and a large random component may be present.  Thus, several different 
volumetric image guidance modalities may be used. 
7.25 
Error Verification  
• 
3D volumetric guidance: cone beam CT, CT on rails, MRI, or other means of 3D 
guidance can be employed.   
7.25 Critical Normal Structures 
• 
Gross tumor volume: will include any intravescal or extravesical tumor 
• 
Clinical Target Volume.  
CTV1: It would consist of GTV + tumor bed. All imaging modalities and information 
available should be used to define the extend of the disease. If not clinically 
contraindicated an MRI T2 cube can be used to aid define the gross tumor volume and 
resection area (tumor bed). 
CTV2: It would consist of CTV1 + bladder + bladder neck 
Rectum: is defined from the ischial tuberosities to the sigmoid flexure.  
Small bowel: is defined by the small bowel in contact with the bladder. It should be 
contoured including 2 cm above the treatment field 
7.27 
Normal Tissue Constraints (NTC) 
Normal tissue constraints (NTC) to define dose. 


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Protocol Version Date: 21JUN2018 
Table 2a. Standard-fractionation  
Structure 
Constraint 
Minor deviation 
Major deviation 
PTV1 
D95%=100 
<99% 
<96% 
 
Min >90% 
<90% 
<85% 
 
Dmax <108% 
>108% 
>110% 
PTV 2 
D95=≥80% 
<80% 
<75% 
 
Min >70% 
<70% 
<65% 
 
 
 
 
Rectum 
V90% <35% 
 
 
Femoral heads 
V45 <1 cc 
V45 <2 cc 
V45 ≥ 2cc 
Small bowel 
Dmax <105% 
 
 
 
100% <10cc 
 
 
• 
The maximum dose without a major deviation will be used for treatment.  
• 
Normal tissue volumes 
• 
Rectum: is defined inferiorly  from the ischial tuberosities and superiorly 
to the sigmoid flexure. 
• 
Small bowel: Individual loops should be contoured including 3 cm above 
and below the target or targets. 
• 
Femoral Heads: Countered to the level of the lesser trochanter. 
7.28 Quality Assurance (Physics check) 
• 
Physicist team at each site is responsible for quality assurance. This is 
per standard of care 
• 
Daily online volumetric imaging will be used. Soft tissue matching will 
be done. If fiducials are available they can be used to as a verification 
aid. 
• 
Coronal, transverse, and sagittal CT slices with overlaid doses 
representing the total dose to be delivered should be available.  
• 
Dose volume histograms (DVH) including, but not limited to, bladder, 
bladder wall, femoral heads, and rectal wall will be available.  
• 
If available, different imaging and biologic-imaging studies can be used 
to define different structures.  DVH will be performed as needed. 
7.29a Treatment Interruptions 
Treatment should be delivered over 20 or 32 consecutive treatments. Unplanned 
interruptions, consecutive or not, for more than 5 treatment days (Monday-Friday) are not 
allowed.  Treatment breaks ≥ 5 days are considered major deviations and not allowed.  If 
treatment interruptions of 5 days or longer are not of medical necessity, arrangements To 


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Protocol Version Date: 21JUN2018 
continue treatment should be done. Major treatment deviations will not exclude patient 
from the trial or for data analysis. 
Treatments should be planned to be delivered on consecutive days, Monday to Friday. 
7.29b Radiation Toxicity 
The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from the National 
Cancer Institute (NCI) will be used for toxicity grading. All patients will be seen weekly 
by the radiation oncologist during radiation therapy.  Any observations regarding radiation 
reactions will be recorded and should include attention toward the following potential side 
effects:  
• 
Rectal irritation manifesting as diarrhea, rectal incontinence, proctitis or rectal 
bleeding. 
• 
Bladder toxicity including urinary frequency/urgency, dysuria, hematuria, 
obstruction, retention and incontinence. 
• 
Presence or absence of erections sufficient for sexual activity and use of 
medications or mechanical aids to enhance erections should be recorded. 
Clinical discretion may be exercised to treat side effects from radiation therapy. 
 
8.0 
Dosage Modification Based on Adverse Events  
The following modifications are suggestions but the treating provider is advised to use clinical judgement 
in dose modifications keeping in mind safety of the patients.    
Dose Limiting Toxicity Definition 
While dose limiting toxicity (DLT) is commonly defined by specified toxicities that occur during cycle 1 
of therapy, within this trial the timeframe for DLT evaluation will include the entire duration of CRT 
therapy (date of first radiation fraction administration to date of last radiation fraction administration) to 
coincide with completion of a standard bladder-sparing CMT schedule in which radiation is administered 
once daily during weekdays for 20-32 fractions (treatments). 
As standard bladder-sparing CMT is known to produce grade 1-2 TRAEs in nearly all patients and grade 
3-4 Treatment-related adverse events (TRAEs) in 35% of patients, treatment related toxicity is expected 
[2, 4].  With standard CMT, however, immune related adverse events (irAEs) are not observed.  
Therefore, in evaluating safety of the new avelumab containing CMT treatment approaches within this 
protocol, severe irAEs or non-immune TRAEs which compromise the ability to deliver CMT are of 
particular interest.   Accordingly, DLT during the safety run-in portion of the protocol will be defined 
as the following:  
a) Prolonged  grade 2 (lasting more than 21 days) or higher irAEs including (hypophysitis, uveitis, , 
hepatitis, and colitis). 
NOTE: Treatment related hypothyroidism that is successfully treated with levothyroxine oral 
supplementation and does not cause a treatment delay in radiation by > 21 days is not considered a DLT 
event.  In the case of suspected irAEs, diagnostic confirmation (supporting labs, imaging, biopsies, etc.) 
should be provided in all reports.  


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Protocol Version Date: 21JUN2018 
b) Grade 2 or higher non-immune TRAEs which cause a delay in radiation therapy by > 21 days.  
c) Any grade myocarditis  
d) Grade 2 pneumonitis 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
 
Do
se 
Le
vel 
Cisplatin ** 
5-FU** 
 
 
 
Mitomycin** 
 
 
 
Avelumab 
1* 
 
35mg/m2 
 
500mg/m2 
 
12mg/m2 
 
10 mg/m2 
-1 
28mg/m2 
400mg/m2 
No dose 
reductions 
No dose 
reductions 
-2 
20mg/m2 
No dose 
reductions 
No dose 
reductions 
No dose 
reductions 
*Dose level 1 refers to the starting dose. 
**Cisplatin, 5-FU, Mitomycin: these are suggested dose levels and are only a guideline 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 5.0* unless 
otherwise specified   
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
General guidance for dose modifications and treatment delays and discontinuation 
Due to the prolonged half-life associated with monoclonal antibodies, no dose reductions of avelumab are 
planned.   
If participant has any grade 3 toxicity with the chemotherapy or immunotherapy, radiation can still continue if 
considered safe by the treating provider. If all therapy is stopped including chemotherapy, immunotherapy and 
radiation then patient will be followed as per the routine follow up for one year.  
 
 


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Protocol Version Date: 21JUN2018 
8.2 
Dose Modification Guidelines for Drug-Related Adverse Events for Avelumab   
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient does 
not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed.  The patient does make 
up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
 
NOTE: If anvelumab therapy is delayed for more than 28 days then discontinue avelumab therapy 
 
CTCAE  
System/Organ/Class 
(SOC) 
ADVERSE 
EVENTS/SYMPTOMS 
Avelumab 
Gastrointestinal Disorders 
Diarrhea/Colitis 
Grade 1  
Continue and initiate supportive care per Section 9.0 
 
Diarrhea/Colitis 
Grade 2  
Delay avelumab therapy 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
During radiation therapy: If  persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Outside radiation therapy: If  persists > 14 days or recurs 
Discontinue avelumab. 
Continue and initiate supportive care per Section 9.0 
 
 
Diarrhea/Colitis 
Grade 3 to 4 
Delay avelumab for Grade 3. 
Permanently discontinue avelumab for Grade 4 or recurrent 
Grade 3. 
Continue and initiate supportive care per Section 9.0 
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. 
 
Skin and subcutaneous tissue 
disorders 
Rash acneiform 
Grade 1 to 2  
Continue and initiate supportive care per Section 9.0 
If persists > 1 to 2 weeks or recurs:  
Delay avelumab therapy  
Consider skin biopsy  
Consider 0.5-1mg/kg/day prednisone or equivalent. Once 
improving, taper steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic infections, and 
resume avelumab therapy following steroids taper. 
 
If worsens:  
Treat as Grade 3 to 4. 
 


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CTCAE  
System/Organ/Class 
(SOC) 
ADVERSE 
EVENTS/SYMPTOMS 
Avelumab 
 
Rash acneiform 
Grade 3 to 4  
Delay avelumab for Grade 3. 
Permanently discontinue for Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1 to 2 mg/kg/day prednisone  or equivalent 
Add prophylactic antibiotics for opportunistic infections 
 
If Grade 3 improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume avelumab therapy 
following steroids taper (for initial Grade 3). 
 
Rash maculo-papular 
Grade 1 to 2  
If persists > 1 to 2 weeks or recurs:  
Delay avelumab therapy  
Consider skin biopsy  
Consider 0.5-1 mg/kg/day prednisone or equivalent. Once 
improving, taper steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic infections, and 
resume avelumab therapy following steroids taper. 
 
If worsens:  
Treat as Grade 3 to 4. 
 
 
Rash maculo-papular 
Grade 3 to 4  
Delay avelumab for Grade 3. 
Permanently discontinue for Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1 to 2 mg/kg/day prednisone  or equivalent 
Add prophylactic antibiotics for opportunistic infections 
 
If Grade 3 improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume avelumab therapy 
following steroids taper (for initial Grade 3). 
General disorders and 
administration site conditions 
Infusion-related reaction  
Grade 1 
Mild transient reaction; infusion 
interruption not indicated; 
intervention not indicated 
• Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening 
 
 
Infusion-related reaction  
Grade 2 
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 
Once the avelumab infusion rate has been decreased by 50% or 
interrupted due to an infusion-related reaction, it must remain 
decreased for all subsequent infusions. If the subject has a 
second infusion-related reaction Grade ≥ 2 on the slower 
infusion rate, the infusion should be stopped and the subject 
should be removed from avelumab treatment.  


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CTCAE  
System/Organ/Class 
(SOC) 
ADVERSE 
EVENTS/SYMPTOMS 
Avelumab 
 
Infusion-related reaction  
Grade 3 or Grade 4 
• Grade 3: Prolonged (for 
example, not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
• Grade 4: Life-threatening 
consequences; urgent 
intervention indicated 
 
• Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject 
• Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any further 
avelumab treatment 
• All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to EMD Serono and 
reported as an SAE if criteria are met.   
Investigations 
Aspartate aminotransferase 
increased 
or Alanine aminotransferase 
increased 
Bilirubin increased 
 
Grade 1 
AST or ALT > ULN to 3.0 x 
ULN and/or Total bilirubin > 
ULN to 1.5 x ULN 
Continue avelumab therapy   
Continue liver function monitoring 
If worsens:  
 Treat as Grade 2 or 3 to 4. 
 
Aspartate aminotransferase 
increased 
or Alanine aminotransferase 
increased 
Bilirubin increased 
 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 
x ULN 
Delay 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. 
 
Aspartate aminotransferase 
increased 
or Alanine aminotransferase 
increased 
Bilirubin increased 
 
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 prednisone or equivalent 
Add prophylactic antibiotics for opportunistic infections  
Consult gastroenterologist/ hepatologist 
Consider obtaining MRI/CT scan of liver and liver biopsy if 
clinically warranted  
 
 
 
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. 


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CTCAE  
System/Organ/Class 
(SOC) 
ADVERSE 
EVENTS/SYMPTOMS 
Avelumab 
 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 
6 x ULN 
 
Delay avelumab therapy 
Increase frequency of  monitoring to every 3 days 
Continue and initiate supportive care per Section 9.0 
Consider renal biopsy 
If returns to  Grade ≤1: 
Taper steroids over at least 1 month, and resume avelumab 
therapy following steroids taper. 
If worsens:  
Treat as Grade 4. 
 
 
 
Grade 4 
Creatinine increased > 6 x ULN 
 
Permanently discontinue avelumab therapy 
Monitor creatinine daily 
1 to 2 mg/kg/day prednisone or equivalent. 
Add prophylactic antibiotics for opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 
 
Cardiac disorders 
Myocarditis 
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. 
Permanently discontinue avelumab. 
 
Immune-mediated myocarditis 
Permanently discontinue avelumab. 
Guideline based supportive treatment as appropriate as per 
cardiology consult.* 
1 to 2 mg/kg/day prednisone or equivalent 
Add prophylactic antibiotics for opportunistic infections. 
 
Once improving, taper steroids over at least 1 month. 
 
If no improvement or worsening, consider additional 
immunosuppressants (e.g. azathioprine, cyclosporine A). 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
Grade 1 
Consider delaying 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. 
 
 


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CTCAE  
System/Organ/Class 
(SOC) 
ADVERSE 
EVENTS/SYMPTOMS 
Avelumab 
 
Pneumonitis 
Grade 2 or higher 
Permanently discontinue avelumab therapy. 
Pulmonary and Infectious Disease consults. 
Continue and initiate supportive care per Section 9.0 
 
Endocrine Disorders 
Grade 1 endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
Continue and initiate supportive care per Section 9.0 
Rule-out secondary endocrinopathies (i.e. hypopituitarism / 
hypophysitis) 
Follow-up Management: Continue hormone 
replacement/suppression and monitoring of endocrine function 
as appropriate. 
 
Grade 2, Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Grade 2, Grade 3 or Grade 4 
hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
Permanently discontinue avelumab therapy 
For Grade 3 or 4 consider hospitalization 
Endocrinology consult 
 
 
 
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 
 
 
 
Other Immune Related 
Adverse Events (irAEs) (not 
described above) 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential irAE 
Delay 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 
Delay avelumab therapy 
1 to 2 mg/kg/day prednisone  or equivalent   
Add prophylactic antibiotics for opportunistic infections  
Specialty consult as appropriate 
 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month and resume avelumab 
therapy following steroids taper. 


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CTCAE  
System/Organ/Class 
(SOC) 
ADVERSE 
EVENTS/SYMPTOMS 
Avelumab 
 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab therapy 
1.0 to 2 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics for opportunistic infections  
Specialty consult as appropriate 
 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month. 
 
Grade 4  
 
Permanently discontinue avelumab therapy 
1.0 to 2 mg/kg/day 
prednisone  or equivalent and/or other immunosuppressant as 
needed 
Add prophylactic antibiotics for opportunistic infections  
Specialty consult. 
 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue avelumab therapy 
Specialty consult 
Abbreviations: 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. 
 
 
NOTE: If anvelumab therapy is delayed for more than 28 days then discontinue avelumab therapy 
 
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment  
of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
• Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent monitoring 
• Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4: treat with high dose corticosteroids 
 
8.3 
Dose Modifications for Cisplatin, 5-FU, and/or Mitomycin ( Based on Interval Adverse 
Events (occurring within a cycle of treatment) 


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Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study. This evaluation will 
monitor for adverse events (all grades), serious adverse events, immune related adverse events, 
and adverse events requiring study drug interruption or discontinuation at each study visit for the 
duration of their participation in the study.   
 Concurrent chemo radiation is not expected to cause any immune related side effects. But since 
the therapy is being combined with avelumab which can induce immune related side effects if 
treating provider assessed an adverse event as immune related then it is recommended to perform 
appropriate work up and confirming the nature of side effect.  
It is expected to observe grade 3-4 gastrointestinal and genitourinary side effects with concurrent 
chemo radiation. Symptom management as per best practices is recommended. It’s appropriate to 
use growth factors for neutropenic complications.  
 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENTa 
ACTION 
Blood and lymphatic 
disorders 
Febrile neutropenia 
(fever without 
clinically or 
microbiologically 
documented 
infection) [ANC 
<1.0 X 109 C/L] 
fever ≥38.3oC) 
Cisplatin , 
5FU  
Delay chemotherapy by 1 week until ANC 
recovers to Grade 0-2 and until fever 
resolves. 
Reduce dose by one level or more for 
subsequent cycles. 
Cardiac Disorders 
Left ventricular 
systolic 
Dysfunction, 
myocardial 
infarction  
Cisplatin , 
5FU  
Grade 3 or higher hold chemotherapy until 
recovers to grade <1.  . 
 
  
   
   
   Gastrointestinal 
disorders 
Vomiting 
≥Grade 3 
Cisplatin , 
5FU   
If not controlled with optimal medication. 
Reduce dose by  one dose level  and use 
reduced level for subsequent cycles 
 
Allergic reaction 
Grade 1 
(eg, mild flushing, 
rash, pruritis) 
Cisplatin , 
5FU or 
Mitomycin 
Stop infusion. After recovery restart the 
infusion as per standard of care 
Immune system 
disorders 
Allergic reaction 
Grade 2-3 
(e.g. moderate rash, 
flushing, mild 
dyspnea, chest 
discomfort, mild 
hypotension) 
Cisplatin , 
5FU or 
Mitomycin 
Stop infusion. Give IV antihistamine 
(diphenhydramine 50 mg IV), IV H2-
receptor antagonist (famotidine 20 mg IV) 
and steroid (dexamethasone 10 mg IV) 
After recovery of symptoms resume 
chemotherapy  as per standard of care 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENTa 
ACTION 
 
Anaphylaxis 
(e.g. one or more of 
the following): 
respiratory distress 
requiring treatment, 
generalized urticaria, 
angioedema, 
hypotension 
requiring therapy) 
Cisplatin, 
5FU or 
Mitomycin 
Stop infusion. give IV antihistamine 
(diphenhydramine 50 mg IV), IV H2-
receptor antagonist (famotidine 20 mg IV) 
and steroid (dexamethasone 10 mg IV) 
Add epinephrine or bronchodilators if 
indicated, report as an adverse event 
Discontinue chemotherapy. 
Investigations 
Neutrophil count 
decreased 
≥Grade 3 (ANC 500 
to <1000/mm3) 
Cisplatin, 
5FU  
Delay chemotherapy by 1 week until 
recovery to Grade 0-2 
Consider reducing dose by one level. Use 
of growth factors is allowed. 
 
Platelet count 
decreased 
≥Grade 2 (<75 x 
109/L) 
Cisplatin, 
5FU   
Delay chemotherapy by 1 week until 
recovery to Grade 1. Consider reducing 
dose by dose 20%  for subsequent cycles 
Investigations 
Bleeding ≥Grade 3 
or requiring 
≥2 platelet 
transfusions 
Cisplatin , 
5FU  
Delay chemotherapy by 1 week until 
bleeding recovers to Grade 0-1 
Permanently discontinue chemotherapy, 
or reduce dose by 20% or more for 
subsequent cycles 
Nervous system 
disorders 
Peripheral motor 
neuropathy 
Grade 2 
Cisplatin   Reduce dose by 20% and use reduced 
level for subsequent cycles 
 
Peripheral motor 
neuropathy 
Grade 3 or higher 
Cisplatin    Discontinue cisplatin  
All other non-
hematologicb 
≥Grade 3 
Cisplatin, 
5FU   
Discontinue chemotherapy, or reduce dose 
by 20% or more and use reduced dose for 
subsequent cycles 
Nephrotoxicity  
GFR <50 ml/min, 
first event  
Cisplatin  
Hold therapy till it recovers above 
50ml/min and restart at one dose level 
lower or more if GFR goes down further. 
If Patient GFR falls below 50ml/min even 
with second dose reduction then omit 
cisplatin and continue with RT alone. 
 
   
 
 
a If a drug is held, omitted, discontinued or dose-reduced, it is the treating provider’s discretion to apply the 
modification to one or both cytotoxic drugs, and the decision should depend on the nature and severity of the 
particular adverse event and its likely causal relation to the agent. 
b For adverse effects ≥Grade 3 commonly associated with radiation such as radiation dermatitis, dry mouth, 
mucositis, thick secretions/saliva, loss of  taste, weight loss, loss of appetite dose modifications for 
chemotherapy will be at the discretion of the treating provider. 
 
**  Use the following to describe actions in the Action column: 


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 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient does 
not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed.  The patient does make 
up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start of the next 
cycle, then the dose will remain lowered for that entire subsequent cycle. If that cycle is completed with no further 
adverse events >Grade 2, then the dose may be increased, at the investigator’s discretion, one level at a time, in 
the following cycles.  
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the two dose-reduction steps 
(levels –1 and –2) will be at the discretion of the treating provider, if the decision is made for the patient to be 
kept on study. These dose reductions must be clearly recorded in reported clinical data.  Patients can also continue 
with RT alone without chemotherapy if the treating provider chooses to hold chemotherapy.  
Treatment at reduced dosage will be administered once the adverse event has come down to grade 1 or less 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, 
and/or antiemetics received from the first day of study treatment administration until 30 days after 
the final dose will be recorded in the medical records. 
Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of 
oral or intravenous treatment with corticosteroids as well as additional anti -inflammatory agents 
if symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
avelumab. 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 8.2 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
9.2 
Blood products and growth factors  
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow published 
guidelines of the Journal of Clinical Oncology 2015;33(28):3199-3212. 
9.21 
Neutropenia 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating 
Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating 
Factor GM-CSF is not allowed in this study. Therapeutic use of G-CSF is allowed in 
patients with Grade 3-4 febrile neutropenia. 


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9.22 
Anemia 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications. 
9.23 
Thrombocytopenia 
Transfusion of platelets may be used if clinically indicated. ITP should be ruled out 
before initiation of platelet transfusion. 
9.3 
Anti-infectives 
Patients with a documented infectious complication should receive oral or IV antibiotics or other 
anti-infective agents as considered appropriate by the treating Investigator for a given infectious 
condition, according to standard institutional practice. 
9.4 
Corticosteroids 
Patients may continue on steroid inhalation therapy. Systemic corticosteroids are known 
immunosuppressive agents that can mitigate the effects of avelumab. Steroids should be generally 
reserved to treat side effects of avelumab. Steroids can be used as primary prevention of nausea 
per institutional guidelines, but steroid doses should be reduced in subsequent cycles if 
nausea/vomiting is absent or very mild (see Section 9.5). 
9.5 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. Nausea and vomiting should 
be treated aggressively, and consideration should be given to the administration of prophylactic 
antiemetic therapy according to standard institutional practice. Patients should be strongly 
encouraged to maintain liberal oral fluid intake. Volume depletion should be corrected before 
initiation of study drug. Study team strongly recommends use of dexamethasone to be restricted 
to 4 mg once a week. We strongly recommend using long acting 5HT-3 inhibitors like 
palonosetrone and Nk1 inhibitor like fosprepitant or olanzapine to avoid delayed nausea esp. with 
cisplatin.  
9.6 
Anti-diarrheals 
Patients should be monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus). In symptomatic patients, infectious etiologies should be ruled out, and 
if symptoms are persistent and/or severe, endoscopic evaluation should be considered. (See 
Section 9.7 for management of treatment-related enterocolitis) 
All patients who experience diarrhea should be advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV 
infusion. 
NOTE: Loperamide/diphenoxylate/atropines should NOT be used for diarrhea symptoms unless: 
(1) it is believed that avelumab-related enterocolitis is unlikely to be present after detailed 
evaluation by gastroenterology, including endoscopy; PLUS (2) approval is documented by a 
gastroenterology specialist. 
9.7 
Immunotherapy-related toxicities 
Patients should be monitored for signs and symptoms of immunotherapy-related toxicities, which 
include but are not limited to the following: 
• 
Pneumonitis 
o For Grade 2 events, treat with systemic corticosteroids (1.0 to 2.0 mg/kg/day prednisone 


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or equivalent).  
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids  (1.0 to 2.0 mg/kg/day 
prednisone or equivalent). Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• 
Diarrhea/colitis 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
o All patients who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids and antidiarrheals. 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids (1.0 to 2.0 mg/kg/day prednisone IV or equivalent). Add prophylactic 
antibiotics for opportunistic infections.  
 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
For T1DM or Grade 3-4 Hyperglycemia: 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
• 
Hypophysitis 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  


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 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
• 
Hepatic 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).  
• 
Treat with IV or oral corticosteroids (1 to 2mg/kg/day prednisone or equivalent.) 
Add prophylactic antibiotics for opportunistic infections 
 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Renal failure or nephritis 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
9.8 
Management of treatment related enterocolitis 
In patients with severe enterocolitis, avelumab will be held and treatment with systemic 
corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. 
When symptoms improve to Grade 1 or less, corticosteroid taper should be started and continued 
over at least 1 month.  
In patients with moderate enterocolitis, avelumab should be withheld and antidiarrheal treatment 
should be started. If symptoms are persistent for more than one week, systemic corticosteroids 
should be initiated (e.g., 0.5 mg/kg/day of prednisone or equivalent). When symptoms improve to 
Grade 1 or less, corticosteroid taper should be started and continued over at least 1 month. 
9.9a 
Concomitant Medications/Vaccinations (Allowed & Prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required. The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the patient’s primary treating provider. 
9.91 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community 
standards of medical care. All concomitant medication will be recorded in the case report 
forms (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and 
IV medications and fluids. If changes occur during the trial period, documentation of 
drug dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded. 
Concomitant medications administered 30 days after the last dose of trial treatment 
should be recorded for SAEs and ECIs as defined in Section 10. 
9.92 
Prohibited Concomitant Medications 


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The following medications are not permitted during the screening and treatment phase 
(including retreatment for post-complete response relapse) of this trial: 
• 
Anti-neoplastic systemic cytotoxic chemotherapy or biological therapy outside the 
clinical trial program  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than avelumab 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine. 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the principal 
investigator. 
NOTE: Use of steroids during chemoradiation for controlling chemotherapy-associated   
is allowed. We recommend only using up to 4mg dexamethasone weekly.  
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Patients may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
9.9b 
Contraception 
Avelumab may have adverse effects on a fetus in utero. Furthermore, it is not known if avelumab 
has transient adverse effects on the composition of sperm. 
For this trial, male patients will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). 
Female patients will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women <45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.); 
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male patients of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following: 
(1) practice abstinence from heterosexual activity; 


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OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity. Use in 
Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with avelumab, the patient will 
immediately be removed from the study. The site will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated. The outcome 
of the pregnancy will be reported to Mayo Clinic and to  EMD Serono  without delay and within 
24 hours to Mayo Clinic and within 2 working days to EMD Serono if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn. If a male subject impregnates his 
female partner the study personnel at the site must be informed immediately and the pregnancy 
reported to Mayo Clinic and to  EMD Serono and followed as described above. 
9.9c 
Use in Nursing Adults 
Since many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, patients who are breast-feeding are not eligible for enrollment. 
Specific additional information follows for individual agents used in this trial. 
9.9c1 
Avelumab 
It is unknown whether avelumab is excreted in human milk. It is recommend that nursing 
mothers not to breast feed for at least one month after final dose.  
9.9c2 
Chemotherapy  
Cisplatin  has been reported to be found in human milk; patients receiving cisplatin 
injection should not breast-feed. It is not known if fluorouracil is present in breast milk. 
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer 
recommends a decision be made to discontinue breastfeeding or to discontinue 
fluorouracil, taking into account the importance of treatment to the mother.   
It is not known if mitomycin is present in breast milk. Due to the potential for serious 
adverse reactions in the breastfed infant, breastfeeding is not recommended by the 
manufacturer. 
Table 6. Pretreatment Medication 
Agent 
Dose 
Route 
Day 
 
DXM 
 
4mg 
 
 
IV or PO 
Prior to weekly cisplatin infusions 
Emend 
  
  
  
150 mg 
  
  
 
IV 
  
Prior to  weekly Cisplatin 
infusions 
Palonosetron 
0.25mg 
IV  
Prior to  weekly Cisplatin 
infusions 
Ondansetron 
8 mg 
IV 
C3D1 (Day 29) of Mitomycin + 
5-FU infusion 
Prochlorperazine 
10 mg 
PO 
Prior to 5-FU infusion (~Day 50) 
 
 




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Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
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) 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, determine the 
timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the routine data 
reporting mechanisms defined by the protocol (see Sections 10.6 and 18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study specific 
consent form, package insert (if applicable), and/or the investigator brochure, (if an investigator 
brochure is not required, otherwise described in the general investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 15.0 of 
the protocol, the study specific consent form, package insert (if applicable), or in the investigator 
brochure (or are not listed at the specificity or severity that has been observed); if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs but have not been observed with the drug 


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under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a commercial 
agent. Therefore, if an expected AE (for the commercial agent) occurs with a higher degree of severity 
or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the protocol or 
the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as the 
investigational agent/intervention (also, investigational drug, biologic, cellular product, or 
other investigational therapy under an IND), the entire combination (arm) is then 
considered an investigational intervention for reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational agent/intervention must be 
assessed as specified in the protocol. In general, only Grade 4 and 5 AEs that are unexpected 
with at least possible attribution to the commercial agent require an expedited report, unless 
hospitalization is required. Refer to Section 10.4 for specific AE reporting requirements or 
exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
• An increased incidence of an expected adverse event (AE) is based on the patients 
treated for this study at their site. A list of known/expected AEs is reported in the 
package insert or the literature, including AEs resulting from a drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 3500A 
for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.p
df 
 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur within this population and do 
not require Expedited Reporting. These events must still be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected adverse reaction (at your study 
site) over that which is listed in the protocol or investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected as an expedited event. 


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System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1 
General disorders and 
administration site 
conditions 
Fatigue  
≤Grade 3 
Malaise 
≤Grade 3 
Skin and subcutaneous 
tissue disorders 
 Rash 
≤Grade 4 
Erythema 
<Grade3 
Gastrointestinal disorders 
Colitis 
<Grade 3 
Nausea 
<Grade 3 
Vomiting 
<Grade 3 
Renal and urinary 
disorders 
Cystitis 
<Grade3 
Injury, poisoning and 
procedural complications Radiation dermatitis 
<Grade 3 
Blood and lymphatic 
system disorder 
Anemia 
<Grade 4 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
      <Grade 3 
 
 
 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse event 
results in hospitalization, then the standard expedited adverse events reporting requirements must be 
followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by investigators 
ONLY if they exceed the expected grade of the event. 
 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” (i.e., 
there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization has 
not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place before 
study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer. 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents  
 
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 




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10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in general, 
include any incident, experience, or outcome that meets all of the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the 
research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
Some unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with adverse events. In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not considered 
an adverse experience for this trial, and if the consent form does not indicate that subjects 
should not get pregnant/impregnate others, then any pregnancy in a subject/patient or a 
male patient’s partner (spontaneously reported) which occurs during the study or within 
120 days of completing the study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable Event/UPIRTSO, 
provide the Reportable Event coversheet and appropriate documentation 
to
. The Mayo Regulatory Affairs Office will 
review and process the submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below. Attribution to treatment or other cause must be 
provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an IND/IDE requires expedited reporting within 24-hours. 
Any death occurring greater than 30 days with an attribution of possible, probable, or 
definite to an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the first 28 
days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 


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• 
Sudden death NOS: A sudden (defined as instant or within one hour of the onset of 
symptoms) or an unobserved cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (including cysts and polyps) – Other 
(Progressive Disease)” under the system organ class (SOC) of the same name. 
Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under an 
IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic Leukemia 
[AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting 
unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational product 
becomes pregnant, the subject taking should notify the Investigator, and the pregnant female 
should be advised to call her healthcare provider immediately. The patient should have 
appropriate follow-up as deemed necessary by her treating provider. If the baby is born with a 
birth defect or anomaly, a second expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the investigator 
must obtain consent from the pregnant woman and the newborn infant’s parent or legal 
guardian before any data collection can occur. A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not obtained, no 
information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases where the 
child/fetus experiences a serious adverse event other than fetal death, the child/fetus is the 
patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for “Pregnancy”, 
“Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure of the fetus to the 
investigational agent(s) or chemotherapy agent(s) should be documented in the “Description of 
Event” section. Include any available medical documentation. Include this 
form: http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/Pregnanc
yReportFormUpdated.pdf 


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10.551 Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy)” under the 
Pregnancy, puerperium and perinatal conditions SOC. Pregnancy should be 
followed until the outcome is known. 
10.552 Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death in utero; 
failure of the product of conception to show evidence of respiration, heartbeat, or 
definite movement of a voluntary muscle after expulsion from the uterus, without 
possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC. 
10.553 Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by cessation of 
life occurring during the first 28 days of life” that is felt by the investigator to be 
at least possibly due to the investigational agent/intervention, should be reported 
expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration - Other (neonatal loss)” under the General 
disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to be 
graded at each evaluation.  
Grading is per CTCAE v5.0 unless alternate grading is indicated in the table below: 
 
 
 
System Organ Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
General disorders and 
administration site 
conditions 
Pain 
X 
X 
Fatigue 
X 
X 
Injury, poisoning and 
procedural complications 
Dermatitis Radiation 
X 
X 
 
 
 
 
 
 
 
Metabolism and nutrition 
disorders 
Anorexia 
X 
X 
Musculoskeletal and 
connective tissue disorders 
Bone pain 
X 
X 
Vascular disorders 
Lymphedema 
X 
X 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
X 
X 
Pulmonary fibrosis 
X 
X 
Renal and urinary disorders 
Hematuria 
X 
X 


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System Organ Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Urinary frequency 
X 
X 
Urinary incontinence 
X 
X 
Urinary retention 
X 
X 
Urinary tract obstruction 
X 
X 
Urinary tract pain 
X 
X 
Urinary urgency 
X 
X 
Gastrointestinal disorders 
Number of stools 
X 
 
Diarrhea 
 
X 
Constipation 
 
X 
Fecal incontinence 
X 
X 
Nausea 
X 
X 
Proctitis 
X 
X 
Rectal hemorrhage 
X 
X 
Vomiting 
X 
X 
 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
10.6232 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with a 
CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as applicable) 
regarding the submission of late occurring AEs following completion of the Active Monitoring 
Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
EMD Serono - Additional Event Reporting Instructions 
The following reportable events must be submitted to EMD Serono within 24 hours (or 
immediately for death or life-threatening events) using the applicable safety report form provided. 
 
• Serious Adverse Events 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 


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• Occupational exposure (even if not associated with an adverse event) 
• Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs. 
 
Contact information for submission of reportable events to EMD Serono: 
 
Fax: 
 
OR 
E-mail
 
 
Specifying: 
• PROTOCOL Number 
• SUBJECT Number 
• SITE Number/PI Name 
• SAE/ONSET DATE 
 
11.0 
Treatment Evaluation   
This study will not use RECIST criteria to evaluate response or progression. The patients enrolled will 
have nonmeasurable disease on imaging and response will be evaluated with biopsy or cytology at 6, 9 
and 12 months post therapy.  
11.1 
Schedule of Evaluations: 
For the purposes of this study, patients should be reevaluated every 12 weeks after registration for 
the first year. The first 12 week evaluation will be a cross sectional imaging preferably same as 
done at the time of registration with CT or MRI of chest abdomen and pelvis. Patient subsequent 
12 week assessment will include cross sectional imaging with office cystoscopy, cytology and 
biopsy (for cause).Biopsy of the tumor bed at 6 months is mandatory.   Patient will also have 
routine blood work and translation and QOL assessments as described in the study table.  
11.2 
Criteria for evaluation and endpoint analysis.  
a. Complete Response  
Complete Response: Negative biopsy and negative urine cytology at 6 months from 
registration  after finishing of concurrent RT and immunotherapy.  Imaging of abdomen and 
pelvis confirming no systemic disease within 4 weeks of cystoscopy should be completed..  
 
b. Progression  
Progression:  Progression in T stage, N stage or M stage both clinically or radiologically. 
Histological confirmation of metastatic disease is at the discretion of the treating provider.  
 
c. Recurrence  
Recurrence: histologically proven first appearance of   muscle invasive bladder cancer, 
clinical evidence of metastatic disease, or treatment with radical cystectomy or radiation to 
the bladder, or death due to any cause after they were confirmed remission at 6 month 
evaluation . 
a. Event :  Histologically proven presence of muscle invasive bladder cancer, clinical 
evidence of nodal or metastatic disease, radical cystectomy, death within 90 days of 
protocol specified treatment. 
 


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d. Performance Status  
Performance Status: Patients will be graded according to the ECOG Performance Status 
Scale. (Appendix I) 
 
12.0 
Descriptive Factors: 
12.1 
Histology: pure urothelial vs mixed histology  
12.2 
Clinical T stage: T2 vs. T3 vs. T4 
 
12.3 
Cohort:  cohort 1 (5-FU + Mitomycin C) versus cohort 2 (Cisplatin) chemotherapy  
NOTE: cohort selection is treating provider’s choice 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Those patients who have experienced unacceptable toxicity may be eligible for retreatment at a 
lower dose (see Section 8.0). 
13.2 
Off Study/Safety Follow-up Visit:  
Patients should be evaluated for any residual toxicities, per test schedule section 4.0.  For patients 
proceeding to cystectomy, this can coincide with traditional post-op visits.  For patients who refuse to 
return to clinic for an in-person visit, recording of patient reported toxicities by telephone is 
acceptable. 
13.3 
Those patients who refuse further treatment will go off treatment and be withdrawn from the 
study. 
13.4 
A patient is deemed ineligible if after registration, it is determined that at the time of registration, 
the patient did not satisfy each and every eligibility criteria for study entry.  The patient may 
continue treatment off-protocol at the discretion of the treating provider as long as there are no 
safety concerns, and the patient was properly registered. The patient will go or off study.  
• 
If the patient received treatment, all data up until the point of confirmation of ineligibility 
must be submitted.  Clinical follow-up will be required per Section 18.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. The patient will 
be taken off study.  
13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are severely violated that evaluability for primary end point is questionable. All 
data up until the point of confirmation of a major violation must be submitted. The patient may 
continue treatment off-protocol at the discretion of the treating provider as long as there are no 
safety concerns, and the patient was properly registered.   
 
13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given.  On-study material and the End of Active Treatment/Cancel Notification Form 
must be submitted.  No further data submission is necessary. 
13.7 
Criteria for Removal from Study 
Patients will be removed from the study for any of the following reasons: 
• 
Completion of all study therapy and follow up. 
• 
Patient non-compliance or request to withdraw from all therapy and follow up.  Patients who 
withdraw from therapy only may continue to be followed for study specified follow up 
secondary endpoints. 


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• 
Pregnancy. 
• 
Unacceptable toxicity that in the treating provider’s discretion places the patient at risk for 
future significant harm. 
• 
Intercurrent illness that prevents continuation of therapy or follow up. 
  


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14.0 
Body Fluid Biospecimens   
14.1 
Collection and Processing  
 
14.11 Optional research specimen(s) collection per protocol IRB 16-005260 will be 
done after consenting for 16-005260 and according to that protocol. All 
collection time points and processing will be done per that protocol. Data from 
IRB 16-005260 may be used for this study after IRB approval. 
15.0 
Drug Information 
15.1 
Avelumab (Bavencio®) 
15.11 Background: Avelumab is a fully human IgG1 antibody directed against PD-L1. 
Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its 
receptors PD-1 and B7.1. This removes the suppressive effects of PD-L1 on anti-
tumor CD8+ T cells, resulting in the restoration of cytotoxic T cell response. 
 
15.12 Formulation: Avelumab is a sterile, clear, and colorless concentrate for solution 
available in a concentration of 20 mg/mL.  Each single-use vial contains 200 
mg of avelumab as a preservative-free acetate-buffered solution (pH 5.2) 
containing Mannitol, and Polysorbate 20 (Tween 20). 
 
15.13 Preparation and storage: Allow each vial to equilibrate to room temperature. 
Avelumab drug product must be diluted in 250 mL of 0.9% saline solution 
(sodium chloride injection) supplied in an infusion bag; alternatively a 0.45% 
saline solution can be used if needed. 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.  
No other drugs should be added to the solution for infusion containing avelumab.  
 
Avelumab drug product must be stored at 2°C to 8°C until use.  If not used 
immediately, the diluted drug product can be stored up to 8 hours at room 
temperature or up to 24 hours at 2°C to 8°C.  Avelumab drug product must not be 
frozen.  
 
15.14 Administration:  Avelumab is administered as a 1-hour IV infusion. Administer 
the diluted solution through an intravenous line containing a sterile, non-
pyrogenic, low protein binding in-line filter (pore size of 0.2 micron). 
 
 
15.15 Pharmacokinetic information: 
Absorption: Avelumab is administered intravenously and is 100% 
bioavailable.  Steady-state concentrations of avelumab are expected to be  


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reached  by the 3rd dosing cycle (10 mg/kg dose every 2 weeks), and the 
accumulation ration  is 1.25. 
Distribution: The geometric mean volume of distribution at steady state for a 
subject receiving 10 mg/kg was 4.72 L. 
Metabolism:  Avelumab is degraded by proteolytic catabolism.  CYP450 does 
not contribute to its metabolism. 
Elimination: The primary elimination mechanism of avelumab is proteolytic 
degradation. Based on population pharmacokinetic analyses in patients with solid 
tumors, the total systemic clearance was 0.59 L/day.  The terminal half-life was 
6.1 days in patients receiving 10 mg/kg every 2 weeks. 
 
  
15.16 Potential Drug Interactions:  Avelumab is not expected to have drug-drug 
interactions with other drugs because it is primarily metabolized through 
catabolic pathways and is not expected to affect the expression of CYP450 
enzymes. 
 
15.17 Known potential toxicities:  Consult the package insert for the most current and 
complete information. 
 
 
Very Common (≥ 10%): Anemia, nausea, diarrhea, vomiting, abdominal pain, 
fatigue, pyrexia, peripheral edema, infusion related reaction, weight decreased, 
decreased appetite, back pain, arthralgia, cough, dyspnea 
 
 
Common (≥ 1% - < 10%): Hypothyroidism, chills, pneumonitis, rash, pruritus, 
rash maculopapular 
 
 
Uncommon (≥ 0.1% - < 1%): Adrenal insufficiency, hyperthyroidism, 
thyroiditis, autoimmune thyroiditis, adrenocortical insufficiency acute, 
hypopituitarism, uveitis, colitis, autoimmune colitis, enterocolitis, autoimmune 
hepatitis, acute hepatic failure, hepatic failure, hepatitis, drug hypersensitivity, 
anaphylactic reaction, aspartate aminotransferase (AST) increased, alanine 
aminotransferase (ALT) increased, blood creatine phosphokinase increased, 
transaminases increased, diabetes mellitus, myositis, Guillian-Barré syndrome, 
tubulointerstitial nephritis, rash pruritic, erythema, rash generalized, rash 
erythematous, rash macular, rash papular, dermatitis exfoliative, erythema 
multiforme, pemphigoid, pruritis generalized. 
 
 
Adverse reactions with observed fatal outcome in the avelumab clinical 
development programs included: immune-related pneumonitis, immune-related 
hepatitis, and immune-related myocarditis. 
 
 15.18 Drug procurement:   
 
Investigational avelumab is provided free of charge to patients by EMD 
Serono a subsidiary of Merck KGaA.  Outdated or remaining drug is to 
be destroyed on-site per procedures and local regulations in place at each 
institution. 
 
 
15.19 Nursing Guidelines: 
15.191 Avelumab  side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 


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Instruct patients to report any side effects to the study team immediately. 
Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt 
intervention of corticosteroids. 
 
15.192 Diarrhea can be seen however is less common than that seen 
with anti-CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to the 
study team immediately. 
  
15.193 Rash/pruirits/dermatitis is seen. Rarely Steven Johnson 
Syndrome has been seen and can be life threatening. Patients should 
report any rash to the study team. Treat per section 9.0 and monitor for 
effectiveness. 
  
15.194 Monitor LFT’s closely as elevations in these levels could 
indicate early onset autoimmune hepatitis. Patients should also be 
instructed to report any jaundice, or right upper quadrant pain to the 
study team immediately. 
 
15.195 Pneumonitis can be seen and may be mild (only seen on 
imaging) to severe. Patients should be instructed to report any SOB, 
dyspnea, cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
 
15.196 Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of  fatigue and “not 
feeling well” . Additional symptoms may be that of nausea, sweating and 
decreased activity tolerance. Instruct patients to report these signs or 
symptoms immediately and obtain appropriate labs as ordered by MD. 
  
15.197 Patients who are started on steroid therapy for any side effects of 
avelumab toxicity should be instructed to take the steroids as ordered, 
and not to discontinue abruptly as symptoms may return and be severe. 
Patients may be on steroid therapy for weeks. Instruct patients to report 
any increase or change in side effects with any dosage decrease as 
patients may need a slower taper. 
  
15.198 Fatigue is common and may or may not be associated with 
immune related side effects. Assess patient’s fatigue level prior to each 
cycle of therapy and report any changes to the study team. 
 
15.199 Other rare side effects include Guillian-Barre syndrome, 
nephritis, myocarditis, infusion reaction, and cytopenias. Instruct patients 
to report and side effects to the study team immediately.  
  
 


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15.2  
Fluorouracil (Adrucil, Efudex, [5FU]) 
15.21 Background: Antineoplastic Agent, Antimetabolite (Pyrimidine Analog). 
Fluorouracil is a fluorinated Pyrimidine Antimetabolite that inhibits thymidylate 
synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, 
interfering with DNA, and to a lesser degree, RNA synthesis. Fluorouracil 
appears to be phase specific for the G1 and S phases of the cell cycle. 
 
15.22 Formulation: Commercially available for injection 50 mg/mL (10 mL, 20 mL, 
50 mL, and 100 mL). 
 
15.23 Preparation, storage, and stability: Store intact vials at room 
temperature and protect from light. A slight discoloration may occur with 
storage but usually does not denote decomposition. Dilute in 50 – 1000 
mL of 0.9% NaCl or D5W. If exposed to cold, a precipitate may form; 
gentle heating to 60ºC will dissolve the precipitate without impairing the 
potency. Solutions in 50 – 1000 mL 0.9% NaCl or D5W or undiluted 
solutions in syringes are stable for 72 hours at room temperature. 
Fluorouracil should not be coadministered with either diazepam, 
doxorubicin, daunorubicin, idarubicin, cisplatin, or cytarabine. However, 
fluorouracil and leucovorin are compatible for 14 days at room 
temperature. Fluorouracil is compatible with vincristine, methotrexate, and 
cyclophosphamide. 
 
15.24 Administration:  Fluorouracil may be given IV push, IV infusion.  
 
Refer to section 7.0 (treatment) administration instructions specific to the 
protocol.  
 
15.25 Pharmacokinetic information: 
Distribution: Vd ~ 22% of total body water; penetrates  extracellular 
fluid, CSF, and third space fluids (e.g., pleural effusions and ascitic fluid) 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; Fluorouracil 
must be metabolized to be active. 
Half-life elimination: Biphasic: Initial: 6-20 minutes; two metabolites, 
FdUMP and FUTP, have prolonged half-lives depending on the type of 
tissue. 
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) 
in 6 hours. 
 
 
15.26 Potential Drug Interactions:  Fluorouracil may increase effects of 
warfarin. Avoid ethanol (due to GI irritation). Avoid black cohosh. 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. 
 
Common known potential toxicities, > 10%:   
Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia. 
Gastrointestinal (route and schedule dependent): Heartburn, nausea, 
vomiting, anorexia, stomatitis, esophagitis, anorexia, diarrhea. GI toxicity 
(anorexia, nausea, and vomiting) is generally more severe with 
continuous-infusion schedules. 


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Emetic potential: <1000 mg: Moderately low (10% to 30%) ≥ 1000 mg: 
Moderate (30% to 60%) 
Hematologic: Leukopenia; Myelosuppressive (tends to be more 
pronounced in patients receiving bolus dosing of FU). Decreased white 
blood cell count with increased risk of infection; decreased platelet count 
with increased risk of bleeding. 
Local: Irritant chemotherapy.  
 
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Dry skin 
Gastrointestinal: GI ulceration 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Cardiac enzyme abnormalities, chest pain, coagulopathy, dyspnea, ECG 
changes similar to ischemic changes, hepatotoxicity; hyperpigmentation of 
nail beds, face, hands, and veins used in infusion; hypotension, palmar-
plantar syndrome (hand-foot syndrome), photosensitization. Cerebellar 
ataxia, headache, somnolence, ataxia are seen primarily in intracarotid 
arterial infusions for head and neck tumors.  
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall 
obtain supplies from normal commercial supply chain or wholesaler. 
 
15.29 Nursing Guidelines:  
15.291 Monitor complete blood count and platelet count.  Instruct patient to 
report signs and symptoms of infection, unusual bruising or bleeding to 
the physician. 
 
15. 292 Administer antiemetics as indicated. 
 
15. 293 Diarrhea may be dose–limiting; encourage fluids and treat 
symptomatically. 
 
15. 294 Assess for stomatitis; oral care measures as indicated. May try vitamin E 
oil dabbed on sore, six times daily.  Cryotherapy recommended with IV 
push administration. 
 
15. 295 Monitor for neurologic symptoms (headache, ataxia). 
 
15. 296 Inform patient of potential alopecia. 
 
15. 297 Those patients on continuous infusion may need instruction regarding 
central intravenous catheters and portable intravenous or IA infusion 
devices. 
 
15.298 5FU–induced conjunctivitis is a common problem.  Advise patient to 
report any eye soreness or redness to the healthcare team. 
 
15.299 Photosensitivity may occur.  Instruct patients to wear sun block when 
outdoors. 


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15.3 
Mitomycin (Mutamycin®): 
15.31  Background: Mitomycin is an antitumor antibiotic that alkylates DNA to 
produce DNA cross-linking (primarily with guanine and cytosine pairs) and 
inhibits DNA and RNA synthesis.  Mitomycin is not cell cycle specific but has 
its maximum effect against cells in the late G and early S phases. 
 
15.32 Formulation: Commercially available for injection as:  
 
Injection, solution reconstituted in 5 mg, 20 mg, and 40 mg vials.  
 
15.33 Preparation and storage:  Store intact, unreconstituted mitomycin at controlled 
room temperature and is stable for the lot life indicated on the package.  Avoid 
excessive heat over 40 ºC.  Reconstituted mitomycin with Sterile Water for Inject 
to a concentration of 0.5 mg/mL is stable for 14 days refrigerated or 7 days at 
room temperature.  Protect reconstituted solution from light.  Diluted mitomycin 
in various IV fluids at room temperature, a concentration of 20 to 40 
micrograms/mL is stable as follows:  in 5% Dextrose Injection – stable 3 hours, 
in 0.9% Sodium Chloride Injection – stable 12 hours, and in Sodium Lactate 
Injection – stable 24 hours.  Administer IV push/bolus or via IV piggyback.  
Consider using a central venous catheter as mitomycin is a vesicant.   
 
15.34 Administration:  Administer by slow IV push/bolus via a freely-running saline 
infusion. 
 
 
15.35 Pharmacokinetic information:  
Metabolism:  Primarily hepatic 
 
Half-life elimination:  17 minutes (30 mg dose) 
 
Excretion: Feces primarily; urine 
 
15.36 Potential Drug Interactions:   
Metabolism/Transport Effects: Substrate P-glycoprotein  
Increased Effect/Toxicity: The levels/effects of mitomycin may be 
increased by P-glycoprotein/ABCB1 inhibitors, vinca alkaloids, 
denosumab, dipyrone, palifermin, pimecrolimus, ronalazine, roflumilast, 
trastuzumab. 
Decreased Effect: The levels/effects of mitomycin may be decreased by 
Echinacea, Lumacaftor, P-glycoprotein/ABCB1 inducers. 
 
 
15.37 Known potential toxicities:  Consult the package insert for the most current and 
complete information. US Boxed Warnings include: Bone marrow suppression, 
hepatotoxicity, carcinogenic and teratogenic. 
 
Common known potential toxicities, > 10%:   
Gastrointestinal: Nausea, vomiting, anorexia 
Hematologic & oncologic:  Bone marrow depression, hemolytic-uremic 
syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) 
Miscellaneous:  Fever 
 
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Alopecia 
Gastrointestinal:  Mucous membrane disease, stomatitis 


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Renal:  Increased serum creatinine 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Adult respiratory distress syndrome (ARDS), bladder spasm (intravesical 
administration), cardiac failure, dyspnea, extravasation reactions, fibrosis 
(bladder; intravesical administration), hepatic sinusoidal obstruction 
syndrome (formerly known as hepatic veno-occlusive disease), interstitial 
fibrosis, malaise, nonproductive cough, pulmonary infiltrates, renal failure 
(irreversible), skin rash, weakness 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
15.39 Nursing Guidelines: 
 
 
 
15.391 Administer antiemetics and antidiarrheals as needed. 
 
 
 
 
15. 392 Monitor CBC and platelet count:  Thrombocytopenia may be cumulative 
and dose–limiting. Instruct patient to report any signs or symptoms of 
infection, unusual bruising or bleeding to the health care team. 
 
 
 
 
15. 393 Premedicate with antiemetics and assess for their effectiveness.  
 
 
 
 
15. 394 Monitor for interstitial pneumonitis and pulmonary fibrosis which may 
respond to corticosteroid therapy. 
 
 
 
 
15. 395 Fatigue is common.  Educate patient to incorporate rest periods in daily 
routine. 
 
 
 
 
15. 396 Monitor for signs of hemolytic uremic syndrome. Characterized by rapid 
fall in hemoglobin, renal failure (rise in creatinine), severe 
thrombocytopenia, with progression to pulmonary edema and 
hypotension. Assess creatinine before administration and  hold dose and 
inform MD if crt. >1.7 mg/dl. 
 
15.397 Mitomycin is a potent vesicant – avoid extravasation. Ensure patency of 
IV before and throughout administration. If extravasation occurs stop 
infusion and refer to your institutions treatment policy. Closely monitor 
skin for signs of tissue necrosis, erythema, and tissue sloughing.  
 
15.398 Interstitial pneumonitis occurs rarely, but can be quite severe and lead to 
ARDS.  Assess baseline pulmonary status at initiation of treatment and 
before subsequent cycles. Instruct patient to report any non-productive 
cough, dyspnea, hemoptysis, or chest pain. 
  
15.4 
Cisplatin (CDDP) 
15.41 Background: Cisplatin inhibits DNA synthesis by the formation of DNA cross-
links; denatures the double helix; covalently binds to DNA bases and disrupts 
DNA function; may also bind to proteins. Cisplatin can also bind two adjacent 


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guanines on the same strand of DNA producing intrastrand cross-linking and 
breakage. 
 
15.42 Formulation: Commercially available for injection as:  
Solution [preservative free]: 1 mg/mL (50 mL, 100 mL, 200 mL) 
 
15.43 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store intact vials at room temperature 
and protect from light. Do not refrigerate solution, a precipitate may form. 
Further dilution stability is dependent on the chloride ion concentration and 
should be mixed in solutions of sodium chloride concentrations at least 0.3% 
NaCl. Further dilutions in 0.9% NaCl, D5/0.45% NaCl, or D5/0.9% NaCl to a 
concentration of 0.05-2 mg/mL are stable for 72 hours at 4ºC to 25ºC. The 
infusion solution should have a final sodium chloride concentration equal to or 
greater than 0.2% NaCl. 
  
15.44 Administration:  Refer to the treatment section for specific administration 
instructions. When administered as sequential infusions, observational studies 
indicate a potential for increased toxicity when platinum derivatives (carboplatin, 
cisplatin) are administered before taxane derivatives (docetaxel, paclitaxel). 
Pretreatment hydration with 1-2 L of fluid is recommended prior to cisplatin 
administration; adequate hydration and urinary output (> 100 mL/hour) should be 
maintained for 24 hours after administration. Hydration may be accomplished by 
adding the appropriate dose of cisplatin to 750 mL 0.5 D5/0.45% NaCl with 25 
grams of Mannitol (approximating 1000 mL final volume) and infused over 2 
hours. The IV rate of administration has varied from a 15- to 120-minute 
infusion, 1 mg/minute infusion, 6- to 8-hour infusion, 24-hour infusion, or per 
protocol; maximum rate of infusion of 1 mg/minute in patients with CHF. 
 
 
15.45 Pharmacokinetic information: 
Distribution: Rapidly into tissue; high concentrations in kidneys, liver, 
ovaries, uterus, and lungs 
Protein binding: >90% 
Metabolism: Nonenzymatic; inactivated (in both cell and bloodstream) by 
sulfhydryl groups; covalently binds to glutathione and thiosulfate 
Half-life elimination: Initial: 20-30 minutes; Beta: 60 minutes; Terminal: 
~ 24 hours; Secondary half-life: 44-73 hours 
Excretion: Urine (>90%); feces (10%) 
 
15.46 Potential Drug Interactions:   
Increased Effect/Toxicity: Delayed bleomycin elimination with 
decreased Glomerular filtration rate. When administered as sequential 
infusions, observational studies indicate a potential for increased toxicity 
when platinum derivatives (carboplatin, cisplatin) are administered before 
taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Sodium thiosulfate and amifostine theoretically 
inactivate drug systemically; have been used clinically to reduce systemic 
toxicity with administration of cisplatin. 


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Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in 
estrogen-dependent tumors.  
 
15.47 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, > 10%:   
Central nervous system: Neurotoxicity: Peripheral neuropathy is dose- 
and duration-dependent 
Dermatologic: Mild alopecia 
Gastrointestinal: Nausea and vomiting  
Hematologic: Anemia, leukopenia (nadir day 18-23, recovery by day 39, 
dose related), thrombocytopenia (nadir day 18-23, recovery by day 39, 
dose related) 
Hepatic: Liver enzymes increased 
Renal: Nephrotoxicity (acute renal failure and chronic renal 
insufficiency) 
Otic: Ototoxicity, manifested as high frequency hearing loss; ototoxicity 
is especially pronounced in children 
 
Less common known potential toxicities, 1% - 10%:  
Local: Tissue irritation 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Alopecia, ageusia, anaphylaxis, aortic thrombosis, autonomic neuropathy, 
bradycardia, cardiac arrhythmia, cardiac failure, cerebrovascular accident, 
extravasation, hemolytic anemia (acute), hemolytic-uremic syndrome, 
hiccups, hypercholesterolemia, hyperuricemia, hypocalcemia, 
hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, 
increased serum amylase, leukoencephalopathy, myocardial infarction, 
neutropenic enterocolitis, optic neuritis, pancreatitis, papilledema, 
peripheral ischemia (acute), phlebitis, SIADH, tachycardia, thrombotic 
thrombocytopenic purpura 
15.48 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.49 Nursing Guidelines:  
15.491 May react with aluminum IV set, forming a black precipitate and losing 
its potency. 
 
15. 492 Assess laboratory values prior to drug administration, especially CBC, 
platelets, creatinine. 
 
15. 493 Patient should be hydrated before administration. Stress post infusion 
hydration maintenance to reduce risk of nephrotoxicity. 
 
15. 494 Administer aggressive antiemetic therapy pre- and post-treatment. 
 


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15.495 Monitor for signs of neurotoxicity and ototoxicity. Instruct patient to 
report any numbness, burning, or tingling in hands and feet to health care team. 
Also instruct patient to report any changes in hearing or ringing in the ears to 
health care team. 
 
15.496 Monitor magnesium and potassium levels, and for signs and symptoms of 
hypomagnesemia and hypokalemia, supplements may be needed. 
 
15.497 Instruct patient about alopecia. 
 
15.498 Use cautiously with loop diuretics as these may increase the risk of 
ototoxicity. 
 
15.499a Monitor for signs and symptoms of allergic reactions. Treat according to 
your institution’s protocol. 
 
15.499bMonitor renal function tests. 
16.0  
Statistical Considerations and Methodology  
16.1 
Overview: This protocol will assess the efficacy and safety of concurrent chemotherapy 
radiation treatment combined with avelumab in patients with muscle invasive bladder 
cancer using a two-stage Simon optimum design.  A safety run-in with 6 patients 
(described in Section 7.0) will be conducted prior to the expansion portion. 
A safety analysis will be conducted after 6 patients have been enrolled and have been 
treated for a minimum of three cycles.  Patients will be treated for the first two cycles 
with avelumab only. Chemoradiation will begin at cycle 3 (Day 29).This will be 
performed to determine whether or not the proposed combination chemotherapy regimen 
+ radiation therapy with avelumab is a safe regimen.  ACCRUAL WILL BE 
TEMPORARILY HALTED between the safety run-in and expansion portion  in order to 
evaluate the concurrent radiation therapy adverse event. This data will be reviewed by the 
Study Chair and Study Statistician. The adverse event stopping rule in Section 16.42 will 
be in effect for patients in the initial safety run-in portion as well as patients in the 
expansion portion (efficacy portion) of this study. If this regimen at the proposed dosages 
is deemed safe, these 6 patients will be considered the first 6 patients in this study. 
Adverse events will continue to be monitored for all subsequent patients per the adverse 
event stopping rule described in section 16.42. 
16.11 Primary Endpoint:  The primary endpoint will be complete response (CR) at 6 months from 
registration.  This study will use the response criteria as described in section 11.0 to evaluate 
response or progression. The patients enrolled will have nonmeasurable disease on imaging 
and response will be evaluated with biopsy or cytology at 6 months post-registration.  All 
patients meeting the eligibility criteria who have signed a consent form, have begun treatment, 
and have not been deemed a major treatment violation during the first cycle of treatment will 
be evaluable for response. 


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16.12 Safety run-in portion:   The safety run-in portion will consist of the first 6 patients enrolled 
on the study.  For a subject to be considered evaluable for dose-limiting toxicity (DLT) the 
subject must have received at least two doses of avelumab for cycles 1-2 and chemoradiation 
for cycle 3 (Day 29). If a subject withdraws from the study within the first 3 cycles of 
treatment for reasons other than adverse events, the subject will be replaced; and only DLTs 
occurring in Cycles 1-3 will be used for establishing safety during the run-in portion. 
However, all adverse event data will be summarized in the final analysis.  These 6 patients 
will be included in the efficacy analysis. Safety for all patients (including the patients in the 
run-in portion ) will continue to be monitored via the Adverse Event Stopping Rule.  Dose 
limiting toxicity during cycle 3 (Day 29; in either portion) will be defined as described in 
section 7.0    
16.2 Statistical Design 
16.21 Decision Rule: The largest success proportion (CR at 6 months post-registration) where the 
proposed treatment regimen would be considered ineffective in this population is 65%, and 
the smallest success proportion that would warrant subsequent studies with the proposed 
regimen in this patient population is 85%. The following two-stage design based on 
properties of the binomial distribution uses 27 patients to test the null hypothesis that the 
true success proportion in a given patient population is at most 65%.  
16.211 Stage I:  Enter 12 patients into the study.  If 8 or fewer successes are observed in the first 12 
evaluable patients, the study will conclude or the investigators will discuss with the, IRB, or 
DSMB to determine if further investigation is warranted.  Otherwise, if 9 or more successes 
are observed in the first 12 evaluable patients, we will proceed to Stage 2.  Accrual will 
continue between Stage 1 and Stage 2 while patients become evaluable for the primary 
endpoint.  
16.212 Stage 2:  Enter an additional 15 patients into the study.  If 20 or fewer successes are 
observed in the first 27 evaluable patients, we may consider this regimen ineffective in this 
patient population.  If 21 or more successes are observed in the first 27 evaluable patients, 
we may recommend further testing of this regimen in subsequent studies in this population.   
16.213 Over Accrual: If more than the target number of patients are accrued, the additional patients 
will not be used to evaluate the stopping rule or used in any decision making process.  
16.22 Sample Size: The two-stage study design to be utilized is fully described in Section 16.21. A 
minimum of 27 evaluable patients are to be accrued onto this study unless undue adverse 
events are encountered. We anticipate accruing an additional 3 patients to account for 
ineligibility, cancellation, major treatment violation, or other reasons. Thus, a maximum of 
30 patients will be accrued onto this study in order to have 27 evaluable patients available 
for the statistical design described in Section 16.21.  There is no pre-specified maximum 
accrual for the two chemotherapy cohorts.  
16.23 Accrual Time and Study Duration: The anticipated accrual rate is approximately 1-2 patients 
per month, based on physician estimate. Therefore, the accrual period for this phase II study 


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is expected to be 20 months. The final analysis can begin approximately 26 months after the 
trial begins, i.e., as soon as the last patient has completed the 6 months post-registration 
clinical follow-up visit. 
16.24 Power and Significance Level: Assuming that the number of successes is binomially 
distributed, the significance level is ≤0.10 and the probability of declaring that this regimen 
warrants further studies (i.e., statistical power) under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following table. 
If the true success proportion is… 
0.65 
0.70 
0.75 
0.80 
0.85 
Then the probability of stopping 
accrual after Stage I is …  
0.65 
0.51 
0.35 
0.21 
0.09 
And the probability of declaring that 
the regimen warrants further studies 
is …  
0.10 
0.22 
0.42 
0.65 
0.85 
 
16.25 Other Considerations: Adverse events, quality/duration of response, and patterns of treatment 
failure observed in this study, as well as scientific discoveries or changes in standard care 
will be taken into account in any decision to terminate the study. 
16.3 Analysis Plan: The analysis for this trial will commence at planned time points and at the time 
the patients have become evaluable for the primary endpoint. Such a decision will be made by 
the Statistician and Study Chair, in accordance with Mayo Clinic Cancer Center (MCCC) 
Standard Operating Procedures, availability of data for secondary endpoints (e.g., laboratory 
correlates), and the level of data maturity. 
16.31 Primary Endpoint 
16.311 Definition:  The primary endpoint of this trial is the proportion of patients who 
achieve a complete response (CR) at 6 months post-registration as defined in 
Section 16.11. 
16.312 Estimation: The proportion of successes will be estimated by the number of 
successes divided by the total number of evaluable patients. Confidence intervals for 
the true success proportion will be calculated using the properties of the binomial 
distribution.  
16.313 Over Accrual: If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any decision 
making processes; however, they will be included in final point estimates and 
confidence intervals. 
16.32 Definitions and Analyses of Secondary Endpoints 


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16.321 Adverse Events: All eligible patients that have initiated treatment will be considered 
evaluable for assessing adverse event rate(s). The maximum grade for each type of 
adverse event will be recorded for each patient, and frequency tables will be 
reviewed to determine patterns. Additionally, the relationship of the adverse event(s) 
to the study treatment will be taken into consideration. 
16.322 Analysis of Patient-Reported Outcomes (EORTC QLQ-30,  EORTCQOL-BLM30) :  
Quality of life will be assessed at screening, at end of avelumab treatment, and EOS 
(12 month after registration).   QOL will be measured using the EORTC QLQ-C30, a 
30-item patient-reported questionnaire about patient ability to function, symptoms 
related to the cancer and its treatment, overall health and quality of life, and 
perceived financial impact of the cancer and its treatment.  28 of the 30 items are 
measured on a 1-4 scale (1=not at all; 4=very much) with the remaining two items 
(overall health and overall quality of life) scored on a 1-7 numeric analogue scale 
(1=very poor; 7=excellent).  The recall period for the EORTC QLQ-C30 is one week.  
The EORTC QLQ-C30 is the product of more than a decade of collaborative research 
and to date, more than 2200 studies using the EORTC QLQ-C30 have been 
registered with the EORTC (Fayers et al, 2001 [EORTC Scoring Manual]).  The 
EORTC QLQ-BLM30 is a 30-item questionnaire for patients with muscle invasive 
bladder cancer (T2, T3, T4a and T4b). The muscle-invasive bladder cancer module 
contains additional items assessing urostomy problems, problems associated with the 
use of a catheter, and body image.    
 
A paper booklet containing all the patient-reported outcomes will be administered in 
clinic at baseline and every cycle visit at Mayo Clinic, and each PRO will be scored 
according to the published scoring algorithm. Scale score trajectories over time will 
be examined using stream plots and mean plots with standard deviation error bars 
overall. Changes from baseline will be statistically tested using paired t-tests, and 
standardized response means (mean of the change from baseline scores at a given 
cycle, divided by the standard deviation of the change scores) will be interpreted 
(after applying Middel’s (2002) adjustment) using Cohen’s (1988) cut-offs: <0.20 = 
trivial; 0.20-<0.50 = small; 0.50-<0.80 = moderate; and >=/0.80 = large. Correlation 
between outcomes will employ Pearson and/or Spearman correlations at individual 
time points. 
16.323 Progression-Free Survival (PFS):  PFS will be defined as the time from registration 
to time of first documentation of progression (as defined in Section 11.b) or death 
due to any cause. Patients last known to be alive and not to have progressed are 
censored at the last day of contact (or at study completion – 12 months).  PFS rate at 
1 year will be estimated using the method of Kaplan-Meier (1958).   
16.324 Recurrence-Free Survival (RFS):  RSF will be defined as the time from documented 
complete response  to the first documentation of recurrence (as defined in Section 
11.c). Patients last known to be alive and not to have recurred are censored at the last 
day of contact (or at study completion – 12 months).  RFS rate at 1 year will be 
estimated using the method of Kaplan-Meier (1958),   
 
16.33 
Exploratory & Correlative Endpoints: See section 2.3 


MC1752 
68  
 
 
Protocol Version Date: 21JUN2018 
16.34  
Translational analyses: Given the small sample size, all translational analyses are 
considered exploratory and no adjustment for multiplicity will be employed. One-sided 
p-values ≤0.10 are considered statistically significant throughout. Results will be used to 
design subsequent confirmatory studies (likely as translational components within the 
subsequent phase III study should this phase II study support the use of this combination 
in a phase III study). 
We will explore the relationship of PD-L1(SP263 and SP142 ),CD8+ by IHC and tumor 
mutational burden ( Foundation Medicine Panel)  and clinical response in order to 
identify if these markers may be predictive of response. Association of Bim    
Expression will be evaluated at using the baseline tissue specimen and explored in 
relation to 6 months post-registration response and subsequently in relation to other 
clinical outcomes such as tumor response and adverse event incidence using two-way 
tables and analyzed using Fisher’s exact tests.   Expression of immune signatures by 
RNA-sequencing (RNA-seq) expression (using the baseline tissue specimen) will be 
evaluated at baseline and explored in relation to clinical outcomes such as progression-
free survival, tumor response, and adverse event incidence using two-way tables and 
box plots and analyzed using Fisher’s exact tests or logistic regression methods, as 
appropriate.  
16.4  
Data & Safety Monitoring 
16.41  
The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.42  
Adverse Event Stopping Rule: The stopping rule specified below is based on the 
knowledge available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend accrual 
because of  unexpected adverse event profiles that have not crossed the 
specified rule below. 
Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (ie, an adverse event with attribute 
specified as “possible”, “probable”, or “definite”) that satisfy the following:  
• if 4 or more patients in the first 10 treated patients (or 40% after 20 patients 
have been accrued) experience a Grade 3 or higher non-hematologic adverse 
event. 


MC1752 
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Protocol Version Date: 21JUN2018 
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
16.5 
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary 
Endpoints (i.e., “Outcome Measures”) along with other required information for this 
study will be reported on ClinicalTrials.gov. For purposes of timing of the Results 
Reporting, the initial estimated completion date for the Primary Endpoint of this study is 
26 months after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has 
completed the 6 months post-registration clinical follow-up. 
16.6  
Inclusion of Women and Minorities 
16.61  
This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.62  
There is no information currently available regarding differential effects of this 
treatment regimen in subsets defined by race, gender, or ethnicity, and there is 
no reason to expect such differences to exist. Therefore, although the planned 
analysis will, as always, look for differences in treatment effect based on racial 
and gender groupings, the sample size is not increased in order to provide 
additional power for subset analyses. 
16.63  Based on prior MCCC studies involving similar disease sites, we expect about 
5% of patients will be classified as minorities by race and 25% of patients will be 
women. Expected sizes of racial by gender subsets are shown in the following 
table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
6 
21 
27 
Ethnic Category: Total of all subjects 
7 
23 
30 
 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
0 
0 
0 
Black or African American 
0 
0 
0 
Native Hawaiian or other Pacific Islander 
0 
0 
0 


MC1752 
70  
 
 
Protocol Version Date: 21JUN2018 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
White 
7 
22 
29 
Racial Category: Total of all subjects 
7 
23 
30 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
17.0  
Pathology Considerations/Tissue Biospecimens 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Research Study 
(Section for more 
information) 
Specimen 
Purpose 
 (check all 
that apply) 
Mandat
ory or 
Optional 
Type of 
Tissue to 
Collect 
Block, 
Slides, Core, 
etc. (# of 
each to 
submit) 
Archived 
tissue 
Process 
at site? 
(Yes or 
No) 
Tempera
Conditi
for Stor
/Shippi
Correlative studies for 
mRNA expression and 
whole genome analysis 
 Correlative Application 
MC1752-C1 
☒  Correlative 
 studies for 
mRNA 
expression and 
whole genome 
analysis 
Optional 
 Formalin 
Fixed 
Paraffin 
Embedded 
 
5 charged 
unstained 
slides 5 
microns 
thick 
sections  
X 
No 
Ambie


MC1752 
71  
 
 
Protocol Version Date: 21JUN2018 
17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
Archived tissue may be collected per table 17.1 through next generation sequencing for 
mRNA expression and whole genome analysis 
 
 Block retrieval and cutting will be determined at a later date. 
17.3 
Correlative Tissue Collection  
17.31 Tissue Kits will not be provided for this protocol. 
17.32 Paraffin Embedded Tissue 
17.321 
Archived tissue may be collected per table 17.1 through next 
generation sequencing for mRNA expression and whole genome 
analysis  
17.322 
 Block retrieval and cutting will be determined at a later date. 
Shipping, accessioning, and processing information will be determined 
at a later date. A modification will be submitted when information is 
available.   
17.4 
Background and Methodology 
17.41 See section 1.5 for correlative background information.  
17.42 Archived tissue may be collected per table 17.1 through next generation 
sequencing for mRNA expression and whole genome analysis. 
 
. 
 
 
 


MC1752 
72  
 
 
Protocol Version Date: 21JUN2018 
 
18.0 
Records and Data Collection Procedures 
18.1 
Data submission instructions 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up 
Not applicable. Patients will be followed until EOS visit (12 months) only.  
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation  
 
This study requires supporting documentation for diagnosis prior to study entry as well as 
for evidence of response to study therapy and progression after study therapy. 18.6
 
Labeling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
19.0 
Budget Considerations 
19.1 
Tests to be research funded: Avelumab Study drug, Avelumab study drug administration, 
ECG, urogram at  EOS visit (12 month after registration), obtaining and processing of 
archived research tissue specimens.   
 
 


MC1752 
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Protocol Version Date: 21JUN2018 
20.0 
References 
1. 
Mak RH, Hunt D, Shipley WU et al. Long-term outcomes in patients with muscle-invasive 
bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of 
Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 
2014; 32: 3801-3809. 
2. 
Gogna NK, Matthews JH, Turner SL et al. Efficacy and tolerability of concurrent weekly low 
dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: 
a report of two sequential Phase II studies from the Trans Tasman Radiation Oncology Group. Radiother 
Oncol 2006; 81: 9-17. 
3. 
Hagan MP, Winter KA, Kaufman DS et al. RTOG 97-06: Initial report of a Phase I–II trial of 
selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, 
and adjuvant MCV combination chemotherapy. International Journal of Radiation 
Oncology*Biology*Physics 2003; 57: 665-672. 
4. 
James  ND, Hussain  SA, Hall  E et al. Radiotherapy with or without Chemotherapy in Muscle-
Invasive Bladder Cancer. New England Journal of Medicine 2012; 366: 1477-1488. 
5. 
Kaufman DS, Winter KA, Shipley W et al. Muscle-invading bladder cancer, RTOG Protocol 99–
06: Initial report of a phase I/II trial of selective bladder-conservation employing TURBT, accelerated 
irradiation sensitized with cisplatin and paclitaxel followed by adjuvant cisplatin and gemcitabine 
chemotherapy. J Clin Oncol 2005; 23. 
6. 
Kaufman DS, Winter KA, Shipley WU et al. The initial results in muscle-invading bladder cancer 
of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin 
and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial 
response. Oncologist 2000; 5: 471-476. 
7. 
Mitin T, Hunt D, Shipley WU et al. Transurethral surgery and twice-daily radiation plus 
paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant 
chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre 
phase 2 trial. The lancet oncology 2013; 14: 863-872. 
8. 
Shipley WU, Winter KA, Kaufman DS et al. Phase III trial of neoadjuvant chemotherapy in 
patients with invasive bladder cancer treated with selective bladder preservation by combined radiation 
therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 
1998; 16: 3576-3583. 
9. 
Tester W, Caplan R, Heaney J et al. Neoadjuvant combined modality program with selective 
organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II 
trial 8802. Journal of Clinical Oncology 1996; 14: 119-126. 
10. 
Tester W, Porter A, Asbell S et al. Combined modality program with possible organ preservation 
for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys 1993; 25: 
783-790. 
11. 
Giacalone NJ, Shipley WU, Clayman RH et al. Long-term Outcomes After Bladder-preserving 
Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the 
Massachusetts General Hospital Experience. Eur Urol 2017. 
12. 
Apetoh L, Ghiringhelli F, Tesniere A et al. Toll-like receptor 4-dependent contribution of the 
immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13: 1050-1059. 
13. 
Sistigu A, Yamazaki T, Vacchelli E et al. Cancer cell-autonomous contribution of type I 
interferon signaling to the efficacy of chemotherapy. Nat Med 2014; 20: 1301-1309. 
14. 
Wu CT, Chen WC, Chang YH et al. The role of PD-L1 in the radiation response and clinical 
outcome for bladder cancer. Sci Rep 2016; 6: 19740. 
15. 
Rosenberg JE, Hoffman-Censits J, Powles T et al. Atezolizumab in patients with locally advanced 
and metastatic urothelial carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909-1920. 


MC1752 
74  
 
 
Protocol Version Date: 21JUN2018 
16. 
Bellmunt J, de Wit R, Vaughn DJ et al. AvelumabAvelumabAvelumab as Second-Line Therapy 
for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376: 1015-1026. 
17. 
Hodge JW, Guha C, Neefjes J, Gulley JL. Synergizing radiation therapy and immunotherapy for 
curing incurable cancers. Opportunities and challenges. Oncology (Williston Park) 2008; 22: 1064-1070; 
discussion 1075, 1080-1061, 1084. 
18. 
Apolo AI, J. R. et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic 
urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: Analysis of safety, clinical activity, 
and PD-L1 expression. J Clin Oncol 34, 2016 (suppl; abstr 4514). 
19. 
Chang SS, Bochner BH, Chou R et al. Treatment of Non-Metastatic Muscle-Invasive Bladder 
Cancer: AUA/ASCO/ASTRO/SUO Guideline. J Urol; 198: 552-559, 2017. 
 
 
 
 


MC1752 
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Protocol Version Date: 21JUN2018 
Appendix I 
ECOG Performance Status 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 


E N G LI S H  
 
Pr ot oc ol Versi o n Date: 2 1J U N 2 0 1 8  
A p pe n di x I I 
E O R T C Q L Q -C 3 0  
 
E O R T C Q L Q -C 3 0 ( versi o n 3) 
We  are i ntereste d i n s o me t hi n gs a b o ut y o u  a n d y o ur  healt h.  Please  a ns wer all of  t he q uesti o ns  y o urself  b y  circli n g  t he n u m ber t hat 
best a p plies t o y o u. T here are n o "ri g ht" or " wr o n g" a ns wers. T he i nf or mati o n t hat y o u pr o vi de will re mai n strictl y c o nfi de ntial. 
 
Pl e a s e  fill i n y o ur  i niti al s: 

 
 
Y o ur  birt h d at e  ( D a y, M o nt h,  Y e ar):  

 
T o d a y' s  d at e  ( D a y, M o nt h,  Y e ar):  
3 1  
 
 
 
1.  D o y o u h a v e a n y tr o u bl e d oi n g str e n u o u s a cti viti e s,  
N ot at 
All  
A 
Littl e  
Q uit e 
a Bit  
V er y 
M u c h  
li k e c arr yi n g a h e a v y s h o p pi n g b a g or a s uit c a s e ? 
1  
2  
3  
4  
2.  D o y o u h a v e a n y tr o u bl e t a ki n g a l o n g w al k ?  
1 
2 
3 
4 
3.  D o  y o u  h a v e  a n y  tr o u bl e t a ki n g a s h ort  w al k  o ut si d e  of  t h e h o u s e ?  
1 
2 
3 
4 
4.  D o  y o u  n e e d  t o st a y  i n b e d  or  a c h air  d uri n g  t h e d a y ?  
1 
2 
3 
4 
5.  
D o y o u n e e d h el p wit h e ati n g, dr e s si n g,  w a s hi n g 
y o ur s elf or u si n g t h e  t oil et ? 
 
1 
 
2 
 
3 
 
4 
D uri n g t h e p a st w e e k:  
 
N ot at  
 
A 
 
Q uit e  
 
V er y  
 
All  
Littl e  
a Bit  
M u c h  
6.  W er e  y o u  li mit e d i n d oi n g  eit h er  y o ur  w or k  or  ot h er  d ail y  a cti viti e s ?  
1 
2 
3 
4 
7.  
W er e y o u li mit e d i n p ur s ui n g y o ur h o b bi e s or ot h er 
l ei s ur e ti m e a cti viti e s ?  
 
1 
 
2 
 
3 
 
4 
8.  W er e y o u s h ort of  br e at h ?  
1 
2 
3 
4 
9.  H a v e y o u h a d  p ai n ?  
1 
2 
3 
4 
1 0. Di d y o u n e e d t o r e st ?  
1 
2 
3 
4 
1 1. H a v e y o u h a d tr o u bl e sl e e pi n g ?  
1 
2 
3 
4 
1 2. H a v e y o u f elt w e a k ?  
1 
2 
3 
4 
1 3. H a v e y o u l a c k e d a p p etit e ?  
1 
2 
3 
4 
1 4. H a v e y o u f elt n a u s e at e d ?  
1 
2 
3 
4 
1 5. H a v e y o u v o mit e d ?  
1 
2 
3 
4 
1 6. H a v e y o u b e e n c o n sti p at e d ?  
1 
2 
3 
4 
 
Please g o o n t o t he ne xt pa ge  


ENGLISH 
 
Protocol Version Date: 21JUN2018 
 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
 
1 
 
2 
 
3 
 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
 
1 
 
2 
 
3 
 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
 
1 
 
2 
 
3 
 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
 
1 
 
2 
 
3 
 
4 
 
For the  following  questions  please  circle  the  number  between   1  and  7  that   best applies to 
you 
29. 
How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
30. 
How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 


ENGLISH 
 
Protocol Version Date: 21JUN2018 
Appendix III EORTC QLQ-BLM30 
 
EORTC QLQ - BLM30 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you 
have experienced these symptoms or problems during the past week. Please answer by circling the number that best 
applies to you. 
 
PLEASE ANSWER QUESTIONS 31 - 37 ONLY IF YOU DO NOT HAVE A UROSTOMY 
 
During the past week: 
Not 
A 
Quite 
Very 
at all 
little 
a bit 
much 
31. 
Have you had to urinate frequently during the day? 
1 
2 
3 
4 
32. 
Have you had to urinate frequently at night? 
1 
2 
3 
4 
33. 
When you felt the urge to pass urine, 
did you have to hurry to get to the toilet? 
 
1 
 
2 
 
3 
 
4 
34. 
Was it difficult for you to get enough sleep, because 
you needed to get up frequently at night to urinate? 
 
1 
 
2 
 
3 
 
4 
35. 
Have you had difficulty going out of the house, 
because you needed to be close to a toilet? 
 
1 
 
2 
 
3 
 
4 
36. 
Have you had any unintentional release (leakage) of urine? 
1 
2 
3 
4 
37. 
Have you had pain or a burning feeling when urinating? 
1 
2 
3 
4 
 
 
PLEASE ANSWER QUESTIONS 38 - 43 ONLY IF YOU HAVE A UROSTOMY 
During the past week: 
Not 
A 
Quite 
Very 
 
at all 
little 
a bit 
much 
38. 
Has urine leaked from your urostomy bag? 
1 
2 
3 
4 
39. 
Did you have problems with caring for your urostomy? 
1 
2 
3 
4 
40. 
Was your skin around the urostomy irritated? 
1 
2 
3 
4 
41. 
Have you felt embarrassed because of your urostomy? 
1 
2 
3 
4 
42. 
Have you been dependent on others for 
caring for your urostomy? 
 
1 
 
2 
 
3 
 
4 
43. 
Did you frequently have to change the urostomy bag? 
1 
2 
3 
4 
 
PLEASE ANSWER QUESTION 44 ONLY IF YOU HAVE USED A CATHETER DURING THE PAST WEEK 
 
44. 
Have you had problems with self-catheterization? 
(inserting a tube in the bladder to pass urine) 
1 
2 
3 
4 
Please go on to the next page 


ENGLISH 
 
Protocol Version Date: 21JUN2018 
During the past week: 
Not 
A 
Quite 
Very 
at all 
little 
a bit 
much 
45. 
Were you worried about your health in the future? 
1 
2 
3 
4 
46. 
Did you worry about the results of examinations and tests? 
1 
2 
3 
4 
47. 
Did you worry about possible future treatments? 
1 
2 
3 
4 
48. 
Have you had a bloated feeling in your abdomen? 
1 
2 
3 
4 
49. 
Have you had flatulence or gas? 
1 
2 
3 
4 
50. 
Have you felt physically less attractive as 
a result of your illness or treatment? 
 
1 
 
2 
 
3 
 
4 
51. 
Have you been dissatisfied with your body? 
1 
2 
3 
4 
52. 
Have you felt less feminine/masculine as 
a result of your illness or treatment? 
 
1 
 
2 
 
3 
 
4 
During the past 4 weeks: 
 
Not 
 
A 
 
Quite 
 
Very 
 
at all 
little 
a bit 
much 
53. 
To what extent were you interested in sex? 
1 
2 
3 
4 
54. 
To what extent were you sexually active 
(with or without sexual intercourse)? 
 
1 
 
2 
 
3 
 
4 
55. 
For men only: Did you have difficulty gaining 
or maintaining an erection? 
 
1 
 
2 
 
3 
 
4 
56. 
For men only: Did you have ejaculation problems 
(e.g. dry ejaculation)? 
 
1 
 
2 
 
3 
 
4 
 
Please answer the following 4 questions only if you 
 
Not 
 
A 
 
Quite 
 
Very 
have been sexually active during the past 4 weeks: 
at all 
little 
a bit 
much 
57. 
Have you felt uncomfortable about being 
sexually intimate? 
 
1 
 
2 
 
3 
 
4 
58. 
Have you worried that you may contaminate 
 
 
 
 
your partner during sexual contact with the 
bladder treatment you have been 
receiving? 
 
1 
 
2 
 
3 
 
4 
59. 
To what extent was sex enjoyable for you? 
1 
2 
3 
4 


ENGLISH 
 
Protocol Version Date: 21JUN2018 
60. 
For Women only: did you have a dry vagina 
or other problems during intercourse? 
 
1 
 
2 
 
3 
 
4 
 
 
© Copyright 1994 EORTC Quality of Life Study Group, version 1.0 All rights reserved. 
 
 


ENGLISH 
 
Protocol Version Date: 21JUN2018 
Appendix IV Patient Information Sheet 
Patient Information Sheet 
Screening & Active Monitoring Phase 
 
Page 1 of 5 
 
 
You have been given a booklet to complete for this study. The booklet contains some 
questions about your health as a patient receiving treatment. Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
 
This booklet contains: 
• The EORTC QLQ-C30: complete during your scheduled clinic visit (Screening, 
end of avelumab treatment, end of study) 
• The EORTC QLQ-BLM30: complete during your scheduled clinic visit 
(Screening, end of avelumab treatment, end of study) 
 
 
 
 
Thank you for taking the time to help us.