Clinical trial NCT03658304
Conditions: Urothelial Carcinoma
Sponsor: University of Florida
Start date: 2018-12-05; Completion date: 2023-10-17
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Results of previous studies suggest that the timing of intravesical mitomycin C administration may impact bladder tumor recurrence rate following radical nephroureterectomy. This is the first study of its kind to attempt to identify the importance of timing of mitomycin C administration relative to bladder tumor recurrence rate following radical nephroureterectomy.This study will investigate the one year bladder tumor recurrence rate in patients with urothelial carcinoma of the upper urinary tract following intraoperative administration of mitomycin C during a nephroureterectomy, as well as the time to bladder tumor recurrence in this patient population.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Mitomycin c
Intervention descriptions: intervention 1: All participants will receive a single 40 mg dose of mitomycin C intraoperatively during their scheduled nephroureterectomy. This single dose will be given through a catheter in the subject's bladder.

Protocol documents:
Prot_SAP_000.pdf: 
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A Single Arm Phase II Trial of the Intraoperative Intravesical Instillation of 
Mitomycin C During Nephroureterectomy for Urothelial Carcinoma of the Upper 
Urinary Tract 
 
Protocol Number: 
UF-GU-001 
IRB #: 
201802090 
 
Coordinating Center: 
University of Florida 
Principal Investigator: 
Paul Crispen, MD 
University of Florida 1600 
SW Archer Road 
Gainesville, FL 32608 
Telephone: (352) 273-8634 
Fax: (352) 273-7515 
Email: paul.crispen@urology.ufl.edu 
Statistician: 
Shu Wang, PhD 
Protocol Managers: 
UFHCC Protocol 
Management Office 
pmo@cancer.ufl.edu 
 
Clinical Phase: 
Phase II 
IND Status: 
IND 141176 
Investigational Agent(s):         
mitomycin C 
Date of Original Protocol: 
January 4, 2018 
Date of Current Protocol: 
September 17, 2020 
NCT# 
NCT03658304 
 
Version of Current Protocol: 
 7.1 
 
PROTOCOL REVISION RECORD Version 7.0, dated 13MAR2020 
  
 
 
 
 
 Version 6.0, dated 18JUN2019 
Version 5.0, dated 2MAY2019 
Version 4.0, dated 25FEB2019 
Version 3.0, dated 16NOV2018 
Version 2.0, dated 15OCT2018 
 Keywords:  urothelial carcinoma; mitomycin c; upper urinary tract; nephroureterectomy 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
ABBREVIATIONS ......................................................................................................................... 3 
Protocol Signature Page .................................................................................................................... 5 
PROTOCOL SYNOPSIS .................................................................................................................. 7 
1. 
BACKGROUND ..................................................................................................................... 11 
2. 
OBJECTIVE ............................................................................................................................ 13 
3. 
STUDY DESIGN .................................................................................................................... 13 
4. 
SELECTION OF SUBJECTS ................................................................................................. 13 
5. 
REGISTRATION PROCEDURES ......................................................................................... 15 
6. 
STUDY PROCEDURES ......................................................................................................... 15 
7. 
STUDY TREATMENT .......................................................................................................... 16 
8. 
TREATMENT DISCONTINUATION ................................................................................... 18 
9. 
STUDY DRUG INFORMATION .......................................................................................... 20 
10. ADVERSE EVENTS .............................................................................................................. 21 
11. STATISTICAL METHODS ................................................................................................... 27 
12. DATA AND SAFETY MONITORING ................................................................................. 28 
13. EMERGENCY PROCEDURES ............................................................................................. 29 
14. ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS ................ 29 
15. REFERENCES ........................................................................................................................ 33 
16. APPENDICES ........................................................................................................................... 35 
Appendix A: SCHEDULE OF EVENTS ........................................................................................ 36 
Appendix B: PERFORMANCE SCALE ........................................................................................ 37 
 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine transaminase (also SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (also SGOT) 
BTR 
bladder tumor recurrence 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CRF 
case report form 
CRO 
Clinical Research Office 
CT 
computed tomography 
      CTCAE 
Common Terminology Criteria for Adverse Events  
CTMS 
clinical trials management system 
DISC 
Data Integrity and Safety Committee 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 


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IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MMC 
mitomycin C 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NSAE 
non-serious adverse event 
PI 
principal investigator 
PMO 
Project Management Office 
POD0 
post-operative day zero 
POD1 
post-operative day one 
PS 
performance status 
RBC 
red blood cells 
RNU 
radical ureteronephrectomy 
SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase   
SGPT 
serum glutamic pyruvate transaminase 
TUR 
transurethral resection 
UF 
University of Florida 
         UFHCC 
University of Florida Health Cancer Center  
US 
United States 
         WBC 
white blood cell 
         WHO 
World Health Organization  
        WOCBP 
Women of Childbearing Potential 


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Protocol Signature Page 
 
A Single Arm Phase II Trial of the Intraoperative Intravesical Instillation of 
Mitomycin C During Nephroureterectomy for Urothelial Carcinoma of the 
Upper Urinary Tract 
 
 
 
 
Principal Investigator Protocol Signature Page 
Signature of Investigator 
Date (DDMMMYYY) 
Printed Name of Investigator 
Name of Facility 
Location of Facility (City/State) 
By my signature, I agree to personally supervise the conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United States Code of Federal Regulations or local 
regulations governing the conduct of clinical studies. 


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STUDY SCHEMA 
 
 
 
 
 
 
Accrual Goal: 53 subjects 
Intraoperative administration of 
mitomycin C during 
nephroureterectomy 
Surveillance for bladder tumor 
recurrence 


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PROTOCOL SYNOPSIS 
 
Title: 
A Single Arm Phase II Trial of the Intraoperative Intravesical 
Instillation of Mitomycin C During Nephroureterectomy for 
Urothelial Carcinoma of the Upper Urinary Tract 
Funding 
Organization: 
University of Florida 
Investigational 
Agent Supplier: 
Commercial supply 
Rationale: 
We have recently completed a retrospective review of our experience at the 
University of Florida of the administration of intraoperative of mitomycin C 
compared to mitomycin C administered post-operative day one or later. 
Results of this study suggest that the timing of intravesical mitomycin C 
may impact bladder tumor recurrence rate following radical 
nephroureterectomy. This is the first study of its kind to attempt to identify 
the importance of timing of mitomycin C administration relative to bladder 
tumor recurrence rate following radical nephroureterectomy. 
Objectives: 
Primary: 
• Determine the one-year bladder tumor recurrence rate in 
patients with urothelial carcinoma of the upper urinary tract 
following intraoperative administration of mitomycin C 
Secondary: 
• Evaluate the time to bladder tumor recurrence in patients with 
urothelial carcinoma of the upper urinary tract following 
intraoperative administration of mitomycin 
• Determine the three-year tumor recurrence rate in patients 
with urothelial carcinoma of the upper urinary tract following 
intraoperative administration of mitomycin C 
Study Design: 
This is a single arm, open label, phase II study. 


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Accrual Goal: 
A total of 53 subjects. 
Inclusion 
Criteria: 
Individuals eligible for study participation must meet the following criteria: 
 
A. Both males and females ≥ eighteen years of age 
B. Clinical diagnosis of urothelial carcinoma of the renal pelvis and/or 
ureter. Clinical diagnosis of urothelial carcinoma may be based upon 
radiographic, pathologic or cytological findings alone or in 
combination with one another.  No other histology is allowed. 
C. The TNM stage of the subject’s disease (using the American Joint 
Committee on Cancer [AJCC] Cancer Staging Manual, 8th Edition) 
must be Tis, Ta, T1, T2, or T3, N0, M0. Subjects may have either a 
high-grade or low-grade tumor. 
D. ECOG performance status of 0-2 
E. Written informed consent obtained from the subject and the ability 
for the subject to comply with all the study-related procedures. 
F. Women of childbearing potential (WOCBP) must be using an adequate 
method of contraception to avoid pregnancy prior to and for at least 
three months after mitomycin C instillation to minimize the risk of 
pregnancy. Prior to study enrollment, women of childbearing potential 
must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional 
pregnancy. 
WOCBP include any woman who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy) or who is not post- 
menopausal. Post- menopause is defined as: 
• Amenorrhea that has lasted for ≥ 12 consecutive months 
without another cause, or 
• For women with irregular menstrual periods who are taking 
hormone replacement therapy (HRT), a documented serum 
follicle-stimulating hormone (FSH) level of greater than 35 
mIU/mL. 
G. Males with female partners of child-bearing potential must 
agree to use physician-approved contraceptive methods (e.g., 
abstinence, condoms, vasectomy) and should avoid conceiving children 
prior to and for three months following mitomycin C instillation. 
H. Subjects must have hemoglobin ≥ 9 g/dL and a platelet count 
≥ 100,000/μL.   


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Exclusion 
Criteria: 
 
Subjects with any of the following will not be eligible for study 
participation: 
A.  Active urothelial carcinoma of the bladder within 12 months prior 
to enrollment 
B. History of adverse reaction to mitomycin C 
C. Subjects must not have evidence of regional or metastatic 
disease. 
D. History of radical cystectomy 
E. Planned radical cystectomy at the time of 
nephroureterectomy 
F. Females or males of childbearing potential who are unwilling or 
unable to use an acceptable method to avoid pregnancy prior to and 
for at least 3 months after mitomycin C instillation. 
G. Females who are pregnant or breastfeeding. 
H. History of any other disease, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that contraindicates 
the use of protocol therapy or that might affect the interpretation of 
the results of the study or that puts the subject at high risk for 
treatment complications, in the opinion of the treating physician. 
I. Prisoners or subjects who are involuntarily incarcerated. 
J. Subjects who are compulsorily detained for treatment of either 
a psychiatric or physical illness. 
K. Subjects demonstrating an inability to comply with the study 
and/or follow-up procedures. 
Efficacy 
Assessments: 
Patients will be evaluated for bladder tumor recurrence every 3 months for 
the first two years and then every 6 months for the third year following 
nephroureterectomy by cystoscopy and urine cytology with UroVysion 
testing if urine cytology results are atypical or suspicious. Patients with 
suspected recurrence of urothelial carcinoma within the bladder will require 
bladder biopsy for histologic confirmation. 


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Statistical 
Considerations: 
The primary endpoint for this study is the bladder tumor recurrence (BTR) rate 
at 1-year post-surgery. A one-sided, one sample exact test of proportion will 
be used to assess the primary endpoint, 1-year BTR rates, with level of 
significance set at 0.10. Time to BTR will be characterized using Kaplan- 
Meier plots. Log-rank tests and Cox proportional hazard modeling will be 
used to examine the impact of baseline characteristics. A p-value of less than 
0.05 will be considered statistically significant. 
In our previous study, there was a 16% recurrence rate for those that received 
mitomycin C on day 0 and a 33% recurrence rate for those receiving it on day 
1 or later. From this we will assume that the underlying proportion of BTR at 
1 year is 25% for our population. A sample size of 53 subjects is needed to 
detect the decrease of 1-year BTR rate from 25% to 12.5% based on Simon's 
optimal two-stage design and to reach more than 80% power with a one-sided 
type 1 error rate 0.10. 
In the first stage, 16 subjects will be recruited and the study will be 
terminated early if 4 or more BTR happens. If the study proceeds to the 
second stage, 53 subjects will be studied. If the total number of BTR at 1- 
year post-surgery is less than 10, the treatment will be considered a success. 
The sample size was calculated using the PASS 16. 
Estimated 
Enrollment 
Period: 
48 months 
Estimated Study 
Duration: 
84 months 


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1. BACKGROUND 
 
1.1 
Urothelial Carcinoma Cancer Therapy 
Urothelial carcinoma is projected to be the sixth most common malignancy in the 
United States in 2017, affecting over 79,000 individuals1. The majority of urothelial 
carcinoma occurs in the bladder, while urothelial carcinoma involving the upper tract is 
relatively rare. Upper tract urothelial carcinoma accounts for less than 10% of 
malignancies of the upper urinary tract2. The incidence of upper tract urothelial 
carcinoma has slowly increased over the past 30 years, and treatment options continue 
to evolve3. Radical nephroureterectomy with bladder cuff excision remains the 
standard surgical management for high-risk upper tract urothelial carcinoma and lower 
risk tumors not amenable to endoscopic management2, 4. Unfortunately, recurrence in 
the bladder is common, occurring in 22-47% of cases4. 
1.2 
Overview of Mitomycin in the Treatment of Urothelial Carcinoma 
Mitomycin C (MMC) is an alkylating agent which cross links DNA between adenine 
and guanine residues thus blocking DNA synthesis and mitosis5. Activity against 
urothelial carcinoma has been documented for over 50 years, including intravesical 
instillation. 
Intravesical MMC presents potential advantages over systemic use including direct 
contact of chemotherapeutic agent with the tumor and limited systemic toxicity. MMC 
is hydrophobic and characterized by a high molecular weight resulting in slow 
diffusion and low capillary permeability, allowing for a deep penetration and persistent 
tissue concentration5. 
Pharmacokinetic studies suggest there should be little systemic absorption of MMC 
from an intact bladder6. Drug concentration has been shown to be more important than 
total dose with duration of exposure and drug concentration being more influential on 
tumor cell kill than dose7. With the recognized importance of drug concentration on 
tumor cell kill the recommended concentration of MMC is 1 mg per ml and complete 
bladder emptying should be performed prior to instillation8. 
The standard intravesical dwell time ranges from 60 to 120 minutes. Prior studies have 
demonstrated a benefit of a 60-minute dwell time over a 30-minute dwell time with a 
significant reduction in tumor recurrence noted in the 60-minute treatment group9. 
The prophylactic efficacy of MMC in decreasing bladder tumor recurrences following 
transurethral resection of bladder tumors is well documented. It is theorized the 
decreased recurrence rates are accomplished via both destroying implanted tumor cells 
after transurethral resection (TUR) and an ablative effect on residual cells at the 
resection site and on small overlooked tumors. A combined analysis randomized trials 
including 2535 patients demonstrated a 20% decrease in tumor recurrence in patients 
receiving a single dose of chemotherapy with TUR compared to TUR alone10. The 
timing of MMC administration has been documented to be an important factor on the 
rate of tumor recurrence following TUR. Early drug administration (within 24 hours) 
was noted to be superior over delayed drug administration (between 7-15 days) in a 
randomized trial with a 30% reduction in tumor recurrence11. 


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These results are further supported by Kassien et al. whose trial demonstrated a 50% 
relative reduction of tumor recurrence when MMC is administered within 24 hours of 
TUR12. Finally, a meta-analysis of studies evaluating TUR alone and TUR with one 
immediate instillation of chemotherapy noted a 39% decrease in the odds of recurrence 
with the addition of a single dose of chemotherapy compared to TUR alone13. 
Two separate prospective trials have demonstrated a single dose of adjuvant intravesical 
chemotherapy with either mitomycin C or pirarubicin reduces the risk of BTR during the 
first year following radical nephroureterectomy15,16. These results were confirmed in a 
meta-analysis by Deng et. al in 2014, with a pooled hazard ratio of 0.38 for patients 
receiving intravesical chemotherapy16. Although the data are strong, the timing of 
intravesical chemotherapy administration varied significantly across these studies. 
Additionally, Lu et. al demonstrated underutilization of intravesical chemotherapy and 
significant heterogeneity of its timing among Society of Urologic Oncology members17. 
It is clear that there is a paucity of evidence regarding the timing of intravesical 
chemotherapy on BTR and further investigation is necessary. 
 
1.3 
Rationale for Current Study 
We have recently completed a retrospective review of our experience at the University 
of Florida of the administration of intraoperative of mitomycin C compared to 
mitomycin C administered post-operative day one or later. A total of 51 patients were 
identified meeting our inclusion criteria. Patients were categorized into two separate 
groups based on the timing of mitomycin C administration: (1) patients who received 
mitomycin C on the day of surgery (POD0) and (2) patients who received mitomycin C 
on post-operative day 1 or later (POD1). Our primary endpoint was BTR rate within the 
first year after surgery. Our secondary endpoint was overall BTR rate during follow up. 
Associations between treatment groups and recurrence rates were assessed using 
Kaplan-Meier plots, log-rank tests, and univariable and multivariable Cox proportional 
hazard models. Mean length of follow-up for each group was 22.1 and 12.5 months, 
respectively (p=0.02). There were no statistically significant differences in baseline 
characteristics of age, gender, race, surgical approach, tumor grade, tumor stage, 
surgical margins, nodal status, concomitant CIS, or history of bladder cancer. 
 
BTR rates at 1 year for the POD0 and POD1 groups were 16% and 33%, respectively 
(p=0.09). Overall BTR rates, including time points beyond the first year, were 23% and 
33%, respectively (p=0.16). Multivariable analysis noted that the POD0 patients had a 
significantly lower rate of BTR in the first year postoperatively (HR=0.082, 95% 
CI=0.01-0.56, p=0.01). Other factors that were associated with a higher rate of BTR 
within the first year were open surgery (HR=7.9, 95% CI=1.18-53.88, p=0.03), positive 
surgical margins (HR=37.89, 95% CI=1.74-825.35, p=0.02), and concomitant CIS 
(HR=10.8, 95% CI=1.08-108.72). Our results suggest that the timing of intravesical 
mitomycin C administration may affect the rate of BTR following radical 
nephroureterectomy (RNU) for urothelial carcinoma. 
 
1.4 
Rationale for Regimen/Doses/Schedule 


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This is the first study of its kind to attempt to identify the importance of timing of 
MMC administration relative to BTR following RNU. Based on these initial results we 
propose a single arm phase II trial to further evaluate the impact of intraoperative 
MMC on BTR. 
2. OBJECTIVE 
 
2.1 
Primary 
• Determine the one-year bladder tumor recurrence rate in patients with 
urothelial carcinoma of the upper urinary tract following intraoperative 
administration of mitomycin C 
2.2 
Secondary 
• Evaluate the time to bladder tumor recurrence in patients with urothelial 
carcinoma of the upper urinary tract following intraoperative administration 
of mitomycin 
• Determine the three-year tumor recurrence rate in patients with urothelial 
carcinoma of the upper urinary tract following intraoperative 
administration of mitomycin C 
 
3. STUDY DESIGN 
 
3.1 
Study Overview 
This is a single arm, open-label, phase II study. Subjects with clinically localized 
urothelial carcinoma of the renal pelvis and/or ureter who are scheduled to undergo 
nephroureterectomy will be intraoperatively treated with mitomycin C during their 
nephroureterectomy procedure. Subjects will then be monitored post-operatively for 
bladder tumor recurrence every three months for the first two years and every six 
months for the third year after their nephroureterectomy. 
 
Screening data will be reviewed to determine subject eligibility. Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study. 
 
Total duration of subject participation will be approximately three years. Total duration 
of the study is expected to be seven years. 
 
4. SELECTION OF SUBJECTS 
 
Subjects with a diagnosis of urothelial carcinoma of the renal pelvis and/or ureter who 
meet the following inclusion and exclusion criteria will be eligible for participation in 
this study. 
 
4.1 Number of Subjects 
A total of 53 subjects will be enrolled on this study. 
 
4.2 Inclusion Criteria 


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Subjects must meet all of the following criteria to be eligible for study participation: 
A. Both males and females ≥ eighteen years of age 
B. Clinical diagnosis of urothelial carcinoma of the renal pelvis and/or ureter. Clinical 
diagnosis of urothelial carcinoma may be based upon radiographic, pathologic or cytological 
findings alone or in combination with one another. No other histology is allowed. 
C. The TNM stage of the subject’s disease (using the American Joint 
Committee on Cancer [AJCC] Cancer Staging Manual, 8th Edition) must be 
Tis, Ta, T1, T2, or T3, N0, M0. Subjects may have either a high-grade or 
low-grade tumor. 
D. ECOG performance status of 0-2 
E. Written informed consent obtained from the subject and the ability for 
the subject to comply with all the study-related procedures. 
F. Women of childbearing potential (WOCBP) must be using an adequate 
method of contraception to avoid pregnancy prior to and for at least 3 
months after mitomycin C instillation to minimize the risk of pregnancy. 
Prior to study enrollment, women of childbearing potential must be 
advised of the importance of avoiding pregnancy during trial participation 
and the potential risk factors for an unintentional pregnancy. 
WOCBP include any woman who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-
menopause is defined as: 
• Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, 
or 
• For women with irregular menstrual periods who are taking hormone 
replacement therapy (HRT), a documented serum follicle-stimulating 
hormone (FSH) level of greater than 35 mIU/mL. 
G. Males with female partners of child-bearing potential must agree to use 
physician- approved contraceptive methods (e.g., abstinence, condoms, 
vasectomy) should avoid conceiving children prior to and for 3 months 
following mitomycin C instillation. 
H. Subjects must have hemoglobin ≥ 9 g/dL and a platelet count ≥ 100,000/μL. 
 
4.3 Exclusion Criteria 
Subjects with any of the following will not be eligible for study participation: 
A.  Active urothelial carcinoma of the bladder within 12 months prior to enrollment 
B. History of adverse reaction to mitomycin C 
C. Subjects must not have evidence of regional or metastatic disease. 
D. History of radical cystectomy 
E. Planned radical cystectomy at the time of nephroureterectomy 
F. Females or males of childbearing potential who are unwilling or unable to use an 
acceptable method to avoid pregnancy prior to and for at least 3 months after 


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mitomycin C instillation. 
G. Females who are pregnant or breastfeeding. 
H. History of any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of protocol therapy or that might affect the interpretation of the 
results of the study or that puts the subject at high risk for treatment complications, in 
the opinion of the treating physician. 
I. Prisoners or subjects who are involuntarily incarcerated. 
J. Subjects who are compulsorily detained for treatment of either a 
psychiatric or physical illness. 
 
4.4 Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
5. REGISTRATION PROCEDURES 
 
All subjects must be registered with the UF Health Cancer Center prior to 
participation in this trial. This is not registration into the trial. Subjects failing to 
meet all study eligibility requirements will not be registered and will be unable to 
participate in the trial. 
 
6. STUDY PROCEDURES 
 
Please see the Schedule of Events located in Appendix A. 
 
6.1 
Screening Evaluations 
Written informed consent must be obtained prior to performing any study-specific 
evaluations or tests. Tests or evaluations performed as standard of care within the 
specified screening period, but prior to informed consent, may be accepted for this 
study and need not be repeated. 
A comprehensive medical history, physical exam, and assessment of ECOG 
performance status will be performed within 60 days pre-operatively. The following 
laboratory assessments will be performed within 60 days pre-operatively, with the 
exception of a urine pregnancy test, which will be performed the day of surgery in 
appropriate patients. Radiographic disease staging will be performed within 90 days 
preoperatively: 
• Laboratory evaluations 
• Complete blood count (CBC), including red blood cell count (RBC), 
white blood cell count (WBC), platelets, hemoglobin, and hematocrit 
• Basic metabolic panel (BMP), including sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, and glucose 
• Urinalysis 


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• Radiographic disease staging 
• CT scan or MRI or PET CT of the abdomen and pelvis 
• Chest X-ray or chest CT or PET CT of chest 
 
6.2 On Study Procedures/Evaluations 
Subjects will undergo a single instillation of mitomycin C during their 
nephroureterectomy as described in section 7.1. An adverse event assessment will be 
performed before and after instillation of mitomycin C the day of nephroureterectomy, 
as well as within 30 days following mitomycin C instillation, during a clinic visit. 
6.3 Follow up/Survival Evaluations 
Subjects will have a follow-up visit every three months (+/- 3 weeks) post-
operatively for two years to assess for bladder tumor recurrence. Subjects will have a 
follow-up visit every six months (+/- 3 weeks) post-operatively the third year to 
assess for bladder tumor recurrence. 
Subjects will have the following procedures at each of these visits: 
• Urinalysis 
• Surveillance cystoscopy 
Urine cytology with reflex UroVysion.  UroVysion testing will be performed if 
urine cytology result is atypical or suspicious. If recurrence of urothelial 
carcinoma within the bladder is suspected at any point, a subject will undergo a 
bladder biopsy to confirm recurrence. Once recurrence has been confirmed, the 
subject will no longer be followed for purposes of this study.   
7. 
STUDY TREATMENT 
 
All subjects entering the screening phase will receive a unique subject number. This 
number will be used to identify the subject throughout the study. Subjects withdrawn 
from the study will retain their subject number. 
 
7.1   Treatment Schedule/Administration 
A urethral catheter will be placed in a sterile fashion in the operating room and all urine 
will be drained. 40 mg of mitomycin C in 40 mL of sterile water will then be 
administered intravesically via a urethral catheter immediately following catheter 
placement. Immediately following mitomycin C instillation, the urethral catheter will be 
clamped for one hour. The nephroureterectomy procedure will start even while the 
urethral catheter is clamped. After this hour has elapsed, the mitomycin C will be 
drained from the bladder and the urethral catheter will be flushed with 100mL-200 mL 
(as clinically indicated) of sterile saline and drained. The urethral catheter will remain in 
place for the remainder of the surgical procedure. Timing of urethral catheter removal 
after the completion of the nephroureterectomy will be based on surgeon discretion. 
 
7.2 Specific Supportive Care 


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7.2.1 Concomitant Therapy 
Relevant medical history should be obtained at screening and include prior 
medications and treatment history. All medications taken within two weeks prior 
to screening will be collected.  
During the study, only concomitant medications used to treat side effects from the 
Mito-C installation will be collected.  Standard of care medications used during 
surgery through discharge will not be recorded.   
However, if another course of anti-cancer therapy is initiated prior to the thirty -day 
follow-up period visit; a record of concomitant medications will no longer be 
performed. 
 
If the use of any concomitant treatments (medications or procedures) becomes 
necessary, the treatment must be recorded, including the name of the drug or 
treatment, dose, route, date, indication for use, expected duration, and frequency of 
treatment. 
 
7.2.2   Allowed Concomitant Therapy 
Supportive measures consistent with optimal patient care will be given throughout the study. 
 
Bladder spasms: 
Anticholinergics should be administered per institutional 
guidelines for treatment or urethral catheter related 
bladder spams if bothersome to the patient. 
 
Dysuria: 
Medications for urinary pain relief should be administered 
per institutional guidelines for pain associated with 
urination. Urinary tract infection should be evaluated with 
a urinalysis prior to starting medications to treat the 
symptom of dysuria. 
 
Nausea:  
       Anti-emetics should be administered per institutional guidelines. 
 
Diarrhea: 
Subjects should be provided with instructions on use of 
loperamide (Imodium) in the event of diarrhea, as well as 
instructions to contact the treating physician. Other anti-
diarrheals are also allowed. Subjects should be given 
mouth care instructions per institutional guidelines. 
7.2.3 Prohibited Concomitant Therapy 
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 


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• Investigational agents other than the study drug in this trial 
• Radiation therapy 
• Live vaccines within 30 days prior to the first dose of trial treatment 
and while participating in the trial. 
 Examples of live vaccines include but are not limited to: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. 
 Seasonal influenza vaccines for injection are generally killed by virus 
vaccines and are permitted. However, intranasal influenza vaccines (e.g. 
Flu-Mist ®) are live attenuated vaccines and are not permitted. 
 
7.3 Dose Modifications 
The National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events 
Version 4 (CTCAE) will be used to grade toxicity 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
 
7.3.1 Dose Modification Table 
No dose modification to the single 40 mg intravesical instillation of mitomycin C 
will be included in the study. No dose reduction is required based on intravesical 
administration and elimination via catheter drainage. Additionally, dose reduction 
is not anticipated based on results of prior randomized trials and published 
retrospective trials. 
 
7.3.2 Supportive Care Guidelines 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, antiemetics, antidiarrheals, analgesics, etc., when appropriate. 
 
7.3.3 Trial Stopping Criteria 
The Stopping Criteria for the study will be based on the occurrence of clinically 
significant and causally related serious adverse reactions higher than Grade 3 (as defined 
by the CTCAE criteria) which are life-threatening and require urgent medical 
intervention. The UFHCC DISC will monitor the study and will meet at regular intervals 
or as events dictate to review any emerging safety data. If serious adverse reactions as 
highlighted do occur, then the UFHCC DISC will be consulted with respect to stopping 
the clinical trial. 
Stopping rule for efficacy corresponds with Simon optimal two-stage design as described 
in section 11.1. An interim analysis will be conducted when 16 subjects are enrolled and 
completed evaluation of the primary endpoint. If 4 or more BTR at 1-year post-surgery are 
observed, the study will be terminated early. 
 
8. TREATMENT DISCONTINUATION 
 
8.1 Removal of Subjects from Study 


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Subjects who discontinue participation in the clinical study on their own or subjects 
who are withdrawn by the investigator, for reasons other than completion of treatment 
or toxicity, will be defined as premature withdrawals. 
Subjects who are not initiated on study drug, but sign informed consent and undergo at 
least some of the screening procedures will be considered screening failures. A record 
of these subjects will be maintained by the study site. 
 
8.2 Criteria for Study Treatment Discontinuation 
A subject will be discontinued from protocol therapy under the following circumstances: 
• Any adverse event which, in the Investigator’s opinion, requires termination of 
the study medication. 
• Substantial non-compliance with the requirements of the study. 
• The subject presents with a beta-HCG test consistent with pregnancy. 
Pregnancy will be reported along the same timelines as a serious adverse event. 
• The subject uses illicit drugs or other substances that may, in the 
opinion of the Investigator, have a reasonable chance of contributing 
to toxicity or otherwise interfering with results. 
• The development of a second malignancy that requires treatment, which would 
interfere with this study. 
• The subject is lost to follow-up. 
• Development of an intercurrent illness or situation which would, in the 
judgment of the investigator, affect assessments of clinical status and the study 
endpoint to a significant degree. 
The Investigator will make every reasonable effort to keep each subject in the study 
unless it is in the subject’s best interests to discontinue participation. A description of 
the reason(s) for withdrawal from the study must be recorded on the case report form 
(CRF). 
 
Relevant visit data should be entered on the CRF and any unused study medication will 
be accounted for and returned for all subjects participating in the study, even for a brief 
period of time. Subjects who discontinue following entry will have relevant information 
completed and recorded on the CRF. All subjects who discontinue because of adverse 
events or clinically significant laboratory abnormalities should be followed up until they 
recover or stabilize, and the subsequent outcome will be recorded. If any subject should 
die during the trial or within 30 days of stopping study treatment, the Investigator will 
inform the UF Health Data Integrity and Safety Committee. 
 
8.3 Replacement of Subjects 
Subjects will be replaced if they do not receive the single intravesical instillation of 
mitomycin C or if the nephroureterectomy is not completed in the protocol for any 
reason, or if the subject wishes to discontinue participation in the protocol, but is not 
discontinued for toxicity or any of the reasons listed in section 8.2. 
 


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9. STUDY DRUG INFORMATION 
 
9.1 Study Drug 
Name 
Mitomycin C 
9.1.1 Identification 
Chemical name: 7-amino-9-
methoxymitosane Chemical 
structure: 
 
Molecular formula: 
15H18N4O5 Molecular 
weight: 334.33 daltons 
Physical description: Mitomycin C is a blue-violet crystalline powder that is heat-stable 
and that is freely soluble in organic solvents. 
 
9.1.2 Packaging and Labeling 
Mitomycin C is packaged in sterile, single use vials. Each vial contains a sterile 
mixture of mitomycin and mannitol in a 1:2 ratio. Each vial contains either 5 mg 
mitomycin C and 10 mg mannitol, 20 mg mitomycin C and 40 mg mannitol, or 40 mg 
mitomycin C and 80 mg mannitol. 
 
9.1.3 Drug Supply 
Mitomycin C will be supplied commercially for this study. 
 
9.1.4 Storage, Handling and Dispensing 
Unreconstituted mitomycin C powder should be stored at controlled room temperature, 
15 to 30°C (59 to 86°F). Mitomycin C powder should also be protected from light. To 
reconstitute mitomycin C powder for administration, add of 40 mL sterile water to 40 
mg mitomycin C powder and shake to dissolve. If mitomycin C powder does not 
dissolve immediately, let stand at room temperature until solution is obtained. Protect 
mitomycin C solution from light. 
 
9.1.5 Contraindications 
Mitomycin C is contraindicated in patients who have had a hypersensitivity reaction 
to it in the past. 
Mitomycin C is FDA pregnancy category D and is contraindicated for pregnant women 
because it can cause fetal harm if administered during pregnancy. Females of 
childbearing potential should be advised to avoid becoming pregnant and should be 


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informed of the potential for harm to the fetus. 
It is unknown whether mitomycin C is excreted in human milk. For this reason, 
women who are breast-feeding should not receive mitomycin C. 
Mitomycin C is also contraindicated for use in patients with thrombocytopenia, 
bleeding disorders, or an increased tendency for bleeding due to other causes. 
 
9.1.6 Special Warnings and Precautions for Use 
Mitomycin C should not be administered intravesicularly to patients with a 
known or suspected bladder perforation. 
 
9.1.7 Adverse Event Profile 
Common side effects of intravesicular treatment with mitomycin C can include bladder 
irritation/inflammation, dysuria, fever, flu-like symptoms, skin rash, malaise, 
hematuria, urinary incontinence, urinary frequency, urine discoloration, and urinary 
urgency. 
Bladder fibrosis and contraction has also been reported following intravesicular treatment 
with mitomycin C, which in rare cases has required cystectomy. Potential complications 
that could result from intravesicular treatment with mitomycin C can include urinary tract 
infection, fever > 101.3 
°F (> 38.5 °C), epididymitis, orchitis, abscess formation, hematuria with clot 
retention, myelosuppression, neutropenia, ureteral obstruction, pneumonitis, 
and hepatitis. 
 
10. ADVERSE EVENTS 
 
10.1 Definitions 
 
10.1.1 Adverse Event 
The term “adverse event” (AE) includes any sign, symptom, syndrome, or illness that 
appears or worsens in a subject during the period of observation in the clinical study and 
that may impair the wellbeing of the subject. The term also covers laboratory findings or 
results of other diagnostic procedures that are considered to be clinically significant 
(e.g., that requires unscheduled diagnostic procedures or treatment measures, or result in 
withdrawal from the study). An AE is therefore any unfavorable and unintended 
symptom or disease temporally associated with the administration of an investigational 
product, whether or not related to that investigational product. 
The adverse event may be: 
• A new illness/condition; 
• Worsening of a sign or symptom of the condition under 
treatment, or of a concomitant illness/condition; 
• An effect of the study drug; or 
• A combination of 2 or more of these factors. 
No causal relationship with the study drug or with the clinical study itself is implied by 
the use of the term “adverse event.” 


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The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents. 
AEs will be recorded in the subject CRF. AEs will be described by duration (start and 
stop dates and times), severity, outcome, treatment and relation to study drug, or if 
unrelated, the cause. 
 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition(s) for which the surgery is required may 
be an adverse event. Planned surgical measures permitted by the clinical study protocol 
and the condition(s) leading to these measures are not adverse events. 
 
When a clear diagnosis is available that explains the abnormal objective findings, this 
diagnosis will be recorded as an adverse event and not the abnormal objective findings 
(e.g., viral hepatitis will be recorded as the adverse event and not the transaminase 
elevation). If a definitive diagnosis is not available, then the sign(s) (e.g., clinically 
significant elevation of transaminase levels) or symptom(s) (e.g., abdominal pain) will 
be recorded as the adverse event. 
Adverse events fall into the categories “serious” and “non-serious.” 
 
10.1.2 Serious Adverse Event 
 
A serious adverse event is one that at any dose of the study drug or at any time during 
the period of observation: 
• Results in death 
• Is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based 
on appropriate medical and scientific judgment, may jeopardize the 
subject or may require intervention (e.g., medical, surgical) to prevent one 
of the other serious outcomes listed above. Examples of such events 
include but are not limited to intensive treatment in an emergency 
department or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization. “Medically important” 
should be marked only if no other serious criteria are met. 
 
An “unexpected SAE” is any SAE for which the nature, specificity or severity is not 
consistent with the currently known adverse event profile of the investigational 
agent(s). 
 
NOTE: The following hospitalizations are not considered SAEs in UFHCC clinical studies: 


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• a visit to the emergency room or other hospital department lasting less 
than 24 hours that does not result in admission (unless considered an 
“important medical event” or a life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending 
of health status (e.g., routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill 
health state that was planned before study entry. Appropriate 
documentation is required in these cases. 
• admission encountered for another life circumstance that carries 
no bearing on health status and requires no medical/surgical 
intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative). 
 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache). Any grade ≥ 3 
adverse events per CTCAE are generally considered severe AEs. 
 
This is not the same as “serious,” which is based on the outcome or action criteria 
usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
10.1.3 Non-Serious Adverse Event 
 
A non-serious adverse event is any adverse event not meeting any of the serious 
adverse event criteria. 
 
10.2 Period of Observation 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures. 
Collection of all SAEs must continue until the postoperative clinic visit which will 
occur within 30 days after mitomycin C instillation. If applicable, SAEs must be 
collected that relate to any later protocol- specified procedure (e.g., a follow-up skin 
biopsy). The investigator should notify the DISC of any SAE occurring after this time 
period that is believed to be related to the investigational product or protocol-specified 
procedure. 
The investigator will begin collecting non-serious adverse event (NSAE) information 
once administration of the investigational product is initiated. This NSAE information 
should also be collected from the start of a placebo lead-in period or other observational 
period intended to establish a baseline status for the subjects. Treated subjects, 
including those who were prematurely discontinued from the study, will be followed for 
any adverse events that occur during the study until 30 days following mitomycin C 
instillation. However, if another course of anti-cancer therapy is initiated prior to the 


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end of this period, collection of adverse events will no longer be performed, with the 
exception of events that may be possibly, probably, or definitely related to the 
investigational agent or are clinically significant. 
 
10.3 Documenting and Reporting of Adverse Events by Investigator  
 
All adverse events must be fully recorded in the subject’s case record form. Documentation must be 
supported by an entry in the subject’s file. A laboratory test abnormality considered clinically 
relevant, e.g., causing the subject to withdraw from the study, requiring treatment or causing 
apparent clinical manifestations, or judged relevant by the investigator, should be reported as an 
adverse event. Each event should be described in detail along with start and stop dates, severity, 
relationship to investigational product, action taken and outcome. 
 
Every attempt should be made to describe the adverse event in terms of a diagnosis that 
encompasses the component signs and symptoms. If only nonspecific signs or symptoms 
are present, then these should be recorded as separate diagnoses on the pages of the case 
report form. 
 
 All subjects who have adverse events, whether considered associated with the use of study 
drug or not, must be monitored to determine the outcome. The clinical course of the 
adverse event will be followed according to accepted standards of medical practice, even 
after the end of the period of observation, until a satisfactory explanation is found or the 
Principal Investigator considers it medically justifiable to terminate follow-up. Should the 
adverse event result in death, a full pathologist’s report should be supplied, if possible. 
 
10.3.1 Assessment of Causal Relationship of Study Drug 
The Investigator will provide an assessment of the potential causal relationship between 
adverse events and study medication by determining whether or not there is a reasonable 
possibility that the event was caused by the study medication. The relationship or 
association of the adverse event to the study medication will be characterized as not 
related, probably not related, possibly related, probably related, or related: 
 
Not Related: There is not a temporal relationship to the study drug administration or 
the adverse event is clearly due only to the progression of the underlying disease state, 
intercurrent illness, concomitant medication, concurrent therapy, or other known 
cause. 
 
Probably Not Related: There is little or no chance that the study drug administration 
caused the adverse event; the event is most likely due to another competing cause, 
including intercurrent illness, disease progression, or expression of the disease state, or 
a reaction to a concomitant medication or concurrent therapy appearing to explain the 
reported adverse event. 
 
Possibly Related: The association of the adverse event with the study drug 
administration is unknown; however, the adverse event is not reasonably attributed 


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to any other condition. 
 
Probably Related: When a reasonable temporal relationship exists between the 
adverse event and the study drug administration; significant symptoms abate upon 
discontinuation of the study drug and there is a reasonable explanation based on known 
characteristics of the study drug and there is no clear association with preexisting 
disease or therapy, intercurrent illness, concurrent therapy or other factor(s). 
 
Related: When the adverse event is a known side effect of the study drug or there is a 
temporal relationship to the administration of the study drug; or the adverse event 
reappears upon re- administration of the study drug (rechallenge); or the significant 
symptoms of the adverse event 
abate upon discontinuation of the study drug (dechallenge). 
 
10.3.2 Intensity of Adverse Events 
The intensity of adverse changes in physical signs or symptoms will be graded 
according to the CTCAE version 4. For all other adverse events not described in the 
CTCAE, the intensity will be assessed by the Investigator using the following 
categories: 
 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no 
medical intervention/therapy required. 
 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may 
be needed; no or minimal medical intervention/therapy required. 
 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible. 
Life-threatening (Grade 4) – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable. 
 
Death (Grade 5) – the event resulted in death. 
 
10.3.3 Action Taken with Study Drug 
 
The action the Investigator took with study drug as a result of the event should be 
recorded as one of the following: 
 
None – No action was taken with regard to the study drug as a result of the adverse event. 
Interrupted – Study drug was stopped due to the adverse event, but was later 
resumed at the same dose. 
Dose decreased – The dose of study drug was decreased as a result of the adverse event. 
Permanently discontinued – The subject was withdrawn from the study due to 
the adverse event. 


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Only one item should be chosen. If multiple actions apply, the following “worst case” 
scenario hierarchy should be used to determine the preferred entry: Discontinued > 
dose decreased > therapy interrupted. 
 
10.3.4 Definition of Outcome 
The outcome of the AE should be recorded as one of the following: 
 
Resolved without sequelae – The subject fully recovered from the adverse 
event with no observable residual effects. 
Resolved with sequelae – The subject recovered from the adverse event with 
observable residual effects. 
Not resolved – The adverse event was present at the time of last observation. 
Death – The subject died as a result of the adverse event. 
 
10.4 Immediately Reportable Events 
 
10.4.1 Serious Adverse Events 
The UFHCC Protocol Management Office (PMO) must be notified of the SAE 
within 24 hours of knowledge of the event by email at PMO@cancer.ufl.edu. 
Serious adverse events (SAE's) must be documented on an FDA MedWatch 3500A form. 
In addition to completing appropriate subject demographic and suspect medication information, 
the report should include the following information within the Event Description of the MedWatch 
3500A form: 
 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the 
adverse event to each investigational product and 
suspect medication 
 
The MedWatch form must be emailed to the UFHCC Project Management Office 
(PMO; pmo@cancer.ufl.edu) and PMO will submit this form to the UFHCC DISC 
Safety Team within 5 days of discovery of the event. The original copy of the 
MedWatch form and any email correspondence must be kept within the Trial Master 
File at the study site. The site investigator is responsible for informing the IRB and/or 
the Regulatory Authority of the SAE as per local requirements. 
 
Follow-up information will be emailed or faxed to the UFHCC PMO using an FDA 
MedWatch 3500A form stating that this is a follow-up to the previously reported SAE 
and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the 


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event has resolved or continues, if and how it was treated, whether the blind was broken 
or not (if applicable), and whether the participant continued or withdrew from study 
participation. 
 
10.4.2 Other Events Requiring Immediate Reporting 
All pregnancies, regardless of outcome, must be reported to the UFHCC DISC, 
including pregnancies that occur in the female partner of a male study subject. All 
pregnancies must be followed to outcome. 
 
Although overdose (dose variance of 10 %) and cancer are not always serious by 
regulatory definition, these events should also be reported to the DISC in an expedited 
manner. In case the overdose did not result in any adverse event, the Investigator 
should report this as “overdose, no adverse event” on the SAE form and provide the 
intended amount, as well as the actual amount, of drug administered. In the event of 
overdose or exaggerated response, appropriate supportive measures should be 
employed. Actual treatment should depend on the severity of the clinical situation and 
the judgment and experience of the treating physician. 
Pregnancies and overdoses should be documented and reported per the SAE reporting 
guidelines in section 10.4.1 above. 
 
10.5 IND Safety Reports Unrelated to this Trial 
IND safety reports not occurring on this trial but involving the study intervention 
(outside SAEs) received from outside sources will be submitted to the Institutional 
Review Board per their guidelines. 
11. STATISTICAL METHODS 
 
The sections below provide an overview of the statistical considerations and analyses. 
 
11.1  Sample Size Determination 
 
The primary endpoint for this study is bladder tumor recurrence (BTR) rate at 1-year post- 
surgery. In our previous study, there was a 16% recurrence rate for those that received 
mitomycin C on day 0 and a 33% recurrence rate for those receiving it on day 1 or later. 
From this, we will assume that the underlying proportion of BTR at 1 year is 25% for our 
population. A sample size of 53 subjects is needed to detect the decrease of 1-year BTR 
rate from 25% to 12.5% based on Simon optimal two-stage design. A sample size of 53 
will allow more than 80% power with one-sided type 1 error rate of 0.10. 
In the first stage, 16 subjects will be recruited and the study will be terminated early if 4 
or more BTR happen. If the study proceeds to the second stage, a total of 53 subjects will 
be studied. If the total number of BTR at 1-year post surgery is less than 10, the treatment 
will be considered a success. Sample size was calculated using PASS 16. 
 


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11.2  Analysis of Primary Endpoint 
A one-sided, one sample exact test of binomial proportion will be used to assess the 
primary endpoint, 1-year BTR rates, with level of significance set at 0.10. The 
proportion with BTR will be estimated, along with a 90% confidence interval. 
 
11.3Analysis of Secondary Endpoint  
Time to BTR will be characterized using Kaplan-Meier plots. Log rank tests and Cox 
proportional hazard modeling will be used to examine the impact of baseline 
characteristics. A p-value of less than 0.05 will be considered statistically significant. 
 
12. DATA AND SAFETY MONITORING 
 
12.1   Data Integrity and Safety Committee 
 
This protocol will be reviewed and monitored by the University of Florida Health 
Cancer Center (UFHCC) DISC in accordance with their policies and procedures. They 
will review and monitor study progress, toxicity, safety and other data from this trial. 
Questions about subject safety or protocol performance will be addressed with the 
sponsor-investigator, statistician, and study team members. Should any major concerns 
arise; the DISC will offer recommendations regarding whether or not to suspend the 
trial. 
 
UFHCC DISC data and safety monitoring activities include: 
• Review of clinical trial conducted for progress and safety 
• Review of all adverse events requiring expedited reporting as defined in the protocol 
• Review of reports generated by data quality control review process 
• Notification of the sponsor-investigator of recommended action 
• Notification of sites coordinated by the UFHCC of adverse events requiring 
expedited reporting and subsequent committee recommendations for study 
modifications 
 
12.2 On-site Monitoring 
UFHCC monitors will make monitoring visits to the trial sites periodically during 
the trial to determine if sites are complying with the protocol. Source documents 
will be reviewed for verification of agreement with data as submitted via the data 
collection system. The site investigator/institution guarantee access to source 
documents by UFHCC or its designee and appropriate regulatory agencies. 
 
The trial site may also be subject to quality assurance audit by any collaborating 
sponsors or their designee as well as inspection by appropriate regulatory agencies. 
 
It is important for the site investigator and their relevant personnel to be available 
during the monitoring visits and possible audits and for sufficient time to be devoted to 


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the process. 
 
12.3 
Principal Investigator Responsibilities 
As part of the responsibilities assumed by conducting this study, the Principal 
Investigator (PI) agrees to maintain and have available for monitoring adequate case 
records (accurate source documents and CRFs) for the subjects treated under this 
protocol. 
The PI will be primarily responsible for monitoring of adverse events, protocol 
violations, and other immediate protocol issues. The study coordinator will collect 
information on subjects enrolled through the use of electronic or paper adverse event 
(AE) forms, CRFs, and informed consent forms. 
 
13. EMERGENCY PROCEDURES 
 
13.1  Emergency Contact 
In emergency situations, the treating physician should contact the Principal 
Investigator by telephone at the number listed on the title page of the protocol. 
 
13.2 Emergency Identification of Investigational Products 
This is a non-blinded, non-randomized study. Thus, there will be no need for unmasking 
procedures, and the identification of the investigational product can be made by simple 
inquiry to the investigational pharmacy. 
 
13.3 Emergency Treatment 
During and following a subject’s participation in the study, the treating physician 
and/or institution should ensure that adequate medical care is provided to a subject for 
any adverse events, including clinically significant laboratory values, related to the 
study. 
 
14. ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
14.1 Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, 
and documentation of this study are designed to ensure that the Principal 
Investigator and Co- Investigators abide by Good Clinical Practice (GCP), as 
described in International Conference on Harmonization (ICH) Guideline E6 and 
in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review Board 
(IRB) approval before initiation of the study. 
The Principal Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities. 


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All potential serious breaches must be reported immediately to the UFHCC DISC 
and IRB of record, if applicable. A serious breach is a breach of the conditions and 
principles of GCP in connection with the study or the protocol, which is likely to 
affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study. 
 
14.2 Institutional Review Board 
Before study initiation, the investigator must have written and dated approval from the 
IRB for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The 
investigator should also provide the IRB with a copy of the Investigator Brochure or 
product labeling, information to be provided to subjects, and any updates. The 
investigator should provide the IRB with reports, updates, and other information (e.g., 
amendments, and administrative letters) according to regulatory requirements or 
institution procedures. 
 
14.3 Compliance with Laws and Regulations 
It is intended that the proposed study be conducted according to the International 
Conference on Harmonization E6 Guideline for Good Clinical Practice (GCP) and the 
Declaration of Helsinki. Please refer to the International Conference on Harmonization 
and GCP: 
http://www.fda.gov/oc/gcp/guidance.html; Declaration of Helsinki: 
http://www.fda.gov/oc/health/helsinki89.html; Code of Federal Regulations, 
Title 21: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm] 
All UF Health Cancer Center investigator-initiated trials, meeting the criteria of the 
FDAAA’s applicable clinical trials, will be registered with ClinicalTrials.gov by the 
Protocol Development Officer or assigned designee. All studies must be registered no 
later than 21 days after enrollment of the first participant. The Protocol Development 
Officer will maintain the responsibility of updating trials registered with 
ClinicalTrials.gov; per the FDA’s updating requirements of information must be updated 
at least every twelve months and the registry must be updated within thirty days of any 
changes in recruitment status or completion of the study. 
 
14.4 Delegation of Investigator Responsibilities 
The Principal Investigator will ensure that all persons assisting with the study are 
adequately informed about the protocol, any amendments to the protocol, the study 
treatments, and their study-related duties and functions. 
The Principal Investigator will maintain a list of Co- Investigators and other 
appropriately qualified persons to whom he has delegated significant study-
related duties. 


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Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks. This study will not use the 
services of study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g., loss of medical licensure; debarment). 
Systems with procedures that ensure the quality of every aspect of the study will be 
implemented. 
 
14.5  Subject Information and Informed Consent 
Before being enrolled in this clinical trial, the subject must consent to participate after 
the nature, scope, and possible consequences of the clinical study have been explained 
in a form understandable to him or her. An informed consent document that includes 
both information about the study and the consent form will be prepared and given to the 
subject. This document will contain all ICH, GCP, and locally required regulatory 
elements. The document must be in a language understandable to the subject and must 
specify the person who obtained informed consent. 
After reading the informed consent document, the subject must give consent in 
writing. The written informed consent will be obtained prior to conducting any 
study-related procedures or tests. The subject’s consent must be confirmed at the 
time of consent by the personally dated signature of the person conducting the 
informed consent discussions. A copy of the signed consent document must be given 
to the subject. 
The PI will retain the original signed consent document. The PI will not undertake any 
measures specifically required only for the clinical study until valid consent has been 
obtained. 
 
14.6 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. 
 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator 
to obtain such permission in writing from the appropriate individual. 
 
Subjects will be told that the IRB, UF Health DISC, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection law. 
 
14.7 Protocol Amendments 
Once the study has started, amendments should be made only in exceptional cases. 
Protocol amendments cannot be implemented without prior written IRB approval 
except as necessary to eliminate immediate safety hazards to subjects. A protocol 


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amendment intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the IRB and CRO are notified within five 
business days. 
All amendments will be submitted to the IRB and written verification that the 
amendment was submitted and subsequently approved is to be obtained. 
 
14.8  Case Report Forms 
The Principal Investigator and/or his/her designee will prepare and maintain adequate 
and accurate participant case histories with observations and data pertinent to the 
study. Study specific Case Report Forms (CRFs) will document safety and treatment 
outcomes for safety monitoring and data analysis. All study data will be entered into 
OnCore® via standardized CRFs in accordance with the CTMS study calendar, using 
single data entry with a secure access account. 
An electronic case report form (eCRF) is required and must be completed for each 
included subject. The completed dataset is the sole property of UFHCC and should not 
be made available in any form to third parties, except for authorized representatives of 
appropriate Health/Regulatory Authorities, without written permission from UFHCC. 
 
14.9 Record Retention 
Study documentation includes all eCRFs, 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 subject 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 all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator. 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. 
 
UF Health Cancer Center requires that all study documentation be maintained for at 
least 6 years from the date of final study publication. No study records may be 
destroyed without prior authorization from UF. 


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15. REFERENCES 
 
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. 
 
2. Rouprêt M, Babjuk M, Compérat E, Zigeuner R, Sylvester RJ, Burger M, et al. 
European Association of Urology Guidelines on Upper Urinary Tract Urothelial 
Cell Carcinoma: 2015 Update. Eur Urol. 2015;68(5):868-79. 
 
3. Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival 
ofpatients with carcinoma of the ureter and renal pelvis in the USA, 1973-
2005. BJU Int. 2011;107(7):1059-64. 
 
4. Rouprêt M, Babjuk M, Compérat E, Zigeuner R, Sylvester RJ, Burger M, et al. 
European Association of Urology Guidelines on Upper Urinary Tract Urothelial 
Carcinoma: 2017 Update. Eur Urol. 2018;73(1):111-22. 
 
5. Serretta V, Gesolfo C, Alonge V, et al. Mitomycin C from birth to adulthood. 
Urologia 2016; 83(suppl 2):s2-s6. 
 
6. Van Helsdingen PJ, De Bruijin EA, Seeborn, HP, et al. Behavior and 
absorption of mitomycin C following multiple intravesical 
administrations. J Pharm Sci. 1988; 77(10):843- 846. 
 
7. Gao X, Au JLS, Badalament RA, et al. Bladder tissue uptake of mitomycin C 
during intravesical therapy is linear with drug concentration in urine. Clin Care 
Res. 1998;4(1):139- 143. 
 
8. Hopkins SC, Buice RG, Matheny R, et al. The stability and antitumor activity of 
recycled (intravesical) mitomycin C. Cancer, 1984;53(10):2063-2068. 
 
9. De Bruijin EA, Sleeboom HP, van Helsdingen PJ, et al. Pharmacodynamics and 
pharmacokinetics of intravesical mitomycin C upon different dwelling times. Int 
J Cancer. 1992;51(3):359-364. 
 
10. Pawinski A, Sylvester R, Kurth KH, et al. A combined analysis of European 
Organization for Research and Treatment of Cancer, and Medical Research 
Council randomized clinical trials for the prophylactic treatment of stage TaT1 
bladder cancer. J Urol. 1996;156(6):1934-1940. 
 
11. Bouffioux C, Kurth KH, Bono A, et al. Intravesical Adjuvant chemotherapy for 
superficial transitional cell bladder carcinoma: results of 2 European 
Organization for Research and 


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Treatment of Cancer randomized trials with mitomycin C and doxorubicin 
comparing early versus delayed instillations and short-term versus long-term 
treatment. J. Urol. 1995;153(3 pt 2):934-941. 
 
12. Kaasinen E, Rintala E, Hellstrom P, et al. Factors explaining recurrence in 
patients undergoing chemoimmunotherapy regimens for frequently recurring 
superficial bladder carcinoma. Eur Urol. 2002;42(2):167-174. 
 
13. Sylvester RJ, Oosterlinck W, van der Meijden APM. A single immediate 
postoperative instillation of chemotherapy decreases the risk of recurrence in 
patients with Stage Ta T1 bladder cancer: a meta-analysis of published results 
of randomized clinical trials. J Urol. 2004;171(6 pt 1):2186-2190. 
 
14. O'Brien T, Ray E, Singh R, Coker B, Beard R, Oncology BAoUSSo. 
Prevention of bladder tumours after nephroureterectomy for primary upper 
urinary tract urothelial carcinoma: a prospective, multicentre, randomised 
clinical trial of a single postoperative intravesical dose of mitomycin C (the 
ODMIT-C Trial). Eur Urol. 2011;60(4):703-10. 
 
15. Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, et al. Prospective 
randomized phase II trial of a single early intravesical instillation of pirarubicin 
(THP) in the prevention of bladder recurrence after nephroureterectomy for upper 
urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J 
Clin Oncol. 2013;31(11):1422-7. 
 
16. Deng X, Yang X, Cheng Y, Liu X, Wu B, Wang Z, et al. Prognostic value 
and efficacy valuation of postoperative intravesical instillation in primary 
urothelial carcinomas of upper urinary tract. Int J Clin Exp Med. 
2014;7(12):4734-46. 
 
17.  Lu DD, Boorjian SA, Raman JD. Intravesical chemotherapy use 
after radical nephroureterectomy: A national survey of urologic 
oncologists. Urol Oncol. 2017;35(3):113.e1-.e7. 


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16. APPENDICES 
 
 
 
 
 
 
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Appendix A: SCHEDULE OF EVENTS 
 
VISIT: 
PROCEDURE: 
PREOPERATIVE SCREENING 
(UP TO 60 DAYS BEFORE DATE 
OF NEPHROURETERECTOMY; 
RADIOLOGIC ASSESSMENTS 
MAY BE PERFORMED UP TO 90 
DAYS PREOPERATIVELY ) 
NEPHROURETERECTOMY 
POST- 
OPERATIVE 
FOLLOW UP1 
Informed Consent 
X 
Medical History 
X 
Physical Exam 
X 
ECOG Performance Status 
Assessment 
X 
CT or MRI or PET CT of the abdomen 
and pelvis
2 
X 
Chest X-Ray or chest CT or PET CT 
of chest
2 
X 
CBC
3 
X 
BMP
4 
X 
Urinalysis 
X 
X 
Urine Pregnancy Test
8 
X 
Mitomycin C Administration
5 
X 
Adverse Event Assessment
e 
X 
Surveillance Cystoscopy 
X 
Urine Cytology 
X 
UroVysion Testing (if indicated)
6 
X 
Bladder Biopsy
7 
X 
1 Subjects will first be monitored for bladder tumor recurrence every three months (± 3 weeks) for the first two years post- 
operatively. Subjects will then have a follow-up visit every six months (+/- 3 weeks) for the third year post-operatively to assess for 
bladder tumor recurrence.  Follow up visits will discontinue upon confirmation of bladder tumor recurrence. 
2 Radiologic disease staging evaluation will be by CT or MRI or PET CT of the abdomen and pelvis and chest X-Ray or chest C or 
PET CT of chest. 
3 Complete blood count (CBC) is to include red blood cell count (RBC), white blood cell count (WBC), platelets, hemoglobin, and 
hematocrit will be completed as described in section 6.1. 
4 Basic metabolic panel is to include sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, and glucose 
will be completed as described in section 6.1. 
5 Mitomycin C is to be administered as described in section 7.1. 
6 UroVysion will be performed if urine cytology result is atypical or suspicious, 
7 A bladder biopsy will be required only if bladder tumor recurrence is suspected based upon cystoscopy or urine testing findings for 
histologic confirmation of recurrence. 
8 Urine pregnancy testing will be completed on the day of the nephroureterectomy prior to the nephroureterectomy. 
9 Adverse event assessment will be as described in section 10  


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Appendix B: PERFORMANCE SCALE 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work) 
2 
In bed < 50% of the time 
Ambulatory and capable of all self-care, but unable to carry out any work activities 
Up and about more than 50% of waking hours 
3 
In bed > 50% of the time 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
100% bedridden Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead