Phase II Study to Evaluate the Response to 2 Induction Courses (12 Intravesical Instillations) of Bacillus Calmette-Guérin (BCG) for High Risk Superficial Bladder Cancer
Phase: PHASE2
Conditions: Bladder Cancer, High Risk Superficial
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Phase II study to evaluate the response to 2 induction courses ( 
Bacillus Calmette-Guérin (BCG) for high risk superfici 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PR 
Principal 
Harry W. Herr, MD 
Investigator/Department: 
12 intravesical instillations) of 
al bladder cancer 
OTOCOL 
Dept of Surgery – Urology 
Co-Principal 
S. Machele Donat, MD 
Investigator(s)/Department: 
Dept of Surgery – Urology 
Investigator(s)/Department: 
Bernard H. Bochner, MD 
Eugene K. Cha, MD 
Jonathan A. Coleman, MD 
Guido Dalbagni, MD 
Timothy Donahue, MD 
Alvin Goh, MD 
Ari Hakimi, MD 
Vincent P. Laudone, MD 
Eugene Pietzak, MD 
Paul Russo, MD 
Jaspreet S. Sandhu, MD 
Robert Charles Smith, MD 
Hikmat Al-Ahmadie, MD 
Oscar Lin, MD 
Daniel D. Sjoberg, MS 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Pathology 
Pathology 
Epidemiology and Biostatistics 
Consenting 
Harry W. Herr, MD 
Professional(s)/Department: 
S. Machele Donat, MD 
Bernard H. Bochner, MD 
Eugene K. Cha, MD 
Jonathan A. Coleman, MD 
Guido Dalbagni, MD 
Timothy Donahue, MD 
Alvin Goh, MD 
Ari Hakimi, MD 
Vincent P. Laudone, MD 
Eugene Pietzak, MD 
Paul Russo, MD 
Jaspreet S. Sandhu, MD 
Robert Charles Smith, MD 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology; 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
Dept of Surgery – Urology 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program 
 
OneMSK Sites 
Manhattan 
Westchester 
Basking Ridge 
Monmouth 
Commack 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
Page 1 of 17 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 2 of 17 
 
 
 
 
Table of Contents 
 
1.0        PROTOCOL SUMMARY AND/OR SCHEMA…………………………………………………..4 
2.0        OBJECTIVES AND SCIENTIFIC AIMS…………………………………………………………4 
3.0         BACKGROUND AND RATIONALE……………………………………………………………..5 
3.1 
Natural History of Bladder Cancer………………………………………………………………5 
3.2 
Recurrence………………………………………………………………………………………..5 
3.3 
Progression……………………………………………………………………………………….6 
3.4 
Priming of the Immune System…………………………………………………………………6 
3.5 
Rationale…………………………………………………………………………………………..6 
4.0        OVERVIEW OF STUDY DESIGN/INTERVENTION ………………………………………    7 
4.1 
Design……………………………………………………………………………………………..7 
4.2 
Intervention……………………………………………………………………………………. ....... 7 
5.0         THERAPEUTIC/DIAGNOSTIC AGENTS……………………………………………………….8 
6.0        CRITERIA FOR SUBJECT ELIGIBILITY…………………………………………………….   8 
6.1 
Subject  Inclusion  Criteria………………………………………………………………………..9 
6.2 
Subject  Exclusion  Criteria……………………………………………………………………. ... 9 
7.0        RECRUITMENT PLAN…………………………………………………………………………    9 
8.0        PRETREATMENT EVALUATION…………………………………………………………….   10 
9.0         TREATMENT/INTERVENTION PLAN………………………………………………………….11 
10.0       EVALUATION DURING TREATMENT/INTERVENTION…………………………………….12 
11.0       TOXICITIES/SIDE EFFECTS……………………………………………………………………12 
12.0      CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT………………13 
13.0     CRITERIA FOR REMOVAL FROM STUDY……………………………………………….     13 
14.0      BIOSTATISTICS……………………………………………………………………………….     14 
15.0      RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research  Participant  Registration…………………………………………………………. ..... 14 
16.0      DAT A M ANAGEMENT ISSUES…………………………………………………………………15 
16.1 
Quality Assurance ........................................................................................................ 15 
16.2 
Data and Safety Monitoring ............................................................................................. 15 
17.0 
PROTECTION  OF HUMAN  SUBJECTS……………………………………………………….16 
17.1 Privacy .................................................................................................................................. 16 
17.2 
Serious Adverse Event (SAE) Reporting .............................................................................. 16 
17.2.1.........................................................................................................................................16 
18.0  INFORMED CONSENT PROCEDURES……………………………………………………….18 
19.0   REFERENCES…………………………………………………………………………………….19 
20.0       APPENDICES……………………………………………………………………………………..19 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 3 of 17 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title: Phase II study to evaluate the response to 2 induction courses (12 intravesical 
instillations) of Bacillus Calmette-Guérin (BCG) for high risk superficial bladder cancer 
The main objective of this study is to evaluate the response rate to 2 induction courses (12 
intravesical insti llations) of BCG, in patients with high risk superficial bladder cancer, at 6 
months after the initiation of therapy. We will enroll BCG naïve patients, as well as patients 
previously treated with BCG who completed therapy 12 months prior to enrollment in this 
study. The current standard of care for patients with high risk superficial bladder cancer is 1 
induction course (6 intravesical instillations) of BCG, but this treatment course has not been 
effecti ve in a randomized trial. The goal of the proposed study is to identify a more effective 
BCG regimen to treat high risk superficial bladder cancer. 
Study Design and Treatment plan 
Patients will be treated with an induction course (6 intravesical instillations) of BCG followed 
by a second induction course (6 intravesical instillations), with a recovery period between 
the 2 treatment courses. 
 
 
 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective 
• To evaluate the response rate (by cystoscopy and cytology) to 2 induction 
courses (12 intravesical instillations) of BCG 6 months after the initiation of 
therapy. 
Secondary Objective 
 
• To establish the proportion of patients who progress to muscle invasi ve 
disease within 6 months of initiation of a 2-induction course (12 intravesical 
instillations) of BCG. 
6 month follow 
up from 
treatment 
initiation 
Treated with 2nd 
induction course (6 
intravesical 
instillations) of BCG 
Treated with 1st 
induction course (6 
intravesical 
instillations) of BCG 
3 month follow 
up from 
treatment 
initiation 
Patients with high 
risk superficial 
bladder cancer 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 4 of 17 
 
 
 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 Natural History of Bladder Cancer 
 
Of the more than 70,000 cases of bladder cancer diagnosed in the United States 
each year, approximately 70% are found to be non-muscle invasive tumors, 25% are 
muscle invasive, and 5% are metastatic [1]. Non-muscle invasive tumors encompass 
non-invasi ve papillary (Ta), invasi ve into the connective tissue (T1), and carcinoma in 
situ (Tis) tumors, with a 60%, 30%, and 10% occurrence, respecti vely. Sixty percent 
to 70% of these tumors will recur within 2 years, whereas 20% to 30% will progress  
to a higher grade or stage during the patient‟s lifetime [2]. High-risk non-muscle- 
invasi ve bladder disease excludes Ta low grade tumors because even though these 
tumors possess a high recurrence rate, they rarely progress to muscle-invasi ve 
disease. On the other hand, T1 tumors represent a heterogeneous group : some T1 
tumors behave in an indolent fashion, respondi ng to conservati ve therapy; others 
behave in a more aggressi ve manner and progress to muscle-i nvasive disease, 
giving them the potential to develop metastatic disease. We currently lack the ability 
to predict how T1 tumors will behave. What we do know is that recurrence of bladder 
tumors is dependent on size, site, multifocality, presence of concomitant Tis, grade, 
and prior history of bladder cancer [3]. At MSK, the current therapy for high-risk non- 
muscle-invasi ve tumors includes transurethral resection (TUR) followed by the 
instillation of BCG weekly for 6 weeks. 
3.3 Recurrence 
 
Recurrence of high-risk non-muscle-invasi ve bladder cancer depends on multiple 
factors as described above. Thirty percent to 90% of patients treated with TUR alone 
experience recurrence within 2 years. In a prospecti ve longitudinal study, the  
National Bladder Cancer Collaborative Group A (NBCCGA) followed 133 patients 
treated with TUR alone and found that the following factors increased recurrence 
rates: tumors >5 cm, multiple tumors, grade 3 disease, concomitant Tis, T1 disease, 
and a positive cytologic finding [4]. The high recurrence rate observed in patients 
treated with TUR alone has led to the use of intravesical immunotherapy with BCG as 
a supplement to help decrease recurrence. Furthermore, multiple randomized trials 
have shown that TUR with BCG has superior recurrence-free rates, compared with 
TUR alone or TUR with intravesical chemotherapy [5, 6]. Thus, TUR with intravesical 
BCG has become the standard of care for patients with high-risk non-muscle-i nvasive 
bladder tumors and has been incorporated into multiple guidelines [3, 7]. 
Unfortunately, an audit of 1021 patients at MSK treated with intravesical BCG for 
high-risk non-muscle-invasi ve bladder cancer revealed that 13.7% (140/1021) of 
these patients did not have a response to therapy at 3 months from the start of BCG 
therapy. Furthermore, 20% (205/1021) and 32% (326/1021) did not have a response 
at 6 and 12 months, respecti vely. When patients without a response at 3 months 
were combi ned with patients with a recurrence at 6 months, 34% of patients 
experienced treatment failure at 6 months [8]. Many new treatments, such as 
intravesical chemotherapies and different dosi ng regimens of BCG, have attempted 
to decrease the high rate of treatment failure among patients with non-muscle-  
invasi ve bladder cancer; however, none have been successful [9]. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 5 of 17 
 
 
 
 
 
 
3.4 Progression 
 
Progression to muscle-invasi ve disease or development of metastasis occurs in 20 to 
30% of patients who present with non-muscle-i nvasive bladder cancer. The NBCCGA 
identified tumor grade, T1 disease, and Tis as indicators of progression. Additionally, 
45% of patients with grade 3 disease experienced progression, the majority of these 
progressing within 24 months [4]. Herr et al. reported that 40% of patients with T1 G3 
disease experienced progression [10]. Both recurrence and progression are 
associated with higher grade and stage of disease. Unfortunately, even with these 
advances in our understanding, we still cannot predict with certainty which tumors will 
progress. Thus, many trials are currently investigating better ways to treat and control 
non-muscle-i nvasive bladder cancer. 
3.5 Priming of the Immune System 
 
BCG therapy causes a strong innate immune response, specifically via the acti vation 
of CD4+ and CD8+ T lymphocytes [11-13]. This response was shown to be the main 
factor responsible for eliminating tumor in a mouse model, and a correlation was 
demonstrated between T cell infiltration and clinical response in patients [14, 15]. In 
vivo studies using urine and blood proteomic and cytometric screens have 
demonstrated that several insti llations of BCG are needed to produce a robust 
immune response [16]. More specifically, whereas the immune system is acti vated 
after the first instillation of BCG, the response is significantly amplified after the third 
treatment. These findings led to the hypothesis that the effects of BCG therapy are 
heightened after priming of the immune system. Furthermore, a recent study showed 
that BCG-specific immunity improved antitumor response in a mouse model of 
bladder cancer [16]. Mice whose bladders were primed with 3 insti llations of BCG, at 
days 0, 7, and 14, had a more robust T cell bladder wall infiltration when compared to 
the control group. The authors of this study also observed BCG dissemination to 
regional lymph nodes and priming of IFN-γ-producing T cells after 1 instillation of 
BCG and that these responses were more robust after repeated instillations. Finally, 
the authors demonstrated that patients with preexisti ng immunity to BCG, those who 
were PPD-positive, responded significantly better to intravesical BCG, compared with 
the PPD-negati ve control group [16]. The authors concluded that patient immunity to 
BCG should be assessed before initiating therapy. If patient immunity is found to be 
insufficient, it should be boosted via priming; this action may improve the response to 
BCG. 
3.6 Rationale 
 
1. The standard care for patients with high-risk non-muscle-invasi ve bladde cancer 
who do not respond to BCG treatment is radical cystectomy. Surgery with radical 
cystectomy is associated with a complication rate of up to 60%, as well as with poor 
self-image owing to external urine collecti ng devices. There is a need for a more 
efficient non-surgical approach for patients with these tumors. 
2. The current treatment regimen of 6 intravesical treatments with BCG is arbitrary. 
The proposed study will test the efficacy of a new regimen of BCG treatments. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
 
 
 
3. The proposed study will attempt to define the acceptable cli nical toxicity profile of 
intravesical BCG. 
4. There is a need to increase the durability of the response to intravesical BCG; the 
treatment regimen in the proposed study will attempt to address this. 
 
5. The proposed study will incorporate recent data that provided new insight into the 
T cell acti vity in response to BCG therapy. Furthermore, we will focus on the idea that 
priming the immune system will result in a more robust immunologic response  
against any tumor that is present. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
The study will use a single-stage phase II design. We are interested in the 2- 
induction BCG therapy if the overall response rate is ≥80% and not interested if the 
overall response rate is ≤66%. The probabilities of a type I error and type II error are 
set at 0.05 and 0.20, respectively. 
We will enroll continue enrolling patients until 75 patients have completed their 
second cystoscopy on study.. On completion of the trial, if ≥52 patients had a 
response, the regimen will be declared effective and of interest. 
4.3 
Intervention 
 
Rationale: The current regimen of 6 intravesical instillations of BCG for high risk 
superficial bladder cancer is arbitrary. No randomized trials have been performed to 
identify the optimal number of intravesical BCG instillations needed to obtain the 
lowest recurrence rates. 
Treatment Plan: Patients with high risk superficial bladder cancer will be treated with 
2 induction courses (12 intravesical instillations total) of BCG. Patients will undergo a 
diagnostic TUR which will include a urine cytology when possible to evaluate their 
bladder tumor/tumors, a past TURBT and urine cytology within 60 days of treatment 
initiation will also suffice. If the pathological characteristics of the tumors result in the 
patient being deemed eligible, they will be asked to enroll in the study. A prior/current 
history and physical examination will also be evaluated. After the first induction 
course (6 intravesical instillations) of BCG, patients will be scheduled for a 
cystoscopy at 3 months (+/- 4 weeks). During this 3 month cystoscopy appointment 
patients will again submit a urine cytology prior to the procedure. If worsening tumor 
is found a TURBT will be scheduled at the physicians discretion. All enrolled patients 
will be evaluated for the primary endpoint, as defined in section 14.0, of the study, 
regardless of whether they recei ved the full course of treatment. 
 
 
 
 
 
 
Treated with 2nd 
6 month follow 
up from 
 
Page 6 of 17 
Treated with 1st 
induction course (6 
intravesical 
instillations) of BCG 
3 month follow 
up from 
treatment 
initiation 
Patients with high 
risk superficial 
bladder cancer 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 7 of 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Agent: BCG for Intravesical Use 
Source of supply: TICE 
 
Licensing agreement: 
 
Mechanism of Action: BCG induces a granulomatous reaction at the local site of 
administration. The exact mechanism of action is unknown. 
Formulation, Packaging, and Storage: BCG is supplied in a box containing 1 vial. Each 
vial contains 1 to 8 × 108 CFU, which is equivalent to approximately 50 mg (wet weight), as 
lyophilized (freeze-dried) powder. The intact vials should be stored refrigerated, at 2° to 8°C 
(36° to 46°F), and should be protected from direct sunlight. The product should not be used 
after the expiration date printed on the label. 
Dosage Regimen and Administration: BCG will be administered at a dose of 1 vial (50 
mg) per instillation. The suspension should be prepared using aseptic technique. The 
administration instructions are as follows: Draw 1 mL of sterile saline (0.9% sodium chloride 
injection USP) at 4o to 25o into a small syringe (e.g., 3 mL) and resuspend 1 vial of BCG. 
Gently swirl until a homogenous suspension is obtained. Avoid forceful agitation, which may 
cause clumping of the mycobacteria. Dispense the cloudy BCG suspension into the top end 
of a catheter-tip syringe that contains 49 mL of sali ne diluent, bringing the total volume to 50 
mL. Gently invert the syringe to mix. After the bladder has been drained, usi ng a Foley 
catheter, gently instill the 50 mL mixture into the patient‟s bladder. 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
• Age eligibility: 18 years and older 
• Sex eligibility: Both 
• Accepts healthy volunteers: No 
 
6.2 
Subject Inclusion Criteria 
 
• Patients must have high risk non-muscle invasi ve urothelial bladder carcinoma (Tis, 
TaHG, or T1) that is pathologically confirmed by the Memorial Sloan Kettering 
Department of Pathology or a documented history of TaHG or T1 non-muscle  
invasi ve urothelial bladder tumors. 
• All visible papillary lesions must be macroscopically resected within 60 days of 
treatment initiation. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 8 of 17 
 
 
 
 
• Absence of urothelial carci noma involving the upper urinary tract (documented by 
radiological imaging or biopsy) preferably within 12 months from the start of 
treatment. Should the imaging or biopsy be performed outside this window it will be 
up to the physicians discretion to re-scan/biopsy. 
• Patients who have received a single dose of mitomyci n C following stagi ng TUR. 
 
 
6.3 
Subject Exclusion Criteria 
 
• Currently being treated or scheduled to have radiation treatment for bladder cancer 
during the study. 
• Treatment with intravesical BCG or chemotherapy for a patient‟s current <T2 tumor 
during the 12 months prior to the current diagnosis. 
• Currently being treated or scheduled to have treatment with any systemic or 
intravesical chemotherapeutic agent during the study. 
• Currently being treated with or having been treated in the last 12 months with any 
investigational drug for high risk superficial bladder cancer. 
• Currently being treated for metastatic transitional cell carci noma. 
• Scheduled to have surgery for bladder cancer during the study. 
• Presence of cli nically significant infections or congenital or acquired 
immunodeficiency. 
 
7.0 
RECRUITMENT PLAN 
 
All MSK patients with a diagnosis of high risk superficial bladder cancer (TaHG, T1, Tis) 
who have not received any treatment within 12 months of the current diagnosis or who have 
a new diagnosis will be offered participation in the protocol. Both sexes and all racial and 
ethnic groups will be eligible to participate in this clinical trial, provided all the other eligibility 
criteria are met. Eligible research subjects will be identified by a member of the patient‟s 
treatment team, one of the protocol investigators, or the research team at MSK. If the 
investigator is a member of the treatment team, he or she will screen their patients‟ medical 
records for suitable research study participants. When a potential participant is identified, 
the investigator will inform the patient about this study and discuss the possibility of 
enrolling. Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study. 
The principal investigator may also screen the medical records of patients with whom he or 
she does not have a treatment relationship, for the limited purpose of identifying patients 
who would be eligible to enroll in the study. The principal investigator would record 
appropriate contact information so that these patients could be approached regarding the 
possibility of enrolling in the study. 
 
If a patient meets the eligibility criteria defined in section 6.0 and agrees to participate in the 
study, one of the Consenti ng Professionals listed on page 1 will conduct the Informed 
Consent process with the patient. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 9 of 17 
 
 
 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of the patient‟s MSK medical records to further assess eligibility. They will use the 
information provided by the patient and/or medical record to confirm that the patient is 
eligible and to contact the patient regarding study enrollment. If the patient turns out to be 
ineligible for the research study, the research staff will destroy all information collected on 
the patient during the initial conversation and medical records review, except for any 
information that must be maintained for screeni ng log purposes. 
 
In most cases, the initial contact with the prospecti ve subject will be conducted by either the 
treatment team, investigator, or research staff worki ng in consultation with the treatment 
team. The recruitment process outlined above presents no more than minimal risk to the 
privacy of the patients who are screened, and minimal protected health information (PHI)  
will be maintained as part of a screeni ng log. For these reasons, we seek a (partial) limited 
waiver of authorization for the purposes of (1) reviewing medical records to identify potential 
research subjects and to obtain information relevant to the enrollment process; (2) 
conversi ng with patients regarding possible enrollment; (3) handling of PHI contai ned within 
those records and provided by the potential subjects; and (4) maintaining information in a 
screeni ng log of patients approached (if applicable). 
 
 
Patients will not be paid to participate in this study. Study participants will be responsible for 
some or all costs associated with the cancer treatment they receive during the study. 
8.1 
PRETREATMENT EVALUATION 
 
Screening 
• Informed Consent 
Pre-Treatment Evaluation 
• History and physical exam 
• TUR or biopsy of bladder tumor (within 60 days of treatment initiation) 
o Urine cytology will be included with this TURBT whenever possible. 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Patients enrolled in the study will receive 6 consecuti ve intravesical BCG treatments. After 
the 3 month follow-up cystoscopy appointment, patients will undergo another set of 6 
intravesical BCG treatments. Each set of BCG treatments will include 6 injections within a 
recommended 6 weeks, a regimen that is within the standard of care. Any delay of 
treatment will be allowable per standard of care BCG treatment procedures. Such 
disruptions may include but are not limited to unforeseen circumstances, institutional 
holidays, or patients‟s schedule. 
9.2 BCG suspension and administration procedures 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 10 of 17 
 
 
 
 
Study participants will undergo intravesical treatment with approximately 1 to 8 x108 
CFU of BCG (1 vial), which is equivalent to approximately 50 mg (wet weight), 
lyophilized (freeze-dried) powder. 
The suspension will be prepared using aseptic technique. The steps are as follows: 
1. Draw 1 mL of sterile sali ne (0.9% sodium chloride injection USP) at 4o to 25o 
into a small syringe (e.g., 3 mL) and resuspend 1 vial of BCG. 
2. Resuspend 1 vial of BCG by gently swirling until a homogenous suspension is 
obtained. Avoid forceful agitation, as this may cause clumping of the 
mycobacteria. 
3. Dispense the cloudy suspension into the top end of a catheter-tip syringe that 
contai ns 49 mL of sali ne diluent, bringing the total volume to 50 mL. 
4. Gently invert the syringe to mix. 
Administration: 
1. Place a small gauge (i.e., 14fr) Foley catheter and empty the patient‟s bladder 
of any residual urine. 
2. Instill the 50 mL of resuspended BCG into the bladder through the Foley 
catheter. 
3. Remove the Foley catheter. 
4. The patient will be instructed not to urinate for a minimum of 1 hour. 
9.3 Monitoring and compliance 
 
The treatment will be instilled in an outpatient MSKCC facility by a trained 
professional. After each treatment, the patient will be assessed for toxicity. If patients 
experience toxicity between the scheduled visits, they will be instructed to contact 
their physician‟s office for further instruction, assessment, or treatment. 
Intravesical BCG does not have systemic interactions. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
3 months (+/- 4 weeks) after initiation of therapy 
• Urine cytology 
• Cystoscopy 
• TUR will be scheduled (at physician‟s discretion) 
6 months (+/- 4 weeks) after initiation of therapy 
• Urine cytology 
• Cystoscopy 
• TUR will be scheduled (at physician‟s discretion) 
 
 
Evaluation 
Pretreatment 
screeni ng 
3 months 
(+/- 4 weeks) after 
initiation of therapy 
6 months 
(+/- 4 weeks) after 
initiation of therapy 
History and physical 
x 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 11 of 17 
 
 
 
 
 
Urine cytology 
x 
x 
x 
Cystoscopy 
x 
x 
Trans-urethral 
resection tumor* 
x 
(within 60 days of 
treatment initiation) 
x 
(*will be scheduled at 
physician‟s discretion) 
x 
(*will be scheduled at 
physician‟s discreton) 
 
11.1 TOXICITIES/SIDE EFFECTS 
• At each follow-up visit, enrolled patients will be evaluated for toxicities and side 
effects due to therapy. As is standard of care a Nursi ng Treatment/Assessment form 
will be used to record any toxicities and side effects. A research assistant will follow 
the patient and maintain a record of toxicities and side effects that are possibly, 
probably or definitely related to protocol therapy and will be documented on the 
CTCAE toxicities form and collected for data entry. Only toxicities that are considered 
Grade > 2, per CTCAE version 4.0 will be captured for this trial. 
 
• Clinically insignificiant symptoms/fi ndings of expected symptoms listed below that 
may be collected in the Nursing Treatment/Assessment form will not be graded or 
attributed on the toxicities forms. 
 
o Symptoms of bladder irritability, which are related to the inflammatory 
response that is induced by BCG, include urgency and frequency of urination, 
cystitis, nocturia, and pelvic pain. Symptoms occur in approximately 60% of 
patients receivi ng intravesical BCG. Symptoms are usually treated with 
symptomatic control using medicines such as propantheline bromide, 
oxybutyni n chloride, and acetaminophen. Symptoms are not related to dose. 
 
o Hematuria is another potential side effect that is also related to the 
inflammatory response induced by BCG. This occurs in approximately 25% of 
patients treated with BCG and is usually self-limiting. 
 
o “Flu-like” symptoms (malaise, fever, and chills) often reflect hypersensiti vity 
reactions to BCG. These symptoms occur in approximately 33% of patients 
and can be treated symptomatically with medicines such as antihistami nes 
and acetaminophen. 
 
o The following adverse events were reported in ≤1% of patients: anemia, BCG 
sepsis, coagulopathy, contracted bladder, diarrhea, epididymitis/prostatitis, 
hepatic granuloma, hepatitis, leukopenia, neurologic (unclassified) symptoms, 
orchitis, pneumonitis, pyuria, rash, thrombocytopenia, urethritis, and urinary 
obstruction. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Patient response/outcome will be assessed by both urine cytology and cystoscopy at 6 
months after initiation of therapy. 
Patients who have a response are those who have no evidence of disease in their bladder 
by both urine cytology and cystoscopy. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-174 A(10) 
Approval date: 27-Nov-2017 
Page 12 of 17 
 
 
 
 
Patients whose disease remains at the same stage or is downstaged without complete 
resolution are considered nonresponders and will be documented as having recurred. Any 
positive result for either cystoscopy or cytology exam will be followed by TURBT at the 
physician‟s discretion. 
Patients with worsening tumor, defined as the upstaging from non-muscle invasi ve to 
muscle invasive disease, or metastatic disease will be documented as disease progression. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops progressi ve disease or experiences an unacceptable 
toxicity, the patient will be referred to receive standard treatment. An unacceptable toxicity is 
defined as severe frequency, dysuria or pain. Patients that cannot tolerate BCG instillations 
and refuse due to side effects are also defined as unacceptable toxicity. These patients will 
be evaluable for the primary endpoint of the study. 
Patients with progressive disease will be considered to have experienced treatment failure, 
and patients with toxicities will have their outcomes ascertai ned 6 months after the initiation 
of the first BCG treatment. The number of patients, who do not complete therapy, and the 
reasons for not completi ng therapy, will be included in the final study report. 
If at any time the patient is found to be ineligible for the protocol as designated in the section 
on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient will be 
removed from the study. 
Patients who are removed from the study due to withdrawal of consent or who are lost to 
follow-up will not be considered evaluable and will be replaced. 
14.0 
BIOSTATISTICS 
 
A  detailed explanation of the study design including the rational for the research can be found in 
section 3.0 of the protocol. 
 
Primary endpoint 
 
The study will employ a single-stage design. We are interested in the 2-induction BCG 
therapy if the overall response rate is ≥80% after the initiation of the first BCG therapy and 
not interested if the overall response rate is ≤66%. The probabilities of a type I error and 
type II error are set at 0.05 and 0.20, respectively. We will conti nue enrolling patients until 
75 patients have completed their second cystoscopy on study. On completion of the trial, if 
≥52 patients had a response, the regimen will be declared effective and of interest. All 
patients who meet the eligibility criteria for the study and enroll in it will be included in the 
analysis, regardless of whether they completed the full 2 BCG induction courses. 
Secondary endpoints 
 
We will also assess the proportion of patients whose disease progresses at 6 months. The 6 
month progression rate will be presented along with a 95% confidence interval based on the 
binomial distribution. 

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Accrual 
 
We estimate 3-5 patients per month will be accrued to this protocol. 
 
15.1 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.2 Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration proc ess registering individuals will be required to 
complete a protocol specific Eligibility Checklist. 
 
The individual signing the Eligibility Checklist is confirming that the partic ipant is eligible 
to enroll in the study. Study staff are responsible for ensuring that all institutional 
requirements necessary to enroll a partic ipant to the study have been completed. See 
related Clinical Researc h Policy and Procedure #401 (Protocol Partic ipant Registration). 
 
 
16.1 DATA MANAGEMENT ISSUES 
 
A research study assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and 
coordination of the activities of the protocol study team. The data collected for this 
study will be entered into Caisis, a secure departmental database. A minimal data set 
will be added to CRDB. Source documentatio n will be available to support the 
computerized patient record. 
16.2 Quality Assurance 
 
Monthly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period, 
and potential problems will be brought to the attention of the study team for 
discussion and action. Random-sample data quality and protocol compliance audits 
will be conducted by the study team at a minimum of once every 6 months, and more 
frequently if indicated. 
16.3 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001.  The 
plans address the new policies set forth by the NCI in the document entitled “Policy of 
the National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which 

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can be found at:  http://ca ncertrials.nci.nih.go v/researc he rs/dsm/inde x.html. 
The 
DSM Plans at MSKCC were established and are monitored by the Clinical Research 
Administration.  The MSKCC Data and Safety Monitoring Plans can be found on the 
MSKCC Intranet at: h ttp://msk web2.mskcc.org /irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for 
data, safety and quality.  There are institutional processes in place for quality 
assurance (e.g., protocol monitoring, compliance and data verification audits, 
therapeutic response, and staff education on clinical research QA) and departmental 
procedures for quality control, plus there are two institutional committees that are 
responsible for monitoring the activities of our cli nical trials programs.  The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III cli nical 
trials, report to the Center‟s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed 
for its level of risk and degree of monitoring required. Every type of protocol (e.g., 
NIH sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, 
etc.) will be addressed and the monitoring procedures will be established at the time 
of protocol activation. 
17.1 PROTECTION OF HUMAN SUBJECTS 
 
17.2 Privacy 
 
MSKCC‟s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The 
use and disclosure of protected health information will be limited to the individuals 
described in the Research Authorization form. A Research Authorization form must 
be completed by the Principal Investigator and approved by the IRB and Privacy 
Board (IRB/PB). 
The recruitment process presents no more than minimal risk to the privacy of the 
patients who are screened and minimal protected health information (PHI) will be 
maintained as part of a screeni ng log. For these reasons, we seek a (partial) limited 
waiver of authorization for the purposes of (1) reviewing medical records to identify 
potential research subjects and obtain information relevant to the enrollment process; 
(2) conversi ng with patients regarding possible enrollment; (3) handling of PHI 
contai ned within those records and provided by the potential subjects; and (4) 
maintaining information in a screeni ng log of patients approached (if applicable). 
17.3 Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 

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• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be li fe threatening, or 
require hospitali zation may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not 
considered an SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or 
intervention. Any events that occur after the 30-day period and that are at least 
possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of 
Serious Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar 
days of the event. The IRB requires a Clinical Research Database (CRDB) SAE 
report be submitted electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org. All other reports should be sent to saemski nd@mskcc .org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org. All other reports should be sent to sae@mskcc .org. 
The report should contai n the following information: 
Fields populated from CRDB: 
• Subject‟s initials 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and ti tle 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 

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• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
 
The PI‟s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: The CRDB SAE report should be completed as per above 
instructions.  If appropriate, the report will be forwarded to the FDA by the SAE staff 
through the IND Office 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenti ng professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form will meet the requirements of 
the Code of Federal Regulations and the Institutional Review Board/Privacy Board of this 
Center. The consent form will include the following: 
1. The nature, objecti ves, potential risks, and potential benefits of the intended 
study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supporti ve care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/i nteractions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenti ng professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenti ng professional will sign the consent form. The participant 
must recei ve a copy of the signed informed consent form. 

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19.0 
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Prescott, S., et al., Intravesical Evans strain BCG therapy: quantitative immunohistochemical 
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Bisiaux, A., et al., Molecular analyte profiling of the early events and tissue conditioning 
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20.0 
APPENDICES 
 
There are no appendices.