GEMINI: An Open-Label, Single-Arm, Phase II Study of Intraoperative Gemcitabine Intravesical Instillation in Patients Undergoing Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma
Phase: PHASE2
Conditions: Stage 0a Renal Pelvis and Ureter Cancer AJCC v8, Stage 0a Renal Pelvis Cancer AJCC v8, Stage 0a Ureter Cancer AJCC v8, Stage 0is Renal Pelvis and Ureter Cancer AJCC v8, Stage 0is Renal Pelvis Cancer AJCC v8, Stage 0is Ureter Cancer AJCC v8, Stage I Renal Pelvis and Ureter Cancer AJCC v8, Stage I Renal Pelvis Cancer AJCC v8, Stage I Ureter Cancer AJCC v8, Stage II Renal Pelvis and Ureter Cancer AJCC v8, Stage II Renal Pelvis Cancer AJCC v8, Stage II Ureter Cancer AJCC v8, Stage III Renal Pelvis and Ureter Cancer AJCC v8, Stage III Renal Pelvis Cancer AJCC v8, Stage III Ureter Cancer AJCC v8, Stage IV Renal Pelvis and Ureter Cancer AJCC v8, Stage IV Renal Pelvis Cancer AJCC v8, Stage IV Ureter Cancer AJCC v8
Sponsor: Mayo Clinic

 
 
 
 
 
GEMINI: An Open-Label, Single-Arm, Phase II Study of Intraoperative 
GEMcitabine INtravesical Instillation in Patients Undergoing Radical 
Nephroureterectomy for Upper Tract Urothelial Carcinoma 
 
NCT04398368 
DATE: Version 4.0 [9/3/2021] 

GEMINI: A Phase II Trial of Gemcitabine Intravesical Instillation for Nephroureterectomy 
Version 4.0 
 
 
Revised 9/3/21 
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GEMINI: An Open-Label, Single-Arm, Phase II Study of Intraoperative 
GEMcitabine INtravesical Instillation in Patients Undergoing Radical 
Nephroureterectomy for Upper Tract Urothelial Carcinoma 
 
Principal Investigator: 
 
Stephen A. Boorjian 
Mayo Clinic 
Department of Urology 
200 1st St. Southwest 
Rochester, MN 55905 
507-284-4015 
boorjian.stephen@mayo.edu 
 
Co-Principal Investigator: 
Vignesh T. Packiam 
University of Iowa Hospitals & Clinics 
200 Hawkins Drive 
Iowa City, IA 52242 
319-356-2421 
vignesh-packiam@uiowa.edu 
Biostatistician: 
Phillip J. Schulte 
Mayo Clinic 
Department of Health Sciences Research 
Harwick 7-06A 
205 3rd Ave. Southwest 
Rochester, MN 55905 
 
Study Product: 
Gemcitabine 
Protocol Number: 
IRB ID 19-009444 
 
 
Version: Version 1.0 [11-20-19], Version 2.0 [9/16/20], Version 3.0 [8/27/21], Version 4.0 
[9/3/2021] 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 6 
STUDY SCHEMA ......................................................................................................................................... 7 
1 
INTRODUCTION ................................................................................................................................. 8 
1.1 
BACKGROUND ................................................................................................................................ 8 
1.2 
INVESTIGATIONAL AGENT ............................................................................................................. 12 
1.3 
PRECLINICAL DATA ...................................................................................................................... 13 
1.4 
CLINICAL DATA TO DATE .............................................................................................................. 13 
1.5 
DOSE RATIONALE ......................................................................................................................... 16 
1.6 
RISKS AND BENEFITS ..................................................................................................................... 17 
2 
STUDY OBJECTIVES ........................................................................................................................ 17 
3 
STUDY DESIGN ................................................................................................................................. 18 
3.1 
GENERAL DESCRIPTION ................................................................................................................. 18 
3.2 
NUMBER OF SUBJECTS ................................................................................................................... 18 
3.3 
DURATION OF PARTICIPATION ........................................................................................................ 18 
3.4 
PRIMARY STUDY ENDPOINT ........................................................................................................... 19 
3.5 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 19 
3.6 
PRIMARY SAFETY ENDPOINTS ........................................................................................................ 19 
3.7 
IDENTIFICATION OF SOURCE DATA ................................................................................................. 20 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 21 
4.1 
INCLUSION CRITERIA ..................................................................................................................... 21 
4.2 
EXCLUSION CRITERIA .................................................................................................................... 21 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................................. 22 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................ 22 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 22 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 23 
5 
STUDY DRUG .................................................................................................................................... 23 
5.1 
DESCRIPTION ................................................................................................................................ 23 
5.2 
TREATMENT REGIMEN ................................................................................................................... 25 
5.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 25 
5.4 
SUBJECT COMPLIANCE MONITORING .............................................................................................. 26 
5.5 
PRIOR AND CONCOMITANT THERAPY .............................................................................................. 27 
5.6 
PACKAGING .................................................................................................................................. 27 
5.7 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................. 27 
5.7.1 
Receipt of Drug Supplies .......................................................................................................... 27 
5.7.2 
Storage ................................................................................................................................... 27 
5.7.3 
Dispensing of Study Drug ......................................................................................................... 28 
5.7.4 
Return or Destruction of Study Drug ......................................................................................... 28 
6 
STUDY PROCEDURES ...................................................................................................................... 28 
6.1 
VISIT 1; PRE-STUDY; REGISTRATION ............................................................................................... 28 
6.2 
VISIT 2; PERI-OPERATIVE; RNU ..................................................................................................... 29 
6.3 
VISIT 3; WEEK 2 ........................................................................................................................... 30 
6.4 
VISITS 4, 5; MONTHS 3, 6 ............................................................................................................... 30 
6.5 
VISIT 6; MONTH 12 ....................................................................................................................... 30 
6.6 
VISIT 7; MONTH 18 ....................................................................................................................... 31 
6.7 
VISIT 8; MONTH 24 ....................................................................................................................... 31 
6.8 
OTHER ASSESSMENTS AT EACH VISIT ............................................................................................... 31 

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6.9 
UNSCHEDULED VISITS ................................................................................................................... 31 
6.10 
OUTSIDE VISITS ............................................................................................................................ 31 
7 
STATISTICAL PLAN ......................................................................................................................... 32 
7.1 
SAMPLE SIZE DETERMINATION ....................................................................................................... 32 
7.2 
STATISTICAL METHODS ................................................................................................................. 33 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 34 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 35 
8.1 
DEFINITIONS ................................................................................................................................ 35 
8.2 
RECORDING OF ADVERSE EVENTS .................................................................................................. 37 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ...................................... 37 
8.3.1 
PI reporting: notifying the Mayo IRB ......................................................................................... 37 
8.4 
STOPPING RULES .......................................................................................................................... 39 
8.5 
MEDICAL MONITORING ................................................................................................................. 39 
8.5.1 
Data and Safety Monitoring Plan .............................................................................................. 39 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 40 
9.1 
CONFIDENTIALITY ........................................................................................................................ 40 
9.2 
SOURCE DOCUMENTS .................................................................................................................... 40 
9.3 
CASE REPORT FORMS .................................................................................................................... 40 
9.4 
RECORDS RETENTION .................................................................................................................... 41 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 42 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 42 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 42 
10.3 
PROTOCOL DEVIATIONS................................................................................................................. 43 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 43 
12 
STUDY FINANCES ............................................................................................................................ 43 
12.1 
FUNDING SOURCE ......................................................................................................................... 43 
12.2 
CONFLICT OF INTEREST ................................................................................................................. 43 
12.3 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................. 44 
13 
PUBLICATION PLAN ....................................................................................................................... 44 
14 
REFERENCES ................................................................................................................................... 44 
15 
ATTACHMENTS ............................................................................................................................... 50 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
 
RNU 
Radical Nephroureterectomy 
UTUC 
Upper Tract Urothelial Carcinoma 
CT 
Computed Tomography 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
Estimated Glomerular Filtration Rate 
LG 
Low Grade 
HG 
High Grade 
NAC 
Neoadjuvant Chemotherapy 
UC 
Urothelial Carcinoma 
NMIBC 
Non-Muscle-Invasive Bladder Cancer 
TURBT 
Transurethral Resection of Bladder Tumor 
BCG 
Bacillus Calmette-Guérin 
UUT 
Upper Urinary Tract 
AJCC 
American Joint Committee on Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Primary Investigators 
 
Stephen A. Boorjian, M.D. 
Department of Urology, Mayo Clinic, Rochester, MN 
Vignesh T. Packiam, M.D. 
Department of Urology, University of Iowa, Iowa City, IA 
 
Co-Investigators 
 
Bradley C. Leibovich, M.D. 
Department of Urology, Mayo Clinic, Rochester, MN 
R. Houston Thompson, M.D. 
Department of Urology, Mayo Clinic, Rochester, MN 
Aaron M. Potretzke, M.D. 
Department of Urology, Mayo Clinic, Rochester, MN 
Goerge K. Chow, M.D. 
Department of Urology, Mayo Clinic, Rochester, MN 
Matthew K. Tollefson, M.D. 
Department of Urology, Mayo Clinic, Rochester, MN 
Timothy D. Lyon, M.D. 
Department of Urology, Mayo Clinic, Jacksonville, FL 
Matvey Tsivian, M.D. 
Department of Urology, Wake Forest University, Winston Salem, NC 
Amir Toussi, M.D. 
Department of Urology, University of Pittsburgh, Pittsburhg, PA 
 
Statistician 
 
Phillip J. Schulte, M.S. 
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Summary 
Title 
GEMINI: An Open-Label, Single-Arm, Phase II Study of 
Intraoperative Gemcitabine Intravesical Instillation in Patients 
Undergoing Radical Nephroureterectomy for Upper Tract 
Urothelial Carcinoma 
Running Title 
GEMINI: A Phase II Trial of Gemcitabine Intravesical Instillation 
for Nephroureterectomy 
Phase 
Phase II 
Methodology 
Open-Label, Single-Arm 
Overall Study Duration 
5 years 
Subject Participation 
Duration 
Minimum 1 year (2-year maximum) 
Single or Multi-Site  
Multi-center; 2 Mayo sites: Rochester, Florida, Additional External 
Sites 
Objectives 
Primary Objective:  
• To assess the efficacy of a single intraoperative intravesical 
instillation of gemcitabine at time of radical 
nephroureterectomy (RNU) to prevent intravesical 
recurrence of urothelial carcinoma (UC) at 1 year in patients 
with clinically localized upper tract urothelial carcinoma 
(UTUC) 
 
Secondary Objectives:  
• To assess time to recurrence for entire duration of follow-up 
• To assess adverse events  
 
Exploratory Objectives: 
• To stratify intravesical UC recurrence free survival by 
tumor grade, neoadjuvant chemotherapy, tumor stage, 
ureteral tumor location, and history of bladder cancer 
• To assess incidence and time to development of muscle 
invasive bladder cancer 
Number of Subjects 
90 
Diagnosis and Main 
Inclusion Criteria 
Newly diagnosed, clinically localized UTUC; Candidate for RNU; 
ECOG 0-2; No prior intravesical UC within 12 months 
Study Product, Dose, 
Route, Regimen 
Intravesical instillation of 2 g Gemcitabine in 100 ml of 0.9% 
Sodium Chloride solution 
Duration of 
Administration 
Single intraoperative intravesical instillation of gemcitabine for at 
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Statistical Methodology 
Based on prior literature, the historical event rate for no treatment 
is expected to be 30% with an estimated 40% relative reduction in 
event rate in the Gemcitabine arm. A sample size of 81 patients 
provides at least 80% power to detect this difference, based on a 
one-sided exact test of proportions with alpha level 0.05. To 
account for loss-to-follow up and dropout due to death, accrual will 
be increased by 10%, yielding a final accrual goal of 90 patients. 
 
Follow-up will require cystoscopy and urine cytology at 3, 6, and 
12 months with mandated histologic confirmation of recurrences.  
 
 
Study Schema 
 
  
 

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1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures. The described study will be conducted in compliance with the protocol, 
Good Clinical Practices standards and associated Federal regulations, and all applicable 
institutional research requirements. 
1.1 
Background 
 
Overview 
 
Intravesical recurrence of urothelial carcinoma following radical nephroureterectomy for upper 
tract urothelial carcinoma is common and contributes considerable morbidity and cost. Two prior 
randomized controlled trials have demonstrated that perioperative instillation of intravesical 
Mitomycin C and Pirarubicin significantly decrease the incidence of subsequent intravesical 
recurrence for these patients. However, utilization of these agents has not been embraced by 
urologists, in part due to concerns for local toxicity. Intravesical gemcitabine is a promising 
agent for use in this setting given demonstrated efficacy and low toxicity in a recent randomized 
controlled trial for non-muscle invasive bladder cancer.1 
 
Upper Tract Urothelial Carcinoma 
 
There are an estimated 549,393 new cases of bladder cancer diagnosed per year worldwide, of 
which 81,190 cases are diagnosed in the United States.2,3 Bladder cancer is the sixth most common 
malignancy in the United States.2 Urothelial carcinoma (UC) is the most common histology of 
bladder cancer and can affect the entire urothelial lining which includes the kidney, ureter, bladder, 
and urethra. Upper tract urothelial carcinoma (UTUC) refers to UC of the kidney and ureter. 
Accounting for 10% of all UC cases, this results in more than 55,000 and 8,000 new cases of 
UTUC per year worldwide and in the United States, respectively.2,3 Although endoscopic 
approaches are utilized in select cases, the standard primary treatment for clinically localized 
UTUC is radical nephroureterectomy (RNU).4 This surgery involves resection of the kidney, 
ureter, and bladder cuff surrounding the ureteral orifice. Mirroring management for UC of the 
bladder, current guidelines state that patients undergoing RNU may benefit from adjuvant and 
neoadjuvant chemotherapy.4,5 There is also emerging literature regarding the benefit of checkpoint 
inhibitors for these patients.6 
 
Intravesical Recurrence after RNU 
 
Approximately 30-50% of patients experience intravesical recurrence of UC after RNU for 
UTUC.7–9 There are numerous identified risk factors for intravesical recurrences, including 
increasing age, ureteral tumor location, prior bladder cancer, increasing tumor stage, concomitant 
carcinoma in situ, and lymph node involvement.10 Gender has shown disparate associations with 
the risk of intravesical recurrence in meta-analyses.10,11 
 

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In addition to the risks of disease progression and cancer-specific mortality, intravesical 
recurrences add patient-level morbidity, as treatment is typically with transurethral resection under 
anesthesia.12 Surveillance for and treatment of these recurrences also add significantly to cost of 
management for this disease.13  
 
Mechanisms for Intravesical Recurrence 
 
There are two presumed mechanisms for intravesical recurrence after RNU: (1) oligoclonal 
recurrence from the “field change” nature of UC that is associated with increased malignant 
potential of the entire urothelium, and (2) monoclonal recurrence from seeding of disrupted tumor 
cells that subsequently implant in the bladder. 
 
The “field change theory” presumes a malignant potential of the entire urothelial tract, primarily 
due to carcinogenic exposure. This oligoclonal model supports independent synchronous and 
metachronous urothelial tumor development throughout the urinary tract. Therefore, if the 
urothelium of the upper tract is predisposed to developing and subsequently develops urothelial 
carcinoma, the urothelium of the lower urinary tract and bladder may also independently be 
susceptible to developing urothelial carcinoma in the future as well. 
 
Meanwhile, the “tumor seeding theory” is that seeding of malignant cells occurs from the upper 
urinary tract (UUT) tumor implanting into the bladder. This monoclonal model for tumor 
dissemination is favored for several reasons. First, there is animal and clinical data for primary 
bladder cancer supporting that urothelial injury predisposes intravesical recurrence specifically in 
those injured sites.14,15 Second, the majority of intravesical recurrences arise within 1 year from 
RNU, suggesting there is a temporal link of recurrences to manipulation of the UUT tumor during 
surgery. Third, while the incidence of intravesical recurrence after RNU for UTUC is 30-50%, the 
incidence of UTUC in the setting of primary bladder urothelial carcinoma is less than 5%.8 The 
low incidence of ascending tumor recurrence likely occurs secondary to lack of urinary reflux from 
the bladder to the ureter and kidney. This pattern is further reflected by low rates of contralateral 
UUT recurrence in only 2-6% of patients with UTUC.16 Finally and most convincingly, there have 
been several genetic studies showing that intravesical recurrences are of monoclonal origin with 
similar genetic make-up to UTUC, consistent with tumor seeding.17,18 In fact, a recent analysis of 
clonal relatedness using somatic mutation data in 29 paired tumor samples from the UUT and 
bladder in patients with intravesical recurrence after RNU for UTUC revealed that 100% of 
samples shared clonal origin.19 
 
Perioperative Intravesical Therapy as a Strategy to Reduce Intravesical Recurrence 
 
Several strategies have been evaluated in reducing intravesical recurrence after RNU. Surgical 
techniques include avoiding entry into the urinary tract, removal of the kidney and ureter en bloc 
with a bladder cuff, and early clipping the ureter prior to extensive manipulation of the kidney to 
avoid seeding of tumor cells down the ureter and into the bladder. However, none of these 
techniques have been evaluated prospectively.  
 
An effective strategy to reduce intravesical recurrence is the perioperative instillation of 
intravesical chemotherapy. This has been reported at various times from completion of RNU to 

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catheter removal. Catheter removal generally occurs after 10-14 days to allow for bladder healing. 
Several institutional reports evaluated perioperative instillation of a variety of intravesical 
chemotherapy agents after RNU, including BCG, anthracyclines (Epirubicin, Pirarubicin 
Doxorubicin), and Mitomycin C +/- cytosine arabinoside.20–22 The mechanism of perioperative 
intravesical therapy presumably targets the “tumor seeding theory”. 
 
Two prospective randomized controlled trials have evaluated the use of perioperative intravesical 
chemotherapy to reduce intravesical recurrence after RNU. The first was the ODMIT-C trial, 
published in 2011— a multi-center trial in the United Kingdom which randomized 284 patients to 
a single postoperative dose of Mitomycin C at time of catheter removal versus standard care 
following RNU for UTUC.23 This trial showed an 11% absolute risk reduction in 1 year 
intravesical recurrence and a 40% relative risk reduction in 1 year intravesical recurrence using 
per protocol analysis. This trial excluded patients with prior history of bladder cancer. A second 
randomized phase II trial was published in 2012 from Japan, evaluating Pirarubicin.24 A total of 
77 patients were randomized to receive a single instillation of Pirarubicin within 48 hours after 
RNU versus saline. The results showed significantly lower rate of 2-year intravesical recurrence 
in the Pirarubicin vs control group (16.9% vs 42.2%). A meta-analysis including the ODMIT-C 
and Pirarubicin assessed the effects of a single-dose intravesical chemotherapy instillation after 
RNU for UTUC, estimated that instillation resulted in a hazard ratio of 0.51 (95% CI 0.32 – 0.82) 
for recurrence and approximately 127 (95% CI 182 to 44) fewer recurrences after 12 months, 
relative to no instillation.25 
 
There are currently ongoing trials for Pirarubicin (NCT02923557, 200 patients), Docetaxel 
(NCT03209206, 84 patients), and Gemcitabine (NCT03062059, 134 patients) in this setting.  
 
Table 1. Randomized Placebo-Controlled Trials of Intravesical Chemotherapy for RNU 
Reference 
Country 
Total 
Patients 
Agent 
Timing 
Anticipated 
Completion  
1-year recurrence; 
Drug vs placebo 
O’Brien et al 
UK 
284 
Mitomycin 
Post-op; 10-14 days 
Completed 
16% vs 27% 
Shintaku et al 
Japan 
77 
Pirarubicin 
Post-op; < 48 hours 
Completed 
16.9% vs 31.8% 
NCT02923557 
China 
200 
Pirarubicin 
Post-op; < 24 hours 
2021 
N/A 
NCT03209206 
Korea 
84 
Docetaxel 
Post-op; < 48 hours 
2022 
N/A 
NCT03062059 
Korea 
134 
Gemcitabine 
Intra-op 
2022 
N/A 
 
Timing of Perioperative Intravesical Therapy 
 
The majority of data for perioperative intravesical chemotherapy describes its use at a delayed 
interval from completion of RNU. For example, the ODMIT-C trial required instillation of 
Mitomycin C at time of decatheterization which occurred at least 1 week following RNU.23 The 
rationale for this time-frame was the concern for risk from extravasation of Mitomycin C from the 
bladder cuff repair, whether that be intraoperative or postoperatively prior to complete bladder 
healing. Exact timing of instillation may be unimportant to reduce recurrence based on the “field 
change theory”. However, timing may be crucial based on the “tumor seeding theory”, since 
implantation may have already occurred prior to a delayed instillation. For this reason, the 
Pirarubicin trial elected to perform instillation within 48 hours of RNU, which may have resulted 
in their relatively larger effect size.24 Unfortunately, the specific timing of instillation was not 
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Based on the seeding theory, the earliest possible instillation of intravesical chemotherapy would 
theoretically result in the greatest reduction of recurrences. This is heavily supported in the bladder 
cancer literature, for which most perioperative intravesical chemotherapy is administered within 
24 hours of transurethral resection of bladder tumor, with some data advocating for immediate 
instillation following resection.26,27 Data is emerging that describes the use of intravesical 
chemotherapy intraoperatively during RNU. The first publication in 2015 described instillation of 
Mitomycin C or Adriamycin for 51 patients at the beginning of the surgical procedure.28 The 
catheter was clamped for up to two hours and unclamped to drain the bladder well before the 
bladder cuff excision was performed.28 There were no adverse events secondary to Mitomycin 
reported in this study.28 A second publication in 2018 confirmed the safety of this technique, 
comparing instillation of Mitomycin C intraoperatively versus postoperatively on post-operative 
day 1 or later.29 Supporting the theory of tumor cell seeding and implantation, patients who 
received immediate intravesical chemotherapy had a lower 1-year rate of intravesical recurrence 
(16% versus 33%).29 There is an ongoing prospective single arm Phase II trial assessing the safety 
and efficacy of intravesical Mitomycin C administered intraoperatively at the start of RNU 
(NCT03658304).  
 
A 2014 survey assessing practice patterns of Society of Urologic Oncology urologists revealed 
that, of those who instilled perioperative intravesical chemotherapy, 33% did so  intraoperatively, 
7% within 3 days of RNU, 37% between 4-7 days of RNU, 20% between 8-14 days of RNU, and 
3% at 14 days after RNU.30 A 2019 poll conducted on Twitter targeting UTUC experts similarly 
showed that 26% and 24% of 170 respondents favor instillation at the beginning of RNU and 
immediately after bladder closure, respectively. 
 
Poor Adoption of Perioperative Intravesical Therapy 
 
The European Association of Urology (EAU) and National Comprehensive Cancer Network 
(NCCN) guidelines recommend instillation of a single perioperative instillation of intravesical 
chemotherapy following RNU.4  
 
Due to the relatively severe side effect profile of anthracycline class agents, Mitomycin C is the 
primary perioperative intravesical therapy utilized in the United States. The 2014 survey 
administered to Society of Urologic Oncology urologists demonstrated that of those who 
administered intravesical chemotherapy at time of RNU, 88% utilize Mitomycin C. However, only 
51% of respondents reported utilizing intravesical chemotherapy, most commonly due to 
perceived lack of data supporting use, personal preference, and office infrastructure.30 Given the 
low national usage of perioperative intravesical chemotherapy for primary bladder urothelial 
carcinoma (0.33%-28%), the true national rate of utilization after RNU is likely substantially 
lower.31,32 
 
Changing Intravesical Therapy Paradigm of Gemcitabine for Urothelial Carcinoma of the Bladder  
 
There is a high incidence of intravesical recurrence following transurethral resection of bladder 
tumor, estimated between 30-80% within 5 years. Since urothelial carcinoma of the bladder is far 
more common than UTUC, strategies to reduce intravesical recurrence have been evaluated for 

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several decades. Numerous randomized clinical trials and meta-analyses have shown that 
perioperative instillation of intravesical chemotherapy reduces disease recurrence and 
progression.33–36 Previously investigated agents primarily include anthracyclines, Thiotepa, and 
Mitomycin C, although other classes of agents have also been evaluated. The most commonly 
utilized agent in the United States is Mitomycin C.37 To reduce recurrences, the EAU and AUA 
guidelines for non-muscle invasive bladder cancer recommend a single postoperative instillation 
of intravesical chemotherapy within 24 hours of transurethral resection of bladder cancer, in 
patients with suspected known low- or intermediate-risk bladder cancer.38,39  
 
However, there has been poor adherence to guidelines recommending use of Mitomycin C 
following transurethral resection of bladder cancer. A survey in 2012 reported that 63% of 
urologists used Mitomycin C routinely.37 Another national sample of United States urologists from 
2012 reported a lower 28% use of postoperative chemotherapy.31 Meanwhile, a study of 
MEDSTAT claims showed a dramatically lower national rate of 0.33%.32 Commonly cited reasons 
for not utilizing postoperative chemotherapy include absolute contraindications such as suspected 
bladder perforation and increased suspicion of high-grade urothelial carcinoma. Other reasons 
include concerns for pharmacy logistics and of toxicity of Mitomycin C.31 The most common 
reported toxicities of Mitomycin C range from low grade (dysuria, transient hematuria) to high 
grade (prolonged chemical cystitis, dystrophic bladder calcifications, perivesical inflammation and 
fibrosis).40,41 There are in fact reports of patients requiring cystectomy due to dystrophic bladder 
changes after Mitomycin C instillation, even if the primary malignancy was eradicated. Drug 
availability, pharmacy logistics, and expense are also considerations.42,43 These concerns share 
similarity to those for administration of perioperative intravesical chemotherapy following RNU. 
 
In an effort to limit toxicity while maintaining reduction in intravesical recurrences, a randomized 
trial of intravesical gemcitabine versus saline following resection of bladder tumor was performed 
and published recently in JAMA in May 2018.1 This trial showed a 12% absolute reduction in 4 
year intravesical recurrences in the gemcitabine versus placebo groups. Strikingly, there was an 
almost identical rate of adverse events between the intervention and control arms. There is 
currently major adoption of this agent post-transurethral resection of bladder tumor in many 
centers across the United States. 
1.2 
Investigational Agent 
 
Gemcitabine hydrochloride 
 
2'-Deoxy-2', 2'-difluorocytidine monohydrochloride (Gemcitabine hydrochloride or Gemcitabine) 
is a pyrimidine analog of deoxycytidine that kills cells by interfering with DNA synthesis. This 
analog also disrupts DNA replication and cell division through the G1/S-phase boundary. After 
this nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing 
DNA strands, which eventually results in the initiation of apoptotic cell death. 
 
Gemcitabine is manufactured as a white to off-white lyophilized powder with a molecular weight 
of 299.66. It is commercially available from multiple distributors in various formulations including 
a liquid 2g/52.6 mL single use vial or in 1 g single-dose vials, which can be reconstituted in 0.9% 
Sodium Chloride solution and further diluted. 

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1.3 
Preclinical Data 
 
There is extensive clinical experience with intravesical Gemcitabine for bladder tumors, from 
numerous early Phase I trials beginning in 2002-2004, followed by more recent Phase II and III 
studies. Prior to these human trials, animal studies confirmed that relatively high doses of 
intravesical Gemcitabine could be safe as well as efficacious in treating orthotopic bladder 
cancer models. Cozzi et al. first studied escalating doses of intravesical Gemcitabine from 
100mg to 3500mg dissolved in 50ml 0.9% Sodium Chloride solution in beagle dogs.44 Doses 
higher than 350mg were associated with increased systemic absorption and toxicity. Witjies et al. 
similarly demonstrated the safety of a 6-week instillation course of 350mg Gemcitabine in a pig 
model, observing minimal bladder wall inflammatory changes.45 Matera et al. administered the 
human equivalent of 1575mg/m2 and 3150 mg/m2 intravesical Gemcitabine to rabbits for 5 or 8 
weeks.46 The lower dose regimen showed no clinical toxicity or drug absorption although the 
higher dose was poorly tolerated.46 Nativ et al. compared 6 instillations of escalating doses of 
0.5mg, 2.5mg, and 10mg intravesical Gemcitabine to 0.9% Sodium Chloride solution in a mouse 
bladder tumor model and found anti-tumor activity in the Gemcitabine groups.47 Brocks et al. 
used instillations of 250ug or 500ug intravesical Gemcitabine in another mouse tumor model, 
which showed good tolerability of the agent and decreased tumor growth compared to controls.48 
These studies paved the way for human trials of intravesical Gemcitabine for urothelial 
carcinoma of the bladder. 
1.4 
Clinical Data to Date 
 
Intravenous Gemcitabine for Solid Malignancies 
 
Intravenous gemcitabine has been utilized in the treatment of metastatic disease across numerous 
solid tumor types, including pancreatic, biliary, breast, and non-small-cell lung cancer.49 Efficacy 
of gemcitabine for advanced UC has been shown since its use in single agent regimens in the 
1980s.50 Regimens subsequently incorporated additional agents to comprise “doublet” and 
“triplet” regimens that largely included cisplatin, carboplatin, and paclitaxel.51,52 The 
contemporary gemcitabine and cisplatin regimen was evaluated in a Phase III trial in 2000 that 
showed comparable survival but decreased toxicity when compared to the historical standard of 
methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in patients with locally advanced 
and metastatic UC .53 More recently, dose-dense gemcitabine plus cisplatin has been shown to 
potentially reduce toxicity in the neoadjuvant regiments for muscle invasive bladder cancer.54 
Overall, gemcitabine has been shown to have activity for muscle-invasive, locally advanced, and 
metastatic urothelial cancer. 
 
Phase I Studies for Intravesical Gemcitabine for NMIBC 
 
Intravesical gemcitabine was first explored for NMIBC in several Phase I trials in the early 
1990s.55–62 Dalbagni et al performed a dose escalation study assessing 500mg, 1000mg, 1500mg, 
and 2000mg intravesical gemcitabine for 18 patients with NMIBC, with detectable plasma 
concentrations only found in two patients receiving 2000mg.55 The instillation regimen in this 
study was fairly intensive, and involved biweekly instillations for a total of three weeks.55 Laufer 
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six weekly instillations at 2-4 weeks following TURBT.56 Plasma concentrations of gemcitabine 
or its metabolite 2’,2’,-difluorodeoxyuridine (dFdU) were measured in patients receiving 1500g 
and 2000g gemcitabine.56 Two similar studies assessed six weekly instillations and measured 
low levels of plasma concentration of gemcitabine, finding a maximum plasma concentration of 
dFdU of 4.19 umol/l.57,58 By contrast, intravenous administration of 1000mg/m2 gemcitabine, 
which is well below the standard therapeutic dose administered in men and women, resulted in a 
peak plasma concentration of 100umol/l.59  
 
Several studies also demonstrated the safety of intravesical gemcitabine in the setting of 
disrupted bladder mucosa and TURBT.60 Palou et al. assessed 10 patients with intravesical 
instillation of either 1,500mg or 2,000mg gemcitabine in 100ml NS within 3 hours of complete 
TURBT.61 There was low local toxicity apart from Grade 1 bladder spasms and mild hypogastric 
discomfort. Furthermore, there was no notable systemic toxicity with minimal detectable serum 
gemcitabine (1.8ug/ml). Buettner et al. performed a multi-center 24 patient study with 
intravesical instillation of 2,000mg/100ml gemcitabine within 1 hour of complete TURBT, and 
observed no toxicities greater than Grade 2.62 The initial monocenter dose escalation phase of 
this trial assessed 500-2,000 mg gemcitabine diluted in either 50ml or 100ml NS.  Interestingly, 
the only dose causing irritative bladder symptoms was 1,000mg/50ml, while higher doses in 
100ml NS caused no adverse effects.  While the primary aim of these studies was to assess 
pharmacokinetics and dose-limiting toxicities for intravesical gemcitabine, promising efficacy 
was also demonstrated, laying groundwork for subsequent larger observational and Phase II 
comparative studies. 
 
Phase II Studies for Intravesical Gemcitabine for NMIBC 
 
Several small Phase II studies assessed the ablative ability of gemcitabine for “marker lesions” 
that were left unresected.63–66 Gontero et al studied 39 mostly pre-treated patients who first 
underwent complete resection of all but one marker tumor and subsequently received 
2,000mg/50ml intravesical gemcitabine weekly for 6 weeks.65 The complete response rate was 
56%, with a median follow-up not reported.65 Maffezini et al performed a similar study in 28 
patients with 4 weeks of instillation of intravesical gemcitabine followed by resection of residual 
lesions, finding a complete response rate of 46%.66  
 
Other Phase II studies assessed intravesical gemcitabine in more standard clinical setting of 
completely resected low risk NMIBC.60,67  Bendary et al assessed 80 patients who underwent 
TURBT for Ta-T1 UC  who were randomized to receive either 6 weekly instillations of either 
intravesical gemcitabine or BCG.67 While there was no statistically significant difference in rates 
of 18-month complete response between groups, gemcitabine resulted in significantly lower rates 
of lower urinary tract symptoms than BCG.67 
 
Phase II Studies for Intravesical Gemcitabine for High Risk and BCG-Unresponsive NMIBC 
 
The impressive safety and efficacy of gemcitabine for low and intermediate risk NMIBC led to 
evaluation in high risk NMIBC as well, particularly in the salvage setting for BCG-unresponsive 
disease.68–74 Bartoletti et al reported a multicenter Phase II trial of 116 intermediate and high risk 
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noting 75% 1-year disease free survival.71  Porena et al performed a randomized controlled trial 
of 64 patients with high risk NMIBC and demonstrated increased recurrences but decreased 
toxicity in patients who received gemcitabine versus BCG, respectively.72  
 
Di Lorenzo and colleagues compared gemcitabine versus additional BCG for patients with 
NMIBC who previously failed a single course of BCG.73  The gemcitabine arm yielded 
developed significant fewer recurrences compared to those receiving BCG, and toxicity was 
similar between arms.73 A single arm SWOG S0353 study was reported by Skinner et al in 2013 
evaluation of intravesical gemcitabine for patients with NMIBC who failed two prior courses of 
BCG.74 For 47 evaluable patients, of whom 89% had high risk disease, there was 21% 2-year 
recurrence-free survival.74  While this trial was limited by inclusion of patient with heterogenous 
T-stages and variable use of maintenance gemcitabine regimens, it provided support that 
intravesical gemcitabine may have efficacy for high risk BCG-unresponsive NMIBC, in addition 
to low and intermediate risk disease. 
 
Phase III Studies for Intravesical Gemcitabine for NMIBC 
 
Three Phase III studies have reported to date on intravesical gemcitabine for NMIBC.1,75,76 Two 
trials predominantly included patients with low to intermediate risk NMIBC; the third trial 
assessed patients with BCG-unresponsive disease.  
 
Böhle et al evaluated 248 patients with clinical evidence of papillary NMIBC who underwent 
TURBT.75 Patients were randomized to a single intravesical instillation of gemcitabine versus 
placebo followed by at least 20 hours of post-instillation irrigation with NS.  Among 109 
evaluable patients, no significant difference in recurrence free survival was observed between 
groups. However, limitations of this trial included a short 30-40 minute duration of instillation, 
and the extended duration of post-instillation NS irrigation. Notably, there was minimal toxicity 
observed with gemcitabine versus placebo.  
 
Addeo assessed 120 patients with NMIBC previously treated with BCG or Epirubicin who were 
randomized to salvage intravesical regimens of either 6-weeks of gemcitabine or 4-weeks of 
Mitomycin C, with single monthly maintenance treatments for one year in those who 
responded.76 Of 109 assessable patients, with median follow-up of 36 months, those receiving 
gemcitabine enjoyed improved recurrence free survival compared to those receiving Mitomycin 
C (72% versus 61%, respectively, p<0.01). There were also significantly lower overall adverse 
events in patients receiving gemcitabine versus Mitomycin C (39% vs 72%, respectively, 
p=0.02).  
 
Messing et al published a large randomized controlled trial in 2018.1 Herein, 406 patients were 
accrued with suspected low grade NMIBC. Patients were randomized to immediate post-TURBT 
intravesical instillation of gemcitabine versus placebo. Notably, patients who received 
gemcitabine enjoyed a 12% increase in 4-year recurrence free survival compared to those who 
received placebo (47% versus 35%, respectively, p<0.001). Within the pathologically confirmed 
low grade NMIBC subset, patients who received gemcitabine had a dramatically lower rate of 
estimated 4-year recurrence versus placebo (34% versus 54%, respectively, p=0.001). There 
were no Grade 4-5 adverse events for patients who received gemcitabine. Remarkably, there was 

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an almost identical distribution of Grade 1, 2, and 3 adverse events in patients who received 
gemcitabine versus placebo. This pivotal trial unequivocally demonstrated the efficacy and 
minimal toxicity of a single post-TURBT instillation of gemcitabine in reducing intravesical 
recurrences within a cohort of patients with mixed high and low grade NMIBC. 
 
Peri-operative Intravesical Gemcitabine during RNU for UTUC 
 
To date, there are no published reports of utilizing intravesical gemcitabine during RNU. There 
is currently one ongoing Phase II trial in Korea that is accruing patients to assess intravesical 
gemcitabine versus placebo for UTUC (NCT03062059). However, this trial’s accrual goal is 
only 134 patients and is therefore unlikely to be adequately powered based on our estimations. 
Following publication of the Messing trial in 2018, off-label use of intravesical gemcitabine at 
time of RNU for UTUC has been increasingly adopted at many major academic centers, despite 
no published evidence to support its use in this setting. (Unpublished, Twitter poll) 
 
The likely benefits of intraoperative instillation of intravesical gemcitabine as a 
chemotherapeutic agent in the setting of RNU for UTUC include: 
1. Established efficacy in preventing recurrence across a spectrum of NMIBC grade and risk 
categories 
2. Improved efficacy with intraoperative instillation (compared to postoperative instillation) 
3. Very low toxicity profile (compared to Mitomycin C) 
4. No need for urine alkalization (compared to Mitomycin C) 
5. Improved speed and ease of preparation by pharmacy (compared to Mitomycin C) 
6. Relatively cheap cost (compared to Mitomycin C) 
 
Summary of Rationale for Intravesical Gemcitabine during RNU for UTUC 
 
In totality, the three Phase III trials of intravesical gemcitabine for primary UC show strong 
evidence that this agent has efficacy in preventing both low and high-risk NMIBC.1,75,76 There is 
now an extensive body of evidence demonstrating the safety and low rate of local or systemic 
toxicity from intravesical administration of gemcitabine for NMIBC.1,55–58,60–76 Given the (1) 
established efficacy but suboptimal side effect profile and utilization of intravesical Mitomycin 
and Pirarubicin for RNU, (2) demonstrated efficacy and rapid adoption of intravesical 
gemcitabine in the corollary setting of post-TURBT NMIBC, (3) extensive aforementioned 
evidence of safety intravesical gemcitabine for NMIBC, and (4) increasing off-label use of 
intravesical gemcitabine for RNU, we feel it is appropriate to proceed to a single-arm Phase II 
trial to evaluate this agent. The efficacy of gemcitabine will be evaluated versus historical 
controls, as the baseline rate of intravesical recurrence has been established. If the safety of 
gemcitabine can be demonstrated, it may be readily adopted in this setting. A randomized Phase 
III trial requires over 400 patients and thus is not feasible at this time. 
1.5 
Dose Rationale  
 
The safe and efficacious dosage of intravesical gemcitabine for prevention of intravesical 
recurrence of UC has been established by large Phase III trials for NMIBC.1,75,76 We will utilize 
the same dosage as these trials: 2,000mg diluted in NS for a total volume of 100ml.1 This agent 

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will be administered via foley catheter in a single intravesical instillation, similar to prior trials of 
chemotherapeutic agents for RNU for UTUC.23,24 Several retrospective series have established 
the safety of intraoperative instillation of Mitomycin C, as well as potentially improved efficacy 
over postoperative instillation.28,29 Thus, we will plan for a single intraoperative instillation of 
gemcitabine at start of RNU in this trial. 
1.6 
Risks and Benefits 
 
Potential risks of the study investigational agent include toxicity associated with systemic 
absorption, allergic response to gemcitabine, cystitis, urinary tract infection, and diminished 
healing of bladder cuff closure. The recent Messing trial utilized intravesical gemcitabine at an 
identical dose and route of administration as this trial, and all of the aforementioned risks except 
for healing of bladder cuff closure (which could not be evaluated) were demonstrated to be 
equivalent to in the setting of post-TURBT instillation. Instillation at start of RNU as planned for 
this trial is a lower risk than post-TURBT instillation in the Messing trial due to lack of bladder 
mucosal disruption and subsequent lymphovenous systemic absorption. With respect to impaired 
healing of bladder cuff closure, this was not observed in two retrospective reports of intravesical 
instillation of Mitomycin C during RNU.28,29 The benefits of the study investigational agent are 
that it may reduce recurrence relative, with a low toxicity profile, to no treatment. The 
investigational agent will result in reduced cost versus other alternative agents. There may be 
oncologic benefit from intraoperative instillation. Should this trial demonstrate these mentioned 
results, application of this knowledge will result in decreased morbidity and cost in the 
management of UTUC for all patients. 
2 Study Objectives 
 
2.1 Primary Objective 
 
The primary objective of this study is to determine the efficacy of a single intraoperative 
intravesical instillation of gemcitabine at time of RNU for clinically localized UTUC in 
preventing intravesical recurrence of UC at one year. 
 
2.2 Secondary Objectives 
 
a. To assess time to recurrence for entire duration of follow-up 
 
b. To assess the qualitative and quantitative toxicities  
 
2.3 Exploratory Objectives 
 
c. To stratify intravesical UC recurrence free survival by tumor grade, neoadjuvant 
chemotherapy, tumor stage, ureteral tumor location, and history of bladder cancer 
 
d. To assess incidence and time to development of MIBC 

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3 Study Design 
3.1 
General Description 
 
This study is an open-label, single-arm, multi-site (within Mayo Clinic) Phase II trial of the 
safety and efficacy of intraoperative intravesical instillation of gemcitabine at time of RNU for 
UTUC. Subjects will be screened at outpatient visit for discussion of nephroureterectomy and 
interested qualified subjects will be offered participation in this trial and consented. Patients will 
receive intraoperative intravesical instillation of gemcitabine at the beginning of RNU for at least 
1 hour. The instilled fluid will be drained prior to resection of the bladder cuff. Patients will 
undergo routine standard of care postoperative surveillance including cystoscopy at 3, 6, 12, 18, 
and 24 months. Subjects will be followed for two years or until trial termination. The primary 
endpoint is 1-year intravesical UC recurrence free survival. Safety and adverse event endpoints 
will be evaluated. Treatment of recurrences will be according to standard clinical protocols. 
 
 
3.2 
Number of Subjects 
 
Estimated final sample size/accrual goal: 90 patients 
 
Anticipated overall accrual over 3 years is 47 patients from Mayo Clinic Rochester, and 13 from 
Mayo Clinic Florida, and 30 from all external sites. 
3.3 
Duration of Participation 
 

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Patients will be followed at a maximum of two years or until the trial is terminated. Follow-up 
will consist of standard of care cystoscopy at 3, 6, 12, 18, and 24 months.  
3.4 
Primary Study Endpoint 
 
The primary endpoint of this study is 1-year intravesical UC RFS.  
 
• RFS will be assessed by cystoscopy and urine cytology at 3, 6, 12, 18, and 24 months. 
Histologic proof of disease recurrence with biopsy will be mandatory although visual 
evidence of disease will be noted. Intravesical low or high-grade UC will be considered 
recurrence. In the event of positive cytology (not atypical or suspicious) but negative 
cystoscopic assessment, malignancy in the contralateral upper tract and urethra should be 
ruled out. If cytology remains the only positive assessment, a repeat second cytology should 
be performed within the next 4 weeks. If the repeat second cytology returns negative, the 
patient will be considered to be free of disease. If repeat second cytology returns positive, the 
patient will be considered to have high-grade disease recurrence. Patients without recurrence 
will be censored at the date of last cystoscopy. Patients who die without any evidence of 
disease recurrence will be censored at time of death. 
3.5 
Secondary Study Endpoints 
 
Key Secondary Endpoints 
 
Key secondary endpoints for this study include time to recurrence and adverse event evaluation. 
 
Exploratory Endpoints 
 
We will stratify RFS by tumor grade, neoadjuvant chemotherapy, tumor stage, ureteral tumor 
location, and history of bladder cancer. Other exploratory endpoints that will be assessed include 
incidence and time to development of MIBC, and overall survival. 
 
• MIBC will be assessed by T2 UC on final pathology of TURBT specimen or T2 UC on final 
pathology of radical cystectomy specimen. 
• Time to MIBC will be defined as the time from date of RNU to date of histologic proof of 
T2 UC. 
• Time to death will be defined as the time from date of RNU to date of death. 
3.6 
Primary Safety Endpoints 
 
Safety will be assessed by several methods. First, adverse events will be collected at all times 
including scheduled time points at time of surgery and each follow-up visit. Adverse events will 
be categorized by grade and further distinguished as serious adverse events. Furthermore, they 
will be designated by each site as not related, unlikely, possible, probably, and definitely related 
to treatment adverse events. These will be confirmed by the PI. Second, lab tests will be 
performed. Third, physical exams will be performed and vital signs will be assessed. These will 
occur at time of RNU and at scheduled follow-up times.  

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The primary specific safety concerns are local bladder toxicity and systemic toxicity. 
Considering local bladder toxicity, specific symptoms to be assessed include hematuria, dysuria, 
bladder spasms, urinary frequency and urinary incontinence. Furthermore, intraoperative and 
postoperative complications will be assessed, specifically with regard to systemic symptoms as 
well as impaired healing of bladder closure or urine leak. 
 
There is extensive existing Phase I-III data documenting limited systemic absorption of 
intravesical gemcitabine, ranging from 0.52% - 5.52%.1,55–58,60–76 Furthermore, systemic adverse 
events were not observed in the large Phase III Messing trial.1 To evaluate systemic toxicity, we 
will monitor for known systemic adverse events of intravenous gemcitabine. These primarily 
include myelosuppression resulting in anemia, thrombocytopenia, neutropenia.77 Other important 
known systemic toxicities from intravenous gemcitabine includes pulmonary toxicity, hepatic 
toxicity, and Hemolytic uremic syndrome toxicity. Less severe side effects from intravenous 
gemcitabine include fever, nausea and vomiting, and rash.  
 
We will assess for these systemic effects at several time points. Intra-operative systemic AEs 
will be monitored by the investigator and recorded in the intra-operative CRF. Post-operative, at 
least one CBC during the peri-operative hospitalization for RNU will be assessed. If any 
cytopenia is noted, a CBC will be repeated at least on a weekly basis until blood counts reach 
pre-treatment levels. We will also perform clinical monitoring (vital signs and physical exam) 
and LFT measurement during the peri-operative hospitalization to assess for pulmonary and 
hepatic toxicity. Regarding Hemolytic uremic syndrome toxicity, the diagnosis of hemolytic 
uremic syndrome will be considered if the patient develops anemia with evidence of 
microangiopathic hemolysis as indicated by elevation of bilirubin, severe thrombocytopenia, 
and/or evidence of renal failure. 
3.7 
Identification of Source Data 
 
The following source data will be recorded on paper documentation by clinical research 
coordinators and recorded on online data capture forms: 
• Demographic information 
• Medical and surgical history 
• Tumor characteristics 
• Vital signs 
• Laboratory results 
• Intra-operative variables 
• Post-operative variables 
• Oncologic Follow-up 
• Adverse Events/Serious Adverse Events 
 
The following source data will not be directly collected in online data capture forms, but will be 
captured in supportive documentation (study source documents, EMR): 
• Clinic visit notes including history and physical exam, plan 
• Imaging records and clinical significance of observations 
• Pathology records and clinical significance of observations 

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• Operative reports 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
• Both males and females age 18 years or older 
• Clinical diagnosis of localized (clinical AJCC stage Ta-T4N0M0) low- and high-grade 
UC of the renal pelvis and/or ureter 
• Plan to undergo RNU 
• Adequate bone marrow, renal and hepatic function 
o Creatinine < 2.2 mg/dL (194 mmol/L) 
o Adequate hematologic function (hemoglobin > 9 g/dL; white blood cell count ≥ 
3000/μL; platelet count >75,000/μL and <500,000/μL) 
o Serum bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine 
aminotransferase levels below 2 times the institution’s upper limits of normal 
• Easter Cooperative Oncology Group (ECOG) performance status score 0 - 2 
• Suitable candidate for surgery at the discretion of the investigator 
• Patient must be capable of giving appropriate approved informed consent or have an 
appropriate representative available to do  
• Patient with a prior malignancy allowed if adequately treated > 3 years ago with no 
current evidence of disease 
• Women of childbearing potential (WOCBP) must have a negative pregnancy urine test 
within 28 days of registration, and be using an adequate method of contraception to avoid 
pregnancy prior to and for at least 6 months after gemcitabine instillation to minimize the 
risk of pregnancy 
• Male patient who has a partner that is a WOCBP must agree to use physician-approved 
contraceptive methods (e.g., abstinence, condoms, vasectomy) and should avoid 
conceiving children prior to and for 6 months following gemcitabine instillation 
4.2 
Exclusion Criteria 
 
• Pure non-urothelial histology; urothelial carcinoma with differentiation allowed 
• Evidence of nodal or distant metastases; enlarged retroperitoneal lymph nodes > 2cm or 
histologically positive lymph nodes 
• History of UC of the bladder within 12 months preceding RNU, or receipt of intravesical 
therapy within 6 months 
• History of or current prostatic urethral, urethral, or contralateral upper tract UC 
• History of radical cystectomy or partial cystectomy 
• Planned radical cystectomy at time of RNU 
• Symptomatic urinary tract infection of bacterial cystitis (once satisfactorily treated, 
patients can enter the study) 
• Patient with any current malignancy except for basal or squamous cell skin cancers, 
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progression or patient morbidity during the trial period (i.e. Gleason 6 prostate cancer, 
renal mass < 3 cm) 
• Women who are pregnant or breastfeeding 
• Prisoners or subjects who are involuntarily incarcerated 
• Inability for adequate follow-up, including concerns for patient compliance or geographic 
proximity  
4.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects will be screened and identified for potential recruitment for the study in the outpatient 
clinic environment by the PI and Co-investigators.  The inclusion and exclusion criteria will be 
discussed with the patient in detail as well as the rationale, the potential benefits, and potential 
risks associated with the study. The recruitment, enrollment, and screening procedures will occur 
in the outpatient clinic setting. If subjects want to proceed with the study, informed consent will 
be obtained by the study coordinator or investigator. The study coordinator will keep the signed 
informed consent and a physical copy of the informed consent will be given to the patient. If the 
patient would like additional time to consider the study, they may sign the consent form at a later 
date, prior to the day of surgery, with the PI, co-investigator, or study coordinator, as long as this 
allows sufficient time for Pharmacy to prepare the drug. 
 
Evaluation and documentation of inclusion and exclusion criteria will be performed by the PI 
and Co-investigators after informed consent is obtained. 
 
Non-English speakers will not be specifically targeted for this study. For non-English speaking 
patients who request it, an interpreter will be used. Advertisements, social media, and letters will 
not be used to recruit patients to this study. Patients will not be paid for participation. 
 
See Section 6.1 for screening procedures. See Section 11 for details regarding informed consent. 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
Patients will be advised that they may voluntarily withdraw from the study at any time, for any 
reason, and it will not affect their medical care or pose adverse safety considerations. Patients 
who withdraw prior to receipt of treatment will be excluded and replaced. However, in these 
cases, appropriate attempts will be made by the investigators to determine the reason for 
withdrawal from the study and to document this reason in the medical record and study files. 
Patients who receive treatment and subsequently withdraw will not be replaced. 
 
In select circumstances, patients will be intra-operatively withdrawn from the study prior to 
receipt of intravesical gemcitabine. The surgical team may decide, per their discretion, to intra-
operatively to withdraw a subject from the study in the following situations: 
 
• Gross hematuria upon catheter insertion 
• Concern for active urinary tract infection  

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• Need for close urine output such that the catheter cannot be clamped  
• Evidence of grossly metastatic disease or intraoperative complication resulting in aborted 
operation 
• Documentation of the reason for withdrawal will be retained in the study files. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
Patients that withdraw prior to RNU or are withdrawn by the surgical team prior to 
administration of intravesical gemcitabine will not undergo any new or follow-up data collection 
for this study. Data previously collected for subjects that withdraw consent will continue to be 
used in the study. Patients who received intravesical gemcitabine and subsequently withdraw 
from the study will not undergo any new or follow-up data collection for this study. The last 
known status of patients who withdraw after receiving intravesical gemcitabine will be reported 
with the study results.  
 
All attempts to locate patients lost to follow-up will also be documented. After three documented 
attempts (i.e. phone call, patient portal message, and/or mail letter) are made without any 
response, no further attempts will be made. 
5 Study Drug  
5.1 
Description 
 
Gemcitabine hydrochloride (brand name – Gemzar® or generic – Gemcitabine), is also called 2'-
Deoxy-2', 2'-difluorocytidine monohydrochloride (beta-isomer). This is a white to off-white or 
translucent water-soluble solid with a molecular weight of 299.66. The empirical formula for 
gemcitabine HCl is C9H11F2N3O4 · HCl. The structural formula is below. 
 
 
 
The anti-cancer mechanism of gemcitabine is to act as a nucleoside analog antimetabolite. 
Gemcitabine is a pyrimidine analog that inhibits both DNA and RNA synthesis. This pyrimidine 
analog is cell-cycle-specific in blocking the cells at the G1/S and is retained in human tumor 
cells for long periods. Studies suggest that gemcitabine is activated by deoxycytidine kinase and 
metabolized intracellularly to form active gemcitabine di- and tri-phosphates. These 
phosphorylated forms of gemcitabine are incorporated into both DNA and RNA. After the 
gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the 

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growing DNA strands which eventually results in the initiation of apoptotic cell death. 
Additionally, gemcitabine diphosphate inhibits ribonucleotide reductase which impairs an 
important tumor nucleotide enzymatic pathway. The gemcitabine di- and tri-phosphates do not 
appear to circulate in plasma in measurable amounts. Additional metabolites have not been 
identified in either plasma or urine. The compound is metabolized principally by the liver to 
form an inactive uridine derivative (dFdU or 2'-deoxy-2',2'-difluorouridine).  
 
Due to its wide use over a long time period for other malignancies, there is considerable existing 
pharmacokinetic knowledge regarding gemcitabine.78 Once administered intravenously, the 
plasma protein binding of gemcitabine is negligible. Gemcitabine is hydrophilic and must be 
transported across the cell membrane. While the majority of gemcitabine is inactivated in the 
liver to dFdU (>90%), a lesser amount is inactivated in the blood to dFdU, with less than 10% of 
unchanged plasma gemcitabine undergoing renal filtration. After administration of a single dose 
of intravenous gemcitabine, urinary excretion of dFdU (99%) accounted for the majority of the 
excreted dose.79 Therefore, the parent drug appears to be almost completely metabolized to the 
inactive dFdU. There is rapid clearance of plasma gemcitabine, with more than 75% of 
gemcitabine metabolized to dFdU and excreted in the urine within 24 hours.79  The half-life of 
gemcitabine ranges from 11 to 26 minutes for patients receiving single dose infusions (1g/m2 to 
2,500 mg/m2) of 1.1 hours or less. Clearance is affected by gender after normalization for BSA. 
The clearance obtained for the female patient for all studies was 46.2 L/hr/m2 and the male's was 
66.8 L/hr/m2. 
 
Considering intravesical pharmacokinetics and systemic absorption, Laufer et al  assessed 
plasma gemcitabine levels before intravesical instillation of gemcitabine and 15, 30, 60, 90, and 
120 minutes after the instillation.56 Gemcitabine was observed in plasma of the 4 patients treated 
with 40 mg/mL in 50 mL in 0.9% Sodium Chloride solution, but not in the patients treated with 
20 mg/mL in 100 mL of 0.9% Sodium Chloride. Peak concentrations in this and several other 
studies were below 1 μg/mL, which were significantly lower than the 10 to 30 μg/mL observed 
after a single intravenous (IV) dose of 1,000 mg/m2 (Lilly 2002). Plasma gemcitabine 
concentrations declined rapidly, even during the 120-minute dwell time, and no gemcitabine was 
detectable in plasma beyond 60 minutes after the instillation of the drug. DFdU was also not 
detected in patients treated with 500 or 1,000 mg of gemcitabine. In the 1,500 mg and 2,000 mg 
groups, plasma concentrations of dFdU increased progressively during the first 60 to 90 minutes 
of dwell time, after which they remained constant during the observation period. The authors 
estimated that based on their PK results and the 120-minute dwell time, the predicted amounts of 
gemcitabine absorbed from the bladder ranged from 10 to 110 mg, corresponding to 0.52% to 
5.52% of the total gemcitabine dose instilled. No dFdU was measured in voided urine, and 61% 
to 100% of the gemcitabine was accounted for in the voided urine. The authors also studied the 
in vitro decomposition at 37°C with gemcitabine incubated with three control urine samples. 
They found no reduction in the concentration of gemcitabine, nor was any production of dFdU 
observed. Minimal systemic absorption based on measured serum gemcitabine levels following 
intravesical gemcitabine administration was confirmed by other six Phase I studies. 55,57,58,61,62 
 
Human Toxicology: Phase I clinical experiences with intravesical gemcitabine have been 
reported in seven studies where dose ranges of 500 to 2,000 mg at concentration of 20 - 40 
mg/ml with 1 to 2 hours of indwelling time were used. Four of these studies were performed in 

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patients who had intact bladder mucosa. The most common side effects reported were urinary 
frequency and hematuria. At 2,000 mg dose level, Grade 3 urinary frequency and local irritation 
were the most common complaints.55,56,58 Grade 3 thrombocytopenia and neutropenia without 
infection was reported in one out of six patients.55 The remaining Phase I studies were performed 
in patients immediately after, within three hours after, and up to 24 hours after transurethral 
resection.61,62 No additional adverse events were noted in these patients. A few cases of renal 
failure of uncertain etiology have been reported with intravenous gemcitabine administration. 
While on study, one patient who received prior mitomycin developed hemolytic uremic 
syndrome requiring dialysis. The relationship of this event to intravenous gemcitabine is not 
known. 
 
Given known fetal and infant risks when gemcitabine is administered to pregnant or lactating 
women, patients who are pregnant or lactating will be excluded from this study. Gemcitabine has 
produced teratogenic effects in mice and rabbits when administered at a dose of < 2 mg/m2. 
Adverse effects included decreased fetal viability, weight and morphologic defects. There is no 
data on gemcitabine administration during human pregnancy, and it is not currently known if 
metabolites are excreted in human milk. However, many drugs are excreted in human milk, and 
there is a potential for adverse effects in nursing infants. Therefore, the use of gemcitabine 
should be avoided in pregnant or nursing women because of the potential hazard to the fetus or 
infant. 
5.2 
Treatment Regimen 
 
Gemcitabine will be prepared as described in Section 5.3, with 2 grams gemcitabine diluted in 
0.9% Sodium Chloride to a total volume of 100mL. This treatment will be administered via 
intravesical route at the start of RNU. The treatment will be instilled via the foley catheter using 
a syringe and the foley catheter will be capped. The dwell time will be at least 1 hour and 
recommended to include time beyond clipping of the ureter. After this period of time the 
intravesical gemcitabine will be drained from the bladder. Irrigation with 0.9% Sodium Chloride 
can optionally be used to rinse the bladder, but is not mandated.  
 
Given that there is a single instillation of drug in this study, there will be no dose modifications. 
Duration of retention of gemcitabine can be shortened by the local investigator if medically 
indicated (e.g. bleeding, concerns for bladder perforation, etc.), which will be recorded in the 
CRF. 
5.3 
Preparation and Administration of Study Drug 
 
Preparation of gemcitabine will be performed by the research pharmacist. Depending on whether 
the liquid or powder formulation is available to each site, Gemcitabine will be formulated 
appropriately to ultimately yield 2g gemcitabine diluted in 0.9% Sodium Chloride to a total 
volume of 100mL, as per prior major studies.1 While the following protocols are for the most 
commonly used formulations of gemcitabine, sites may utilize other formulations of gemcitabine 
and perform local preparation protocols so long as the final volume of each agent is 100mL and 
the final concentration of gemcitabine is 2g/100mL. 
 

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For liquid formulations such as 2g/52.6mL single use vials, the general preparation protocol is as 
follows. A 100mL bag of 0.9% Sodium Chloride will be used and 52.6mL will be wasted from 
this using a syringe and needle. Afterwards 52.6mL will be withdrawn from the single use vial 
and injected into the bag of 0.9% Sodium Chloride to yield 2g gemcitabine diluted in 0.9% 
Sodium Chloride to a total volume of 100mL. 
 
For powder formulations such as the 1g single use vials, the general preparation protocol is as 
follows. The drug will be reconstituted with 25 mL of 0.9% Sodium Chloride injected into the 1 
gram vial. The vial will be shaken to dissolve. This dilution yields a gemcitabine concentration 
of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder 
(1.3 mL for the 1 gram vial). The total volume upon reconstitution for a single vial will be 26.3 
mL. Withdrawal of 26.3 mL of the vial contents will provide 1 gram of gemcitabine. The 
procedure will be repeated with a second 1 gram vial to reach the 2 gram dose for treatment. The 
total volume upon reconstitution for two vials will now be approximately 52.6mL. A 100mL bag 
of 0.9% Sodium Chloride will be used and 52.6mL will be wasted from this using a syringe and 
needle. Afterwards 52.6mL of the reconstituted gemcitabine will be injected into the bag of 0.9% 
Sodium Chloride to yield 2g gemcitabine diluted in 0.9% Sodium Chloride to a total volume of 
100mL.  
 
The diluted gemcitabine solution should be a clear, colorless to light straw-colored solution. The 
solution should be inspected visually for particulate matter and discoloration. If particulate 
matter or discoloration is found, do not administer. Gemcitabine solutions are stable for 24 hours 
at controlled room temperature 20° to 25°C (68° to 77°F). Solutions of gemcitabine should not 
be refrigerated, as crystallization may occur. 
 
 
The treatment will be formulated within 24 hours of use. After formulation, the treatment will be 
kept in a secure location within the pharmacy with limited access to prevent unintended or 
unauthorized use of the drug. Prior to the start of RNU, the drug will be sent to the operating 
room pharmacy and then the operating room. An inventory tracking system will be used to 
document drug prep time, lot number, and additional pharmacy prep information.  
 
Handling Precautions: Institutional hazardous drug policies must be followed. Gemcitabine is a 
toxic material which could cause skin and eye irritation. Ingestion or inhalation exposure of 
sufficient quantities could result in decreased white and red blood cells, hypospermatogenesis, 
gastrointestinal disturbances, and other signs of toxicity. The compound was positive in one of 
three tests for mutagenicity. Laboratory animal studies indicate that compounds in this 
therapeutic class may be reproductive toxins and may induce fetal malformations. Contact or 
inhalation should be avoided. The urine and solution drained after the foley catheter is 
unclamped should be discarded as hazardous waste according to local, state and federal policies. 
 
See Section 6.2 for details of drug administration. 
5.4 
Subject Compliance Monitoring 
 
Given that all treatments given to study subjects in this trial are under anesthesia during RNU, 
subject compliance monitoring is not applicable as an issue for this study. 

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5.5 
Prior and Concomitant Therapy 
 
There are no prohibited concomitant or prior therapies and no drug wash out periods for this 
trial.  
 
There will not be required concomitant therapies administered for this trial. In the event of local 
adverse events, standard local protocols for post-operative oral analgesics, anticholinergics, 
antispasmodic medications will be permitted, such as phenazopyridine, oxybutynin, and 
tolterodine. Utilization of medications in the outpatient setting for adverse event treatment will 
be recorded in the CRF. All prescribed medications in the outpatient setting will be reviewed and 
recorded in the subject files prior to surgery.  
5.6 
Packaging 
 
A total of 100mL of 0.9% Sodium Chloride with gemcitabine will be packaged in a single 
100mL bag. There will be a label on the bag that this agent is to be used for the IRB number of 
the study. The label will read: “IRB number: Gemcitabine 2g in 100mL 0.9% Sodium Chloride.” 
The label will include the statement: "Caution: New Drug--Limited by Federal law to 
investigational use."  
5.7 
Receiving, Storage, Dispensing and Return 
5.7.1 Receipt of Drug Supplies 
 
Gemcitabine will be kept on inventory by the research pharmacy for each site that participates in 
this trial. At Mayo Clinic gemcitabine will be held in an investigational refrigerator for inventory 
management. Each site may use their favored supplier and formulation when ordering 
gemcitabine, since gemcitabine already is held on inventory at most centers for multiple FDA-
approved indications, as well as already commonly utilized in off-label fashion for intravesical 
instillation for patients with UTUC and primary bladder cancer. 
 
Regarding receipt of drug supplies, standard local pharmacy protocol should be followed, 
including inventory, filling out a receipt log, counting and verification of drug within each 
shipment, and logging of discrepancies, damaged, or unusable drug within each shipment. 
5.7.2 Storage 
 
Depending on formulation, gemcitabine should be stored appropriately as per package insert. 
There are no lighting specifications for storage. Special handling, contact precautions, and 
disposal procedures will be used during handling of the treatments at this time as outlined in 
Section 5.4 and by the Occupational Safety and Health Administration 
(http://www.osha.gov/SLTC/hazardousdrugs/index.html).  
 
For the powder formulation, gemcitabine is supplied as a lyophilized powder in sterile vials 
containing 1,000 mg of gemcitabine as the hydrochloride salt (expressed as the free base), 
mannitol, and sodium acetate. The lyophilized product should be stored below 30°C. Once 

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reconstituted, this formulation of gemcitabine should be kept at controlled room temperature 
(20°C to 25°C, with excursions permitted between 15°C and 30°C), and should not be 
refrigerated as crystallization can occur.  
 
For the liquid formulation, the single use vial is stored at 2°C to 8°C. 
5.7.3 Dispensing of Study Drug 
 
The drug will be dispensed to each subject as described in Sections 5.3 and 5.6. Regular study 
drug reconciliation will be performed to document drug assigned, drug dispensed, drug returns, 
and drug remaining.  This reconciliation will be logged onto local inventory systems such as 
Vestigo®.  
5.7.4 Return or Destruction of Study Drug 
 
Gemcitabine that will not be used will be discarded per local institutional departmental 
guidelines for cytotoxic waste destruction. Drug destroyed on site will be documented as per 
standard local departmental protocol. 
6 Study Procedures 
 
6.1 
Visit 1; Pre-study; Registration 
 
Registration for this study must occur prior to treatment, at approved institutions, and for patients 
who meet all eligibility requirements. Patients will be allowed to enroll along in any number of 
other clinical trials including but not limited to perioperative chemotherapy, immunotherapy, or 
other systemic therapies. 
 
Potential study subjects will be identified by study staff, have their medical history reviewed, 
vitals taken, and a physical examination performed. The patient’s weight and performance status 
will be recorded. Screening review of eligibility criteria and determination of the patient’s 
eligibility based on the aforementioned information will be performed. The patient will then be 
provided ample time to review the informed consent document, discuss the study procedures and 
contents of the informed consent document, and have all questions answered. If patients are 
agreeable to registration to the study, informed consent must be obtained either at that time or a 
future date prior to RNU. All patients with signed informed consent must be entered and 
registered into the REDCap database to generate a trial number. 
 
The following procedures will be required: 
• Baseline CBC, BMP, and LFTs will be obtained. If this bloodwork was performed within 
28 days of registration at an outside facility, these outside results may be used to satisfy 
this requirement with copies retained in study files. 
• Baseline vital signs will be obtained: blood pressure, heart rate, temperature 
• Histologic proof of upper tract urothelial carcinoma will not be required.  

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• Urinalysis will be obtained within 28 days of RNU. In event of symptomatic UTI within 
28 days of RNU, a urine culture should be obtained and the patient treated with full 
course of antibiotics, with RNU and instillation will be postponed until resolution. In the 
case of asymptomatic bacteriuria, the use of prophylactic antibiotics and postponement of 
the treatment is left to the discretion of the PI.  
• A CT Urogram with delayed imaging allowing visualization of the ureters and 
cystoscopy will be required within 6 months of registration. If history of bladder cancer, a 
cystoscopy within 3 months of registration is required. If delayed CT imaging is not 
possible then retrograde pyelograms may be performed during cystoscopy to evaluate for 
ureteral filling defects. If these were more performed within 6 months of registration, 
these will be ordered and scheduled within that time frame. In the event that a CT scan 
with contrast is prohibited by renal function, an MRI with contrast of the abdomen and 
pelvis should be performed instead.  
• The study coordinator will confirm the contact information of the outside laboratory 
facility at the time of the screening visit and will request outside laboratory, imaging, and 
pathology results if not already available in the institutional medical record. However, all 
study eligibility requirements; including a review of current medical conditions and 
medications as well as written informed consent must be documented by study staff and 
reviewed for acceptability by an Investigator prior to enrolling the subject into the study. 
• Documentation of any subjects who were consented but subsequently failed the screening 
requirements, including the reason for screen failure, will be retained in study files. A 
screening/enrollment log will be maintained. 
• Women of childbearing potential (WOCBP) must have a negative pregnancy urine test 
within 28 days of registration, and be using an adequate method of contraception to avoid 
pregnancy prior to and for at least 6 months after gemcitabine instillation to minimize the 
risk of pregnancy. All females are considered WOCBP unless they have at least 12 
months since the last menstrual bleeding, or are without a uterus and/or both ovaries, or 
has been surgically sterile for at least 6 months prior to registration. Prior to study 
enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
trial participation and the potential risk factors for an unintentional pregnancy. 
• 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 6 months following gemcitabine instillation. 
 
If patients are enrolled to this trial and subsequently receive neoadjuvant therapy (chemotherapy, 
immunotherapy, or other systemic therapy) repeat laboratory (CBC, BMP, and LFTs) and 
imaging (CT and cystoscopy) is recommended prior to RNU. 
 
6.2 
Visit 2; Peri-operative; RNU 
 
RNU will be performed in a standard fashion, including removal of the kidney, ureter, and 
bladder cuff. Bladder cuff removal will be mandatory and is considered standard of care. Open, 
laparoscopic, and robotic approaches will be permitted. It will be recommended that the ureter be 
clipped distal to suspected location of tumor prior to manipulation or mobilization of the kidney 
and upper tract. If a ureteral stent is present this may be removed, or left in situ with a clip placed 

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on the stented ureter. It will be recommended that instillation of the intravesical treatment be 
performed at the start of RNU, for at least 1 hour, and preferably at least 30 minutes following 
clipping of the ureter. The performance of lymphadenectomy will be left to investigator 
discretion. 
 
At the time of RNU, the intravesical instillation of gemcitabine will be performed. During 
hospitalization laboratory work and imaging will be obtained as needed by the surgical team but 
will not be mandated by this study protocol. Patient reported toxicity and adverse events will be 
noted but not formally collected during the peri-operative hospitalization. The patients’ catheter 
may be removed at any time per discretion of the surgical team, as soon as 1 day following RNU 
and up to 14 days following RNU if no clinical concern for a urine leak. Utilization of a 
cystogram prior to de-catheterization will be at the discretion of each surgical team, and will not 
be required. Utilization of antibiotics around time of de-catheterization will be encouraged but 
not required. 
6.3 
Visit 3; Week 2 (+/- 1 week) 
 
At the first post-operative visit at Week 2 (7-21 days) following RNU, history and physical 
exam, vital signs, adverse event evaluation, and laboratory testing will be obtained including 
CBC, BMP, and LFTs.  
 
Adverse event evaluation is encouraged to be performed at time of decatherization, should it fall 
within the 7-21 day window. If Grade 3 or greater adverse events are present at this evaluation, 
an additional repeat assessment of adverse events should be performed at Week 4. 
 
Laboratory tests may be performed more often at the discretion of the treating investigator. If 
cytopenias or liver function test abnormalities are observed, patients should be followed weekly 
until these laboratory test abnormalities have resolved.  
6.4 
Additional Possible Visit; Week 4 (+/- 1 week) 
 
At this visit, which is performed if needed based on Visit 3, history and physical exam and vital signs will be 
performed. Adverse event evaluation is performed only if Grade 3 or greater adverse events are present on Visit 3. 
Repeat laboratory tests may be performed at the discretion of the treating investigator. 
6.5 
Visit 4; Month 3 (+/- 1 month) 
 
The 3-month visit will consist of routine standard of care surveillance following RNU. This 
includes history and physical exam, vital signs, adverse event evaluation, cystoscopy with urine 
cytology, and an assessment of disease recurrence. If suspicion for disease recurrence is noted on 
cystoscopy or urine cytology, histologic proof will be required with bladder biopsy or 
transurethral resection of bladder tumor.  
 
6.6 
Visit 5; Month 6 (+/- 1 month) 
 

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The 6-month visit consists of the same required studies as the 3-month visit, including history 
and physical exam, vital signs, adverse event evaluation, cystoscopy with urine cytology, 
assessment of disease recurrence, and histologic proof of disease recurrence, if present.  
6.7 
Visit 6; Month 12 (+/- 1 month) 
 
The 12-month visit consists of the same required studies as the 3-month visit, including history 
and physical exam, adverse event evaluation, cystoscopy with urine cytology, assessment of 
disease recurrence, and histologic proof of disease recurrence, if present. In addition, CT with IV 
contrast to assess for metastatic disease will be encouraged, but not required at this time.  
6.8 
Visit 7; Month 18 (+/- 1 month) 
 
The 18-month visit consists of the same required studies as the 3-month visit, including history 
and physical exam, vital signs, adverse event evaluation, cystoscopy with urine cytology, 
assessment of disease recurrence, and histologic proof of disease recurrence, if present.  
6.9 
Visit 8; Month 24 (+/- 1 month) 
 
The 24-month visit consists of the same required studies as the 3-month visit, including history 
and physical exam, vital signs, adverse event evaluation, cystoscopy with urine cytology, 
assessment of disease recurrence, and histologic proof of disease recurrence, if present. In 
addition, CT with IV contrast to assess for metastatic disease will be encouraged, but not 
required at this time.  
6.10 Other assessments at each visit  
 
At 3-month follow-up and subsequent follow-up visits, adjunctive urine testing may be obtained 
per investigator discretion but is not mandated per this trial. Patients deemed at increased risk for 
systemic progression may have increased frequency of CT imaging per investigator discretion. 
Other oncologic outcomes that will be assessed at all time points include development of muscle-
invasive bladder cancer, progression, cancer specific survival, and overall survival, as described 
in Section 3.5. 
6.11 Unscheduled visits 
 
An unscheduled visit may be performed at any time during the trial if deemed necessary by the 
investigator, for assessment of safety, or at the patient’s request. The date, reason, and procedures 
performed at the unscheduled visit, and additional information should be recorded in the patient’s 
file and the CRF. 
6.12 Outside visits 
 
While the above visits are encouraged to occur at study sites, it will be acceptable for 
documentation to be obtained from outside sites, an assessment for disease recurrence may be 
made based on outside cystoscopy, cytology, and clinical notes. If assessments are being 

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performed at outside sites, the study coordinator will call the patient to perform adverse event 
evaluation and document the discussion in a communication note 
 
Schedule of Events 
REQUIRED TIMEPOINTS 
PRE-
STUDY 
PERI-
OP 
Wk 
2 
Wk 
4 
Mo 
3 
Mo 
6 
Mo 
12 
Mo 
18 
Mo 
24 
 
Visit 1 
Visit 2 
Visi
t 3 
Opti
onal 
Visi
t 4 
Visi
t 5 
Visi
t 6 
Visi
t 7 
Visi
t 8 
PHYSICAL 
 
 
 
 
 
 
 
 
 
History and Physical Exam 
X 
 
X 
 
X 
X 
X 
X 
X 
Adverse Event Evaluation 
 
 
X 
Xg 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
 
X 
X 
X 
X 
X 
X 
X 
Weight and Performance Status 
X 
 
 
 
 
 
X 
 
 
Disease Assessment 
Xd 
 
 
 
X 
X 
X 
X 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY 
 
 
 
 
 
 
 
 
 
CBCa 
Xd 
 
Xf 
 
 
 
 
 
 
BMPb 
Xd 
 
Xf 
 
 
 
 
 
 
LFTsc 
Xd 
 
Xf 
 
 
 
 
 
 
Urinalysis 
Xd 
 
 
 
 
 
 
 
 
Pregnancy Test 
Xd,j 
 
 
 
 
 
 
 
 
IMAGING 
 
 
 
 
 
 
 
 
 
CT with IV Contrast 
Xe 
 
 
 
 
 
Xi 
 
Xi 
Cystoscopy 
Xe 
 
 
 
Xh 
Xh 
Xh 
Xh 
Xh 
TREATMENT 
 
 
 
 
 
 
 
 
 
Intravesical Gemcitabine 
 
X 
 
 
 
 
 
 
 
a: Complete Blood Count including hemoglobin, white blood cell and platelet count 
b: Basic Metabolic Panel including creatinine, sodium, potassium, chloride, glucose 
c: Liver Function Tests including SGOT (AST), SGPT (ALT), alkaline phosphatase, total bilirubin 
d: To be performed within 28 days of registration 
e: To be performed within 6 months before registration 
f: CBC and LFTs must be obtained 7-14 days post-instillation. Lab tests may be performed more often 
at the discretion of the treating investigator. If cytopenias or liver function test abnormalities are 
observed, patients should be followed weekly until these laboratory test abnormalities have resolved. 
g: This evaluation only performed if Grade 3 or greater AE noted at Week 2 evaluation. 
h: Urine cytology should be performed. Histologic confirmation of recurrence required. 
i: Encouraged but optional 
j: Only required in women of child-bearing potential. All females are considered WOCBP unless they 
have at least 12 months since the last menstrual bleeding, or are without a uterus and/or both ovaries, 
or has been surgically sterile for at least 6 months prior to registration 
 
 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
The sample size was determined as follows. A recent meta-analysis of patients who underwent 
RNU for UTUC found an intravesical recurrence rate of 29% at median follow-up 22 months.80 

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The recent trial by Messing et al assessing intravesical gemcitabine for urothelial carcinoma of 
the bladder found 4 year intravesical recurrence rates of 35% for gemcitabine versus 47% for 
placebo, or a 12% 4-year absolute risk reduction.1 The ODMIT-C trial was powered assuming a 
relative reduction in event rate of 50%, and found a relative reduction of intravesical recurrence 
using Mitomycin C of 40%. Thus, based on this prior literature, we want to demonstrate a 40% 
relative difference in 1-year recurrence, assuming a baseline recurrence rate of 30% with no 
treatment and thus, recurrence rate for gemcitabine of 18%. This corresponds both with the 12% 
4-year absolute risk reduction with Gemcitabine seen in the Messing trial as well as the 40% 1-
year relative risk reduction seen in the ODMIT-C trial.  
 
A sample size of 81 patients provides at least 80% power to detect a 40% relative reduction in 1-
year UC intravesical recurrence free survival (absolute rate = 18%) compared to a historic 
reference rate of 30%, based on a one-sided exact test of proportions with alpha level 0.05. 
 
Given the timing of drug administration, ineligible patients (determined during surgery) and 
dropout are expected to be very low. To account for loss-to-follow up and dropout due to death, 
we plan to enroll an additional 10% of patients, with a final accrual goal of 90 patients. 
 
Mayo Clinic Rochester performs approximately 40-60 RNUs per year. Once inclusion/exclusion 
criteria are applied, and accounting for patient participation, the anticipated accrual would be 25 
patients a year from Rochester. An additional 5 patients per year may be accrued each from 
Mayo Clinic Arizona and Florida. Therefore, a total of 64 patients are expected to be accrued 
from Rochester and 13 from Arizona and 13 from Florida. We anticipate completing accrual 
within 3 years, with an additional 1-2 years to complete follow-up and analysis. 
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Descriptive statistics and frequency distributions will be calculated, as appropriate for all 
variables. Continuous data will be summarized as mean (standard deviation), median (25th-75th) 
percentiles, and range as appropriate.  Categorical data will be summarized as percentage. 
Baseline values for demographic, clinical, and outcome variables (primary and secondary) will 
be tabulated.  
 
Adverse events categorized below will be summarized and organized by organ system, with the 
number and percent of patients experiencing the adverse event at least once and the number of 
patients exposed. 
• All adverse events graded by severity 
• Adverse events not related, unlikely, possible, probably, or definitely related to treatment 
• Serious adverse events 
 
Primary Hypothesis and Endpoint 
 

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We hypothesize that a single intraoperative intravesical instillation of gemcitabine at time of 
RNU for clinically localized UTUC will result in 40% relative improvement in 1-year 
intravesical UC RFS compared to historical controls. 
 
The primary endpoint of 1-year intravesical UC RFS will be evaluated utilizing a one-sided exact 
test of proportions with alpha level 0.05.  
 
 
Safety Endpoint 
 
Adverse events will be described and analyzed qualitatively.  AEs will be grouped into 
categories and numerically described. 
 
Exploratory Endpoints 
 
We will also assess 2-year intravesical UC RFS, incidence of MIBC, time to MIBC, and time to 
death using appropriate methods. Since administrative censoring is likely for some individuals 
prior to 2 year assessment, overall time-to-recurrence will be assessed through 2 year follow up 
using survival analysis methods.  Subjects with recurrence observed between scheduled visits 
(unscheduled visit) will have time of event set to the next scheduled visit and all scheduled 
observations will be analyzed based on the scheduled visit date assuming right censored data for 
dropout or administrative censoring at 2 years.  Kaplan-Meier estimates will describe estimated 
event rates at 2 years. Time to MIBC and time to death will be analyzed similarly. 
 
In addition, stratified analysis will be performed to assess the effect of tumor grade, neoadjuvant 
chemotherapy, tumor stage, ureteral tumor location, and history of bladder cancer. 
 
Interim Analysis 
 
No interim analysis will be performed for this study. 
 
Handling of Missing Data 
 
We anticipate little dropout or missing data for the primary endpoint as assessments are part of 
standard care in this patient population. Complete case data will be evaluated the primary 
endpoint. Secondary endpoints are assessed using time-to-event data and will use available data, 
censoring at loss to follow up. 
 
Multiplicity 
 
A single primary endpoint is specified a priori.  Secondary endpoints will be assessed without 
adjustment for multiple comparisons.  
7.3 
 Subject Population(s) for Analysis 
 

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The full analysis dataset for efficacy and safety outcomes includes patients meeting 
inclusion/exclusion criteria, providing consent, and with initiation of intravesical instillation as 
described in Section 6.2.  Patients with protocol violations during instillation will continue to be 
monitored and evaluated for safety and efficacy.  A secondary analysis of efficacy outcomes will 
include patients treated per protocol. 
8 Safety and Adverse Events 
8.1 
Definitions 
 
This study will utilize NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.3 for both data collection and reporting of all toxicities and for serious adverse events. A copy 
of the CTCAE Version 4.3 can be downloaded from the CTEP home page (http://ctep.cancer.gov). 
All appropriate treatment areas should have access to a copy of the CTCAE Version 4.3. 
 
Additional criteria for safety and adverse events are defined and outlined below. 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, monitoring reports, interim findings, product labeling change) that in the 
opinion of the local investigator may adversely affect the rights, safety, or welfare of the 
subjects or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Adverse Event (AE) 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 

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• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the PI may have adversely 
affected the rights, safety, or welfare of the subjects or others, or substantially compromised 
the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
The study treatment follow-up period is defined as the duration of time from initiation of study 
procedures to the end of the study treatment follow-up. Adverse events must be reported during 
the study treatment follow-up period.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the PI until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled 
visit, the PI should instruct each subject to report, to the PI, any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to participation 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if they reflect organ 
toxicity from drug or treatment effect and requires repeat testing. For patients with post-operative 
abnormalities in laboratory testing including CBC, BMP, and LFTs, repeat testing may be 
performed at the discretion of the treating investigator. If cytopenias or liver function test 
abnormalities are observed, patients should be followed weekly until these laboratory test 
abnormalities have resolved. Since only one administration of the drug is given, dose alterations 
and scheduling changes are not applicable. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
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this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination. This may begin with a standard non-
leading question, such as “How have you felt since the last visit?” In addition, and adverse event 
signs of symptoms that are observed will be documented. If an adverse event worsens in 
intensity, it should be recorded as a new adverse event. If an adverse event gets milder in 
intensity, it continues as the first report until the patient is recovered. 
 
Information on all adverse events should be recorded immediately in the source document, and 
also in the appropriate adverse event section of the electronic CRF. These will be recorded in a 
single adverse event document locally. All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should be recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriate action necessary 
to protect the study participant and then complete the Study Adverse Event Worksheet and log.  
The PI will evaluate the event and determine the necessary follow-up and reporting required to 
the IRB. The PI will make record of the date the adverse event report is reviewed.   
8.3.1 PI reporting: notifying the Mayo IRB 
 

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The PI will report to the Mayo (central) IRB any unanticipated problems involving risks to 
subjects (UPIRTSOs) and Non-UPIRTSOs according to the Mayo IRB Policy and Procedures. 
Any serious adverse event (SAE) which the PI has determined to be a UPIRTSO will be reported 
to the Mayo IRB as soon as possible but no later than 5 working days after the investigator first 
learns of the problem/event. 
 
Given that this is a multi-site clinical trial, the PI will report unanticipated problems and serious 
adverse events to participating investigators in addition to the IRB. 
 
For this protocol, only directly related SAEs/UPIRTSOs will be reported to the IRB. The 
information will be reported to the IRB in a de-identified manner. 
 
Information collected on the adverse event online report form: 
• Subject’s name 
• Medical record number  
• Disease/histology (if applicable) 
• The date the adverse event occurred  
• Description of the adverse event 
• Relationship of the adverse event to the research (drug, procedure, or intervention) *  
• If the adverse event was expected 
• The severity of the adverse event** 
• If any intervention was necessary 
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution 
 
* Relationship Index  
The relationship of an AE to the drug (gemcitabine) is a clinical decision by the PI based on all 
available information at the time of the completion of the CRF and is graded as follows: 
 
1. Not related: a reaction for which sufficient information exists to indicate that the etiology is 
unrelated to the study drug; the subject did not receive the study medication or the temporal 
sequence of the AE onset relative to administration of the study medication is not reasonable or 
the event is c1early related to other factors such as the subject' s clinical state, therapeutic 
intervention or concomitant therapy. 
 
2. Unlikely: a clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration which makes a causal relationship improbable and in which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
 
3. Possible: a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but which could also be explained by concurrent disease 
or other drugs or chemicals; information on drug withdrawals may be lacking are unclear. 
 
4. Probable: a clinical event including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 

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drugs or chemicals and which follows a clinically reasonable response on withdrawal (de-
challenge): re-challenge information is not required to fulfi1 this definition. 
 
5. Definite: a reaction that follows a reasonable temporal sequence from administration of the 
drug, or in which the drug level has been established in body fluids or tissues, that follows a 
known or expected response pattern to the suspected drug, and that is confirmed by improvement 
on stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure (re-challenge). 
 
** Severity Index  
The maximum intensity of an AE during a day should be graded according to the definitions 
below and recorded in details as indicated on the CRF. If the intensity of an AE changes over a 
number of days, then separate entries should be made having distinct onset dates.  
 
1. Mild: AEs are usually transient, requiring no special treatment, and do not interfere with 
patient’s daily activities. 
 
2. Moderate: AEs typically introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
 
3. Severe: AEs interrupt a patient's usual daily activity and traditionally require systemic drug 
therapy or other treatment. 
8.4 
Stopping Rules  
 
Study stopping rules are outlined in the Data and Safety Monitoring Plan, Section 8.5.1. 
8.5 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see Section 10 “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
8.5.1 Data and Safety Monitoring Plan 
 
A Data and Safety Monitoring Plan will be in place in a separate document. The PI will review 
confidential safety reports every 6 months from the central study statistician. The PI will be 
responsible for decisions regarding possible termination and/or early reporting of the study. 
 
Regular study monitoring will include an assessment of accrual, adverse events and study 
outcome (see attached Data and Safety Monitoring Plan). Planned study monitoring will occur 
bi-annually and as needed. NCI guidelines for study monitoring will be followed, recognizing 
that it often takes approximately 6 months for regulatory approvals at the institutions before an 
accrual rate can accurately be assessed.  
 

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Regarding accrual, at the start of year 3 (at the latest), if accrual is below 50% of projected, the 
trial will be assessed for an amendment to reflect actual accrual, with implications on study 
relevance and feasibility to be discussed with study PI and other investigators. 
 
Regarding adverse events, a concerning frequency of SAEs will trigger consideration of possible 
termination and/or early reporting of the study by the PI. 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
9.3 
Case Report Forms 
 
Data will be captured at each participating site by qualified study staff who will perform primary 
data collection from source-document reviews to electronic case report forms (eCRF) via 
REDCap. REDCap is endorsed by Mayo Clinic’s Clinical Trial Management System (CTMS) as 
described below. Data reported in the eCRF derived from source documents should be consistent 
with the source documents or the discrepancies should be explained. Data will be entered for this 
study utilizing one or a combination of the following methods:  
 
1. Data may be captured electronically, without use of paper. 

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2. Data may be transcribed from the Electronic Medical Record (EMR-an electronic 
source that must be available for review) into the REDCap system, without use of 
paper. 
3. Data may be captured on paper (considered source documentation) and 
transcribed into the REDCap system, BUT paper documentation must be retained 
and available for review. 
 
REDCap 
 
The Mayo Clinic Center for Clinical and Translational Science (CCaTS) offers a web-based, 
self-managed, customizable data management solution to investigators and study teams. This 
solution, Research Electronic Data Capture (REDCap), supports data collection via data 
collection instruments and surveys. 
 
REDCap is a secure, web-based application designed to support data capture for research studies, 
providing:1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for importing data from external 
sources. 
 
REDCap was created in 2004 at Vanderbilt University. It is a secure web platform for building 
and managing online databases and surveys. REDCap's streamlined process for rapidly creating 
and designing projects offers a vast array of tools that can be tailored to virtually any data 
collection strategy. 
 
REDCap is suitable for research projects with low- to medium-complexity data collection 
requirements and is available at no charge to all Mayo investigators. The REDCap Consortium, a 
vast support network of collaborators, is composed of thousands of active institutional partners in 
over one hundred countries who utilize and support REDCap in various ways. 
 
REDCap is HIPAA-compliant with built-in user right controls and audit trails for data security 
and tracking. 
 
REDCap (Research Electronic Data Capture) data collection projects rely on a thorough study-
specific data dictionary defined in an iterative self-documenting process by all members of the 
research team with planning assistance from the RIC. The iterative development and testing 
process results in a well-planned data collection strategy for individual studies. REDCap 
provides secure, web-based applications that are flexible enough to be used for a variety of types 
of research, provide an intuitive interface for users to enter data and have real time validation 
rules (with automated data type and range checks) at the time of entry. These systems offer easy 
data manipulation with audit trails and reporting for reporting, monitoring and querying patient 
records, and an automated export mechanism to common statistical packages (SPSS, SAS, Stata, 
R/S-Plus). 
9.4 
Records Retention 
 

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The PI will maintain records and essential documents related to the conduct of the study.  These 
will include subject case histories and regulatory documents. Subject-specific data and Case 
Report Forms will be inputted electronically and maintained by the central study statistician. 
Subject names or other directly identifiable information will not appear on any reports, 
publications, or other disclosures of clinical study outcomes. 
 
The PI will retain the specified records and reports for the longer of the following specifications; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. For Mayo Clinic sites only; as outlined in the Mayo Clinic Research Policy Manual –
“Retention of and Access to Research Data Policy” 
http://mayocontent.mayo.edu/research-policy/MSS_669717   
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
Periodic study monitoring will be provided by staff from the Mayo Clinic Office of Research 
Regulatory Support. Monitoring may include but will not necessarily be limited to review of the 
study regulatory documents, source data and database entries throughout the duration of the 
study to help ensure the completeness, validity and integrity of the data. Original signed 
informed consent forms will be reviewed. Written monitoring reports with findings and 
recommended and suggested corrective actions will be provided to the PI, who will subsequently 
provide them to the IRB at time of annual continuing review. 
 
Either of the co-PIs, assisted by delegated study staff, will also monitor study conduct and 
documents. Co-PI and study staff meetings will be held monthly, during which time 
correspondane will also take place with external site co-investigators. 
 
A written Data and Safety Monitoring Plan is a separate document from this protocol (Section 
15). 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the PI, 
and government regulatory agencies, of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 

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10.3 Protocol Deviations 
A protocol deviation is a departure from the study protocol and/or study related documents. The 
departure may be either on the part of the subject, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly. 
All-important deviations related to study inclusion or exclusion criteria, conduct of the trial, 
patient managements or patient assessment should be addressed in study source documents and 
reported to the PI. Protocol deviations must be submitted to the local or central IRB per  
guidelines. The site PI/study staff is responsible for knowing and adhering to their IRB 
requirements. Protocol deviations are not allowed. If a subject's eligibility is in question, please 
contact the PI. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and institutional 
research policies and procedures. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the PI before commencement of this study. 
12 Study Finances 
12.1 Funding Source 
 
Mayo clinic patient accrual, and central statistical and regulatory support will be funded 
internally by Mayo Clinic. Non-Mayo Clinic sites will locally fund their own accrual of subjects 
and regulatory support. Additional funding from other internal and external funding mechanisms 
will be applied for, and if awarded, will primarily be applied for sites unable to provide local 
internal funding. 
12.2 Conflict of Interest 
 

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Any study team member 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 a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study PI prior to participation in this study. 
12.3 Subject Stipends or Payments 
 
There will not be any subject stipend/payment in this study. 
13 Publication Plan 
 
The primary responsibility for the publication of results will be the PI. Information from the 
study will not be passed on to third parties unless first approved by the PI. The study will be 
registered to ClinicalTrials.gov prior to subject recruitment and the results will be reported once 
final analysis is completed. In the event of early study termination, the results will be reported 
within 12 months of study termination. Additional secondary analyses of the data will be 
published at the discretion of the PI.  
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15 Attachments 
 
1. DSMP 
2. IND Exemption