A Phase II Trial for the Use of Intravesical Gemcitabine and Docetaxel (GEMDOCE) in the Treatment of BCG naïve Non-muscle Invasive Urothelial Carcinoma of the Bladder
Phase: PHASE2
Conditions: Urothelial Carcinoma Bladder, Bladder Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Protocol Title 
A Phase II trial for the use of Intravesical Gemcitabine and 
Docetaxel (GEMDOCE) in the treatment of BCG naïve Non-
muscle invasive Urothelial Carcinoma of the Bladder 
IRB00241941 
NCT04386746 
5/25/2023

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Study Personnel 
 
Principal Investigator:  
Max Kates, MD 
Assistant Professor of Urology and Oncology 
James Buchanan Brady Urological Institute 
Johns Hopkins Hospital 
600 N. Wolfe Street, Marburg 401c 
Baltimore, MD 21287 
 
Study Statistician:  
Bruce Trock, M.P.H Ph.D. 
Director, Division of Epidemiology 
James Buchanan Brady Urological Institute 
 
 
 

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SYNOPSIS 
TITLE 
A Phase II trial for the use of Intravesical 
Gemcitabine and Docetaxel (GEMDOCE) in 
the treatment of BCG naïve Non-muscle 
invasive Urothelial Carcinoma of the 
Bladder  
SHORT TITLE 
Phase II study of GEMDOCE in BCG naïve NMIBC patients 
PHASE  
II 
OBJECTIVES 
Primary Objectives: 
 
 
Determine the complete response (CR) rate of NMIBC 
subjects treated with intravesical gemcitabine/docetaxel 
 
Secondary Objectives: 
 
 
Determine safety of NMIBC subjects treated with intravesical 
gemcitabine/docetaxel 
 
 
Determine the 12-month, and 24-month recurrence-free 
survival (RFS) rates of NMIBC subjects treated with 
intravesical gemcitabine/docetaxel 
 
 
Determine the cystectomy free survival rates of NMIBC 
subjects treated with intravesical gemcitabine/docetaxel  
 
 
Determine how variant histology attenuates 12-month RFS 
and surgical upstaging rates among NMIBC subjects treated 
with intravesical gemcitabine/docetaxel  
 
 
To assemble a blood, urine, and tissue bank (with pre and 
post treatment samples) to assess molecular correlates for 
response to intravesical GemDoce.  
 
 
Determine how RNA expression changes, including 
molecular subtypes attenuate 12-month RFS and surgical 
upstaging rates among NMIBC subjects treated with 
intravesical gemcitabine/docetaxel  
 
 
Determine how tumor DNA mutations, 
rearrangements/fusions, copy number alterations, tumor 
mutational burden impact clinical outcomes (e.g. CR rate, 
12m RFS, surgical upstaging) among NMIBC subjects 
treated with intravesical gemcitabine/docetaxel 

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 
Determine how tumor mutational burden attenuates 12-month 
RFS and surgical upstaging rates among NMIBC subjects 
treated with intravesical gemcitabine/docetaxel  
 
 
Determine associations between baseline- and post-
treatment T lymphocyte subset ratios and 12-month RFS and 
surgical upstaging rates among NMIBC subjects treated with 
intravesical gemcitabine/docetaxel  
STUDY 
DESIGN 
This study is a single arm open label Phase II trial investigating the 
safety and efficacy of intravesical gemcitabine/docetaxel for patients 
with non-muscle invasive bladder cancer.  A Simon’s 2-stage design 
will be used with an interim analysis between stage one and stage 
two. Translational correlates will be derived from prior signatures 
known to predict systemic chemotherapy response in muscle invasive 
bladder cancer.   
 
 
ELIGIBILITY 
CRITERIA  
Primary Inclusion Criteria 
 
Subject must meet all of the following applicable 
inclusion criteria to participate in this study: 
 
1. Histologically confirmed intermediate or high-risk non-
muscle invasive urothelial carcinoma of the bladder 
(Ta, T1, or Tis stage) on TURBT obtained within 90 
days of registration defined according to modified 
EORTC risk criteria summarized as follows  
 
 
Risk Group
Characteristics
Low-risk Tumors 
Initial or recurrent tumor > 12 
months after resection with all 
of the following: 
•  Solitary tumor 
•  Low-grade 
•  < 3 cm 
•  No CIS
Intermediate-Risk Tumors 
All tumors not defined in the 
two adjacent categories 
(between the category of low- 
and high-risk)
High-risk Tumors 
Any of the following: 
•  T1 tumor 
•  High-grade 
•  CIS 
•  Multiple and recurrent and 
large (> 3 cm) Ta low-grade 
tumors (all conditions must be 

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met for this point on Ta low-
grade tumors)
 
NOTE #1:  Low-risk tumors as defined above are 
not eligible. 
 
NOTE #2:  Mixed histologies are permitted, 
provided a component of urothelial carcinoma is 
present. 
 
NOTE #3:  All patients with HGT1 should undergo 
a restaging TURBT. 
 
 
2. ECOG (WHO) performance status 0,1, or 2. 
 
3. Age ≥ 18 years old at time of consent 
 
4. Evidence of post-menopausal status or negative urinary or 
serum pregnancy test for female pre-menopausal patients 
is required.  Women will be considered post-menopausal if 
they have been amenorrheic for 12 months without an 
alternative medical cause.  The following age-specific 
requirements apply:  
 
 
Women <50 years of age would be considered post-
menopausal if they have been amenorrheic for 12 
months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing 
hormone and follicle-stimulating hormone levels in the 
post-menopausal range for the institution or underwent 
surgical sterilization (bilateral oophorectomy or 
hysterectomy).  
 
 
Women ≥50 years of age would be considered post-
menopausal if they have been amenorrheic for 12 
months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause 
with last menses >1 year ago, had chemotherapy-
induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, 
bilateral salpingectomy or hysterectomy). 
 
5. Subjects who give a written informed consent obtained 
according to local guidelines 
 
 
Primary Exclusion Criteria 

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1. Subjects with muscle-invasive (i.e. T2, T3, T4), locally 
advanced unresectable, or metastatic urothelial carcinoma as 
assessed on baseline radiographic imaging obtained within 90 
days prior to study registration.  The required radiographic 
imaging includes: 
 
 
Abdomen/Pelvis – CT scan 
 
 
Chest – chest x-ray or CT scan 
2. Subjects with concurrent upper urinary tract (i.e. ureter, renal 
pelvis) urothelial carcinoma of any stage.  (NOTE: Subjects 
with history of non-invasive (Ta, Tis) upper tract urothelial 
carcinoma that has been definitively treated with at least one 
post-treatment disease assessment (i.e. cytology, biopsy, 
imaging) that demonstrates no evidence of residual disease 
are eligible). 
3. Subjects with another active second malignancy with an 
estimated overall survival from the second malignancy of < 12 
months.  Subjects with another second active malignancy that 
are deemed to have an estimated overall survival of >12 
months are eligible. 
4. Subjects who have received the last administration of an anti-
cancer therapy including chemotherapy, immunotherapy, and 
monoclonal antibodies ≤ 4 weeks prior to starting study drug, 
or who have not recovered from the side effects of such 
therapy 
5. Subjects who have had radiotherapy ≤ 4 weeks prior to 
starting study drug, or who have not recovered from 
radiotherapy toxicities. 
6. Pregnant or breast-feeding women 
7. Subjects unwilling or unable to comply with the protocol. 
8. Patients with prior systemic gemcitabine or docetaxel use for a 
non-bladder malignancy may enroll and receive treatment. 
STATISTICAL 
CONSIDER 
ATIONS 
 
Study Design/Endpoints 
 
Simon's two-stage design (Simon, 1989) will be used. The null 
hypothesis that the true 3 month complete response rate is 35% will 
be tested against a one-sided alternative. In the first stage, 18 
patients will be accrued. If there are 6 or fewer responses in these 18 
patients, the study will be stopped. Otherwise, 8 additional patients 
will be accrued for a total of 26. The null hypothesis will be rejected if 
14 or more responses are observed in 26 patients. This design yields 
a type I error rate of 0.0377 and power of 80% when the true 
response rate is 60%. 
 
Standard life table methods will be used to analyze RFS for each arm 
of the study and for each sub-type within arms of the study 
separately.  We will report 3, 6, 12 and 24-four month RFS with 90% 
confidence bounds.   

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The proportion of toxicities by type and grade according to the revised 
Common Terminology Criteria for Adverse Events (CTCAE) v5 will be 
reported with exact 95% confidence intervals.  All patients who 
receive at least one dose of the study drug(s) will be evaluable for 
toxicity.  
 
TOTAL  
NUMBER OF 
SUBJECTS 
N = 26 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 24 months 
ESTIMATED 
STUDY 
DURATION  
Estimated 36 months 

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TABLE OF CONTENTS 
 
Table of Contents 
 
Study Design/Endpoints................................................................................................................................. 6 
1 
Background and Rationale .................................................................................................... 12 
1.1 
Study Disease .................................................................................................................................... 12 
1.1.1 
Non-muscle Invasive Urothelial Carcinoma of the Bladder (NMIBC) ................................... 12 
1.1.2 
Current Management of Initial NMIBC ............................................................................................... 12 
1.1.3 
Issues with BCG supply ............................................................................................................................. 12 
1.2 
Rationale for Intravesical Chemotherapy in Non-Muscle Invasive Bladder Cancer 13 
1.3 
Rationale for a Single Arm Two-Stage Clinical Trial Design ............................................ 15 
1.4 
 Summary ............................................................................................................................................ 15 
2 
Study Objectives and Endpoints ........................................................................................ 16 
2.1 
Objectives ........................................................................................................................................... 16 
2.1.1 
Primary Objective ....................................................................................................................................... 16 
2.1.2 
Secondary Objectives: ............................................................................................................................... 16 
2.2 
Endpoints ........................................................................................................................................... 17 
2.2.1 
Primary Endpoint ........................................................................................................................................ 17 
2.2.2 
Secondary Endpoints ................................................................................................................................. 17 
3 
Eligibility Criteria ....................................................................................................................... 17 
3.1 
Primary Inclusion Criteria ........................................................................................................... 17 
3.2 
Primary Exclusion Criteria........................................................................................................... 19 
4 
Subject Registration ................................................................................................................ 19 
5 
Treatment Plan ........................................................................................................................... 20 
5.1 
Induction Drug administration .................................................................................................. 20 
5.2 
Maintenance Drug administration ............................................................................................ 20 
5.3 
Allowed Concomitant Medications............................................................................................ 20 
5.4   
Contraception ................................................................................................................................... 21 
5.4.1 
Female patient of child-bearing potential ......................................................................................... 21 
5.4.2 
 Male patients with a female partner of childbearing potential ............................................... 21 
5.4.3 
 Female partners (of childbearing potential) of male patients ................................................ 21 
5.4.4  Definition of Childbearing Potential .................................................................................................... 21 
5.4.5 
 Classification of Contraceptive Options ............................................................................................ 23 
5.4   Prohibited Concomitant Medications and Other Restrictions and Precautions ............ 23 
6 
Toxicities and Dose Delays/Dose Modifications .......................................................... 23 
6.1  
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions ................................................................ 24 
6.2 
Protocol Therapy Discontinuation ............................................................................................ 26 
6.3 
Protocol Discontinuation .............................................................................................................. 26 
7 
Study Calendar & Evaluations ............................................................................................. 27 
8 
Biospecimen Studies and Procedures ............................................................................. 30 

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8.1 
Tumor Tissue Studies .................................................................................................................... 30 
8.2 
Immunohistochemistry Analyses .............................................................................................. 30 
8.3  
Gene Expression Analyses ............................................................................................................ 30 
8.4  
Urine Marker Processing and Analysis .................................................................................... 31 
8.5  
Blood Processing and Analysis ................................................................................................... 31 
8.6  
Confidentiality of Biospecimens ................................................................................................ 32 
9 
Criteria for Disease Evaluation ............................................................................................ 32 
9.1 
Tumor Response .............................................................................................................................. 32 
9.1.1 
 Evaluable Population Definitions ........................................................................................................ 32 
9.1.2 
 Methods for Evaluation of Tumor Response .................................................................................. 32 
9.1.3 
 Methods for Evaluating Pathologic Stage ......................................................................................... 33 
9.1.4 
 Tumor Response Definitions ................................................................................................................. 35 
9.1.5 
Tumor IHC Staining Intensity Definitions ......................................................................................... 36 
9.2 
Survival Analyses ............................................................................................................................. 36 
9.2.1 
Relapse-Free Survival (RFS) ................................................................................................................... 36 
9.2.2 
 Overall Survival (OS) ................................................................................................................................ 37 
9.2.3 
 Cancer-Specific Survival (CSS) .............................................................................................................. 37 
10 
 Drug Administration ........................................................................................................... 37 
11 
 Adverse Events ..................................................................................................................... 37 
11.1 
Definitions .......................................................................................................................................... 37 
11.1.1 
Adverse Event (AE) ............................................................................................................................... 37 
11.1.2 
Serious Adverse Event (SAE) ............................................................................................................ 38 
11.1.3 
Unexpected Adverse Event ................................................................................................................ 38 
11.1.4 
Relatedness .............................................................................................................................................. 39 
11.2 
Reporting ............................................................................................................................................ 39 
11.2.1 
Adverse Events ....................................................................................................................................... 39 
11.2.2 
Serious Adverse Events (SAEs) ........................................................................................................ 39 
11.2.3 
Requirements for Reporting Pregnancy or Maternal exposure ......................................... 40 
12 
 STUDY DESIGN AND POWER ........................................................................................ 40 
13 
Trial Management ................................................................................................................. 41 
13.1 
Monitoring ......................................................................................................................................... 41 
13.2    Data Management ............................................................................................................................. 41 
14 
References ............................................................................................................................... 41 

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1 
BACKGROUND AND RATIONALE 
 
1.1 
Study Disease 
 
1.1.1 Non-muscle Invasive Urothelial Carcinoma of the Bladder (NMIBC) 
 
Bladder cancer is the 5th most common cancer in the United States, with an 
estimated 80,470 individuals newly diagnosed in 2019.(1) 70% of patients will 
harbor an early stage at diagnosis, defined by non-muscle invasive disease 
(NMIBC) with invasion limited to the mucosal epithelium (Ta, Tis) and immediate 
connective tissue layer beneath the mucosa (T1).  High risk NMIBC, affecting 
more than 30,000 patients each year, is defined by carcinoma in situ (CIS), high 
grade Ta or T1 tumors.  Intermediate risk bladder cancer is defined by recurrent, 
large (>3cm), or multifocal low-grade bladder cancer. 
 
 
1.1.2 Current Management of Initial NMIBC 
 
Transurethral resection of bladder tumor (TURBT) followed by intravesical 
bacillus Calmette-Guerin (BCG) immunotherapy is the standard 1st line 
treatment. While up to 35% of patients have long term sustained remissions with 
intravesical BCG, 40-60% will have tumor recurrence within 2 years.(2) 
Ultimately, 40% of these high risk NMIBC patients will progress to muscle 
invasive stages and require radical cystectomy, or complete bladder removal. 
Progression to metastatic disease and ultimately bladder cancer death occurs in 
20-30% of these patients.(3,4) In 2019, 17,670 are estimated to die of bladder 
cancer, with many of these patients beginning with early stage disease.(1) 
 
1.1.3 Issues with BCG supply 
In July 2012, Sanofi Pasteur announced that it was halting production of the 
Connought strain of BCG, after inspectors identified manufacturing problems in 
the only plant in which it was produced.  In 2016, Sanofi announced that the BCG 
program would be shut down permanently.(5) In the United States, United 
Kingdom, and several other countries, this left oncoTICE BCG, produced by 
Merck, as the only available strain and producer of BCG.  This monopoly over 
production and distribution became catastrophic for patients when increased 
demand and manufacturing issues led to a worldwide shortage of BCG in 2014-
2015. The British department of health noted that 6000 British patients would be 
affected by the shortage of BCG, and recommended switching to intravesical 
chemotherapy if BCG is in low supply. (6,7) During the shortage thousands of 
patients were left with inadequate BCG dosing regimens without evidence-based 
alternatives in their place.  This left many patients at our institution and nationally 
with increased uncertainty and anxiety regarding the best steps towards treating 
their cancer, as evidenced by numerous patient blogs and articles written at that 

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time(8–10).  Since February 2018, we are in the midst of another ongoing global 
TICE® (Merck) shortage, with many institutions with limited or no BCG supply.  
Given the tenuous supply of BCG worldwide, the formal study of alternatives is 
essential for patients. 
 
1.2 
Rationale for Intravesical Chemotherapy in Non-Muscle Invasive Bladder 
Cancer 
 
Thus far, attempts to discover alternatives to BCG have primarily rested on 
studies involving single agent intravesical chemotherapy instillations. Most 
recently, a randomized controlled trial was performed comparing intravesical  
chemohyperthermia with intravesical mitomycin C (MMC) versus BCG for 
patients with intermediate and high risk NMIBC. Although the study closed 
prematurely and was underpowered, in the analysis of per-protocol treated 
patients, 2 year recurrence free survival (RFS) approached 81.8% among those 
receiving hyperthermic MMC compared to 64.8% among those receiving 
BCG.(11)  This study demonstrated the potential non-inferiority of chemotherapy 
when given through a novel delivery platform and when given with a 
maintenance program. 
 
Intravesical gemcitabine and cisplatin take their intellectual justifications from 
their use as the 1st line systemic agents in advanced bladder cancer.(12)  
Similarly, systemically administered taxane therapies (both paclitaxel and 
docetaxel) have been combined with gemcitabine and cisplatin to treat metastatic 
disease.(13–15)  As these drugs are all currently employed in combination 
regimens for systemic disease, and all have been previously tested intravesically 
in prior human trials, there is a strong rationale to investigate the clinical efficacy 
and safety of intravesical chemotherapy regimens combining these agents. 
 
Gemcitabine, a deoxycytidine analogue, inhibits DNA synthesis and is a 
commonly used drug in metastatic bladder cancer patients. Intravesical 
gemcitabine has been studied in multiple Phase I and II trials.  It appears to have 
very little systemic absorption, with plasma levels immeasurable or quite low, and 
metabolite difluorodeoxyuridine levels that reach at most 5 μM in the blood, 
suggesting that low levels of the drug reach systemic circulation.(16)  Thus, 
although myelosuppression is a serious side effect when gemcitabine is used 
intravenously, it has a very favorable toxicity profile when administered 
intravesically. Due to the reported efficacy and low toxicity profile, gemcitabine 
has been favorably compared to other intravesical agents such as mitomycin C 
(MMC), and has shown improved or similar efficacy to BCG in other 
settings.(17,18) In a Phase II study of 30 patients with NMIBC who had failed 
BCG treatment (2 or more induction courses) and refused cystectomy, 15 (50%) 
had complete responses following intravesical gemcitabine treatment, though 
durable response were limited with 1yr RFS of 21% among those with initial 
CR.(19)  Additionally, in a prospective, randomized trial of patients (n=120) with 
intermediate risk NMIBC, no differences between gemcitabine and 1/3 strength 

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BCG were observed.(20)    This study is particularly relevant in the current era of 
BCG shortage as 1/3 dosing is a common strategy to conserve BCG at many 
centers.  There is also evidence that gemcitabine may be as or more efficacious 
than BCG for patients who recur after 1 course of BCG. In a multicenter 
prospective randomized trial of patients with NMIBC who recurred after 1 course 
of intravesical BCG, gemcitabine was associated with a 1 yr recurrence-free 
survival rate of 47% compared to only 13% for patients who underwent a 2nd 
course of BCG.(21) While this study was hypothesis generating, its results were 
not incorporated into guidelines or clinical practice due to the study’s significant 
limitations, notably its small scale (40 patients/group), and 2 year recurrence free 
survival rates of 19% with gemcitabine vs 3% for BCG. These RFS rates were far 
lower than any prior trial, and thus the validity of the study was questioned in the 
absence of larger patient cohorts and further studies validating its results.(22)  
 
In 2006, the first phase I trial (n=18) investigating intravesical docetaxel for the 
treatment of NMIBC with BCG failure was completed.(23)  All patients failed BCG 
with a mean of 3 prior intravesical induction treatments. In a second clinical trial 
of intravesical docetaxel (n=13), it was found that monthly maintenance therapy 
extended the durability of response to induction treatment for a selected group of 
patients with BCG-refractory NMIBC, and might decrease the overall risk of 
recurrence in high-risk NMIBC.(24)  One and 3-year recurrence-free survival 
rates for the entire cohort were 40% and 25%, respectively.(25)  There is thus a 
promising clinical efficacy for intravesical docetaxel in a population heavily 
pretreated (mean 3 inductions) with BCG, and justification to study this therapy 
when there is tumor recurrence after the 1st BCG induction. 
 
In 2015, Steinberg et. al. published the first known study of sequential 
gemcitabine and docetaxel (GEM/DOCE) as salvage therapy for patients with 
NMIBC, and demonstrated a 54% 1 year and 34% 2 year recurrence free 
survival, in addition to a 66% recurrence free survival at first surveillance.(26) At 
our institution, GEM/DOCE has been administered following the treatment 
protocol established by Steinberg et. al. since 2013.  The 25 BCG 
unresponsive/relapsing patients treated at our institution have had a 49% 1-year 
high grade recurrence free survival (HG-RFS) and 34% 2-year HG-RFS with a 
median HG-RFS was 6.5 months.  
 
At our institution, among patients undergoing BCG treatment who have already 
recurred after 1 course of BCG, 2 year recurrence free survival is 33%--this is 
much different than the 50-70% 2 yr RFS after the 1st induction course, and is 
more on par with other 2nd line intravesical chemotherapies that are typically 
studied after 2 or more BCG associated recurrences.  There is likely a biologic 
mechanism that explains this response pattern, however, the exact mediators of 
BCG resistance are not clear.  Similarly, while deleterious DNA mutations in 
genes responsible for DNA damage repair (DDR) have been associated with 
response to systemically administered cisplatin in muscle-invasive bladder 
cancer patients, predictors of response or resistance to intravesical 

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chemotherapy treatments including gemcitabine and docetaxel are uncertain.  
Identifying predictive biomarkers of intravesical BCG and chemotherapy 
response is an area our group is actively studying.  Our plan is to seek funding 
from another organization for a translational component of this trial that 
compares responders and nonresponders to each treatment (BCG vs 
chemotherapy) and assesses whether there is a molecular signature 
characteristic of those that respond to BCG immunotherapy vs chemotherapy. 
 
 
Given the encouraging preliminary efficacy data in BCG relapsed and 
unresponsive populations, the critical need to develop non-BCG therapy 
approaches, and the improved opportunity for biomarker discovery in a more 
homogenous patient population, we aim to move combination intravesical 
GEM/DOCE chemotherapy up in the treatment algorithm to those who are naïve 
to BCG. 
 
1.3 
Rationale for a Single Arm Two-Stage Clinical Trial Design 
 
A Simon’s single arm two-stage study design was chosen for several reasons. At 
the time of this writing (March 2020), a worldwide BCG shortage was underway 
and one of the central purposes of this trial is to provide patients with a 
reasonable, on-protocol alternative.  Secondly, in order to fully ensure that the 
proposed Gem/Doce regimen is non-inferior to BCG, a 1st stage analysis to 
determine efficacy or futility is appropriate. 
 
1.4 
Summary 
 
In summary, a strong rationale exists to study combination intravesical 
gemcitabine/docetaxel in BCG naïve high risk nonmuscle invasive bladder:  
 
1) NMIBC represents a common, sizeable patient population. 
 
2) Intravesical BCG therapy, which has been the accepted standard of care in 
NMIBC patients, is fraught with frequent drug shortages. 
 
3)  Recent monotherapy intravesical chemotherapy trials have demonstrated 
similar outcomes between BCG and chemotherapy. 
 
4) Intravesical gemcitabine/docetaxel is a commonly used, safe therapy for BCG 
unresponsive NMIBC and for BCG naïve NMIBC in times of shortage, with 
efficacy approaching that of BCG in retrospective series. 
 
5) Safety and efficacy data from this trial will prove helpful in assessing 
development strategies for a larger scale randomized trial with practice-
changing impact in the BCG-naïve population. 
 

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6) Urine cytology and bladder tumor biopsies are usually considered standard in 
the baseline evaluation and follow-up care of patients with NMIBC.  As such, 
this trial presents a unique environment by which to discover and validate 
biomarkers to predict intravesical chemotherapy response and understand 
mechanisms of resistance. 
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
 
 
Determine the complete response (CR) rate of NMIBC subjects treated with intravesical 
gemcitabine/docetaxel 
 
2.1.2 Secondary Objectives: 
 
 
 
Determine safety of NMIBC subjects treated with intravesical gemcitabine/docetaxel 
 
 
Determine the 12-month, and 24-month recurrence-free survival (RFS) rates of NMIBC 
subjects treated with intravesical gemcitabine/docetaxel 
 
 
Determine the cystectomy free survival rates of NMIBC subjects treated with 
intravesical gemcitabine/docetaxel  
 
 
Determine how variant histology attenuates 12-month RFS and surgical upstaging rates 
among NMIBC subjects treated with intravesical gemcitabine/docetaxel  
 
 
To assemble a blood, urine, and tissue bank (with pre and post treatment samples) 
to assess molecular correlates for response to intravesical GemDoce.  
 
 
Determine how RNA expression changes, including molecular subtypes attenuate 12-
month RFS and surgical upstaging rates among NMIBC subjects treated with 
intravesical gemcitabine/docetaxel  
 
 
Determine how tumor DNA mutations, rearrangements/fusions, copy number 
alterations, tumor mutational burden impact clinical outcomes (e.g. CR rate, 12m RFS, 
surgical upstaging) among NMIBC subjects treated with intravesical 
gemcitabine/docetaxel 
  
 
Determine how tumor mutational burden attenuates 12-month RFS and surgical 
upstaging rates among NMIBC subjects treated with intravesical gemcitabine/docetaxel  
 
 
Determine associations between baseline- and post-treatment T lymphocyte subset 
ratios and 12-month RFS and surgical upstaging rates among NMIBC subjects treated 
with intravesical gemcitabine/docetaxel  

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2.2  
Endpoints 
 
2.2.1 Primary Endpoint 
 
 
 The complete response (CR) rate of BCG-naive NMIBC subjects treated with 
intravesical gemcitabine/docetaxel is defined as the proportion of patients who 
demonstrate no evidence of recurrent high grade urothelial carcinoma of the 
bladder of any stage at the 3-month post-treatment disease assessments.    
 
2.2.2 Secondary Endpoints 
 
 The 12-month relapse-free survival (RFS) rates of BCG-naive NMIBC subjects 
treated with intravesical gemcitabine/docetaxel is defined as the proportion of 
patients with no evidence of recurrent high grade urothelial carcinoma of the 
bladder of any stage at the post-treatment tumor assessments performed at least 
12 months after the initiation of study treatment     
 
 The 24-month relapse-free survival (RFS) rates of BCG-naive NMIBC subjects 
treated with intravesical gemcitabine/docetaxel is defined as the proportion of 
patients with no evidence of recurrent high grade urothelial carcinoma of the 
bladder of any stage at the post-treatment tumor assessments performed at least 
24 months after the initiation of study treatment  
 
 The safety profile of BCG-naive NMIBC subjects treated with intravesical 
gemcitabine/docetaxel will be assessed by NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5. 
 
 The association between 1) DNA and RNA based genomic changes, 2) tumor 
mutational burden, 3) immune cell populations and RFS will be assessed from 
DNA and RNA derived from pre treatment bladder tumor. 
 
 
3 ELIGIBILITY CRITERIA 
 
3.1 
Primary Inclusion Criteria 
 
Subject must meet all of the following applicable inclusion criteria to participate in 
this study: 
 
1. Histologically confirmed intermediate or high-risk non-muscle invasive urothelial 
carcinoma of the bladder (Ta, T1, or Tis stage) on TURBT obtained within 90 
days of registration defined according to modified EORTC risk criteria 
summarized as follows  

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Risk Group
Characteristics
Low-risk Tumors 
Initial or recurrent tumor > 12 
months after resection with all 
of the following: 
•  Solitary tumor 
•  Low-grade 
•  < 3 cm 
•  No CIS 
Intermediate-Risk Tumors 
All tumors not defined in the 
two adjacent categories 
(between the category of low- 
and high-risk)
High-risk Tumors 
Any of the following: 
•  T1 tumor 
•  High-grade 
•  CIS 
•  Multiple and recurrent and 
large (> 3 cm) Ta low-grade 
tumors (all conditions must be 
met for this point on Ta low-
grade tumors)
 
NOTE #1:  Low-risk tumors as defined above are not eligible. 
 
NOTE #2:  Mixed histologies are permitted, provided a component of 
urothelial carcinoma is present. 
 
NOTE #3:  All patients with HGT1 should undergo a restaging TURBT. 
 
 
2. ECOG (WHO) performance status 0,1, or 2. 
 
3. Age ≥ 18 years old at time of consent 
 
4. Evidence of post-menopausal status or negative urinary or serum pregnancy test 
for female pre-menopausal patients is required.  Women will be considered post-
menopausal if they have been amenorrheic for 12 months without an alternative 
medical cause.  The following age-specific requirements apply:  
 
 
Women <50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone and 
follicle-stimulating hormone levels in the post-menopausal range for the 
institution or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).  
 

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 
Women ≥50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced menopause with 
last menses >1 year ago, had chemotherapy-induced menopause with last 
menses >1 year ago, or underwent surgical sterilization (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy). 
 
5. Subjects who give a written informed consent obtained according to local 
guidelines 
 
 
3.2 
Primary Exclusion Criteria 
 
1. Subjects with muscle-invasive (i.e. T2, T3, T4), locally advanced unresectable, or 
metastatic urothelial carcinoma as assessed on baseline radiographic imaging 
obtained within 90 days prior to study registration.  The required radiographic 
imaging includes: 
 
 
Abdomen/Pelvis – CT scan 
 
 
Chest – chest x-ray or CT scan 
2. Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) urothelial 
carcinoma of any stage.  (NOTE: Subjects with history of non-invasive (Ta, Tis) 
upper tract urothelial carcinoma that has been definitively treated with at least 
one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that 
demonstrates no evidence of residual disease are eligible). 
3. Subjects with another active second malignancy with an estimated overall 
survival from the second malignancy of < 12 months.  Subjects with another 
second active malignancy that are deemed to have an estimated overall survival 
of >12 months are eligible. 
4. Subjects who have received the last administration of an anti-cancer therapy 
including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks 
prior to starting study drug, or who have not recovered from the side effects of 
such therapy 
5. Subjects who have had radiotherapy ≤ 4 weeks prior to starting study drug, or 
who have not recovered from radiotherapy toxicities. 
6. Pregnant or breast-feeding women 
7. Subjects unwilling or unable to comply with the protocol. 
8. Patients with prior systemic gemcitabine or docetaxel use for a non-bladder 
malignancy may enroll and receive treatment. 
 
4 
SUBJECT REGISTRATION 
 
All subjects must be registered through the dedicated JHH GBCI RedCap 
database, with this trial marked as “registered”. A subject is considered 
registered when an “On Study” date is entered into RedCap. 

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Subjects must be registered prior to starting protocol therapy. Subjects must 
begin therapy within 60 days of registration.  
 
 
5 
TREATMENT PLAN 
 
5.1 
Induction Drug administration 
 
Upon successful screening and registration, subjects will undergo the following 
treatment.   
  
GEM/DOCE induction is given intravesically in sequential order once a week for 
six consecutive weeks. One gram of gemcitabine in 50 ml of sterile water is 
slowly instilled into the bladder via a Foley catheter and the catheter is clamped 
for 60 minutes. The bladder is then drained and 40 mg of docetaxel in 50 ml of 
NSS is then slowly instilled via the Foley catheter into the bladder. The catheter 
is again clamped for 60 minutes. The docetaxel is then drained and catheter 
removed and the patient is questioned regarding discomfort, instructed to remain 
well-hydrated and to notify a physician with any adverse reactions, questions, or 
concerns. The patient may have the option of leaving the urology clinic with the 
docetaxel instilled with the understanding that it must remain in the bladder for 60 
minutes. The patient is instructed to put a capful of bleach in the toilet prior to 
urinating and flushing the toilet. 
 
Gemcitabine and docetaxel are given per standard of care. As such, if the 
standard of care guidelines should change, there is allowance for adjustment in 
the dosing of gemcitabine and docetaxel under the discretion of the investigator.  
 
5.2 
Maintenance Drug administration 
For patients with a CR, CIS, or LgTa histologies after induction therapy, the 
maintenance program will be monthly GEM/DOCE instillations for up to 2 years 
from time of diagnosis on pathology, with cystoscopic and cytologic evaluations 
every 3 months. 
 
Any deviations from the standard GEM/DOCE induction or maintenance 
schedule will be recorded in the study database.  
 
 
5.3 
Allowed Concomitant Medications 
 
Use of full-dose anti-coagulation (i.e. warfarin, enoxaparin, rivaroxaban, etc.) is 
permitted at the site investigator’s discretion. 
 
Use of antibiotics concurrent with study drugs is allowed. 
 

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5.4   Contraception 
 
5.4.1 Female patient of child-bearing potential 
 
Females of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least 1 highly effective method of contraception as 
described in the table below from the time of screening and must agree to 
continue using such precautions for 90 days after the last dose of GEM/DOCE 
combination therapy. Non-sterilized male partners of a female patient must use 
male condom plus spermicide throughout this period. Cessation of birth control 
after this point should be discussed with a responsible physician. Not engaging in 
sexual activity for the total duration of the drug treatment and the drug washout 
period is an acceptable practice; however, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of birth control. 
Female patients should also refrain from breastfeeding throughout this period. 
 
5.4.2  Male patients with a female partner of childbearing potential 
 
 
Non-sterilized males who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from screening 
through 90 days after receipt of the final dose of GEM/DOCE combination 
therapy.  Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male patients should refrain from sperm 
donation throughout this period. 
 
5.4.3  Female partners (of childbearing potential) of male patients 
 
Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (see table below). 
 
5.4.4  Definition of Childbearing Potential 
 
Females of childbearing potential are defined as those who are not surgically 
sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal.  Women will be considered post-menopausal 
if they have been amenorrheic for 12 months without an alternative medical 
cause. The following age-specific requirements apply:  
 
 Women <50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone and 
follicle-stimulating hormone levels in the post-menopausal range for the 

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institution or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).  
 
 Women ≥50 years of age would be considered post-menopausal if they 
have been amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments, had radiation-induced menopause with 
last menses >1 year ago, had chemotherapy-induced menopause with last 
menses >1 year ago, or underwent surgical sterilization (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy). 
 

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5.4.5  Classification of Contraceptive Options 
 
Highly effective methods of contraception, defined as one that results in a low 
failure rate (i.e., less than 1% per year) when used consistently and correctly are 
described below.  Note that some contraception methods are not considered 
highly effective (e.g. male or female condom with or without spermicide; female 
cap, diaphragm, or sponge with or without spermicide; non-copper containing 
intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). 
 
Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods
Hormonal Methods
 Copper T intrauterine device 
 Levonorgestrel-releasing 
intrauterine system (e.g., 
Mirena®)a 
 
 Etonogestrel implants: e.g., 
Implanon or Norplan 
 Intravaginal device: e.g., 
ethinylestradiol and etonogestrel 
 Medroxyprogesterone injection: 
e.g., Depo-Provera  
 Normal and low dose combined 
oral contraceptive pill 
 Norelgestromin/ethinylestradiol 
transdermal system 

Cerazette (desogestrel)
a 
This is also considered a hormonal method 
 
 
5.4   Prohibited Concomitant Medications and Other Restrictions and Precautions 
 
Any medicinal herbal preparation unless prescribed by the site investigator. All 
concomitant medications including prescribed medicinal herbal 
preparations must be documented. 
 
Any administration of any anti-cancer therapies (investigational or approved) 
within 12 weeks prior to study drug is prohibited.  
 
Alcohol consumption while on study is strongly discouraged due to the potential 
to confound interpretation of hepatotoxic events. 
 
 
6 TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be 
used to grade adverse events.  Subjects enrolled in this study will be evaluated 

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clinically and with standard laboratory tests before and at regular intervals during 
their participation in this study as specified in Study Calendar & Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse 
events, and adverse events requiring study drug interruption or discontinuation 
as specified in Study Calendar & Evaluations.   
 
6.1  
Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions  
 
 
Guidelines for dose modifications and management of immune-mediated 
adverse events are outlined in the following tables. 
 
 
 
General Guidelines 
 
Dose Modifications
Toxicity Management
Drug administration modifications of study drug/study 
regimen will be made to manage potential immune-
related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v5. 
 
In addition to the criteria for permanent discontinuation 
of study drug/study regimen based on CTC 
grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
 
 
 
Recurrence of a previously experienced Grade 
3 treatment-related AE following resumption of 
dosing 
 
Grade 1 
No dose modification 
 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1.  If toxicity 
worsens, then treat as Grade 3 or Grade 
4.  Study drug/study regimen can be 
resumed once event stabilizes to Grade 
≤1. 
 
Grade 3 
Depending on the individual toxicity, study 
drug/study regimen may be permanently 
discontinued. Please refer to guidelines 
below. 
 
 
Grade 4 
Permanently discontinue study drug/study 
regimen. 
 
 
 
AE  Adverse event; CTC  Common Toxicity Criteria; CTCAE  Common Terminology Criteria for Adverse Events; 
IV  intravenous; NCI  National Cancer Institute; PO  By mouth.

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Intravesical Treatment Reactions 
 
Severity Grade of 
the Event (NCI 
CTCAE 
version 5)
Dose Modifications
Toxicity Management
Any Grade 
Note: Dose modifications are not 
required for AEs not deemed to be 
related to study treatment 
(i.e., events due to underlying 
disease) or for laboratory 
abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1
No dose modifications.
Treat accordingly, as per institutional standard.
Grade 2
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
Specifically, for hematuria or 
dysuria in the absence of infection 
the study drug may be given,
Treat accordingly, as per institutional standard.
Grade 3
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 
2 within 7 days or resolve to ≤Grade 
1 or baseline within 14 days, 
resume study drug/study regimen 
administration.  Otherwise, 
discontinue study drug/study 
regimen.
Treat accordingly, as per institutional standard.
Grade 4 
 
Discontinue study drug/study 
regimen (Note: For Grade 4 labs, 
decision to discontinue should be 
based on accompanying clinical 
signs/symptoms, the Investigator’s 
clinical judgment, and consultation 
with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or 
equal to Grade 2, please discuss with Study Physician.” 
AE  Adverse event; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
 

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6.2      Protocol Therapy Discontinuation 
 
In addition to discontinuation from therapy related to toxicities, a subject will also 
be discontinued from protocol therapy and followed per protocol under the 
following circumstances outlined below.  The reason for discontinuation of 
protocol therapy will be documented on the electronic case report form (eCRF)  
  
 Documented disease progression, as defined by: 
o Evidence of progression to muscle invasive disease on transurethral 
biopsy. 
 
 Documented disease recurrence, as defined by: 
o Evidence of HGT1 disease on transurethral biopsy at the 3 month post-
treatment evaluation. 
o Evidence of any high grade bladder cancer (including CIS, HgTa, or 
HGT1) at the 6 month post treatment evaluation or any timepoint 
thereafter. 
o Note that patients with HgTa or CIS at the 3 month post treatment 
evaluation may stay on study at the discretion of the treating physician. 
o Similarly, patients with low grade Ta disease at any timepoint may stay on 
study at the discretion of the treating physician. 
 
 
 
Investigator determines a change of therapy would be in the best interest of 
the subject 
 
 
Subject requests to discontinue protocol therapy, whether due to 
unacceptable toxicity or for other reasons 
 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted 
for further scheduled study assessments. The outcome of that discussion 
should be documented in both the medical records and in the eCRF. 
 
 
Female subject becomes pregnant  
 
 
Protocol induction therapy is interrupted for ≥ 21 days.  
 
6.3      Protocol Discontinuation  
 
If a subject decides to discontinue from the protocol (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments as 
thoroughly as possible. A complete final evaluation at the time of the subject’s 
protocol withdrawal should be made with an explanation of why the subject is 
withdrawing from the protocol. If the reason for removal of a subject from the 
study is an adverse event, it will be recorded on the eCRF. 

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7 STUDY CALENDAR & EVALUATIONS  
 
Study Day 
 
Screening 
(0-60 days pre-
study) 
Induction 
 
Maintenance Instillation 
 
Day 
1 
Day 
8 
Day 
15 
Day 
22
Day 
29
Day 
35
3 
mont
hs 
6 
mont
hs 
9 
mont
hs 
12 
mont
hs14 
24 
months/
End of 
Study 
Visit 12, 
13, 14 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X
 
 
 
 
 
 
 
 
 
 
 
Vital signs to include BP, weight, 
ECOG PS; height at screening 
only 
X 
 
 
 
 
 
 
 
 
 
 
 
AEs & concomitant medications  
X
X 
X 
 
 
 
X 
X
X
CBC w/differential 
X 
X8
 
 
 
 
 
X8
 
 
X8
 
CMP 
X 
 
 
 
 
 
 
 
 
 
 
 
GEM/DOCE instillation 
 
X3,5
X 
X 
X 
X 
X 
monthly5
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
monthly 
Urine pregnancy test 
X5 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or if clinically 
indicated, CT chest  
X11 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI abdomen/pelvis  
X11
 
 
 
 
 
 
 
 
 
 
 
Cystoscopy 
X1 
 
 
 
 
 
 
X9
quarterly 
Urine cytology  
X2 
 
 
 
 
 
 
X 
quarterly 
Bladder Biopsy/TURBT 
X1 
 
 
 
 
 
 
X9
At urologist discretion 
Blood sample (Plasma, Serum, 
PBMC) 
X4 
 
 
 
 
 
 
X6 
 
 
X6 
 
Urine sample 
X4 
 
 
 
 
 
 
X6 
 
 
X6 
 
Tumor Tissue  
X1 
 
 
 
 
 
 
X9 
 
 
X10 
 
 
 

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1 
Cystoscopy with TURBT at screening should be performed within 90 days of study 
registration.   
 
2 
Urine cytology sample at screening should be performed within 90 days of starting study 
therapy.   
 
3 
Study treatment should begin within 60 days of study registration.  
 
4 
Correlative blood (PBMC, plasma, serum) and urine samples should be obtained after 
eligibility is confirmed and prior to starting study therapy.  They may be obtained prior to or 
on Day 1 provided they are obtained prior to initiation of study therapy. 
 
5 
All induction treatments may be performed ± 5 days of the intended treatment dates and ± 
10 days of the intended treatment dates for maintenance treatments. Patients should 
receive 6 treatments in 9 weeks.  Treatments may be administered anywhere where they 
are routinely given (ie they do not need to be administered at a study site).  If treatments are 
performed at an outside institution, patients must be assessed every 3 doses for a toxicity 
evaluation. Assessment can be via telephone.  
 
6 
Post-treatment correlative assessments will occur at the 3-month and 12-month time points 
within ± 7 days of the cystoscopy or instillation.  
 
7 
Cystoscopy and urine cytology at the 3- and 12-month disease assessments may be 
performed within ± 14 days of the 3- and 12-months post-initiation of study therapy dates 
(i.e. 3- and 12-months after Day 1 date).  
 
8 
CBC will be drawn up to 10 days prior to Day 1. If screening CBC was drawn within 10 days 
prior to Day 1, it does not need to be repeated for Day 1. CBC will be drawn up to 10 days 
prior to 3- and 12-month maintenance instillation.    
 
9 
Tumor tissue will be collected if biopsy (at urologist’s discretion) occurred at 3-month 
cystoscopy.  
 
10 Tumor tissue will be collected, if biopsy (at urologist’s discretion) occurred at 12-month 
cystoscopy.  
 
11 Chest X-ray or if clinically indicated, CT chest, and CT or MRI abdomen/pelvis at screening 
should be performed within 90 days of study registration. 
 
12 End of study visit (if applicable) will occur if anytime during the study the patient decides to 
stop early, relapse, if the doctor decides it is in the patient’s best interest to stop, or if it’s 
been 24 months from time of diagnosis on pathology. Urine analysis, cystoscopy, urine 
cytology, and biopsy (at urologist’s discretion) will be performed if applicable. 
 
13 AEs considered related to study drug(s) will be followed until resolution to Grade ≤ 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. All SAEs should be followed until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. Refer to Section 11.2 for additional 
details. 
 

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14 If the patient should exit the study prior to the 12 month and 24 month timepoint from the 
start of the initial instillation treatment, the patient will be followed for information regarding 
survival outcome (i.e. disease progression and death) and the tumor assessments 
performed at least 12 months and 24 months after the initiation of study treatment.  
 
Note: In order to minimize the need for research-only in-person visits, telemedicine 
visits may be substituted for in-person clinical trial visits or portions of clinical trial visits 
where determined to be appropriate and where determined by the investigator not to 
increase the participants risks. Prior to initiating telemedicine for study visits the study 
team will explain to the participant, what a telemedicine visit entails and confirm that the 
study participant is in agreement and able to proceed with this method. Telemedicine 
acknowledgement will be obtained in accordance with the Guidance for Use of 
Telemedicine in Research. In the event telemedicine is not deemed feasible, the study 
visit will proceed as an in-person visit. Telemedicine visits will be conducted using 
HIPAA compliant method approved by the Health System and within licensing 
restrictions.

 
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8 
BIOSPECIMEN STUDIES AND PROCEDURES 
 
8.1 
Tumor Tissue Studies 
 
20 unstained 5 micron thick sections (as tissue availability permits) from both the pre- 
and post-treatment tumor samples will be cut unto slides for correlative investigations.   
 
If available, three to five individual 1.0 mm diameter cores containing at least 
approximately 75% tumor cellularity will be obtained (as tissue availability permits) from 
representative pre- and post-treatment formalin fixed paraffin embedded (FFPE) tissue 
blocks.  FFPE block coring kit supplies, methodology, and shipping instructions are 
detailed in the study Clinical Lab Manual.  Some of the cores from each case will be 
incorporated in tissue microarrays (TMAs) with subsequent sections from these TMAs 
being stained with H&E and IHC; while other cores from each case with utilized for DNA 
and RNA. 
 
For all correlative studies analyzing sample DNA or RNA, if sufficient DNA/RNA is not 
available from the core biopsy samples, and as tissue availability permits, additional 
tumor and immune cells may be enriched from the subject’s pre- and post-treatment 
tumor slides by macro-dissection under the direction of Dr. Andres Matoso.   
 
Tissue samples will be transferred to Veracyte for DNA/RNA sequencing. De-identified 
clinical outcome data (i.e. responder/non-responder) correlating to each sample will be 
shared with Veracyte. An MTA will be secured between JHU and Veracyte prior to 
transfer and sharing. 
 
8.2 
Immunohistochemistry Analyses 
 
IHC analyses may be performed on tumor tissues with recurrent disease. For correlative 
IHC analyses, IHC on TMA cores will be performed using antibodies acquired from 
commercial sources at the IHC pathology core facility as follows: Immunohistochemistry 
(IHC) for PD-1 (Cell Marque, Rocklin, CA; dilution 1:100), PD-L1 (Spring Bioscience, 
Pleasanton, CA for clone SP142 dilution 1:100 - DAKO, Santa Clara, CA for clone 
22C3 predilute)  and markers of tumor infiltrating lymphocytes (TILs) CD3 (DAKO, 
dilution 1:100), CD8 (CellMarque; predilute),  CD4 (Ventana; predilute), FoxP3 (Abcam, 
Cambridge, MA; dilution 1:100), will be performed on 4 µm thick paraffin sections of the 
tissue microarray masterblock on the Ventana Discovery Autostainer (Ventana Medical 
Systems), Ventana Benchmark Ultra Autostainer (Ventana). Staining will be scored in 
blinded manner with respect to BCG response status by a GU pathologist.  As tissue 
availability permits and new data emerges, additional IHC stains of relevance may be 
performed in addition to those listed above. 
 
8.3  
Gene Expression Analyses 
 
All of these procedures will be performed in the Johns Hopkins Greenberg Bladder 
Cancer Institute’s (GBCI’s) dedicated Genomics Core (Director: Woonyoung Choi, 

 
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PhD).  Sequential extraction of total RNA and DNA is performed using a modified 
version of a protocol jointly developed by the Southwest Oncology Group’s Tissue Bank 
and TCGA.  Briefly, RNA is isolated using the High Pure FFPE miRNA isolation kit 
(Roche) according to the manufacturer’s instructions. The key variable in the protocol is 
time in proteinase K (3 hours), which promotes optimal RNA quality and yield.  The 
pellets created after the proteinase K digestion step are then used for total DNA 
purification using the QIAmp DNA FFPE kit (Thermo Fisher). RNA and DNA purity and 
integrity are measured by NanoDrop ND-1000 and Agilent Tapestation.  Whole 
transcriptome RNA sequencing and panel DNA are performed using Ion Torrent’s 
AmpliseqRNA platforms (Thermo Fisher, Inc).  The GBCI’s panel was developed in 
consultation with Peter Black and Alex Wyatt at the University of British Columbia, 
consists of 50 of the most frequently mutated genes in NMIBCs and MIBCs, and 
contains the DDR mutations highlighted in previous studies.  Dr. Wyatt has also 
developed a strategy to estimate total mutational burden (TMB) from the results 
generated with this panel(27).  Libraries are prepared using 10-20 ng purified RNA or 
20-40 ng purified DNA according to the manufacturer’s instructions, and libraries are 
sequenced on an Ion S5 XL sequencer in the Genomics Core.  Primary analyses of the 
data are performed using Torrent Suite Software package provided on the S5 XL’s 
server. Aligned and normalized data are downloaded directly from the server, and the 
total time from library preparation to data analysis is approximately 48 h for 16 samples.  
As tissue availability permits and new data emerges, additional gene expression 
platform analyses of relevance may be performed (e.g. Nanostring, HTG EdgeSeq, etc.) 
in addition to those listed above. 
 
 
8.4  
Urine Marker Processing and Analysis 
 
Urine Sample Processing 
 
A clean catch urine sample (20cc) will be collected at baseline and at the 3- and 12-
month disease assessment dates from each subject. Urine samples will be banked and 
stored in the Brady Urology Biorepository. The exact list of urine markers may be 
modified according to new target identification and emerging translational science, but 
will likely include metabolomic and gene methylation analyses, as well as immune and T 
cell profiling. A Streck tube urine sample will also be collected at baseline, 3m, and 12m 
for ctDNA studies. 
 
Urine samples will be transferred to Predicine for the aforementioned analyses. No data 
will be transferred with the samples. An MTA will be secured between JHU and 
Predicine prior to transfer.  
 
8.5  
Blood Processing and Analysis 
 
Blood will be collected for germline DNA in order to determine somatic mutations in the 
tumor tissues.  Blood samples will be banked and stored in the Brady Urology 
Biorepository. 

 
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8.6  
Confidentiality of Biospecimens 
   
Samples that are collected will be identified by a subject’s study number assigned at the 
time of registration to the trial. Any material issued to collaborating researchers will be 
anonymized and only identified by the subject’s study number. 
 
9 
CRITERIA FOR DISEASE EVALUATION 
 
For the purposes of this study, subjects should be evaluated for tumor response at the 
specified post-treatment time points.  Any metastatic progression will be evaluated in 
this study using the international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1) (see Eisenhauer EA et al. 
New response evaluation criteria in solid tumors: revised RECIST guideline (version 
1.1). Eur J Can, 2009.45:p.228-247).  
 
9.1 
Tumor Response  
 
9.1.1  Evaluable Population Definitions 
 
Evaluable for toxicity.  All subjects will be evaluable for toxicity from the time of their first 
study drug treatment. 
 
Evaluable for tumor response.  Only those subjects who have received at least one 
dose of study therapy, and undergo a restaging cystoscopy with urine cytology will be 
considered evaluable for tumor response.  These subjects will have their tumor 
response classified according to the definitions stated below.  (Note:  Subjects who 
exhibit objective disease progression prior to the end of Cycle 1 will also be considered 
evaluable.) 
 
Evaluable for Pathologic Staging.  Only those patients who have received at least one 
dose of study therapy, and undergo post-treatment cystectomy will be considered 
evaluable for pathologic staging.  These patients will have their pathologic staging 
classified according to the definitions stated below.  
 
9.1.2  Methods for Evaluation of Tumor Response 
 
The post-treatment tumor response will be determined based on the cystoscopic and/or 
bladder biopsy results (if biopsy indicated) and urine cytology results obtained during 
post-treatment tumor assessments.   
NOTE: At time points where bladder biopsies are not required by the protocol, patients 
with absence of tumor recurrence on cystoscopy and urine cytology will be classified as 
T0.  Patients with high grade UC on urine cytology but T0 stage on bladder biopsy with 
no evidence of upper tract UC will be classified as Tis.   
 

 
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These categories are summarized below. 
 
Tx 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Ta 
Non-invasive papillary carcinoma which does not invade the lamina propria 
Tis 
Carcinoma in-situ 
T1 
Tumor invades into the lamina propria but not into the muscularis propria 
T2 
Tumor invades into the muscularis propria 
 
Table 6: Biopsy T-stage 
 
9.1.3  Methods for Evaluating Pathologic Stage 
 
The post-treatment pathologic stage will be determined in patients who undergo a post-
treatment cystectomy and will be determined based on the cystectomy pathology 
staging results.  The staging definitions are summarized below. 
 
Tx 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Ta 
Non-invasive papillary carcinoma which does not invade the lamina propria 
Tis 
Carcinoma in-situ 
T1 
Tumor invades into the lamina propria but not into the muscularis propria 
T2 
Tumor invades into the muscularis propria 
T2a 
Tumor invades into the inner half of the muscularis propria 
T2b 
Tumor invades into the outer half of the muscularis propria 
T3 
Tumor invades into the perivesical tissue 
T3a 
Tumor microscopically invades the perivesical tissue 
T3b 
Tumor macroscopically invades the perivesical tissue 
T4 
Tumor invades into adjacent organs 
T4a 
Tumor invades the prostatic stroma, uterus, or vagina 

 
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T4b 
Tumor invades into the pelvic wall or abdominal wall 
 
Table 7: Pathologic T-stage 
 
Nx 
Lymph nodes cannot be assessed 
N0 
 
No lymph node metastases 
N1 
Single regional lymph node metastasis in the true pelvis (hypogastric, 
obturator, external iliac, or presacral lymph node) 
N2 
Multiple regional lymph node metastases in the true pelvis (hypogastric, 
obturator, external iliac, or presacral lymph nodes) 
N3 
Lymph node metastases to the common iliac lymph nodes 
 
Table 8: Pathologic N-stage 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
Table 9: Pathologic M-stage 
 

 
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9.1.4  Tumor Response Definitions 
 
9.1.4.1 Complete Response  
 
Complete response (CR) is defined by a post-treatment cystoscopy with bladder biopsy 
if clinically indicated with the following T-stages: T0.  In addition, patients must 
demonstrate an absence of high grade urothelial carcinoma on urine cytology.  NOTE: 
Patients with urine cytology samples demonstrating urothelial cell atypia but no 
definitive high grade urothelial carcinoma with an initial post-treatment bladder biopsy 
tumor stage of T0 are considered complete responders. 
 
9.1.4.2 Incomplete Response 
 
Incomplete response (IR) is defined by the presence of low-grade Ta urothelial 
carcinoma at the initial post-treatment tumor assessment in subjects with previous 
baseline high-grade papillary urothelial carcinoma (Ta/T1) or CIS.  NOTE: Patient’s with 
incomplete response at the initial post-treatment tumor assessment may continue and 
complete the maintenance therapy portions of the study.  
 
9.1.4.3 Non-Response 
 
Non-response (NR) is defined by persistent high-grade urothelial carcinoma of any T-
stage or the presence of low-grade T1 urothelial carcinoma at the initial post-treatment 
tumor assessment.  NOTE: Non-response patients with high-grade or low-grade T1 
tumors at the initial post-treatment tumor assessment will discontinue study therapy.  
Non-response patient’s with pre-treatment CIS and/or high grade Ta tumors with 
persistent CIS and/or high grade Ta tumors may continue on study and receive 
maintenance therapy.  Patients with a post-treatment high grade urine cytology with no 
evidence of tumor recurrence in the bladder (either visually on cystoscopy or by bladder 
biopsy/TURBT) should have full staging performed including cytology evaluations of the 
upper urinary tracts and biopsy of the prostatic urethra.  If the workup of the upper 
urinary tracts and the prostatic urethra demonstrates no evidence of high grade 
disease, the patient may continue on study and receive maintenance therapy.     
  
 
9.1.4.4 Late Complete Response 
 
Late complete response (LCR) is defined in patients demonstrating IR at the initial post-
treatment bladder biopsy who on a subsequent bladder biopsy obtained 6 months after 
the start of study treatment demonstrate the following T-stages: T0.  NOTE: Patients 
with urine cytology samples demonstrating urothelial cell atypia but no definitive high 
grade urothelial carcinoma with a 6 month post-treatment bladder biopsy tumor stage of 
T0 are considered late complete responders. 
 

 
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9.1.4.5 Progression to Muscle Invasion 
 
Progression to muscle invasion (pMI) is a post-treatment TURBT with the following T-
stages: T2-T4b.  For subjects who undergo cystectomy, progression to muscle invasion 
(pMI) is defined by post-cystectomy tumor stages with the following T-stages: T2-T4b. 
 
9.1.4.6 Progression to Metastatic Stage 
 
Progression to metastatic stage (pMet) is a post-treatment subject with the following M-
stages at any time point as assessed pathologically, radiologically, or clinically: M1.   
 
9.1.4.7 
Rate of Cystectomy 
 
Rate of cystectomy (CystR) is defined as the proportion of subjects who undergo a post-
treatment cystectomy for any reason.   
 
 
9.1.5 Tumor IHC Staining Intensity Definitions 
 
For validated IHC targets, standardized IHC staining intensity cutoffs will be utilized.  
For all other IHC targets, IHC staining will be categorized as: 
 
0
< 1% cells stained
1+
1 to < 5% cells stained
2+
5 to < 10% cells stained
3+
> 10% cells stained
 
9.2 
Survival Analyses 
 
9.2.1 Relapse-Free Survival (RFS)  
 
RFS is defined as the duration of time from start of treatment to time of first documented 
high grade bladder tumor of any stage, progression or death, whichever occurs first.   
 
NOTE: Low-grade non-muscle invasive bladder tumors detected in follow up do not 
qualify as a relapse event. 
 
9.2.1.1 12-month Relapse-Free Survival (12m-RFS) 
 
12m-RFS is defined as the proportion of patients alive and with no evidence of high 
grade bladder tumor of any stage as assessed by post-treatment tumor assessments 
performed at least 12 months after the initiation of study treatment.   
 

 
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9.2.1.2 24-month Relapse-Free Survival (24m-RFS) 
 
24m-RFS is defined as the proportion of patients alive and with no evidence of high 
grade bladder tumor of any stage as assessed by post-treatment tumor assessments 
performed at least 24 months after the initiation of study treatment.   
 
9.2.2  Overall Survival (OS) 
 
 
OS is defined as the duration of time from start of treatment to time of death. 
 
9.2.3  Cancer-Specific Survival (CSS) 
 
CSS is defined as the duration of time from start of treatment to time of death due to 
bladder cancer. 
 
 
10  
DRUG ADMINISTRATION 
Docetaxel and Gemcitabine are both commonly used pharmaceutical formulations, and 
their preparation will be according to routine institutional pharmacy protocols. 
 
 
11  
ADVERSE EVENTS 
 
The descriptions and grading scales found in the NCI CTCAE v5 will be utilized for AE 
assessment. A copy of the CTCAE v5 can be downloaded from the CTEP website at 
http://ctep.cancer.gov.  
 
11.1 Definitions 
 
11.1.1 Adverse Event (AE) 
 
An AE is any untoward medical occurrence whether or not considered related to the 
study drug that appears to change in intensity during the course of the study. The 
following are examples of AEs:  
 
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result 
of an AE (e.g., surgical insertion of central line) should not be recorded as an AE.  

 
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Disease progression should not be recorded as an AE, unless it is attributable to the 
study regimen by the site investigator. 
 
11.1.2 Serious Adverse Event (SAE) 
 
A SAE is an adverse event that: 
 
 Results in death. NOTE: Death due to disease progression should not be 
reported as a SAE, unless it is attributable by the site investigator to the study 
drug(s).  Please see additional information regarding reporting death below. 
 
 Is life-threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe) 
 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified 
procedures such as administration of chemotherapy, central line insertion, 
metastasis interventional therapy, resection of primary tumor, or elective surgery, 
will not be considered serious adverse events. 
 
 Results in persistent or significant disability/incapacity 
 
 Is a congenital anomaly or birth defect 
 
 Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions not resulting in 
hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Unexpected Adverse Event 
 
For this study, an AE is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current IB, prescribing information or when it 
is not included in the informed consent document as a potential risk. Unexpected also 
refers to AEs that are mentioned in the IB as occurring with a class of drugs or are 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.   
 

 
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11.1.4 Relatedness 
 
AEs will be categorized according to the likelihood that they are related to the study 
drug(s). Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s) 
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.2 Reporting 
 
11.2.1 Adverse Events  
 
 AEs will be recorded regardless of whether or not they are considered related to 
the study drug(s).   
 
 All AEs will be recorded in the subject’s medical record and on the appropriate 
study specific eCRF form within RedCap. 
 
 AEs should be proactively followed up.  Every effort should be made to obtain a 
resolution for all events, even if the events continue after discontinuation/study 
completion.  AEs considered related to study drug(s) will be followed until 
resolution to Grade ≤ 1 or baseline, deemed clinically insignificant, and/or until a 
new anti-cancer treatment starts, whichever occurs first. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1  Site Requirements for Reporting SAEs  
 
 SAEs will be reported on the SAE Submission Form within 1 business day of 
discovery of the event.   
 
 SAEs include events related and unrelated to the study drug(s).  
 
 All SAEs will be recorded in the subject’s medical record and on the appropriate 
study specific eCRF form within RedCap.   
 
 SAEs should be proactively followed up.  Every effort should be made to obtain a 
resolution for all events, even if the events continue after discontinuation/study 
completion. 

 
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 If a subject discontinues from treatment for reasons other than disease 
progression, and therefore continues to have tumor assessments; drug or 
procedure-related SAEs must be captured until the patient is considered to have 
confirmed PD and will have no further tumor assessments. 
 
 The site investigator is responsible for following all SAEs until resolution, until the 
subject returns to baseline status, or until the condition has stabilized with the 
expectation that it will remain chronic, even if this extends beyond study 
participation. 
 
 
11.2.3 Requirements for Reporting Pregnancy or Maternal exposure 
 
If a patient becomes pregnant during the course of the study, study drug(s) should be 
discontinued immediately.  
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) should be 
followed up and documented even if the patient was discontinued from the study.  
 
Site investigators (or designees) are responsible for submitting these safety reports to 
their respective IRBs, as per their IRB policies. 
 
12  
STUDY DESIGN AND POWER 
 
Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that the true 
3 month complete response rate is 35% will be tested against a one-sided alternative. In 
the first stage, 18 patients will be accrued. If there are 6 or fewer responses in these 18 
patients, the study will be stopped. Otherwise, 8 additional patients will be accrued for a 
total of 26. The null hypothesis will be rejected if 14 or more responses are observed in 
26 patients. This design yields a type I error rate of 0.0377 and power of 80% when the 
true response rate is 60%. 
 
Standard life table methods will be used to analyze RFS for each arm of the study and 
for each sub-type within arms of the study separately.  We will report 3, 6, 12 and 24-
four month RFS with 90% confidence bounds.   
 
The proportion of toxicities by type and grade according to the revised Common 
Terminology Criteria for Adverse Events (CTCAE) v5 will be reported with exact 95% 

 
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confidence intervals.  All patients who receive at least one dose of the study drug(s) will 
be evaluable for toxicity.  
 
 
13 TRIAL MANAGEMENT  
 
13.1 Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019). The SMC 
Subcommittee will determine the level of patient safety risk and level/frequency of 
monitoring. 
 
13.2    Data Management 
 
All information will be collected on study-specific case report forms (CRFs) by study staff. 
These data will be reviewed for completeness and accuracy by the Principal 
Investigator. Protocol-specified source documents and copies of all  study-related 
documentation will be retained at the site. It is the responsibility of the Principal 
Investigator to keep all data and essential documentation for a minimum of 5 years after 
the end of the trial. 
 
 
 
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