Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer (CIRTiN-BC): A Phase II, Single-Arm Trial
Phase: NA
Conditions: Bladder Cancer
Sponsor: University of Texas Southwestern Medical Center

 
STU2021-0114, Woldu, FormA-ResearchProtocol-V54-12.9.2022, Mod_5, 12-19-22 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
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Title: Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder 
Cancer (CIRTiN-BC): A Phase II, Single-Arm Trial 
 
 
Principal Investigator(s): 
Solomon Woldu, M.D. 
 
 
 
 
 
 Version 2.0 – December 9, 2022 
 
 
NCT Number: NCT04779489 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
STU2021-0114, Woldu, FormA-ResearchProtocol-V54-12.9.2022, Mod_5, 12-19-22 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
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STU-2021-0114 
 
Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer (CIRTiN-BC): 
A Phase II, Single-Arm Trial 
 
 
Principal Investigator:  
Solomon Woldu, M.D. 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
Department of Urology 
 
 
 
 
2001 Inwood Road, WCB3 Floor 4 
 
 
 
 
Dallas, TX 75390 
 
 
 
 
(214) 648-9558 
 
 
 
 
solomon.woldu@utsouthwestern.edu 
 
Co-Principal Investigators or Lead Sub-Investigator(s): 
 
 
 
 
 
 
 
Vitaly Margulis, M.D. 
 
 
 
 
Department of Urology 
 
 
 
 
 
Raqibul Hannan, M.D. 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
Jeffrey Howard, M.D. 
 
 
 
 
Department of Urology 
 
 
 
 
 
Aurelie Garant, M.D. 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
Suzanne Cole, M.D. 
 
 
 
 
Department of Medical Oncology 
 
 
Biostatistician: 
 
Karabi Nandy, Ph.D. 
 
 
 
 
Department of Population and Data Sciences 
 
Study Drug/Treatment: 
PULSAR (Personalized ULtrafractionated Stereotactic Adaptive 
Radiotherapy) 
 
Funding Source:  
Internal – Urology 
 
NCT Number:  
NCT04779489 
 
Initial version: 
Version 1.1 
 
 
Amended: 
 
Not Applicable 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 

 
STU2021-0114, Woldu, FormA-ResearchProtocol-V54-12.9.2022, Mod_5, 12-19-22 (1) 
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This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018; 07/2020; 07/2022 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version #_____________________________ 
PROTOCOL TITLE 
Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer (CIRTiN-BC): 
A Phase II, Single-Arm Trial 
 
 
Principal Investigator (PI) Name: __Solomon Woldu, M.D.____ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
STU2021-0114, Woldu, FormA-ResearchProtocol-V54-12.9.2022, Mod_5, 12-19-22 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016, 12/2018; 07/2020; 07/2022 
 

Protocol Number SCCC#09821 
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i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 1 
STUDY SCHEMA.............................................................................................................. 3 
STUDY SUMMARY .......................................................................................................... 4 
1.0 BACKGROUND AND RATIONALE ........................................................................ 5 
1.1 
Disease Background........................................................................................................ 5 
1.2 
Sterotactic Ablative Radiotherapy (SAbR)....................................................................... 5 
1.3 
Immune Checkpoint Inhibitor Therapy............................................................................. 7 
1.4 
Study Rationale ............................................................................................................... 8 
1.5 
Correlative Studies .......................................................................................................... 9 
2.0 .......................................................................................................... STUDY OBJECTIVES
.............................................................................................................................................. 9 
2.1 
Primary Objectives ........................................................................................................... 9 
2.2 
Secondary Objectives ...................................................................................................... 9 
2.3 
Primary endpoints ............................................................................................................ 9 
2.4 
Secondary Endpoints....................................................................................................... 9 
3.0 ....................................................................................................... SUBJECT ELIGIBILITY
............................................................................................................................................ 10 
3.1 
Inclusion Criteria ............................................................................................................ 10 
3.2 
Exclusion Criteria ........................................................................................................... 12 
4.0 .............................................................................................................. TREATMENT PLAN
............................................................................................................................................ 13 
4.1 
Pulsar Dose and Techniques ........................................................................................ 13 
4.2 
Techinical Factors and Considerations ....................................................................... 134 
4.3 
Simulation and Imaging Guidance ............................................................................... 174 
4.4 
Treatment Planning and Target Volumes .................................................................... 175 

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4.5 
Dosimetry ..................................................................................................................... 175 
4.6 
Normal Tissue Dose Constraints ................................................................................. 175 
4.7 
Radtiation Therapy Quality Assurance ........................................................................ 187 
4.8 
Concomitant Medications/Treatments ......................................................................... 187 
 
4.9 
Other Modalities or Procedures  
 
 
 
 
17 
 
4.10 
Duration of Therapy 
 
 
 
 
 
 
17 
 
4.11 
Duration of Follow-up 
 
 
 
 
 
 
17 
 
4.12 
Removal of Subjects from Protocol Therapy 
 
 
 
18 
 
4.13 
Subject Replacement 
 
 
 
 
 
 
18 
5.0 ....................................................................................................... STUDY PROCEDURES
............................................................................................................................................ 18 
5.1 
Screening/Baseline Procedures .................................................................................... 18 
5.2 
Procedures During Treatment ....................................................................................... 19 
5.3 
Follow-up Procedures .................................................................................................... 19 
5.4 
Time and Events Table .................................................................................................. 19 
5.5 
Removal of Subjects from Study ................................................................................... 20 
6.0 .......................................................................................... MEASUREMENT OF EFFECT
............................................................................................................................................ 20 
6.1 
Antitumor Effect ............................................................................................................. 20 
6.2 
Safety/tolerability ........................................................................................................... 24 
7.0 .............................................................................................................. ADVERSE EVENTS
............................................................................................................................................ 24 
7.1 
Adverse Event Monitoring ............................................................................................. 24 
7.2 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the SCCC 
DSMC and/or HRPP ................................................................................................................... 27 
7.3 
Stopping Rules .............................................................................................................. 29 
8.0 ........................................................................... CORRELATIVES/SPECIAL STUDIES
............................................................................................................................................ 29 
9.0 ................................................................................. STATISTICAL CONSIDERATIONS
............................................................................................................................................ 29 
9.1 
Study Design/Study Endpoints ...................................................................................... 29 

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9.2 
Sample Size and Accrual .............................................................................................. 30 
9.3 
Data Analyses ................................................................................................................ 30 
10.0 ................................................................................................... STUDY MANAGEMENT
............................................................................................................................................ 31 
10.1 
Conflict of Interest .......................................................................................................... 31 
10.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 31 
10.3 
Registration Procedures ................................................................................................ 31 
10.4 
Data Management and Monitoring/Auditing .................................................................. 32 
10.5 
Adherence to the Protocol ............................................................................................. 33 
10.6 
Amendments to the Protocol ......................................................................................... 34 
10.7 
Record Retention ........................................................................................................... 34 
10.8 
Obligations of Investigators ........................................................................................... 34 
11.0 ..................................................................................................................... REFERENCES
............................................................................................................................................ 35 
12.0 ...................................................................................................................... APPENDICES
............................................................................................................................................ 37 

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LIST OF ABBREVIATIONS  
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
cN+ 
Clinically Node-Positive 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCT 
Downstaging chemotherapy 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
ICI 
Immune Checkpoint Inhibitor 
IDE 
Investigational Device Exemption 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
MIBC 
muscle invasive bladder cancer 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NACT 
Neoadjuvant chemotherapy 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PULSAR 
Personalized ULtrafractionated Stereotactic Adaptive Radiotherapy 

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RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
Recurrence Free Survival 
SAbR 
Stereotactic Ablative Radiotherapy 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SoC 
Standard of Care 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility: 
- cT1-T4a, bulky cN1-3, cM0 bladder cancer 
 
- planning ICI therapy due to: 
 
- ineligible/refusing platinum based DCT or 
 
- failure to respond to platinum based DCT 
  
- ECOG 0-1 
- eligible for RC and PULSAR 
nonresectable disease 
(e.g. development of distant 
metastases) 
SoC ICI per FDA approved dose/schedule 
 
PULSAR 12 Gy x 3 fractions, 12-16 day intervals, 
starting 1-2 weeks after ICI initiation 
 
continue SoC ICI for a further 4-8 weeks 
 
further SoC ICI permitted at clinician 
discretion 
 
management/surveillance per SoC 
restaging imaging (per SoC) 
 
resectable disease 
radical cystectomy/pelvic lymph 
node dissection 
(primary endpoint: completion of 
PULSAR + RC) 
manage per SoC 

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STUDY SUMMARY 
Title 
Checkpoint Inhibitor and Radiation Therapy in Bulky Node-Positive 
Bladder Cancer (CIRTiN-BC): A Phase II, Single-Arm Trial 
Short Title 
CIRTiN-BC 
Protocol Number 
 STU-2021-0114 
Phase 
Phase I/II 
Methodology 
Single-arm safety/efficacy trial 
Study Duration 
36 months 
Study Center(s) 
Single center at UT Southwestern Medical Center, with potential 
expansion to Parkland Hospital and John Peter Smith Hospital 
Objectives 
To evaluate the safety and efficacy of PULSAR in patients with bulky 
node-positive bladder cancer on immune checkpoint inhibitor therapy 
due to ineligibility for or failure to respond to downstaging chemotherapy 
Number of Subjects 
27 
Diagnosis and Main 
Inclusion Criteria 
bladder cancer with bulky regional lymph node metastases, planning 
immune checkpoint inhibitor therapy due to ineligibility for downstaging 
chemotherapy or failure to respond to downstaging chemotherapy 
Study Product(s), Dose, 
Route, Regimen 
PULSAR (personalized ultrafractionated stereotactic ablative 
radiotherapy) 30 Gy in 3 fractions 
Duration of administration 
3 fractions at 12 - 16 day intervals 
Reference therapy 
standard of care with systemic therapy alone, followed by radical 
cystectomy if treatment response 
Statistical Methodology 
Proportion of patients completing the study will be calculated and the trial 
will be deemed successful if the number of patients completing the 
protocol exceeds the futility threshold of 60%. Progression-free survival, 
the secondary endpoint, will be estimated by the Kaplan-Meier method 
and compared with historic controls using the log-rank test. 
 
 
 

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 1.0    BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Muscle invasive bladder cancer (MIBC) has high metastatic potential and warrants 
aggressive treatment. Standard-of-care treatment in MIBC involves platinum-based 
neoadjuvant chemotherapy (NACT) followed by radical cystectomy (RC) with pelvic 
lymph node dissection (PLND) and urinary diversion1–3. Bladder-conserving 
chemoradiation therapy is an appropriate alternative in select patients, though it is used 
in only a minority of cases in the United States4. Bladder cancer carries significant 
morbidity and mortality and has been cited as the most expensive malignancy to 
manage, on a per-patient basis, in the United States5,6. 
 
Metastatic spread to regional lymph nodes is an adverse prognostic factor in bladder 
cancer. In several large case series reported without use of neoadjuvant chemotherapy, 
patients with pathologically positive lymph nodes (pN+) at radical cystectomy had 5-year 
overall or disease-specific survival rates of only 22-30%7–10. The addition of neoadjuvant 
chemotherapy (NACT) or downstaging chemotherapy (DCT) in patients with clinically 
positive lymph nodes (cN+) improves outcomes, particularly in those who achieve a 
pathologic complete response to DCT11,12. However, patients who fail to respond to 
downstaging or neoadjuvant chemotherapy have an especially poor prognosis, with a 5-
year overall survival rate of only 16% in one recent series13. It should also be noted that a 
significant proportion (up to 25-50%) of patients with bladder cancer are ineligible for 
chemotherapy due to medical comorbidities14. 
 
We recently reviewed the outcomes of patients undergoing radical cystectomy at UT 
Southwestern with bulky cN+ bladder cancer15. Among the subset of patients who did not 
receive or failed to respond to DCT, the 2-year progression-free survival was only 30%, 
despite aggressive salvage treatment. Importantly, a majority of patients (84%) in the 
study received downstaging chemotherapy and all were medically eligible for 
chemotherapy. This suggests that chemo-ineligible patients presenting with cN+ disease 
were not offered curative treatment. Direct comparisons with historic literature are 
difficult, due to widely varying definitions of cN+ disease; however, the progression-free 
survival of our bulky cN+ cohort closely parallels that of the cN2-3 and cM1a cohorts 
within one large published series11, confirming that our bulky cN+ cohort represents an 
especially high-risk population. 
 
From the preceding data it is apparent that patients with cN+ bladder cancer who are 
ineligible for or who fail to respond to downstaging chemotherapy are an unfortunate 
group with particularly poor outcomes. One potential avenue for improvement is the 
combination of stereotactic ablative radiotherapy (SAbR) and immune checkpoint 
inhibitor (ICI) as downstaging therapy prior to radical cystectomy. We anticipate that 
patients will benefit from the demonstrated anti-tumor effects of both treatment 
modalities. Additionally, combining the immunomodulatory effects of SAbR with the 
stimulatory effects of ICI may result in a synergistic effect more beneficial than either 
modality alone. 
 
1.2 
Stereotactic Ablative Radiotherapy (SAbR) and Personalized Ultrafractionated 
Stereotactic Adaptive Radiotherapy (PULSAR) 
 
Stereotactic Ablative Radiation (SAbR), also known as Stereotactic Body Radiation 
Therapy (SBRT), is defined by the American Society of Radiation Oncology as a precise 
and specialized form of cancer treatment “whereby high doses of radiation are delivered 

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in large fraction sizes over a short course of treatment, generally limited to 5 or fewer 
fractions.”16 Metastasis-directed therapy with SAbR has attracted interest in a variety of 
malignancies due to promising early clinical results and a favorable toxicity profile. In the 
Phase II SABR-COMET trial, patients with cancer (primarily breast, lung, colorectal, and 
prostate) and up to five sites of metastasis were randomized to receive metastasis-
directed SAbR (8-30 Gy in 1-10 fractions) versus standard of care. The use of SAbR 
resulted in an improvement in 5-year overall survival from 18% to 42% (p = 0.006) and in 
5-year progression-free survival from ~3% to 17% (p = 0.001)17. Grade ≥2 adverse 
events were noted in 29% of patients and treatment-related deaths in 4.5%18. 
 
In the Phase II ORIOLE trial, men with prostate cancer and 1-3 sites of metastatic 
disease were randomized to receive metastasis-directed SAbR (20-48 Gy in 3-5 
fractions) versus standard of care. SAbR resulted in improved progression-free survival 
(median not reached vs 5.8 months, p = 0.002) with no grade ≥3 toxic events19. These 
results of these trials support a significant recurrence-free and overall survival benefit for 
metastasis-directed SAbR in oligometastatic cancer. 
 
There is limited data on the use of metastasis-directed treatment in urothelial carcinoma. 
In one report, 22 patients with oligometastatic urothelial carcinoma (64% with regional 
lymph node metastases) underwent conventional intensity-modulated radiation therapy 
(25-56 Gy) and achieved long-term (≥ 6 yrs) survival in 36%, with most representing 
patients with pelvic nodal disease20. In another series, 19 patients with metastatic 
urothelial carcinoma received SAbR to a total of 25 different metastatic lesions and 
achieved a local control rate of 68%. No grade ≥3 toxic events were noted. More recently, 
in a small Phase I trial, patients with metastatic urothelial carcinoma received SAbR (24 
Gy in 3 fractions) to a single metastatic lesion, either concurrently or sequentially with the 
immune checkpoint inhibitor pembrolizumab. One patient (6%) experienced a grade 3 
adverse event. Four out of nine patients (44%) in the concurrent-treatment group had a 
clinical response in sites of disease other than the irradiated lesion21. 
 
The use of SAbR in pelvic lymph nodes has been extensively described in the prostate 
cancer literature. Roughly 60% of the patients in the aforementioned ORIOLE trial had 
lymph node-only metastases and, as mentioned, none suffered major toxic events19,22. 
The Phase II STOMP trial, in which 55% of patients had node-only metastases and 81% 
of patients in the intervention arm received SAbR, likewise reported no grade ≥2 adverse 
events22. Two additional retrospective case series recently described outcomes in 
patients undergoing SAbR for oligometastatic prostate cancer. In one series, 94 patients 
underwent SAbR (median 24 Gy in 3 fractions) to pelvic lymph nodes with a 14% rate of 
grade 1-2 toxicity and no grade ≥3 events23. In a second series, 40 patients received 
SAbR (35-40 Gy in 5 fractions) to various sites of nodal metastasis (nearly all within the 
pelvis) with a single case of grade 2 and a single case of grade 3 toxicity24. Based on 
these results, use of SAbR in pelvic lymph nodes appears to be safe and well tolerated, 
with only minimal toxicity. 
 
A further refinement beyond conventional SAbR, developed at UT Southwestern, is 
personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR). PULSAR 
adapts to tumor shrinkage, minimizing radiation-associated side effects. The PULSAR 
dose schedule mimics the vaccine booster regimen by spacing out treatments, allowing 
for a full cycle of antigen presentation and immune response to occur before successive 
doses of radiation.  
 
In this trial, we propose a shift in the paradigm in how radiotherapy is combined with 
immunotherapy. Current standards of delivering SAbR entail delivering 1 to 5 fractions, 
consecutively daily or every other day. We hypothesize that the delivery of radiotherapy 
can be optimized in patients receiving immunotherapy and propose a radiotherapy 

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paradigm, which we termed: Personalized Ultra-fractionated Stereotactic Adaptive 
Radiotherapy or PULSAR.     
 
PULSAR sets its premise on delivering radiotherapy over intentionally longer, infrequent 
intervals between each radiation treatment, in contrast to historical schedules (i.e. daily 
fractions) in an effort to activate the immune system and avoid the potentially 
immunosuppressive effect from ablative radiotherapy. The interval between each fraction 
can be irregular, episodic, or triggered, depending on the response profile for each 
individual patient and can elicit additional tumor kill as well as an in situ vaccination 
booster, which, in combination with systemic immunotherapy, can synergize and improve 
disease control. Moreover, each radiotherapy fraction can be adapted in real time, 
depending on changes with the patient and disease status (e.g. anatomy, tumor 
microenvironment, systemic markers, patient status). This novel radiation treatment 
strategy has been supported by preclinical data in murine studies performed by our group 
(manuscript in preparation).  
 
To our knowledge, the neoadjuvant use of SBRT with the new PULSAR regimen or 
without concomitant use of immune checkpoint inhibition for bladder cancer has not been 
studied previously. We will conduct our study of PULSAR in patients with locally 
advanced bladder cancer, as PULSAR is suited to target and kill primary and nodal sites, 
while providing an opportunity to prime the immune system with novel tumor-associated 
antigens and vaccinate the immune system in situ.  
 
1.3 
Immune Checkpoint Inhibitor Therapy 
 
Immune checkpoint inhibitor (ICI) therapy has assumed increasing importance in the 
management of bladder cancer. ICI agents function to nonspecifically stimulate the 
patient’s immune response and decrease tumor immune evasion by inhibiting negative 
regulators of the immune response. In bladder cancer, most interest has attached to 
monoclonal antibodies which block the immunosuppressive surface receptor PD-1 or its 
ligand PD-L125. 
 
Three PD-1 or PD-L1 inhibitors (avelumab, nivolumab, and pembrolizumab) are FDA-
approved for second-line use in platinum-refractory advanced bladder cancer, based on 
clinical trials which showed objective response rates of 15-20%26–30. Two agents 
(atezolizumab and pembrolizumab) are FDA-approved for first-line use in patients who 
are ineligible for platinum-based chemotherapy, based on clinical trials showing objective 
response rates of 25-30% in this setting31,32. Finally, avelumab has recently gained FDA 
approval for use as maintenance therapy following initial response to chemotherapy in 
advanced/metastatic bladder cancer, with clinical trials demonstrating an improvement in 
median overall survival from 14 to 21 months33. 
 
More recent efforts have explored a role for ICI treatments in the neoadjuvant setting. 
Two clinical trials, ABACUS and PURE-01, explored the use of neoadjuvant 
atezolizumab and pembrolizumab respectively, and reported pathologic complete 
response (pCR, meaning ypT0 N0) rates of 31% and 37%, respectively34,35. While 
several other ongoing trials exist in this space, only a single trial has enrolled significant 
numbers of patients with clinical node-positive disease. In this trial, NABUCCO, patients 
with cN+ disease represented 42% of total enrollment. Neoadjuvant treatment with dual 
ICI agents (the PD-1 inhibitor nivolumab and the CTLA-4 blocker ipilimumab) resulted in 
an overall pCR rate of 46%36. 
 
Given their widespread clinical use in bladder and other malignancies, the adverse effect 
profile of ICI agents is well characterized. In the second-line trials cited above, for 
example, grade ≥3 adverse events occurred in 5-18% of patients and most notably 

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included autoimmune reactions at various sites including pneumonitis, colitis, and 
hepatitis26–30. 
 
In addition to the well described direct anti-tumor effects of SAbR and ICI treatment, 
mounting preclinical and clinical evidence also suggests a synergistic effect of the two 
modalities. SAbR has multiple immune-stimulating properties, including the induction of 
immunogenic tumor cell death and initiation of tumor antigen presentation37–40. 
Furthermore, SAbR causes local inflammation, which attracts dendritic cells to the tumor, 
thereby improving tumor neoantigen presentation41,42. The promotion of immune anti-
tumor activity by radiation has been linked to increased expression of tumor-infiltrating 
immune cells and MHC class I, dendritic cell activation and enhanced tumor antigen 
cross-presentation, T-cell receptor repertoire expansion, and increased PD-L1 
expression. Therefore, therapy with SAbR, which increases PD-L1 expression by both 
the tumor and the immune cells, has the potential to induce responses in those patients 
that do not respond or progress after an initial response to an ICI. As discussed above, 
the PULSAR technique is designed to further improve the immunomodulatory properties 
of SAbR. 
1.4 
Study Rationale 
 
The proposed study is a Phase I/II, single arm, single institution trial of PULSAR (next-
generation SAbR) therapy prior to radical cystectomy in patients with bulky, clinically 
node positive bladder cancer who are planned to initiate ICI due to ineligibility for 
platinum-based chemotherapy or failure to achieve complete clinical response to 
platinum-based chemotherapy. Current NCCN guidelines recommend “downstaging 
systemic therapy” (i.e., downstaging chemotherapy and/or ICI) for such patients as 
standard of care, with consolidation radical cystectomy in patients who respond to 
treatment43. However, our recent institutional experience demonstrates that even patients 
who do undergo radical cystectomy have poor outcomes, and patients who are medically 
ineligible for systemic chemotherapy are likely not being offered curative treatment at 
all15. Unfortunately, despite poor outcomes in cN+ patients, they are frequently excluded 
from clinical trials. For example, of the numerous trials involving the use of ICI agents in 
the neoadjuvant setting, only one (NABUCCO) enrolled significant numbers of cN+ 
patients and these still amounted to less than 50% of the total36. There is therefore an 
urgent need for new clinical trials in this space. 
 
Stereotactic ablative radiotherapy (SAbR) and immune checkpoint inhibitor (ICI) therapy 
both have demonstrated anti-tumor effects in the metastatic setting, as well as favorable 
and well characterized safety profiles. The rationale for adding PULSAR (next-generation 
SAbR) to ICI is that 1) the additive effect of both modalities is likely greater than either 
modality alone; 2) the morbidity and recovery period of radical cystectomy frequently 
preclude patients from receiving additional lines of treatment, and additional treatments 
are therefore likely best given prior to surgery; and 3) as detailed above, PULSAR may 
potentiate the effects of ICI by increasing tumor neoantigen exposure to immune 
surveillance and by increasing levels of PD-L1 expression within the tumor, thus 
enhancing response to ICI. 
 
The rationale for proceeding with radical cystectomy after ICI + PULSAR treatment is that 
1) radical cystectomy remains the standard of care in patients who respond to treatment 
and is felt to be the only potentially curative option in advanced disease; 2) cystectomy 
will debulk the primary tumor, thus reducing disease burden as well as the systemic 
effects of the immunosuppressive tumor microenvironment; and 3) other modalities 
including repeat transurethral resection and imaging are not sufficiently predictive of a 
complete response to treatment to justify omission of cystectomy44. 
 

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Patients will be restaged prior to radical cystectomy and those with disease deemed 
unresectable (e.g., interval development of distant metastases or unacceptably high 
surgical risk) will be managed according to the standard of care for metastatic disease, 
i.e., without curative intent. It should be noted that patients on ICI frequently experience a 
“pseudoprogression” phenomenon in which tumor size transiently increases following 
treatment initiation due to tumor immune infiltration45. Patients will therefore not be 
excluded from undergoing cystectomy solely on the basis of enlarging pelvic lymph 
nodes after ICI and RECIST criteria will not be applied in this setting. 
 
In confining our analysis to patients with platinum-ineligible or platinum-refractory bulky 
cN+ disease, we wish to focus on a subset of patients with particularly poor outcomes 
and limited access to other modalities of treatment. Our hope is that combined-modality 
treatment with ICI + PULSAR + RC will increase the proportion of patients with bulky cN+ 
disease who undergo curative treatment, improve rates of pathologic complete response 
(pCR) prior to surgery, reduce rates of disease recurrence (which, in the context of 
bladder cancer, is an excellent proxy for cancer-specific survival), and ultimately improve 
patient quality of life without increasing short-term surgical complications. 
 
1.5 
Correlative Studies 
 
No correlative studies are planned.  
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To determine the feasibility of radical cystectomy after ICI + PULSAR in bulky 
cN+ bladder cancer patients who are ineligible for or fail treatment with platinum 
based chemotherapy. 
2.2 
Secondary Objectives 
 
2.2.1 
To determine the 2-year progression-free survival (PFS) in patients with cN+ 
bladder cancer in all enrolled patients, and in the subset of patients completing 
the full protocol of ICI + PULSAR + RC. 
2.3 
Primary Endpoints 
 
2.3.1 
 The primary endpoint of the study is feasibility of RC after ICI + PULSAR, 
defined as the proportion of enrolled patients who complete three courses of PULSAR 
followed by radical cystectomy while remaining on ICI therapy, within sixteen weeks of 
initiation of PULSAR. It is anticipated that reasons for protocol non-completion may 
include progression to nonresectable disease and patient intolerance of treatment. 
2.4 
Secondary Endpoints 
 
2.4.1 
 Progression free survival (PFS): Primary disease progression will be defined as 
any of the following. Progression-free survival will be measured from the date of the first 
PULSAR treatment. 
 
1. Emergence of new sites of disease or locoregionally recurrent disease as 
defined by RECIST 1.1 criteria. 

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2. Pathologic demonstration of recurrent or metastatic disease (e.g. core needle 
biopsy, fine needle aspirate, diagnostic pericentesis). 
3. Initiation of a patient on palliative or salvage treatment due to clinical concern 
for disease progression. 
4. For patients with intraoperative concern for grossly incomplete disease 
resection (R2), the date of the first postoperative imaging study showing 
disease progression by RECIST 1.1 criteria (i.e., 20% increase in the sum of 
the diameters of all lesions, with an absolute increase of at least 5 mm; or the 
appearance of any new lesion). 
 
 
 
3.0 
SUBJECT ELIGIBILITY Subject Eligibility 
Eligibility waivers are not recommended; however, if warranted, prior approvals are required per 
Section 11.6.1. Subjects must meet all inclusion and exclusion criteria to be registered to the 
study. Study treatment may not begin until a subject is registered.  Once registered, a subject is 
still required to meet all inclusion and exclusion criteria on the first day of treatment, prior to 
treatment. 
3.1 
Inclusion Criteria 
 
3.1.1 
Bladder cancer, confirmed pathologically on transurethral resection of bladder 
tumor (TURBT) or on bladder biopsy. Pure urothelial, variant urothelial, or any 
proportion of squamous cell carcinoma are permitted. Questions about eligibility 
may be resolved by consultation with UTSW pathology but formal pathologic 
review is not required. 
 
3.1.2 
Bulky, clinically node positive disease (cN+) defined as: 1) a single pelvic lymph 
node of ≥ 1.5 cm largest diameter on CT or MRI; or 2) multiple pelvic lymph 
nodes ≥ 1 cm largest diameter on CT or MRI. Pathologic confirmation is not 
required. Imaging to establish eligibility must have been obtained no more than 
60 days prior to trial enrollment. The scans must be personally reviewed by the 
enrolling clinician. For imaging studies obtained outside of UT Southwestern, 
imaging review of node status and sign off by the enrolling investigator is 
required. Review and sign off by a UTSW radiologist is optional in ambiguous or 
questionable cases, but is not mandatory. 
 
3.1.3 
Age ≥ 18 years. 
 
3.1.4 
ECOG performance status 0-1. 
 
3.1.5 
Appropriate candidate for radical cystectomy, as determined by the treating 
urologist. 
 
3.1.6 
Appropriate candidate for stereotactic ablative radiotherapy, as determined by 
the treating radiation oncologist. 
 
3.1.7 
Patient is planned to initiate or is within 1-3 weeks of initiation of FDA-approved 
immune checkpoint inhibitor therapy based on ineligibility to receive platinum-
based downstaging chemotherapy (DCT) (Cohort 1, as detailed below) or failure 
to achieve clinical complete response to platinum-based DCT (Cohort 2, as 
detailed below). 
 
Cohort 1 (chemotherapy-ineligible) – either of: 
 

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- patient staged with bulky cN+ disease as defined above, medically 
ineligible to receive any platinum-based chemotherapy or, after 
appropriate and documented counseling, refusing to receive any-
platinum-based chemotherapy; or 
 
- patient staged with bulky cN+ disease as defined above, medically 
ineligible to receive cisplatin-based chemotherapy, with PD-L1 positive 
tumor (according to methodology described in the FDA approval label for 
the respective ICI agent) 
 
Cohort 2 (chemotherapy non-responding) – any of: 
 
- patient, initially staged with bulky cN+ disease as defined above, with 
radiologic progression after two cycles of platinum-based DCT (per 
RECIST 1.1 criteria: ≥20% increase in summed short-axis diameter of 
visible lesions with ≥ 5 mm absolute increase) 
 
- patient, initially staged with bulky cN+ disease as defined above, failing 
to achieve radiologic complete response after three or four cycles of 
platinum-based DCT (failure of all enlarged lymph nodes to decrease to 
< 1 cm short-axis diameter) 
 
- patient, initially staged with bulky cN+ disease as defined above, failing 
to achieve radiologic complete response after one or two cycles of 
platinum-based DCT which was discontinued due to patient intolerance 
 
- patient, initially not staged with bulky cN+ disease as defined above, 
who progresses to cN+ disease as defined above after two or more of 
cycles of platinum-based DCT 
 
3.1.8 
Permitted downstaging chemotherapy regimens are gemcitabine/cisplatin 
(gem/cis), gemcitabine/carboplatin (gem/carbo), and 
methotrexate/vinblastine/doxorubin/cisplatin (MVAC, in any dose variant). 
 
3.1.9 
Permitted immune checkpoint inhibitor agents are those FDA-approved for 
platinum-ineligible (Cohort 1) or platinum-refractory (Cohort 2) bladder cancer: 
atezolizumab or pembrolizumab for Cohort 1; avelumab, nivolumab, or 
pembrolizumab for Cohort 2. If additional immune checkpoint inhibitor (anti-PD1, 
anti-PD-L1, and/or anti-CTLA4) agents are approved for use in advanced 
urothelial carcinoma during the study, these agents will be permitted as well. 
 
 
3.1.10 Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 90 days following 
completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 

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3.1.11 Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Medical or anatomic contraindication to any of the study treatment modalities 
(radical cystectomy, stereotactic ablative radiotherapy, immune checkpoint 
inhibitor therapy). 
 
3.2.2 
Non-urothelial histology (other than pure squamous cell, which is permitted) 
including pure adenocarcinoma, pure small cell carcinoma, sarcoma, lymphoma, 
non-genitourinary primary (e.g. colorectal). 
 
3.2.3 
Metastatic (cM1) disease, defined as 1) lymph nodes ≥ 1 cm above the aortic 
bifurcation (cM1a), or metastases to bone, brain, or any visceral site (cM1b). 
Patients with a single enlarged retroperitoneal lymph node will be eligible with an 
adequately performed lymph node biopsy showing no metastatic disease or with 
a PET scan showing absence of FDG avidity. 
 
3.2.4 
Second primary malignancy, except: 1) non-metastatic (cM0) prostate cancer, 2) 
non-metastatic (cM0) endometrial cancer, 3) non-melanoma skin cancer, 4) 
cervical squamous cell carcinoma in situ, 4) any AJCC Stage I/II or organ-
confined primary malignancy for which the patient has undergone curative 
treatment and has been without evidence of disease for three years. 
 
3.2.5 
Prior pelvic radiation therapy. 
 
3.2.6 
Autoimmune disease rendering the patient ineligible for ICI. 
 
3.2.7 
Treatment with any immunosuppressive agent within 14 days of study entry, 
excluding topical or inhaled corticosteroids or adrenal-replacement steroids. 
 
3.2.8 
End stage renal disease requiring dialysis. 
 
3.2.9 
HIV infection, unless stable on HAART with CD4+ count > 400. 
 
3.2.10 Subjects may not be receiving any other investigational agents for the treatment 
of the cancer under study. 
 
3.2.11 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to atezolizumab, avelumab, durvalumab, nivolumab, 
pembrolizumab, or other agents used in study. 
 
3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia (other than atrial fibrillation / atrial flutter), or psychiatric illness/social 
situations that, in the opinion of the investigator, would limit compliance with 
study requirements. 
 
3.2.13 Subjects must not be pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
 
 
 
 

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4.0 
TREATMENT PLAN 
4.1 
PULSAR: Dose and Techniques 
 
Patients are eligible for the trial if they have bulky, clinically node-positive (cN+) bladder 
cancer and have either recently initiated (within ≤ 1 week) or are planned to initiate 
immune checkpoint inhibitor (ICI) therapy due to either 1) ineligibility for/refusal of 
platinum-based downstaging chemotherapy; or 2) failure to achieve a complete clinical 
response to platinum-based downstaging chemotherapy. Patients will initiate PULSAR 
treatment 1-2 weeks after initiating ICI. PULSAR will be administered in 3 fractions of 12 
Gy each (36 Gy total) at 12-16 day intervals and patients will undergo radical cystectomy 
with bilateral extended pelvic lymph node dissection within 4-8 weeks after completion of 
PULSAR. ICI therapy will be administered according to the FDA-approved dosing route 
and schedule and will be continued during PULSAR treatments. 
 
PULSAR treatment will be initiated 1-2 weeks after the patient is initiated on an FDA-
approved ICI agent. PULSAR will be administered in 3 fractions of 12 Gy each at 12-16 
day intervals. Target areas will include the region of the bladder containing the primary 
tumor (confirmed, if necessary, on office flexible cystoscopy at UTSW) and to up to five 
targetable, pathologically enlarged bulky lymph nodes (as deemed feasible by the 
treating radiation oncologist). Non-enlarged pelvic lymph nodes will be spared to 
minimize adverse effects on the tumor immune response. 
4.1.1 
PULSAR will be delivered with the targeting, planning, and directing of treatment 
fields guided to a target based on known 3D coordinates related to reliable 
fiducial markers. This differs from conventional radiation therapy in which 
treatment is guided by skin or bony landmarks assumed to correlate to the target 
volume based on the initial simulation. Treatment will account for inter/intra-
fractional errors with careful dosimetry that delivers an ablative dose to the 
involved lesions while respecting normal tissue constraints. In the event that 
fiducial placement is deemed unfeasible or unsafe, or would result in an 
unacceptable delay in treatment, fiducial placement may be omitted and targeting 
based on a combination of pre-treatment imaging and findings on flexible 
cystoscopy. 
4.1.2 
Radiation Therapy Prescription Dose 
The treating radiation oncologist can choose to deliver 10 or 12 Gy per fraction 
depending on the clinical circumstances, i.e. anatomical location and adjacent 
organs-at-risk. Each radiation therapy fraction will encompass the 95% of the 
planning target volume, and is considered compliant to the protocol. The 
following table lists the acceptable range of dose per fraction, with preference for 
the higher dose if safely achievable. Any dose delivered that is beyond the 
recommended doses will be considered an unacceptable variation. 
 
Number of fractions 
Dose per fraction 
Total dose 
3 
10-12 Gy 
30-36 Gy 
4.1.3 
Prescription Interval 
Each PULSAR fraction may be delivered every 2 weeks to potentiate the synergy 
between ICI and radiotherapy, until the completion of the prescribed number of 
fractions. PULSAR may be held if the patient does not have any targetable 
disease. Each PULSAR treatment and date of treatment delivery will be 
recorded.   

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4.1.4 
Radiation Treatment Concerns and Concurrent Medications 
Analgesic premedication to avoid general discomfort during long treatment 
durations is recommended when appropriate. 
4.2 
Technical Factors and Considerations 
4.2.1 
Physical Factors  
Only photon (x-ray) beams produced by linear accelerators with photon energies 
of 4-15 MV will be allowed. Cobalt-60 and charged particle beams (including 
electrons, protons, and heavier ions) are not allowed. Restriction of photon beam 
energies > 10 MV but less than 15 MV will be based on clinical appropriateness 
taking into account distance the beam must travel to the target. 
4.2.2 
Dose Verification at Treatment 
In-vivo dosimeter measurements (e.g., diode, TLD) may be obtained for surface 
dose verification for accessible beams. This information is not required by the 
protocol. 
4.2.3 
Treatment Platforms 
The trial allows most commercially available photon or proton producing 
treatment units. Treatment units should include image guidance. Both 3D 
conformal and intensity-modulated radiation therapy (including volumetric-
modulated arc therapy (VMAT)) are allowed. Proton or other charged particle 
units are not allowed in this study. Other specialized accelerators (e.g., the 
CyberKnife® or Tomotherapy) are allowed as long as they meet the technical 
specifications of the protocol. 
4.3 
Simulation and Image Guidance 
4.3.1 
Patient Positioning 
Patients will be positioned in a stable position that allows accurate reproducibility 
of the target between treatments.  Positions uncomfortable for the patient should 
be avoided so as to prevent uncontrolled movement during treatments.  A variety 
of immobilization systems may be utilized including stereotactic frames that 
surround the patient on three sides and large rigid pillows (conforming to patients 
external contours) with reference to the stereotactic coordinate system.  Patient 
immobilization must be reliable enough to ensure that the Gross Tumor Volume 
(GTV) does not deviate beyond the confines of the Planning Treatment Volume 
(PTV) with any significant probability (i.e. < 5%). 
4.3.2 
Image Guidance 
Isocenter or reference point port localization images should be obtained on the 
treatment unit immediately before treatment to ensure proper alignment of the 
geometric center (i.e. isocenter) of the simulated fields. These IGRT images can 
be obtained with planar kV imaging devices or cone-beam CT equipment. For 
treatment systems that use kV imaging but also allow EPID imaging using the 
treatment beam, orthogonal images verifying the isocenter also should be 
obtained. 
4.4 
Treatment Planning and Target Volumes 
4.4.1 
Image Acquisition 
Computed tomography will be the primary image platform for targeting and 
treatment planning. The planning CT scans must allow simultaneous view of the 

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patient anatomy and fiducial system for stereotactic targeting. CT scan with IV 
contrast is recommended unless the patient has allergy to contrast or renal 
insufficiency.  Axial acquisitions will be required with spacing ≤ 3.0 mm between 
scans. Images will be transferred to the treatment planning computers. 
4.4.2 
Target Volumes 
 
The target lesion will be outlined by an appropriately trained physician and 
designated the gross tumor volume at the primary site (GTVp) and nodal site(s) 
GTVn. The targets will generally be drawn using appropriate windowing based on 
location of the primary tumor and metastatic lymph nodes. Given that this 
treatment will adapt to changes in tumor dimension, the clinical target volume 
(CTV) will correspond to the GTVp/GTVn with no added margin. A 5 mm 
planning target volume (PTV) margin will be added to account for setup and 
intermal motion. 
. 
4.5 
Dosimetry 
4.5.1 
Intensity Modulated Radiation Therapy (IMRT) 
IMRT, including volumetric-modulated arc therapy (VMAT) and modulated 
charged particles is allowed in this study. The number of segments (control 
points) and the area of each segment should be optimized to ensure deliverability 
and avoid complex beam fluences. Ideally, the number of segments should be 
minimized, and the area of each segment should be maximized (the aperture of 
one segment from each beam should correspond to the projection of the PTV 
along a beam’s eye view). 
4.5.2 
Dose Calculations 
For purposes of dose planning and calculation of monitor units for actual 
treatment, this protocol will require tissue density heterogeneity correction.  
 
Successful treatment planning will require accomplishment of all of the following 
criteria: 
1.  Maximum dose: The treatment plan should be created such that 100% 
corresponds to the maximum dose delivered to the patient. This point must 
exist within the PTV. 
2.  Prescription isodose: The prescription isodose surface must be ≥ 60% and 
< 90% of the maximum dose. 
3.  Prescription Isodose Surface Coverage: The prescription isodose surface 
will be chosen such that 95% of the target volume (PTV) is conformally 
covered by the prescription isodose surface (PTV V95%RX = 100%) and 99% 
of the target volume (PTV) receives a minimum of 90% of the prescription dose 
(PTV V90%RX > 99%). 
4.6 
Normal Tissue Dose Constraints 
4.6.1 
The following table lists the specific organ and dose fractionation constraints on 
normal tissue. Given the irregular, long intervals between each radiotherapy 
fraction, total dose will be calculated to a particular organ-at-risk to ensure safety 
of radiation therapy. Exceeding these dose tolerances by more than 2.5% 

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constitutes a minor protocol violation.  Exceeding these dose tolerances by more 
than 5% constitutes a major protocol violation. 
Three Fraction 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Optic Pathway 
<0.2 cc 
15.3 Gy 
17.4 Gy 
neuritis 
Cochlea 
 
 
14.4 Gy 
hearing loss 
Brainstem (not medulla) 
<0.5 cc 
15.9 Gy 
23.1 Gy 
cranial neuropathy 
Spinal Cord and medulla 
<0.35 cc 
15.9 Gy 
22.5 Gy 
myelitis 
Cauda Equina 
<5 cc 
21.9 Gy 
25.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
22.5 Gy 
25.5 Gy 
neuropathy 
Esophagus* 
<5 cc 
27.9 Gy 
32.4 Gy 
esophagitis 
Brachial Plexus 
<3 cc 
22 Gy 
26  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
pericarditis 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
39 Gy 
43 Gy 
impairment of 
pulmonary toilet 
Bronchus- smaller 
airways 
<0.5 cc 
25.8 Gy 
30 Gy 
stenosis with 
atelectasis 
Rib 
<5 cc 
40 Gy 
50 Gy 
Pain or fracture 
Skin 
<10 cc 
31 Gy 
33 Gy 
ulceration 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
ulceration/fistula 
Bile duct 
 
 
36 Gy 
stenosis 
Duodenum* 
<5 cc 
22.5 Gy 
30 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
20.7 Gy 
28.5 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
28.8 Gy 
45 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
43 Gy 
30.3 Gy 
47 Gy 
proctitis/fistula 
Ureter 
 
 
40 Gy 
stenosis 
Bladder wall 
<15 cc 
17 Gy 
33 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
25 Gy 
 
impotence 
Femoral Heads  
<10 cc 
24 Gy 
 
necrosis 
Renal hilum/vascular 
trunk 
15 cc 
19.5 Gy 
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc for 
males and 
950cc for 
females*** 
10.8 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
 
 
V-11.4Gy<37% 
Pneumonitis 
Liver 
700 cc*** 
17.7 Gy 
 
Basic Liver Function 
Renal cortex (Right & 
Left) 
200 cc*** 
14.7 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
***or one third of the “native” total organ volume (prior to any resection or volume reducing 
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4.7 
Radiation Therapy Quality Assurance 
Drs. Iyengar and Vo will perform a radiation therapy quality assurance review after 
complete data of the first 10 cases enrolled at the University of Texas Southwestern 
Medical Center followed by a final review after complete data for the remaining cases are 
completed. These cases will be reviewed within 3 months after this study has reached 
the target accrual or as soon as complete data for all cases enrolled has been received, 
whichever occurs first. 
4.8 
Concomitant Medications/Treatments 
Any ICI agent approved for use in advanced urothelial carcinoma may be used in this 
study. Currently approved agents for use in the second line setting (i.e., after 
chemotherapy or Cohort 2) include atezolizumab, avelumab, duvalumab, nivolumab, and 
pembrolizumab. Approved agents for use in the first line setting (i.e., in chemotherapy-
ineligible or Cohort 1) include atezolizumab and pembrolizumab. Patients are eligible if 
they are planned to initiate ICI, or if they are within 1-3 weeks of initiation of an approved 
ICI agent. Subjects should receive at least two, and may receive up to four, doses of ICI 
concurrent with PULSAR prior to undergoing surgery. PULSAR will be initiated no less 
than one week after receipt of the first dose of ICI. 
 
This use of ICI is considered a standard of care therapy. The drug will be administered 
and managed by the treating medical oncologist. Continuation beyond the study period 
per standard of care is at the discretion of the treating medical oncologist. If additional 
immune checkpoint inhibitor (anti-PD1, anti-PD-L1, and/or anti-CTLA4) agents are 
approved for use in advanced urothelial carcinoma during the study, these agents will be 
permitted as well. If FDA approval is withdrawn or if agents are voluntarily withdrawn by 
the manufacturers for the relevant clinical indications, the agents will not be permitted for 
new study enrollments. Patients already on such agents will be permitted to remain in the 
study. Switching from one approved agent to another while on the study is permitted at 
the treating clinician’s discretion. 
4.9 
Other Modalities or Procedures 
No other modalities of treatment are planned. Patients are expected to receive any and 
all indicated interventions according to the usual standard of care. 
4.10 
Duration of Therapy 
The trial therapy will be considered complete when patients finish the third of three 
fractions of PULSAR. “In the absence of treatment delays due to adverse events, 
treatment may continue until that point or until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Subject decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
4.11 
Duration of Follow Up 
All follow up after radical cystectomy represents the standard of care. Patients will be 
followed for adverse outcomes for 90 days following radical cystectomy. After that point, 
subjects will only be followed for progression-free and overall survival for two years from 
the date of first PULSAR treatment or disease recurrence, whichever occurs first.  

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4.12 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for treatment discontinuation 
and the date of discontinuation. The subject should be followed-up per protocol.  
4.13 
Subject Replacement 
Any subjects removed from the study that have not completed at least one fraction of 
radiation should be replaced by additional recruitment of study subjects. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 60 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 
Informed Consent 
5.1.2 
Medical history 
Complete medical and surgical history, history of infections 
5.1.3 
Demographics 
Age, gender, race, ethnicity 
5.1.4 
Review subject eligibility criteria 
5.1.5 
Review previous and concomitant medications 
Including history of chemotherapy and history of any antibiotic treatment within 
three months of study enrollment 
5.1.6 
Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 
Performance status 
Performance status evaluated prior to study entry according to Appendix A. 
5.1.8 
Hematology 
Complete blood count with differential. 
5.1.9 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin. 
5.1.10 Pregnancy test (for females of child bearing potential) 
See section 3.1.6.1 for definition.  

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5.1.11 Tumor assessment 
CT or MRI of chest, abdomen, and pelvis with IV contrast, when possible. 
Additional imaging may be obtained at the treating clinician’s discretion. Baseline 
imaging to determine eligibility must have been obtained within 60 days of trial 
enrollment. 
5.2 
Procedures During Treatment 
5.2.1 
At time of each PULSAR Fraction 
• Physical exam, vital signs, history 
• Toxicity assessment 
5.2.2 
At time of radical cystectomy 
• Physical exam, vital signs, history 
• Toxicity assessment 
5.2.3 
30 days after radical cystectomy 
• Physical exam, vital signs 
• Toxicity evaluation 
• Hematology (standard of care) 
• Serum chemistries (standard of care) 
5.2.4 
90 days after radical cystectomy 
• Physical exam, vital signs 
• Toxicity evaluation 
• Hematology (standard of care) 
• Serum chemistries (standard of care) 
• Restaging imaging (standard of care) 
5.2.5 
Every 6 months x 2 years 
• Chart review and/or patient contact to determine recurrence and vital status 
 
5.3 
Follow-up Procedures 
Subjects will be followed at the 30 and 90 day timepoints (± 4 weeks) following radical 
cystectomy. After that time frame, patients will be followed  
• 
Procedure 
5.4 
Time and Events Table  
 
 
 
Screening 
PULSAR 
Q12-16d 
x 3 fractions 
Post 
PULSAR, 
pre RC 
Post RC 
(30 days) 
 
Post RC 
(90 days) 
Follow up 
q6mo 
x 2 yrs 
Procedures 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Eligibility verification 
X 
 
 
 
 
 
History and Physical Exam 
X 
X 
X 
X 
X 
 
Performance Status 
X 
X 
X 
X 
X 
 
(Re)staging Imaging1 
X 
 
X 
 
X 
 
Toxicity Evaluation 
 
X 
X 
X 
X 
 
Blood Draw2 
X 
X 
X 
X 
X 
 

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Pregnancy Test (if 
applicable)3 
X 
 
 
 
 
 
PULSAR treatment4 
 
X 
 
 
 
 
Chart review / recurrence 
status 
 
 
 
 
 
X 
 
1 CT or MRI with IV contrast, if possible. Imaging to determine eligibility must have been performed within 
60 days of enrollment. All imaging used within the study represents standard of care. Additional imaging 
may be obtained at the treating clinician’s discretion. 
2 Blood draws after surgery represent standard of care 
3 Only in females of child-bearing potential, as defined in section 3.1. 
4 SAbR treatments to be administered in three fractions at 12-16 day intervals. 
 
 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject demonstrates disease progression (unless continued treatment with 
study drug/treatment is deemed appropriate at the discretion of the investigator); 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 
6.0 
MEASUREMENT OF EFFECT 
6.1 
Antitumor Effect 
 
Response and progression following radical cystectomy (as distinct from criteria for trial 
eligibility, which are defined in section 3.1.2 above), will be evaluated in this study using 
the new international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST v 1.1) Committee [Eur J Cancer. 2009;45(2):228-247]. Changes in only 
the largest diameter (unidimensional measurement) of the tumor lesions are used in the 
RECIST v1.1 criteria. 

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6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with PULSAR. 
 
Evaluable for objective response. Only those subjects who have measurable 
disease present at baseline, have received at least one PULSAR treatment, and 
have had their disease re-evaluated will be considered evaluable for response. 
These subjects will have their response classified according to the definitions 
stated below. (Note: Subjects who exhibit objective disease progression prior to 
the end of treatment will also be considered evaluable.) 
6.1.2 
Disease Parameters 
Measurable Disease: Tumor lesions: Must be accurately measured in at least 
one dimension (longest diameter in the plane of measurement is to be recorded) 
with a minimum size of: 
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
2. 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable) 
3. 20 mm by chest x-ray. 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the 
node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of 
these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or 
followed. 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
For this reason, and because of the potential for pseudoprogression as 
discussed above, the pelvic lymph nodes will not be considered evaluable at the 
initial restaging scan following PULSAR and prior to radical cystectomy. 
 
Non-measurable disease.  
All other lesions are considered non-measurable, including small lesions (longest 
diameter < 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) 
as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 

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Target lesions.  
All measurable lesions up to a maximum of five lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions 
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the five target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and not more than 60 days before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Conventional CT and MRI. These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the 
chest, abdomen, and pelvis.  
 
Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
6.1.4      Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm (the sum may not be “0” if there are 
target nodes).  Determined by two separate observations conducted not 
less than 4 weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (SLD) of target lesions, taking as reference the baseline 
SLD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): > 20% increase in the SLD taking as 
reference the smallest SLD recorded since the treatment started (nadir) 
and minimum 5 mm increase over the nadir.   

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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest SLD 
since the treatment started. There can be no unequivocal new lesions. 
 
While on study, should a chosen Target lesion become non-evaluable, 
document as Not Evaluable (NE). 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
 
(Non-CR/Non-PD): Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
 
While on study, should a chosen Non-Target lesion become non-
evaluable, document as Not Evaluable (NE). 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The subject’s best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Time point response: patients with target (+/– non-target) disease. 
Target lesions 
Non-target lesions 
New 
lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive disease, PR = partial 
response, SD = stable disease. 
 
Time point response: patients with non-target disease only. 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 

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Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive disease 
A ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised. 
 
6.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease 
is objectively documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
PULSAR treatment to time of progression. Progression is defined as any of: 
 
1. Radiologic disease progression, as defined by RECIST 1.1 criteria above. 
2. Pathologic demonstration of recurrent or metastatic disease (e.g. core needle 
biopsy, fine needle aspirate, diagnostic pericentesis). 
3. Initiation of a patient on salvage or palliative treatment due to clinical concern 
for disease progression. 
4. For patients with documented concern (by the operating surgeon) for grossly 
incomplete disease resection (R2) including bulky unresectable lymph nodes, 
the date of the first postoperative imaging study showing disease progression 
by RECIST 1.1 criteria. 
 
6.2 
Safety/Tolerability 
 
Analyses will be performed for all subjects having received at least one fraction of 
radiation. The study will use the CTCAE version 5.0 for reporting of adverse events.  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
7.0 
ADVERSE EVENTS 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies. Adverse events are reported in a routine manner at 

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scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline or is stable in the opinion of the investigator;  
➢ there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
➢ death. 
 
7.1.1 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, 
clinical event, or disease, temporarily associated with the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the 
research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed consent, 
through 90 days post treatment will be considered acute adverse events. 
Late Adverse Events  
Adverse events occurring in the time period from the end of acute monitoring, to 1 year 
post treatment, will be defined as late adverse events. In addition, the study team will 
review encounters in a select specialty category relevant to study endpoints. These 
select specialties include hospitalizations, medical oncology, radiation oncology, and 
urology records and will be limited in scope based on categorization of events (GU/GI) 
and also the type of records that will be queried (hospitalizations, medical oncology, and 
radiation oncology). 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse 
events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log 
according to the general guidelines provided by the NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 

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Serious Adverse Events  
OHRP and the UTSW IRB define serious adverse events as those events, occurring at 
any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Is life-threatening (places the subject at immediate risk of death from the event      
             as it occurred); 
• 
Results in inpatient hospitalization1,2 or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring >24 hour inpatient admission to the hospital would be a serious 
adverse event for any research participant; likewise, in a study investigating end-stage 
cancer care, any hospitalization or death which occurs during the protocol-specified 
period of monitoring for adverse and serious adverse events would be a serious adverse 
event, even if the event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor 
treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be 
reported either as a routine AE or in an expedited report. 
7.1.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 

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• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.2 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting to the 
SCCC DSMC and/or HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur up to the end of the acute adverse events 
reporting period as defined in section 7.1.1. Any event that occurs more than 30 days 
after the last dose of and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported as indicated in the sections below. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
• 
the drug package insert (if applicable); 
• 
the current Investigator’s Brochure (if applicable) 
• 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
 
7.2.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
SAEs and UPIRSOs at all sites, which occur in research subjects on protocols for which 
the SCCC is the DSMC of record, require reporting to the DSMC regardless of whether 
IRB reporting is required. All SAEs occurring during the protocol-specified 
monitoring period and all UPIRSOs should be submitted to the SCCC DSMC within 
5 business days of the study team members awareness of the event(s). In addition, 
for participating centers other than UTSW, local IRB guidance should be followed for 
local reporting of serious adverse events or unanticipated problems. 

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The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are submitted to the SCCC 
DSMC Coordinator. This may be facilitated by the IIT project manager, study team, sub-
site or other designee. Electronic versions of the eIRB Reportable Event report; FDA Form 
#3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC. 
 
UT Southwestern and affiliates will submit documentation via the SAE submission portal.  
All subsites participating in multi-center study may utilize the Serious Adverse Event 
Template and submit to the IIT Project Manager, or designee. The DSMC Coordinator will 
route the form to the DSMC Chair who determines if immediate action is required.  Follow-
up eIRB reports, and all subsequent SAE or UPIRSO documentation that is available are 
also submitted to the DSMC Chair who determines if further action is required via the same 
process. (See Appendix V of the SCCC DSMC Plan for instructions on how to submit SAEs 
through the portal and for a template Serious Adverse Event Form which may be utilized 
by subsites on multi-center IIT studies). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the IIT Project Manager or designee ensures that all 
participating sites are notified of the event and resulting action, according to FDA 
guidance for expedited reporting. DSMC Chair reviews all SAEs and UPIRSOs upon 
receipt from the DSMC Coordinator.  The DSMC Chair determines whether action is 
required and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
Telephone reports to Urology CRO, 214-645-8787 
 
Written reports to: 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, 
etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, not 
included in the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation 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.  Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 

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For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working days of 
PI awareness. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, 
and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
policy_9.5reportable.pdf (utsouthwestern.edu)  
7.3 
Stopping Rules 
If the incidence of Grade 3 or higher adverse events convincingly exceeds 50%, a 
threshold we are comfortable with given the potential benefit of the regimen as well as 
our experience in managing the side effects in this patient population, we will temporarily 
halt the study and carefully review the available data at that point in order to suggest a 
potential modification. If we determine that high rates of adverse events are intrinsically 
related to protocol and no modification will reasonably decrease this rate to an 
acceptable threshold (below 50%), then we will terminate the study. 
8.0 
CORRELATIVES/SPECIAL STUDIES 
 
Patients have the option to enroll on the UTSW tissue protocol (STU 072010-098) for the collection 
for sera, PBMC and available tumor tissue to be collected before and during treatment. The protocol 
consent will include consent for use of tissues in future studies, e.g. molecular profiling. 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
 
This is a single institution, single arm, phase II trial. We hypothesize that the combination 
of standard-of-care ICI with PULSAR will be feasible and does not result in delays in 
treatment. We define a target rate of protocol completion (completion of radical 
cystectomy within sixteen weeks of initiation of PULSAR) of 90%, with a lower boundary 
of futility at 60%. 
 
The secondary endpoint is efficacy, defined by 2-year recurrence-free survival.  
 
As discussed above, we additionally plan to assess safety (defined by the 90-day rate of 
Clavien-Dindo Grade ≥ III complications following radical cystectomy); pathologic 
outcomes; rates of residual disease at surgery; and ureteroenteric anastomotic stricture 
rate. 
 
If the incidence of Grade 3 or higher treatment-related adverse events convincingly 
exceeds 50%, a threshold we are comfortable with given the potential benefit of the 
regimen as well as our experience in managing the side effects in this patient population, 
we will temporarily halt the study and carefully review the available data at that point in 
order to suggest a potential modification. If we determine that high rates of adverse 
events are intrinsically related to protocol and no modification will reasonably decrease 
this rate to an acceptable threshold (below 50%), then we will terminate the study. 

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9.2 
Sample Size and Accrual 
 
For the primary endpoint of feasibility, we define a target rate of protocol completion 
(completion of radical cystectomy within sixteen weeks of initiation of PULSAR) of 90%, 
with a lower boundary of futility at 60%. A sample size of 24 patients provides 91% power 
to reject a 60% completion rate at a two-sided alpha of 0.05. Of note, this sample size 
was employed in the recent NABUCCO trial, which addressed a similar high-risk patient 
cohort36. Allowing a 10% drop out rate increases the desired enrollment to a total of 27 
patients. Given the desired enrollment of 27 patients and the three-year trial period, this 
will require accrual of nine patients per year across all sites.  
 
For the secondary endpoint of progression-free survival, the trial-eligible subset of our 
recently published historic series of cN+ bladder cancer patients achieved a 2-year 
recurrence-free survival rate of 30%15. A sample size of 24 patients provides 90% power 
to detect a 27% absolute increase in 2-year recurrence free survival with a one-sided 
alpha of 0.10 using the Kaplan-Meier log-rank test. 
9.3 
Data Analyses 
 
The primary endpoint, protocol completion, will be assessed by calculating the proportion 
of patients completing radical cystectomy within sixteen weeks of initiating PULSAR 
treatment. If the proportion of patients undergoing cystectomy exceeds 60%, the null 
hypothesis (that use of ICI+PULSAR+RC is not feasible) will be deemed to have been 
rejected. 
 
For the secondary endpoint, progression-free survival will be determined as described 
above, and will be reported by means of Kaplan-Meier survival curves, median 
progression-free survival time, and proportion of patients without progression at two 
years. Comparison will be made to the trial-eligible subset of patients in a historic control 
series using the log-rank test. The 2-year progression-free survival rate in the historic 
cohort was 30%. The null hypothesis will be rejected if the one-sided p value for the 
comparison is less than 0.10. 
 
Additional planned analyses include the following, all of which will be reported with simple 
descriptive statistics (n / N and percentage):  
 
Major complication rate: A major surgical complication will be defined as any 
postoperative complication of Clavien-Dindo Grade III or higher. 
 
Pathologic outcomes: Pathologic outcomes will be defined as follows, based on the final 
surgical pathology report: 
 
1. Pathologic complete response: no viable disease remaining in the specimen 
(ypT0 N0). 
2. Pathologic non-muscle-invasive downstaging: primary tumor without muscle 
invasion, and no viable disease in lymph nodes (≤ypT1 N0). 
3. Pathologic organ-confined downstaging: primary tumor confined to detrusor 
muscle, and no viable disease in lymph nodes (≤ypT2 N0). 
4. Nodal complete response: no viable disease in lymph nodes, regardless of 
primary tumor stage (ypTany N0). 
 
 
Residual disease: Residual disease at surgery will be defined as follows: 
 

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1. Microscopic residual disease (R1) will be defined as any positive soft tissue 
margin on the final surgical pathology report, excluding carcinoma in situ at 
ureteral margins. 
2. Gross residual disease (R2) will be defined as any grossly positive tissue 
margin reported on a pathology report, or the operating surgeon’s subjective 
report of grossly unresectable disease including bulky matted lymph nodes. 
 
Ureteroenteric stricture rate, defined as the need for procedural intervention performed 
for decompression of an obstructed kidney (e.g. percutaneous nephrostomy tube or 
surgical revision of ureteroenteric anastomosis), unless due to known or suspected 
disease recurrence. 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
 
10.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the 
informed consent discussion. 
10.3 Registration Procedures 
All subjects must be registered with the UTSW Research Office before enrollment on 
study. 
 
New subjects will receive a number beginning with 01 upon study consent such that the 
first subject consented is numbered 01, the second subject consented receives the 
number 02, etc.  
 
Upon confirmation of eligibility and enrollment as per the afore-mentioned instructions, 
the subject will be assigned a secondary number in the order of enrollment. For example, 
subject 01 will become 01-01 upon enrollment. If subject 02 screen fails, and subject 03 
is the next subject enrolled, subject 03 will become 03-02 and so-on.  

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A lead-in identifier for each study site will be used.  For example, the first patient consented 
and enrolled at the first site will be participant 01-001-01. The second participant enrolled 
at the second site might be 02-003-02, and so on.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study id in Velos upon updating the status to enrolled. 
 
The numbering schema should clearly identify the site number; the sequential number of 
the subject enrolled as well as the status of the subjects enrolled so that the number of 
subjects consented versus the number of subjects actually enrolled may be easily 
identified.   
 
10.4 
Data Management and Monitoring/Auditing 
For this trial, UTSW SCCC is using an internal secured EDC for the electronic data 
capture of case report forms for this SCCC Investigator Initiated Trial.  This will be used 
for electronic case report forms in accordance with Simmons Comprehensive Cancer 
Center requirements, as appropriate for the project 
 
In order to facilitate remote source to case report form verification, the Simmons 
Comprehensive Cancer Center study team will require other institutions participating in 
this trial as sub-sites to enter data into the selected EDC system and upload selected de-
identified source materials when instructed.  
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT and/or the CRO 
Multi-Center IIT Monitor. This review includes but is not limited to accuracy of case report 
forms, protocol compliance, timeless and accuracy of Velos entries and AE/SAE 
management and reporting. Documentation of trial monitoring will be maintained along 
with other protocol related documents and will be reviewed during internal audit.   
 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 
Toxicity reviews will be performed annually. These reviews will be documented and 
reviewed annually. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs in real time as they are reported and reviews 
adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The Quality Assurance 
Coordinator (QAC) works as part of the DSMC to conduct regular audits based on the 
level of risk. Audit findings are reviewed at the next available DSMC meeting.  In this 
way, frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is 
determined by the DSMC Chairman and a number of factors such as the phase of the 
study; the type of investigational agent, device or intervention being studied; and 

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monitoring required to ensure the safety of study subjects based on the associated risks 
of the study. Protocol-specific DSMC plans must be consistent with these principles.  
10.5 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
10.5.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 
➢ Reporting requirement: Exceptions are non-emergency deviations that require 
prospective IRB approval before being implemented. Call the IRB if your 
request is urgent. If IRB approval is not obtained beforehand, this constitutes 
a major deviation. For eligibility waivers, studies which utilize the SCCC-
DSMC as the DSMC of record must also obtain approval from the DSMC 
prior to submitting to IRB for approval. 
10.5.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
• avoid immediate apparent harm, and/or 
• protect the life or physical well-being of subjects or others 
➢ Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
10.5.3 Serious Noncompliance (formerly called major deviations or violations): 
include any departure from IRB-approved research that: 
• Increase risk of harm to subjects; and/or adversely affects the rights, safety, or 
welfare of subjects (any of which may also be an unanticipated problem); 
and/or  
• 
Adversely affects the integrity of the data and research (i.e. substantially 
compromises the integrity, reliability, or validity of the research 
➢ Reporting requirement: Serious Noncompliance must be promptly  
reported to the IRB within 5 working days of PI awareness. 
 
.  
 
10.5.4   Continuing Noncompliance: includes a pattern of repeated noncompliance (in  
 
             one or more protocols simultaneously, or over a period of time) which continues   
 
            after initial discovery, including inadequate efforts to take or implement corrective  
 
            or preventive action within a reasonable time frame. 
➢ Reporting requirement*: Continuing Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 

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10.5.4 Noncompliance (that is neither serious nor continuing; formerly called 
minor deviations: include any departure from IRB-approved research that: 
• Does not meet the definition of serious noncompliance or continuing 
noncompliance  
➢ Reporting requirement: Noncompliance that is neither serious nor 
continuing should be tracked and summarized in the progress report at the 
next IRB continuing review, or notice of study closure, whichever comes first. 
10.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
10.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 
 

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11.0 
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12.0 
APPENDICES 
 
Appendix A. Eligibility Checklist 
 
 

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Appendix A. Eligibility Checklist 
 
INCLUSION criteria: 
 
 age ≥ 18 years 
 
 ECOG performance status (circle): 0  /  1 
 
 bladder cancer, stage cT1 or higher: pure urothelial, urothelial variant (in any proportion), squamous 
cell carcinoma (in any proportion) 
 
presence/proportion of variant histology: __________________________ 
 
AJCC 8th edition clinical tumor stage assigned by treating clinician: ________ 
 
 clinical concern for bulky node positive disease on imaging, defined as either: 
 
 a single pelvic lymph node ≥ 1.5 cm largest axis diameter or 
 
 multiple pelvic lymph nodes ≥ 1.0 cm largest axis diameter (cN2-3) 
 
diameter of largest node: ________ cm 
 
number of enlarged nodes: ________ 
 
date of imaging used to determine eligibility: ________ modality (circle): CT  /  MRI  /  PET 
 
AJCC 8th edition clinical nodal stage assigned by treating clinician: ________ 
 
if radiology consultation obtained, please specify radiologist: ___________________ 
 
 ineligibility for, or failure to respond to, platinum-based downstaging chemotherapy (MVAC, 
gemcitabine/cisplatin, gemcitabine/carboplatin): 
 
 ineligible for platinum chemotherapy (Cohort 1) based on (check all that apply): 
 
 inadequate renal function 
 
 preexisting neuropathy 
 
 patient refusal after adequate counseling 
 
 cisplatin-ineligible, carboplatin-eligible with positive PD-L1 
 
 other medical contraindication, please specify: ____________________ 
 
 failure to respond to platinum chemotherapy (Cohort 2), based on: 
 
 patient with bulky cN+ disease and radiologic disease progression after ≥ 2 cycles of 
chemotherapy 
 
 patient with bulky cN+ disease and failure to achieve radiologic complete response 
after ≥ 3 cycles of chemotherapy 
 

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 patient with bulky cN+ disease failing to achieve radiologic complete response after 1-
2 cycles of chemotherapy which was discontinued due to patient intolerance 
 
 patient progressing to bulky cN+ disease after ≥ 2 cycles of chemotherapy 
 
 plan by treating medical oncologist to initiate treatment with an approved immune checkpoint inhibitor 
treatment, or initiation of an approved checkpoint inhibitor within the three weeks prior to trial enrollment 
(please circle agent) 
 
 Cohort 1 (chemo-ineligible): atezolizumab  /  pembrolizumab 
 
 Cohort 2 (chemo-non-responding): avelumab  /  nivolumab  /  pembrolizumab 
 
 candidate for radical cystectomy, as determined by treating urologist 
 
 candidate for radiation therapy, as determined by treating radiation oncologist 
 
 ability to provide informed consent 
 
 negative pregnancy test (female of child-bearing age) 
 
 agrees to use adequate contraception or female not of child-bearing age 
 
 
EXCLUSION criteria - confirm absence of all of the following: 
 
 pure adenocarcinoma, pure small cell carcinoma, sarcoma, lymphoma, non-genitourinary primary 
tumor, or other non-urothelial histology except squamous cell carcinoma 
 
 metastatic disease (including lymph nodes ≥ 1 cm above the aortic bifurcation, unless accompanied by 
a negative lymph node biopsy or negative PET scan) 
 
 second primary malignancy, except (check if applicable): 
 
 cM0 prostate cancer 
 
 cM0 endometrial cancer 
 
 non-melanoma skin cancer 
 
 cervical squamous cell carcinoma in situ 
 
 any AJCC Stage I/II or organ-confined primary malignancy in remission for ≥ 3 years following 
curative treatment 
 
 prior pelvic radiation therapy 
 
 autoimmune disease resulting in ineligibility for immune checkpoint inhibitor 
 
 treatment with an immunosuppressive agent within 14 days of study entry, except (check if 
applicable): 
 
 topical or inhaled corticosteroids 
 
 adrenal-replacement steroids 
 

Protocol Number SCCC#09821 
________________________________________________________________________ 
STU2021-0114, Woldu, FormA-ResearchProtocol-V54-12.9.2022, Mod_5, 12-19-22 (1) 
, Version 1.3 
40 
 end-stage renal disease requiring dialysis 
 
 HIV infection, unless stable on HAART with CD4+ count of > 400 
 
 receipt of other investigational agents or treatment modalities 
 
 history of true allergic or anaphylactic reaction to atezolizumab, avelumab, durvalumab, nivolumab, 
pembrolizumab, or other similar agent 
 
 uncontrolled intercurrent illness including active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia (other than atrial fibrillation / atrial flutter), or psychiatric 
illness resulting in inability to safely undergo the study or complete study requirements 
 
 pregnancy or current breastfeeding