Clinical trial NCT02324582
Conditions: Bladder Cancer
Keywords: Urinary Bladder Neoplasms Mycobacterium bovis Programmed Cell Death 1 Receptor pembrolizumab
Sponsor: Southern Illinois University
Start date: 2015-06-01; Completion date: 2023-03-27
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single center Phase I safety and efficacy study of MK-3475 therapy used in combination with bladder infused BCG treatment for patients, 18 years or older, with high risk superficial bladder cancer (cancer not yet involving the muscle of the bladder wall) who have had removal of their bladder tumor. Patients will be enrolled to a single treatment group of a fixed dose of MK 3475 and BCG.

Detailed description:
Bladder cancer is the fifth most common cancer in the United States. This is a single center Phase I safety and efficacy study of MK-3475 therapy used in combination with bladder infused BCG treatment. The study will determine the safety of administering MK-3475 at a fixed dose every three weeks in conjunction with intravesicular BCG treatment in non-muscle invasive bladder cancer patients who had recurrence after two courses of induction (6 doses) intravesical therapy (two BCG courses, or one BCG course and one other approved intravesical therapies) administered within 12 months, or after one induction (6 doses) and one maintenance (3 doses) intravesical therapy (BCG). Subjects will have confirmation of bladder cancer non-invasive to the muscle. Approximately 20 subjects will be screened to treat 15 eligible subjects with high risk superficial bladder cancer who have had transurethral resection of their bladder tumor.

The rationale for the use of the indicated dose of TICE® BCG is based upon FDA approved and commercially provided package insert/ instructions for use of the product. BCG installation has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation.

The first 3 subjects will be treated at a dose of 100 mg MK-3475 to ensure safety for the combination. If no safety or efficacy issues are present, dosing will be escalated to 200 mg MK-3475 every 3 weeks.

Arms: arm 1: 3 subjects will be treated at a dose of 100 mg MK-3475 at 100 mg every 3 weeks (Q3W) intravenously (IV) for 6 doses and 1 vial intravesicular BCG suspended in 50 ml preservative-free saline once per week of 6 weekly doses 12 subjects will be treated at a dose of 200 mg MK-3475 at 100 mg every 3 weeks (Q3W) intravenously (IV) for 6 doses and 1 vial intravesicular BCG suspended in 50 ml preservative-free saline once per week of 6 weekly doses
Interventions: intervention 1: Intravenous MK-3475/ Intravesical BCG
Intervention descriptions: intervention 1: 6 cycles (each cycle is 21 days) of pembrolizumab will be given over 9 weeks in combination with BCG. BCG treatment will begin on Day 1 of cycle 3 of pembrolizumab.

Protocol documents:
Prot_SAP_000.pdf: 
Product:  MK-3475  
 
Protocol/Amendment No.:  Amendment 5, October 21, 2019 
 
 
 
Page 1 of 89 
 
 
SPONSOR: Southern Illinois University School of Medicine 
 
CO-PRINCIPAL INVESTIGATORS: 
 
Shaheen Alanee, MD, MPH (Henry Ford Health System) 
Krishna Rao, MD, PhD 
 
TITLE: Phase I Study of MK-3475 in Combination with BCG for Patients with 
High Risk Superficial Bladder Cancer 
 
IND NUMBER: 125979 
 
NCT NUMBER: NCT02324582 
 
SCI PROTOCOL NUMBER:  014-001SBC 
 
MERCK INVESTIGATOR TRIAL NUMBER:  IISP Sana (Previously Alanee) 51637 
 
ORIGINAL PROTOCOL DATE: 05 Nov 2014 
REVISION DATES: Revision 1, 01 March 2015; Revision 2, 07 April 2015, Revision 3, 
14 March 2016; Amendment 5, 21 October 2019 
AMENDMENT DATES:  
Amendment 1, 28 March 2016, Revision 1, 22 April 2016 
 
 
 
 
Amendment 2, 27 July 2016, Revision 1, 31 Jan 2017 
 
 
 
 
Amendment 3, 20 April 2017, Revision 1, 08 August 2017 
 
 
 
 
Amendment 4, 27 September 2018 
 
 
 
 
Amendment 5, 21 October 2019 
 
FUNDING AGENT: MERCK & Co., Inc. 
 
 


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PRINCIPAL INVESTIGATOR CONTACT: 
 
Krishna Rao, MD, PhD 
Associate Professor 
Division of Hematology/ Oncology 
Department of Internal Medicine 
PO Box 9677 
Simmons Cancer Institute 
Springfield, IL 62794-9677 
217-545-7969 
krao@siumed.edu 
James O. Peabody, M.D. 
Senior Staff Physician 
Henry Ford Hospital  
Vattikuti Urology Institute 
2799 W. Grand Blvd, K9 
Detroit, MI 48202 
(313) 916-2064 
jpeabod1@hfhs.org 
 
Collaborator:  
Shaheen Alanee, MD, MPH, MBA 
Physician 
Detroit, MI 48202 
      shaheen.alanee@gmail.org 
 
PROJECT MANAGER:  Kathy Robinson, PhD 
Assistant Professor of Research, Division of Hematology & Oncology 
PO Box 19677, Springfield, IL 62794-9677 
217-545-1946,  krobinson@siumed.edu 


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Sub-Investigators 
Name 
Title 
Address 
Phone 
Email 
Bradley Schwartz, DO 
Professor 
PO Box 19665 
Springfield, IL 62794-9665 
217-545-7362 
bschwartz@siumed.edu 
Dodie Gazda, ANP 
Nurse Practioner 
PO Box 19678 
Springfield, IL 62794-9678 
217-545-7969 
dgazda@siumed.edu  
Aziz-Ur-Rehman Khan, MD 
Executive Director of SCI at SIU 
Professor & Chief 
Division of 
Hematology & 
Oncology 
PO Box 19678  
Springfield, IL 62794-9678 
217-545-7969 
akhan@siumed.edu  
Krishna Rao, MD, PhD 
Associate Professor 
PO Box 19678  
Springfield, IL 62794-9678 
217-545-7969 
krao@siumed.edu  
Swati Pathak, MD 
Assistant Professor 
PO Box 19678  
Springfield, IL 62794-9678 
217-545-7969 
spathak57@siumed.edu  
Edem Agamah, MD 
Associate Professor 
PO Box 19678  
Springfield, IL 62794-9678 
217-545-6828 
eagamah@siumed.edu  


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TABLE OF CONTENTS 
 
 
 
 
 
 
 
         Page 
1.0 
Trial Summary 
 
 
 
 
 
 
 
 
6 
2.0 
Trial Design  
 
 
 
 
 
 
 
 
6 
3.0 
Objectives & Hypothesis(es) 
 
 
 
 
 
 
8 
4.0 
Background & Rationale 
 
 
 
 
 
 
 
9 
5.0 
Methodology  
 
 
 
 
 
 
 
 
14 
6.0 
Data Safety Review Team  
 
 
 
 
 
 
35 
7.0 
Trial Flow Chart 
 
 
 
 
 
 
 
 
36 
8.0 
Trial Procedures 
 
 
 
 
 
 
 
 
41 
9.0 
Assessing and Recording Adverse Events  
 
 
 
 
53 
10.0 
Statistical Analysis Plan 
 
 
 
 
 
 
 
61 
11.0 
Labeling, Packaging, Storage and Return of Clinical Supplies  
 
6 
12.0 
Administrative and Regulatory Details 
 
 
 
 
 
63 
13.0 
List of References 
 
 
 
 
 
 
 
 
67 
14.0 
Appendices 
 
 
 
 
 
 
 
 
 
71 
Revisions/Amendments 
Date  
05 Nov 2014, Revision 1 
01 March 2015 
01 March 2015, Revision 2 
07 April 2015 
14 March 2016, Revision 3 
14 March 2016 
28 March 2016, Amendment 1 
28 March 2016 
22 April 2016, Amendment 1, Revision 1 
22 April 2016 
27 July 2016, Amendment 2 
27 July 2016 
31 Jan 2017, Amendment 2, Revision 1 
31 Jan 2017 
20 April 2017, Amendment 3 
20 April 2017 


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Remainder of Page Intentionally Left Blank 
 
 
 
 
 
 
 
20 April 2017, Amendment 3, Revision 1 
08 August 2017 
27 September 2018, Amendment 4 
27 September 2018 
21 October 2019, Amendment 5 
21 October 2019 


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1.0 
TRIAL SUMMARY 
Abbreviated Title 
MK-3475/BCG in HRSBC 
Trial Phase 
Phase I/II 
Clinical Indication 
Superficial High Risk Bladder Cancer 
Trial Type 
Open Label, Non-Randomized, Un-Blinded 
Type of Control 
N/A 
Route of Administration 
Intravenous MK-3475/Intravesical BCG 
Trial Blinding 
N/A 
Treatment Groups  
Single treatment group of high risk superficial bladder cancer; 
combination treatment with MK-3475 and BCG 
Number of Trial Subjects 
15 
Estimated Duration of Trial 
60 months 
Duration of Participation 
28 months 
 
 
 
2.0 
TRIAL DESIGN 
2.1 
Trial Design 
This is a multicenter Phase I/II safety and efficacy study of MK-3475 (pembrolizumab) 
therapy used in combination with bladder infused BCG treatment for subjects, 18 years or 
older, with pathologically documented high risk superficial bladder cancer despite having 
received 2 courses of induction therapy or BCG treatment followed by maintenance BCG.  
Subjects will have confirmation of bladder cancer non-invasive to the muscle. 
Approximately 20 subjects will be screened to treat 15 eligible subjects.  Subjects will be 
enrolled to a single treatment group of a fixed dose of MK 3475 and BCG. 
 
 


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2.2 
Trial Diagram 
 
 
 
 
 
Subject diagnosed with high risk 
superficial bladder cancer 
Subject receives first induction 
therapy with BCG 
Subject has documented 
recurrence of high risk 
superficial bladder cancer. 
Start treatment with MK-3475 at 200 mg Q3W IV 
(First 3 subjects will be treated at 100 mg Q3W) two 
weeks after surgery. 
Start intravesicular BCG treatment 6 weeks after first 
dose of MK-3475 treatment (6 weekly doses of BCG). 
Continue treatment with MK-3475 at 200 mg Q3W IV for 
6 weeks after last dose of BCG. 
Evaluate for response to treatment with office cystoscopy and 
cytology (Patients with suspicious lesions, or positive bladder 
cytology, will be evaluated with bladder biopsy under anesthesia.) 
Subject treated with at least 
one course of maintenance 
BCG 
Subject treated with second course of 
intravesical BCG, mitomycin, gemcitabine, 
or BCG/interferon within a 12 month time 
period. 
Subject has documented 
recurrence of high risk 
superficial bladder cancer (CIS 
and T1 and Ta that are not 
muscle invasive) and is eligible 
for consent and full screening. 
T1 and Ta subjects require 
restaging to rule out muscle 
invasive bladder cancer.  


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3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis 
Objective:  To determine the safety of administering MK-3475 at a fixed dose of 200 mg 
every three weeks in conjunction with intravesicular BCG treatment in high risk non-muscle 
invasive bladder cancer patients who have failed 2 courses of induction therapy or 1 course 
of BCG induction therapy followed by maintenance therapy.  The first 3 subjects will be 
treated at a dose of 100 mg to ensure safety for the combination.  If no safety or efficacy 
issues are present dosing will be escalated to 200 mg every 3 weeks.  
Hypothesis:  MK-3475 can be delivered safely in combination with intravesicular BCG 
therapy in patients with non-muscle invasive high risk superficial bladder cancer who have 
failed 2 courses of induction therapy or 1 course of BCG induction therapy followed by 
maintenance therapy. 
3.2 
Secondary Objective 
Objective:  To determine the 19 week and the 3, 12, and 24 month post-treatment visit 
complete response rate with combined MK-3475 and intravesicular BCG therapy for non-
muscle invasive superficial bladder cancer patients who have failed 2 courses of induction 
therapy or 1 course of BCG induction therapy followed by maintenance therapy. 
3.3 
Exploratory Objective (Appendix G) 
(1) 
Objective:  To examine pre- and post-treatment (MK-3475/BCG) bladder biopsy 
specimens for PD-1, PDL-1, and CD3 
(2) 
Objective:  Whole exome sequencing of subjects’ germline DNA and formalin fixed, 
paraffin embedded tissue will be performed with correlation of mutations to treatment 
outcomes. 
(3) 
Objective:  To collect blood and urine specimens from enrolled subjects for 
development of blood and urine assays for response to treatment 
(4) 
Objective:  Immune-profiling of bladder exudate and blood from patients treated 
with combination of BCG and MK-3475 for high risk transitional cell carcinoma of 
the bladder 


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4.0 
BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD_L2) 
[7; 8].  The structure of murine PD-1 has been resolved [9].  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [7; 10; 11; 12].  The mechanism by which PD-
1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [13; 14].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells [15; 16].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17].  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [13; 18; 19; 20].  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs.  Binding of either PD ligands to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [13].  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) [21].  This 


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suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
4.1.2 
Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 
Rationale for the Trial and Selected Subject Population 
Bladder cancer is the fifth most common cancer in the United States [22].  The predominant 
histological type is transitional cell carcinoma accounting for > 90% of bladder tumors in 
Europe and USA.  Seventy percent of bladder tumors are superficial at presentation and 
include carcinoma in situ (cis), Ta, and T1 disease.  CIS of the bladder is a less common 
high-grade diffuse surface-spreading lesion confined to the urothelium accounting for 1% to 
4% of the primary tumors and occurs concomitantly with a papillary tumor in 13% to 20% of 
bladder cancer patients.  The remainder of superficial bladder cancers extend above the 
surface of the epithelium in papillary lesions (Ta), or invade into the submucosal layer (T1) 
without invading into the muscularis propria of the bladder wall.  Despite conservative 
management by endoscopic resection, 60% to 70% of superficial tumors recur, and 20% to 
30% of recurrent tumors will progress to a higher stage or grade [23].  For superficial urinary 
bladder cancer, one of the established primary treatment modalities involves the direct 
infusion of Bacille Calmette-Guerin (BCG) into the bladder, and this procedure is 
recommended to those with intermediate or high risk of recurrence or stage progression. 
BCG installation has been used to treat non-muscle-invasive bladder cancer for more than 30 
years.  It is one of the most successful biotherapies for cancer in use.  Despite long clinical 
experience with BCG, the mechanism of its therapeutic effect is still under investigation.  
Available evidence suggests that urothelial cells (including bladder cancer cells themselves) 
and cells of the immune system both have crucial roles in the therapeutic antitumor effect of 
BCG. The possible involvement of bladder cancer cells includes attachment and 
internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG 
and/or cancer cell antigens to cells of the immune system.  Immune system cell subsets that 
have potential roles in BCG therapy include CD4 (+) and CD8 (+) lymphocytes, natural 
killer cells, granulocytes, macrophages, and dendritic cells.  Bladder cancer cells are killed 
through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL 
(tumor necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct 
action of BCG [24].  For bladder CIS, BCG is considered as the primary standard [25] and 
the only treatment option available that has been shown to be effective aside from removing 
the bladder [26].  BCG has also been shown to decrease the rate of progression of superficial 
bladder cancer into more invasive forms of the disease [27-31]; however, only two thirds of 


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patients respond to BCG, and one third of the responders will develop recurrent disease, 
which is associated with a poor prognosis [32; 33].  Given that the only other accepted 
standard treatment for high risk superficial urothelial cancer is radical cystectomy, 
identification of active agents in this disease is clearly warranted. 
The blockade of immune checkpoints of the pathway involving programmed death 1 (PD-1) 
and its ligands, CD274 (PD-L1) and CD273 (PD-L2), has been shown recently to be 
effective in cancer therapy.  As more clinical trials evaluating immune checkpoint-targeted 
drugs are published, the potential of these agents in managing treatment resistant cancers is 
becoming more obvious [34; 35].  PD-1 is an inhibitory cell-surface receptor that can be 
stimulated to be expressed by T cells, B cells, natural killer (NK) T cells, monocytes, and 
dendritic cells (DC) [29].  PDL2 is expressed mainly by DCs and macrophages, whereas 
PDL-1 is widely expressed by hematopoietic, non-hematopoietic, and tumor cells [36; 37].  
Higher expression of PDL-1 in cancer is associated with decreasing survival since tumors 
can evade the immune system by the inhibitory action of PD-1 [38-40].  Clinical trials with 
murine antibodies targeting PD-1 and PDL-1 have shown very promising results in advanced 
cancers.  In a study by Brahmer et al., a total of 207 patients- 75 with non-small-cell lung 
cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with 
ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer - 
were all given anti-PD-L1 antibody.  The median duration of therapy was 12 weeks (range, 2 
to 111).  Among patients with a response that could be evaluated, an objective response (a 
complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with 
renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer.  
Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up [34].  
In a recent study presented in an abstract form at the 2014 annual meeting of the American 
Society of Clinical Oncology, humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 
was administered to a non-randomized cohort of 411 ipilimumab-naive (IPI-N) and IPI-
treated (IPI-T) melanoma patients.  The authors observed that among the 365 patients with 
measurable disease at baseline, over all response rate by RECIST was 40% (95% CI 32%-
48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T patients, and that the responses were 
durable.  Median progression free survival by RECIST was 24 weeks in IPI-N and 23 weeks 
in IPI-T patients and median overall survival (OS) was not reached, with 1-year overall 
survival of 71% in all patients.  The authors then concluded that MK-3475 showed durable 
responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T 
melanoma patients (http://meetinglibrary.asco.org/content/133842-144). 
PD-L1 expression, a marker for response to anti-PD-1 agents, was observed in 7% of pTa, 
16% of pT1, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression in these tumors 
was also associated with high-grade disease and tumor infiltration by mononuclear cells.  In 
addition, PD-L1 expression was found to be extremely abundant in the BCG-induced bladder 
granulomata in patients failing BCG treatment [41].  Recent pharmacokinetic studies 
showing efficacy of anti-PD-1 agents in advanced melanoma and other cancers supports 
combining these agents with BCG treatment in patients with high risk superficial bladder 
cancer to provide these patients with an alternative to radical cystectomy if they fail BCG 
alone.  Previous experience with immunologic response supports dosing patients with anti-


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PD-1 agents 2-3 weeks before BCG treatment, which would allow the bladder to be primed 
for BCG with the hopes of a greater number of complete responses to BCG [42].  This 
combination, if successful, could help patients avoid cystectomy; a complicated surgery with 
very high complication and readmission rates, and one that permanently alters a patient’s 
quality of life [43]. 
4.2.2 
Rationale for Dose Selection/Regimen/Modification 
The dose regimen of 200 mg Q3W (every 3 weeks) of pembrolizumab is planned for all 
urothelial cancer trials.  Available PK results in subjects with melanoma, NSCLC, and other 
solid tumor types support a lack of meaningful difference in PK exposures obtained at a 
given dose among tumor types.  An open-label Phase 1 trial (PN001) in melanoma subjects 
was conducted to evaluate the safety and clinical activity of single agent pembrolizumab.  
The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 
mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors.   All 
three dose levels were well tolerated and no dose-limiting toxicities were observed.   This 
first in human study of pembrolizumab showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg 
Q2W).   No maximum tolerated dose (MTD) has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.   The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses.   For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.   The overall response rate (ORR) was 
26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set 
(FAS)).   The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-
related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups or lower in the 10 mg/kg group. 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a 
given dose among tumor types.   Population PK analysis has been performed and has 
confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab to a 
clinically meaningful extent.   Taken together, these data support the use of lower doses (with 
similar exposure to 2 mg/kg Q3W) in all solid tumor indications.  The dose of   2 mg/kg 
Q3W is being evaluated in NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is 
being evaluated in head and neck cancer in PN012, which are expected to provide additional 
data supporting the dose selection. 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on 
simulation results indicating that 200 mg will provide exposures that are reasonably 
consistent with those obtained with 2 mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with 
maximal clinical response.   A population PK model, which characterized the influence of 


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body weight and other patient covariates on exposure, has been developed using available 
data from 476 subjects from PN001.   The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some 
tendency for individual values to range slightly higher with the 200 mg fixed dose.  The 
slight increase in PK variability predicted for the fixed dose relative to weight-based dosing 
is not expected to be clinically important given that the range of individual exposures is well 
contained within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg to 
provide similar efficacy and safety.   The population PK evaluation revealed that there was 
no significant impact of tumor burden on exposure.  In addition, exposure was similar 
between the NSCLC and melanoma indications.  Therefore, there are no anticipated changes 
in exposure between different tumor types and indication settings. 
To ensure the safety and efficacy, the first 3 subjects will be dosed at 100 mg rather than 200 
mg every 3 weeks.  If the first 3 patients do not have any significant safety or efficacy issues 
the dose will be escalated to 200 mg every 3 weeks. 
4.2.3 
Rationale for Endpoints 
4.2.3.1 
Complete Response Endpoint 
The study will determine the complete response rate at 19 weeks, 3 months post treatment 
visit, 12 months post treatment visit, and 24 months post treatment visit based on multiple 
previous studies that used approximate follow up to predict long-term disease survival in 
patients with superficial bladder cancer.  Previous research showed up to a 50% recurrence 
rate at 3 months of follow-up in high risk superficial bladder cancer patients, which was 
similar to the cohort of patients included in this study.  In a study by Skinner et al., a total of 
58 patients were enrolled in a study for gemcitabine in superficial bladder cancer, and 47 
were evaluable for response.  Median patient age was 70 years (range 50 to 88).  Of the 
evaluable patients 42 (89%) had high risk disease, including high grade Ta in 12 (26%), high 
grade T1 in 2 (4%) and carcinoma in situ in 28 (60%) with or without papillary lesions.  At 
the initial 3-month evaluation only 47% of patients were free of disease [44].  Sylvetser et al. 
analyzed data on 2596 patients with non muscle invasive bladder cancer, and derived a 
simple scoring system based on six clinical and pathological factors: number of tumors, 
tumor size, prior recurrence rate, T category, carcinoma in situ, and grade to predict 
recurrence.  The probabilities of recurrence at one year were up to 61%.  At five years, the 
probability of recurrence was up to 78 % [45]. 
4.2.3.2 
Biomarker Research 
To better determine patients who would benefit from the combinations of BCG and MK-
3475, if proven effective and possibly better select patients for phase II, biomarker research 
will be performed to investigate immunologic and genetic biomarkers for treatment response.  
Pre- and post-treatment bladder biopsy specimens will be examined for PD-1, PDL-1, and 
CD3 as immunologic markers for response to MK-3475.  Whole exome sequencing of 


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subjects’ germline DNA and formalin fixed, paraffin embedded tissue will be performed with 
correlation of mutations to treatment outcomes of both BCG and MK-3475. 
5.0 
METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Diagnosis/Condition for Entry into the Trial 
Subjects must have pathologically documented, after restaging resection, high grade 
transitional cell superficial bladder cancer (Ta, T1), or pathologically documented CIS after 
initial resection for recurrent/ persistent disease after 2 induction intravesical therapy courses 
within one year or one course of BCG induction followed by maintenance. 
 Pathology review and reports may be obtained from an outside hospital prior to entry into 
the study.  However, all pathology specimens utilized for enrollment purposes must be 
re-read by a local study site pathology department. 
 Subjects may be consented for screening before or after transurothelial bladder resection 
for restaging depending on when they are seen by site staff. 
5.1.2 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have pathologically documented high grade transitional cell superficial bladder cancer 
(Ta, T1) at time of restaging, or have pathologically documented high grade CIS of the 
bladder at time of initial resection for recurrent/persistent high risk transitional cell 
superficial bladder cancer. 
 All pathology specimens used for enrollment are required to be read by the 
research site pathology laboratory. 
4. Subject must also meet one of the following criteria: 
Recurrent/Persistent Disease Despite 2 Induction Intravesical Therapy Courses 
 Treatment with 2 courses of BCG in a 12 month time period 
 Treatment with BCG and mitomycin in a 12 month time period 
 Treatment with BCG and gemcitabine in a 12 month time period 


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 Treatment with BCG and BCG/interferon combination in a 12 month time 
period 
Or  
Recurrent/Persistent Disease Following: 
 One BCG treatment in addition to at least one maintenance course of BCG 
5. Have provided tissue from an archival tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion.  Tissue must be obtained from the most recent transurothelial 
bladder resection. 
 Tumor block or 10 unstained formalin fixed paraffin embedded slides from 
trans-urethral resection of bladder tumor for reflection of tumor prior to 
treatment with investigational product. 
6. Have a performance status of 0-2 on the ECOG Performance Scale (Appendix A). 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 28 days of treatment initiation. 
Table 1: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
≤1.5 X upper limit of normal (ULN) OR 
Measured or calculateda GFR can also be 
used in place of creatinine 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN or Direct bilirubin below 
Direct bilirubin 
≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
Activated Partial Thromboplastin Time 
(aPTT) 
 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per the CKD-EPI equation (Appendix B) 
8. Female subject of childbearing potential should have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication.  If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 


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9. Female subjects of childbearing potential must be willing to use an adequate method of 
contraception as outlined in Section 5.52 – Contraception, for the course of the study 
through 120 days after the last dose of study medication (Reference Section 5.5.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year. 
NOTE: 
Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
10. Male subjects of child bearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.5.2- Contraception, starting with the first dose of 
study therapy through 120 days after the last dose of study therapy. 
NOTE: 
Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
5.1.3 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Currently has active or progressive metastatic disease. (Chest X-ray, Computerized 
Tomography [CT] urogram or Magnetic Resonance Imaging [MRI] and urogram are 
allowed to ascertain the superficial nature of the disease when indicated, but not required.  
If urogram protocol is not available or contrast allergy/poor renal function precludes such 
imaging, then non-contrast CT or MRI of the abdomen/pelvis within 90 days of study 
entry will suffice.) 
2. Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks of the first dose of treatment. 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
4. Has had a prior monoclonal antibody within 4 weeks before study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier. 
5. Has had prior systemic chemotherapy, targeted small molecule therapy, or radiation 
therapy for bladder cancer. 
6. If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy. 
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy.  Upper urinary 


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tract transitional cell carcinoma is also allowable on study as high risk transitional cell 
carcinoma is commonly multifocal, and intraluminal BCG therapy is also used for 
treatment of upper urinary tract lesions in a manner similar to that of bladder tumors. 
8. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
10. Has an active infection, including a concurrent febrile illness, requiring systemic therapy. 
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 4 months after the 
last dose of trial treatment. 
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways) including anti-CD40 and anti-OX40 antibodies. 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Has known active Hepatitis B (e.g., HBs Ag reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
17. Has known active tuberculosis.  Subjects will not be specifically tested for the study; 
however, subjects who are tested within 28 days of beginning study or while on study and 
test positive with the PPD test before treatment should have active tuberculosis ruled out 
before therapy begins for their superficial bladder cancer. 
18. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
19. Has an active urinary tract infection, gross hematuria, or known broken mucosal barrier 
of the bladder. 
20. Less than 14 days post bladder biopsy, TUR, or traumatic catheterization. 


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21. Evidence of muscle invasive bladder cancer. 
22. Current Pneumonitis or has a history of (non-infectious) pneumonitis that required 
steroids. 
NOTE: 
Patients in frequent contact with immunosuppressed individuals should 
be carefully assessed for potential benefits and risks of BCG therapy 
before initiating treatment. 
5.2 
Trial Treatments 
The treatments to be used in this trial are outlined below in Table 2. 
Table 2: Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475a, b 
100 mg 
Every 21 days 
IV infusion 
6 cycles 
Experimental 
MK-3475b 
200 mg 
Every 21 days 
IV infusion 
6 cycles 
Experimental 
BCG 
1 vial 
Every 7 days 
Bladder 
Instillation 
6 cycles 
Approved 
a The first 3 subjects will be dosed at 100 mg.  If the Data Safety Review Team approves, the dose will be 
escalated to 200 mg with the fourth subject enrolled.  
b The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.2.3.3.  BCG 
treatment may be interrupted or delayed as per the instructions for use supplied with BCG (Section 5.2.1.1.3). 
BCG: One vial of BCG suspended in 50 ml preservative-free saline.  BCG is to be given through a urinary 
catheter (intravesically) into the bladder.  BCG treatment will occur once per week for 6 weeks.  BCG 
treatment will commence on the 3rd cycle of treatment with MK-3475, Week 7.  BCG is a FDA approved 
treatment and will be supplied commercially through the study site pharmacy. 
5.2.1 
BCG Treatment 
5.2.1.1 
BCG treatment will be according to Institutional standard for the site; 
however, the BCG will be provided by MERCK due to the BCG shortage to ensure 
completion of the study. 
For patients with multi-focal disease, it is highly recommended that the patient have a 
urologic stent and catheter placed prior to the first pembrolizumab treatment to allow 
for stabilization of the mucosa prior to the start of treatment with BCG.  Placement will 
be at the discretion of the treating physician. 
5.2.1.1.1 
Dose Selection 
The rationale for the use of the indicated dose of BCG is based upon FDA approved and 
commercially provided package insert/instructions for use of the product.  Dosing for the 
intravesical treatment of carcinoma in situ and for the prophylaxis of recurrent papillary 
tumors consists of one vial of BCG suspended in 50 ml preservative-free saline.  The 


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preparation of the BCG suspension will be completed using aseptic technique and according 
to FDA approved labeling and use information.  Patients with multi-focal disease may have 
treatment with more than one vial to ensure treatment of all tumor sites (generally kidney or 
ureter in addition to bladder).  Essentially to allow for proper treatment, it is anticipated that 
one vial will be used to treat each organ/distinct urologic structure. 
5.2.1.1.2 
Preparation 
Consult FDA approved package insert for instructions on BCG preparation (Appendix C has 
the insert for TICE® BCG, there are other manufacturers of BCG that may also be utilized.) 
5.2.1.1.3 
Dose Delay 
BCG treatment will be withheld for Grade >2 hematuria, Grade >1 fever and drug-related 
Grade 4 hematologic toxicities, and all other non-hematological toxicity Grade ≥3 adverse 
effects, including laboratory abnormalities, and severe or life-threatening AEs.  Treatment 
should be postponed until resolution of febrile illness, urinary tract infection, or gross 
hematuria and adverse effect resolution to Grade < 1.  The treating Investigator who is a 
qualified physician may delay treatment for Grade 1 and 2 adverse effects if the treating 
Investigator believes it is in the best interest of the patient.  In the event of a grade 1 or 2 
immune related adverse event requiring corticosteroid treatment, BCG treatment may be 
delayed for up to 2 weeks with the expectation that steroid treatment will be discontinued 
prior to the next BCG treatment cycle.  A delay of longer than 2 weeks will permanently 
discontinue the patient from BCG treatment within the study or permanent withdrawal of the 
patient from the study.  The choice will be at the discretion of the treating Investigator.  
Steroid treatment for grade 3 or higher immune mediated events will require discontinuation 
of BCG treatment and/or withdrawal from the study. 
Instillation of BCG with an actively bleeding mucosa may promote systemic BCG infection.  
Therefore, treatment will be postponed for at least two weeks following transurethral 
resection, biopsy, traumatic catheterization, or gross hematuria. 
Patients will be asked to report any fever or flu-like symptoms to their treating Investigator 
immediately, as well as any systemic manifestations increasing in intensity with repeated 
instillations, or local symptoms (frequency, urgency, burning sensation with urination) 
lasting more than 2-3 days.  If a patient develops persistent fever or experiences an acute 
febrile illness consistent with BCG infection, BCG treatment will be discontinued and the 
patient immediately evaluated and treated for systemic infection.  Intravesical instillations of 
BCG will also be postponed during treatment with antibiotics, since antimicrobial therapy 
may interfere with the effectiveness of BCG. 
5.2.1.1.4 
Monitoring for Systemic Dissemination of BCG 
To ensure early identification of systemic BCG infection, subjects will be monitored for 
symptoms of systemic infection.  For each cycle of BCG treatment, subjects will be 
telephoned on Days 2-4 (Treatment is Day 1) of Treatment Weeks 7-12 to inquire about any 


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symptoms they may be experiencing.  In addition to this, each patient will be provided with a  
thermometer and diary and asked to record oral temperatures each morning and evening 
throughout the BCG treatment (Weeks 7-12) and for recording of any other symptoms they 
may be experiencing. 
5.2.1.2 
Timing of Dose Administration 
BCG treatment should be administered beginning on Day 1 of Cycle 3 (Week 7) of MK-3475 
after all procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 7.0).  BCG treatment will be repeated every 7 days at weeks 8, 9, 10, 11, and 12. 
BCG treatment may be administered up to 1 day before or after the scheduled date (at 7 days) 
due to administrative reasons. 
All trial treatments will be administered on an outpatient basis and according to institutional 
standards 
5.2.1.3 
Drug/Treatment 
BCG is given through a urinary catheter (intravesically) into the bladder.  BCG will be 
instilled into the bladder according to institutional standards based on FDA approved 
indications for treatment of bladder cancer.  Additional lesions in patients with multi-focal 
disease will be treated per intuitional standards and directed by the treating urologist.  The 
treatment will be given once a week for 6 weeks. 
5.2.1.4 
Risks/Adverse Effects of BCG Treatment 
For specific information, please see package insert in Appendix C. 
Common Side Effects (>20%) 
Dysuria (painful urination) 
Urinary frequency 
Flu-like symptoms 
Hematuria (blood in urine) 
Fever 
Less Common Side Effects (4-20%) 
Malaise/ fatigue 
Cystitis (inflammation of the bladder) 
Urgency 
Nocturia 
Cramping or pain in bladder 
Chills 
Nausea 
Incontinence 
Rare Side Effects (<4%) 
Anemia 


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BCG sepsis 
BCG infection in other organs 
Coagulopathy 
Contracted Bladder 
Epididymitis/prostatitis 
Hepatic Granuloma 
Hepatitis 
Leukopenia 
Orchitis 
Pneumonitis 
Urinary obstruction 
Subjects may develop symptoms of bladder irritability related to the inflammatory response 
induced by BCG, as well as hematuria following BCG intravesicular treatment.  The 
symptoms typically begin 4-6 hours after instillation and last 24-72 hours.  The irritative side 
effects are usually seen following the third instillation, and tend to increase in severity after 
each administration.  The irritative bladder adverse effects can usually be managed 
symptomatically with products such as pyridium, propantheline bromide, oxybutynin 
chloride and acetaminophen.  Symptom management will be at the discretion of the treating 
Investigator.  If the patient develops hematuria, then treatment must be postponed until urine 
is clear again.  See dose modification/delay (section 5.2.1.5) for further instruction.  No dose 
reduction or antibiotic treatment has been proven to prevent or decrease bladder irritation 
related to BCG. 
Subjects may develop “Flu-like” symptoms (malaise, fever, and chills) which often reflect 
hypersensitivity reactions, and can be treated symptomatically with antihistamines 
(Prophylactic treatment with antihistamine before subsequent BCG courses is left to the 
discretion of the provider.). 
The most serious complication of BCG is disseminated BCG sepsis with associated 
mortality.  In addition, infections have been reported in lung, liver, bone, bone marrow, 
kidney, regional lymph nodes, and prostate in patients who have received intravesical BCG.  
Some male genitourinary tract infections (orchitis/epididymitis) have been resistant to 
multiple drug anti-tuberculous therapy and required orchiectomy.  These complications were 
reported in less than 1% of patients. 
5.2.1.5 
Dose Modification for BCG 
BCG dose modification has not been shown to reduce toxicity; therefore, no dose 
modifications will be attempted in this trial. 
5.2.1.6 
Over Dosage 
Over dosage occurs if more than one vial (per treated organ/urologic structure) of BCG is 
administered per instillation.  If over dosage occurs, the patient should be closely monitored 
for signs of active local or systemic BCG infection.  For acute local or systemic reactions 


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suggesting active infection, an infectious disease specialist experienced in BCG 
complications should be consulted. 
5.2.2 
MK-3475 Treatment 
5.2.3 
Dose Selection/Modification 
5.2.3.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 - 
Background and Rationale. 
A fixed dose of 100 mg MK-3475 will be given on Day 1 +/‒3 days of a 21 day cycle for up 
to 6 cycles for the first 3 subjects.  If one subject of the three requires the dose of MK-3475 
to be withheld or discontinued, the 100 mg cohort will be expanded to 6 subjects.  If two out 
of three or two out of six subjects develops toxicity that requires the dose to be withheld or 
discontinued, the dose will not be escalated to 200 mg MK-3475 every 3 weeks.  All 
remaining subjects will be treated at 100 mg MK-3475 every 3 weeks for 6 cycles. 
The Data Safety Review Team will make a determination if dose escalation to 200 mg is 
possible.  The Data Safety Review Team automatically meets after 3 subjects have been 
enrolled and treated; however, a meeting may be called sooner, if deemed necessary. 
5.2.3.2 
Formulation/ Preparation 
MK-3475 is provided as a liquid solution (100 mg/vial) in Type I glass vials intended for 
single use only.  The drug product is stored as a stable liquid solution under refrigerated 
conditions (2°C-8°C).  The liquid product is intended for IV administration.  The liquid drug 
product can be further diluted with normal saline in IV containers made of polyvinyl chloride 
(PVC) or non-PVC material.  The infusion solution should be immediately administered.  If 
not used immediately, vials and/or IV bags may be stored at 2-8°C for up to a cumulative 
time of 20 hours.  If refrigerated, the vials and/or IV bags should be allowed to equilibrate to 
room temperature prior to subsequent use.  MK-3475 solutions may be stored at room 
temperature for a cumulative time of up to 6 hours.  This includes room temperature storage 
of reconstituted drug product solution and liquid drug product in vials, room temperature 
storage of infusion solution in the IV bag and the duration of infusion. 
Please see the Investigators Brochure for additional drug formulation information. 
5.2.3.3 
Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment.  Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 3 below.  See Section 
5.4.1 for supportive care guidelines, including use of corticosteroids. 


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Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose; Refer to Error! Reference 
ource not found. – Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  Subjects should be placed back on study therapy within 3 weeks of the 


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scheduled interruption, unless otherwise discussed with the Sponsor.  The reason for 
interruption should be documented in the patient's study record. 
5.2.4 
Schedule Modification for Combination Therapy 
The dosing schedule of the combination therapy will not be altered except on an individual 
drug basis (such as holding either individual BCG or MK-3475 therapy) if the time period is 
for 2 weeks or less.  That is to say holding either of the two medications included in the 
combination therapy for less than two weeks should not affect the dosage schedule for the 
other medication.  Patients will be discontinued from the trial if one of the two medications is 
held for more than 2 weeks because of toxicity.  BCG treatment may continue, after a 2 week 
hold, outside of the study at the discretion of the treating Investigator. 
5.2.5 
Timing of Dose Administration 
Trial MK-3475 treatment (100 or 200 mg fixed dose) should be administered on Day 1 of 
each cycle after all procedures/assessments have been completed as detailed on the Trial 
Flow Chart (Section 7.0).  MK-3475 treatment may be administered up to 3 days before or 
after the scheduled Day 1 of each cycle due to administrative reasons.  Subjects may be 
dosed no less than 18 days from the previous dose.  If treatment is held for greater than 3 
cycles (or 63 days) subject will be withdrawn from investigational product treatment 
permanently. 
All trial treatments will be administered on an outpatient basis unless the patient is currently 
admitted to the hospital for another purpose which does not exclude treatment with BCG or 
MK-3475 or enrollment into the study. 
MK-3475 will be administered as a 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 5.2.3.3).  Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps from site to site, a window of −5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: −5 min/+10 min). 
The Procedure Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
5.2.6 
Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, Investigator and subject will know the 
treatment administered. 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The Investigator should discuss any questions regarding this 


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with the Sponsor.  The final decision on any supportive therapy or vaccination rests with the 
Investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, the Sponsor, and the subject. 
5.3.1 
Acceptable Concomitant Medications 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF), 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug, dosage, 
frequency, route, and date should also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 9.0. 
5.3.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than MK-3475 
 Radiation therapy 
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.   Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG (with the 
exclusion of BCG for treatment), and typhoid (oral) vaccine.  Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed. 
 Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of steroids for treatment of 
a grade 1 or 2 immune mediated adverse event may delay BCG treatment for up to 2 
weeks with the expectation that steroid treatment will be discontinued prior to the next 
BCG treatment cycle.  A delay of longer than 2 weeks will permanently discontinue the 


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patient from BCG treatment within the study or permanent withdrawal of the patient from 
the study.  The choice will be at the discretion of the treating Investigator.  Steroid 
treatment for grade 3 or higher immune mediated events will require discontinuation of 
BCG treatment and/or withdrawal from the study. 
 The use of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor. 
 Drug combinations containing immunosuppressants and/or bone marrow depressants 
and/or radiation.  The above mentioned therapies interfere with the development of the 
immune response and should not be used in combination with BCG. 
 Antimicrobial therapy may interfere with the effectiveness of BCG treatment.  If 
antimicrobial therapy is required, BCG treatment should be delayed as appropriate. 
Subjects who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial 
treatment or delayed in the case of antimicrobial treatment.  Subjects may receive other 
medications that the Investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below.  Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased.  For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care.  The treatment guidelines are intended to be applied when 
the Investigator determines the events to be related to pembrolizumab. 
Note: 
If after the evaluation the event is determined not to be related, the 
Investigator does not need to follow the treatment guidance (as outlined 
below).  Refer to Section 5.2.1 for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
 


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 Pneumonitis: 
 For Grade 2 events, treat with systemic corticosteroids.  When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
 For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
 Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
 All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
 For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
 For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids. 
 When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 Hypophysitis: 
 For Grade 2 events, treat with corticosteroids.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks.  Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 


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 For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids.  When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks.  Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment.  Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
 Grade 3-4 hyperthyroidism 
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks.  
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 Hepatic: 
 For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
 For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
 When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
 For Grade 2 events, treat with corticosteroids. 
 For Grade 3-4 events, treat with systemic corticosteroids. 
 When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 


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 Management of Infusion Reactions: 
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion. 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 Supportive Care for Suspected Primary Adrenal Insufficiency 
If symptoms are suggestive of an endocrinopathy and the patient is not in adrenal 
crisis, endocrine laboratory results should be evaluated before corticosteroid therapy 
is initiated.  Endocrine work-up will include TSH and free T4 levels to determine if 
thyroid abnormalities are present.  TSH, prolactin, ACTH, and a morning cortisol 
level will help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency.  Grade 1 or 2 endocrine toxicity without adrenal crisis may resolve 
spontaneously if a patient has no or minimal symptoms, but patients will be 
monitored closely, with guidance from an endocrinologist; otherwise, short-term, 
high-dose corticosteroids (e.g., dexamethasone 4 mg every six hours or equivalent) 
with relevant hormone replacement (e.g., levothyroxine, hydrocortisone, sex 
hormones) will be administered.  Patients in adrenal crisis (characterized by a 
constellation of symptoms suggestive of severe dehydration, hypotension, or shock) 
will be treated as a medical emergency and given intravenous injections of 
glucocorticoids and large volumes of intravenous saline solution with dextrose. 
 
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Table 4: Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the Investigator. 
 
None 
Grade 2 
Requires infusion interruption ,but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 
hours 
 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include, but is not limited to,: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the Investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise, dosing will be held until 
symptoms resolve. The subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include, but is not limited to,: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the Investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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5.5 
Diet/Activity/Other Considerations 
5.5.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.5.2 
Contraception 
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if MK-
3475 has transient adverse effects on the composition of sperm. 
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following: 
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 


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• 
vasectomy of a female subject’s male partner 
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only) 
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
5.5.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to 
manufacturer’s safety division without delay and within 24 hours if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).  The study Investigator will make every 


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effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to the Sponsor.  If a male subject impregnates his female partner, the 
study personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor and to manufacturer’s safety division and followed as described above and in 
Section 9.1.2. 
5.5.4 
Use in Nursing Women 
It is unknown whether MK-3475 is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the Investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the Investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 8.1.5.1. 
5.7 
Subject Replacement Strategy 
Subjects who have been screened and enrolled will be included in an intent-to-treat 
population.  However, if a subject has been enrolled and subsequently treated or attempted 
treatment (IV insertion with MK-3475 preparation) with at least 1 cycle of MK-3475, the 
patient will not be replaced.  If a screened subject withdraws prior to first treatment cycle, 
that subject may be replaced. 
5.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
Stopping Rules: 
The number of patients (15) planned for this study is not sufficient to represent the 
population as a whole nor is it sufficient to complete a powerful statistical analysis. 
The first 3 subjects will be treated at 100 mg every 3 weeks for 6 cycles.  If one subject 
of the three subjects requires the dose of MK-3475 be withheld or discontinued, the 100 
mg cohort will be expanded to 6 subjects.  If two out of three or two out of six subjects 


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develop toxicity that requires the dose to be withheld or discontinued, the dose will be not 
be escalated to 200 mg MK-3475 every 3 weeks.  All remaining subjects will be treated 
at 100 mg MK-3475 every 3 weeks for 6 cycles. 
For study subject safety, if there is any fatal toxicity or morbidity event related to the 
study treatment or procedures, or if one or more of the 15 subjects treated experience a 
grade 4 toxicity, then subject accrual will be suspended and all data pertaining to the 
events will be reviewed by the Study Investigators and Data Safety Review Team to 
determine if there is the need for any corrective actions. 
Once that review is completed and any appropriate action is taken, subject accrual will 
begin again, if the Data Safety Review Team members have approved continuation of the 
study.  If there is a second fatal treatment/morbidity event related to the study treatment 
or procedures, the study will be terminated.  If 4 of 15 subjects experience grade 4 
toxicities, the accrual will be suspended and reviewed for added appropriate measures.  If 
5 subjects experience grade 4 toxicity, the study will be terminated. 
Non-local safety reports will be evaluated as they are received.  Tabulations of the reports 
will be provided to the Data Safety Review Team with access to the full reports for 
completeness of review. 
4. Plans to modify or discontinue the development of the study drug 
In the event the investigational product is no longer available, ample notification will be 
provided so appropriate adjustments to subject treatment can be made. 
6.0 
DATA SAFETY REVIEW TEAM 
6.1 
Data/Efficacy Review 
A Data Safety Review Team will be formed to evaluate the safety of the combination of the 
treatments as well as to objectively comment on any apparent decreased efficacy.  The first 
three subjects will be treated at 100 mg rather than the full 200 mg every 3 weeks.  Once the 
first three subjects have completed therapy and no adverse events have called for an earlier 
meeting, the Data Safety Review Team will meet to discuss the escalation of the dose to 200 
mg.  If one subject of the three subjects requires the dose of MK-3475 be withheld or 
discontinued, the 100 mg cohort will be expanded to 6 subjects.  If two out of three or two 
out of six subjects develop toxicity that requires the dose to be withheld or discontinued, the 
dose will not be escalated to 200 mg MK-3475 every 3 weeks.  All remaining subjects will 
be treated at 100 mg MK-3475 every 3 weeks for 6 cycles. 
The Data Safety Review Team will again evaluate the patient safety and efficacy response 
after 7 and 10 subjects have completed the treatment regimen.  The committee will also be 
charged with enforcing the stopping rules.  All adverse event data, as well as patient response 
to treatment, will be presented to the committee and the committee will be allowed to 


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deliberate in a closed session to advise on the continued enrollment of subjects and to 
propose any protocol amendments to enhance the study. 
 
Remainder of Page Intentionally Left Blank


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7.0 
TRIAL FLOW CHART 
7.1 
Study Flow Chart 
Trial Period 
Screening 
Phase 
Treatment Week/Cycle 
End of Treatment 
Post Treatment 
Treatment Week/ 
Title 
Screening 
Visita 
1 
4 
7* 
8* 
9* 
10* 
11* 
12* 
13 
16 
19 
Discontinuation 
Safety FU 
20 
Follow-Up Visit 
Scheduling 
Window (Days) 
-28 to -1 
+/-
3 
+/- 
3 
+/-
1 
+/-
1 
+/-
1 
+/- 1 
+/-1 
+/-1 
+/-
3 
+/-
3 
+/-
3 
At time of 
Discontinuation 
30 days Post 
discontinuation 
3,6,9,12,18,24 Post 
cyst 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
Identification carde 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
concomitant  
Medication Reviewf 
X 
X------------------------------------------------------------------------------------------X 
 
Post-study anti-
cancer therapy 
statusg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Recurrence statusg 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Questionnairesh 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Phone Call*h 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial Period 
Screening 
Phase 
Treatment Week/Cycle 
End of Treatment 
Post Treatment 
Treatment Week/ 
Title 
Screening 
Visita 
1 
4 
7 
8 
9 
10 
11 
12 
13 
16 
19 
Discontinuationc 
Safety FUc 
20 
Follow-Up Visitd 
Scheduling 
Window (Days) 
-28 to -1 
+/-
3 
+/- 
3 
+/-
1 
+/-
1 
+/-
1 
+/- 1 
+/-1 
+/-1 
+/-
3 
+/-
3 
+/-
3 
At time of 
Discontinuation 
30 days Post 
discontinuation 
3,6,9,12,18,24 Post 
cyst 
Clinical Procedures/ Assessments 
Restaging Ta T1 
tumors/ Possible 
Transurethral 
Resectioni 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Adverse 
Eventsj 
X 
X-----------------------------------------------------------------------------------------------X 
 
Physical Examk 
Xk 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Xk 
Xk 
 
Performance 
Statusl 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
Vital Signs and 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-Raym 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary 
Function Testsm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/ Assessments: Analysis provided by Local Laboratory 
CBC w/ differential 
X 
Xr 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
CMP 
X 
Xr 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Urinalysis 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
T3, FT4, and TSH 
X 
 
 
X  
 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy Test 
 (Urine or β-HCG) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTTn 
As clinically 
indicated 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Hepatitis Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial Period 
Screening 
Phase 
Treatment Week/Cycle 
End of Treatment 
Post Treatment 
Treatment Week/ 
Title 
Screening 
Visita 
1 
4 
7 
8 
9 
10 
11 
12 
13 
16 
19 
Early Discontinuationb 
Safety 
FUc 
20 
Follow-Up Visitd 
Scheduling 
Window (Days) 
-28 to -1 
+/-
3 
+/- 
3 
+/-
1 
+/-
1 
+/-
1 
+/- 1 
+/-1 
+/-1 
+/-
3 
+/-
3 
+/-3 
At time of 
Discontinuation 
30 days 
Post 
disconti
nuation 
3,6,9,12,18,24 months 
Post cyst 
Study Treatment 
BCG* 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
MK 3475 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Efficacy Measurements 
Cystoscopyo 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Biopsy (if clinically 
indicated)o 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Tumor Biopsies/ Archival Tissue Collection/ Correlative Studies Blood 
Specimen 
CollectionP 
Xr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xp 
 
aScreening Visit: No study required procedures should be conducted (unless part of routine care) prior to the signing of the informed 
consent document. Screening Visit laboratory procedures may be used for Day 1 Cycle 1 if completed within 10 days of Day 1 Cycle 
1. Restaging imaging of CT urogram or CT/ MRI of abdomen/ pelvis that occurs within 90 days of study entry is acceptable. 
bEarly Discontinuation Visit: All Subjects who discontinue treatment early for any reason should undergo all procedures listed in the 
Flow Chart for Discontinuation Visit. 
cIf a subject has completed all study treatment, the subject should complete the 30 day Safety Follow-Up Visit procedures listed in the 
Flow Chart. 
dFollow-Up Visits should occur at approximately 3, 6, 9, 12, 18, and 24 months from Week 19 cystoscopy.  It is expected that follow 
up data will be collected from routine office visits which generally occur every three months in this population.  There may be a shift 
in schedules if the participant has been given maintenance therapy or was found to have a recurrence.  Subject will complete final set 


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of Questionnaires at the 3 month visit.  Follow–Up information may be collected via medical record and document review only.  
However, patient contact via phone or in person may occur if information is not available via chart review. 
eSubject Identification card may be given at any time after consent process has occurred and prior to treatment on Day 1 Cycle 1. 
fPrior and concomitant medications will include any medications taken within the 28 days prior to consent and through the safety visit 
and will include prescribed, over-the counter and herbal/alternative remedies. 
gPost–study treatment anti-cancer therapy and recurrence status may be collected through follow-up chart review. 
hQuestionnaires: AUA IPSS and QOL will be completed prior to any treatment or procedures scheduled for that visit.* To monitor for 
systemic dissemination of BCG infection, daily phone calls of days 2-4 of each cycle of BCG treatment (Weeks 7-12) will occur to 
monitor for fever and symptoms of systemic infection.  Subjects will each be given an oral thermometer and a diary to record oral 
temperature twice daily (morning and evening) and to record any symptoms they may be having.  The diary will be utilized Days 1-7 
for each of the 6 BCG cycles (Weeks 7-12). 
iTrans-urethral Resections: All TUBR will occur as part of SOC and as clinically indicated. Screening cystoscopy/TURBT window is 90 
days prior to the start of treatment. 
jAdverse Events will be collected from time of main study informed consent through 30 days post last study drug infusion/treatment. 
kPhysical Exam: Full physical exams are required at screening and at the 30 day follow up.  All other exams may be symptom 
directed. 
lPerformance status: ECOG performance status scale should be used to measure performance status. 
mECG, Chest X-ray, and Pulmonary Function Tests will be completed prior to Day 1 Cycle 1 and will only be repeated as clinically 
indicated. 
nPT/INR and aPTT will be completed prior to all resections/ possibly biopsies as standard of care.  All other monitoring of PT/INR 
and aPTT will only be completed as clinically indicated (i.e. if on Coumadin). 
oCystoscopy will be performed as standard of care, but will be considered measures for efficacy.  Biopsy will be performed as 
clinically indicated. 


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pSpecimen Collection/Correlative studies: Whole blood, serum, and urine will be collected at time of consent or may be collected at 
any time prior to treatment on Day 1 of Cycle 1.  Specimens for correlative study will also occur at each visit through Week 19, repeat 
cystoscopy (12 visits).  Saliva will be collected only at baseline.  Tumor tissue will only be collected at Week 19 biopsy, if a biopsy is 
clinically indicated at the time of cystoscopy.  Specimen collection is requested at the 3, 6, 9, 12, 18, and 24 month follow up visits if 
subject is being treated locally at the site, though not required.  Tissue will only be collected if a biopsy is clinically indicated at time 
of cystoscopy. 
qChest X-rays performed in the  90 days window prior to the screening visit are acceptable. 
rCBC, CMP, and correlative labs do not need to be repeated on Day 1 Cycle 1 if they were completed within 10 days prior to Day 1 
Cycle 1 during screening.


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8.0 
TRIAL PROCEDURES 
8.1 
Trial Procedures 
The Trial Flow Chart - Section 7.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety.  In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
8.1.1 
Administrative Procedures 
8.1.1.1 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
The principles of informed consent are described by Federal Regulatory Guidelines (Code of 
Federal Regulations, Title 21, Volume 1, Part 50, Revised April 1, 2013) and the Office for 
Human Research Protections (Code of Federal Regulations 45 CFR 46).  They must be 
followed to comply with federal regulations for the conduct and monitoring of clinical 
investigations. 
8.1.1.1.1 
General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  The case history for each subject shall 
document that informed consent was obtained prior to participation in the study and before 
any study related procedure(s) was performed.  Original signed consent forms must be filed 
in the site study binder or in each subject’s study file. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 


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form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
8.1.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
8.1.1.3 
Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The Investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent. 
8.1.1.4 
Medical History/Demographics 
A medical history will be obtained by the Investigator or qualified designee who is 
participating in the study (qualified physician or nurse practitioner listed as associated study 
personnel).  Medical history will include demographics, height, and weight, and all active 
conditions, and any condition diagnosed within the prior 10 years that is considered to be 
clinically significant by the Investigator.  History will also include the past and current use of 
alcohol, tobacco, and other illicit drugs and performance status as assessed by the ECOG scale 
(Appendix A).  Details regarding the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as medical history.  Appropriate data will be 
captured in the CRF while all other data will be recorded in the source documents. 
8.1.1.5 
Prior and Concomitant Medications Review 
8.1.1.5.1 
Prior Medications 
The Investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Prior medications will include prescription, over the 
counter, and herbal/alternative therapies.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 


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8.1.1.5.2 
Concomitant Medications 
The Investigator or qualified designee will record medications, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 9.  Concomitant medications must be reviewed with the prohibited 
medications list to ensure patient safety. 
8.1.1.5.3 
Questionnaires 
The American Urologic Association Symptoms Index and the Quality of Life Questionnaires 
(Appendix D) will be administered as outlined in Section 7.  Subjects will be provided time 
and space to complete the questionnaires.  A study coordinator will be on hand for any 
questions the subject may have.  All answers will remain confidential and subjects will be 
instructed to answer all questions as honestly and completely as possible.  
8.1.1.6 
Disease Details and Treatments 
8.1.1.6.1 
Disease Details 
The Investigator or qualified designee will obtain prior and current details regarding disease 
status.  Disease details include, but are not necessarily limited to, symptoms associated with 
the disease, pathological and laboratory reports, imaging reports, treatments and response to 
treatments. 
8.1.1.6.2 
Prior Treatment Details 
The Investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
8.1.1.6.3 
Subsequent Anti-Cancer Therapy Status 
The Investigator or qualified designee will review all new anti-neoplastic therapy/treatment 
initiated after the last dose of trial treatment.  If a subject initiates a new anti-cancer 
therapy/treatment within 30 days after the last dose of trial treatment, the 30 day Safety 
Follow-up Visit must occur before the first dose of the new therapy.  Once new anti-cancer 
therapy has been initiated, the subject will move into survival follow-up at 3, 6, 9, 12, 18, and 
24 months post treatment visits. 
8.1.1.7 
Assignment of Screening Number 
Eligible subjects will be approached by consenting providers or research nurse to participate 
in this study.  Subjects who do not meet the pathological criteria for enrollment will be 
considered a screen fail.  Those subjects who meet pathological inclusion/exclusion criteria 
will be fully screened for other tests and procedures.  Subjects will be assigned a 5-6 character 
ID code with the first three or four being the site code (a letter site code assigned to the site by the 
Sponsor) followed by a two digit number for a subject identifier beginning with 01 and each 
newly enrolled subject the subsequent number for that site.  For example, SCI-03 would 


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represent the third patient enrolled at site SCI.  Assigned subject numbers will only be used 
once.  If a patient should be a screen failure, that number will be resigned and the next patient 
assigned the sequential number until enrollment is met.  If a subject receives any part of the 
investigation treatment design and must discontinue treatment for any reason, they will not be 
replaced. 
To register a subject, the following documents must be on file with the research nurse or data 
manager: 
 Signed subject consent/HIPAA authorization form 
 Copy of required laboratory test results 
 Copy of the pathology report confirming high risk superficial transitional cell 
carcinoma histology 
 Copy of the most recent history and physical dictation/record 
 Any other documentation needed to verify inclusion/ exclusion criteria 
The research nurse or data manager will verify eligibility with the Principal Investigator.  To 
complete the registration process, the Project Manager will: 
 Assign a subject study number 
 Register the subject on the study 
8.1.1.8 
Trial Compliance 
Subjects who, in the opinion of the treating Investigator and study staff, would not be 
compliant with study procedures and requirements should not be enrolled in the study.  
Patients who “no show” for more than 1 required visit for non-emergent or non-health related 
events may be considered non-compliant and discontinued from the study at the discretion of 
the treating Investigator. 
8.1.2 
Clinical Procedures/Assessments 
Subjects diagnosed with T1 and Ta tumors require restaging after failure of BCG and one 
course of maintenance or failure after BCG plus one of the following: mitomycin, 
gemcitabine, or BCG/interferon.  Subjects receiving bladder tumor resection at outside 
institutions are eligible for the study; however, pathology slides must be reviewed by the 
site’s pathology department.  Each subject will receive a total of 6 cycles of treatment with 
MK-3475 at a dose of 100 (first 3 subjects) or 200 mg on Day 1 of a 21 day cycle.  Two 
cycles of MK-3475 will occur prior to BCG intravesical treatment (weekly doses for 6 
weeks) with concurrent treatment (MK-3475 and BCG) starting on cycle 3 and ending the 
third week of cycle 4.  MK-3475 will then be continued as a single agent for 2 additional 
cycles after the last dose of BCG was administered. 
 


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8.1.2.1 
Transurethral Resection of Tumor 
Transurethral resection of bladder tumor is routine care for this population.  Generally 
superficial bladder cancer subjects have 2 such resections as routine care prior to initial BCG 
therapy.  The first generally occurs after cystoscopy and confirmation of malignancy via 
biopsy.  The second generally occurs approximately 6 weeks following the first resection; 
however, timing may be extended if the subject is referred from an external clinic.  A repeat 
resection may occur as part of restaging for recurrent/persistent disease after failed 
intervesical therapy to confirm pathology and cytology for localized high grade (G3) 
transitional cell carcinoma (urothelial carcinoma) of the bladder that is stage Ta, T1, and/or 
CIS. 
8.1.2.2 
Adverse Event (AE) Monitoring 
The Investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently, if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (Appendix E).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  AEs will be recorded from the time the subject signs the 
consent through 30 days post the last study treatment. 
Please refer to section 9.0 for detailed information regarding the assessment and recording of 
AEs. 
8.1.2.3 
Full Physical Examination 
The Investigator or qualified designee will perform a complete physical examination 
including vital signs (heart rate, blood pressure, temperature, respiratory rate) during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical examination should be performed during screening and the 30 day 
Safety Visit. 
8.1.2.4 
Directed Physical Examination 
For cycles that do not require a full physical examination per the Trial Flow Chart, the 
Investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to trial treatment administration.  Directed physical examinations will also 
collect vital signs including heart rate, blood pressure, temperature, respiratory rate. 
8.1.2.5 
Vital Signs 
The Investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 7.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 


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8.1.2.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The Investigator or qualified designee will assess ECOG status (Appendix A) at screening, 
prior to the administration of trial treatment at Week 7, Week 13, Week 19 and 
discontinuation of trial treatment or Safety Follow up visit as specified in the Trial Flow 
Chart. 
8.1.2.7 
Twelve-Lead Electrocardiograms (ECG) 
During the screening period, a 12-lead ECG will be performed with the subject in a 
recumbent or semi-recumbent position after 5 minutes of rest.  Interpretation may be by the 
Investigator or a qualified designee.  ECGs completed within 90 days of the screening visit 
will be acceptable for the study, unless a suspected cardiac event has occurred in that 90 day 
period. 
8.1.2.8 
Chest X-Ray 
A chest X-ray, both PA and lateral views, will occur at screening to confirm non-metastatic 
disease as well as to provide a baseline evaluation for pulmonary status.  X-Rays completed 
within the 90 days prior to the screening visit are acceptable. 
8.1.2.9 
Pulmonary Function Tests (PFT) 
Baseline PFTs will occur at screening to assess lung volume, capacity, rate of flow, and gas 
exchange.  Throughout the course of the study, additional PFTs will be performed if 
clinically indicated.  If DLCO decreases by greater than 10%, the subject will be considered 
to have interstitial lung disease if no other obvious reason for the decrease.  The following 
will be collected: 
 
Vital Capacity (VC) 
 
Functional Residual Capacity (FRC) 
 
Total Lung Capacity 
 
Forced Vital Capacity (FVC) 
 
Forced Expiratory Volume (FEV) 
 
Forced Expiratory Flow (FEF)Peak Expiratory Flow Rate (PEFR) 
8.1.3 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual. 


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8.1.3.1 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.  
The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-
trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit 
and by sample type per subject can be found in the Procedure Manual. 
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment.  If screening laboratory tests occur within this window, they do not have to be 
repeated on Day 1 of Cycle 1.  After Cycle 1, pre-dose laboratory procedures can be 
conducted up to 72 hours prior to dosing.  Results must be reviewed by the Investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment. 
 
 
 
 
 
 
 
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Table 7: Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other-only at specific time points 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
 Calcium 
 
Hepatitis Panel  
 
 Chloride 
 
            HA AbIgM, HBsAg 
            HBcAb-IgM, HC Ab 
 
 Glucose 
 
TSH, free T4, prolactin, ACTH, and 
morning cortisol in case of suspected 
adrenal insufficiency  
 
 Creatinine 
 
Ketonuria testing in suspected 
hyperglycemia cases  
 
Potassium  
 
 
 
Sodium  
 
Urine for correlative studies 
 
 Total Bilirubin 
 
Blood for correlative studies 
 
 Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
 Total protein 
 
 
 
 Blood Urea Nitrogen 
 
 
 
 
 
 
 
 
 
 
† Perform on women of childbearing potential only.  If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 


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8.1.3.2 
Pharmacokinetic/Pharmacodynamic Evaluations 
Serum and whole blood will be collected at screening and at Week 19 for possible 
pharmacodynamics evaluation.  No pharmacokinetic studies are scheduled for this study. 
Specimens may be stored until completion of study at local site. 
8.1.3.2.1 
Blood Collection for Serum MK-3475 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedure Manual.  Specimens may be stored until completion of study at local site. 
The time points for blood sampling are described in Section 7 – Trial Flow Chart. 
8.1.3.2.2 
Blood Collection for Anti-MK-3475 Antibodies 
Sample collection, storage, and shipment instructions for blood samples will be provided in 
the Procedure Manual.  The time points for blood sampling are described in Section 7 – Trial 
Flow Chart.  Specimens may be stored until completion of study at local site. 
8.1.4 
Tumor Imaging and Assessment of Disease 
Chest X-ray, computerized tomography (CT) urogram or magnetic resonance imaging (MRI) 
urogram are allowed to ascertain the superficial nature of the disease when indicated 
according to the standard of care.  If urogram protocol not available or contrast allergy/poor 
renal function preclude such imaging, then non-contrast CT or MRI of the abdomen/pelvis 
within 90 days of study entry will suffice. 
Disease assessment will occur via an evaluation under anesthesia with cystoscopy, cytology, 
and random bladder biopsies (if indicated for positive findings on cystoscopy or cytology).  
Assessment will be performed at week 19 (approximately 6 weeks after the last dose of BCG 
treatment).  Assessment will also occur at 3 months, 6 months, 9 months, 12 months, 18 
months, and 24 months post treatment visit as per standard of care for the local site.  Due to 
recurrence or maintenance therapy, it is expected that assessments may not fit exactly at 
these time points.  If assessment not completed at that time point, indicate not done on the 
case report form. 
8.1.5 
Correlative Studies Specimen Collection 
Tumor tissue will be collected at time of clinical biopsy (archival specimen will suffice) at 
baseline during transurethral bladder resection (if possible) and at Week 19, if a biopsy is 
clinically indicated.  A minimum of 10 paraffin embedded slides are needed for baseline 
evaluation.  Serum, whole blood, and urine will be collected at baseline prior to Day 1, Cycle 
1 treatment, Week 4, 7, 8, 9, 10, 11, 12, 13, 16, prior to treatment and at Week 19 prior to 
cystoscopy.  Saliva will be collected at baseline only. Sample collection, storage and 
shipment instructions for blood and urine samples will be provided in the Procedures 
Manual.  If subjects are followed locally, specimens will be collected if available at 3 month, 
6 month, 9 month, 12 month, 18 month, and 24 month post treatment completion visits. 


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8.1.5.1 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 9.0 − Assessing and 
Recording Adverse Events. 
Patients may withdraw from the study at any time for any reason, and without prejudice to 
further treatment.   In addition, patients can be withdrawn by the Investigator because of 
unacceptable toxicity.   Patients who are withdrawn or are removed from the study will be 
required to have an off-study clinic visit at the time of discontinuation, and a 30-day follow-
up safety visit. 
Subjects can be withdrawn from the study for any of the following reasons: 
Adverse Event: If a subject suffers an adverse event, which in the judgment of the 
Investigator, the Study Sponsor, or the Data Safety Review Team presents an 
unacceptable consequence or risk to the subject, the subject can be withdrawn from 
the study. 
Administrative: After consultation, a subject can be withdrawn from the study for 
the following administrative reasons: 1) failure to complete the protocol-specified 
evaluations or 2) failure to comply with protocol requirements. 
Withdrawal of Informed Consent: A subject can withdraw his consent to 
participate in the study at his own request or be withdrawn from participation in the 
study at the request of his legally authorized representative at any time for any reason. 
Evidence of Progressive Disease: The Investigator can withdraw a subject from the 
study if there is a CT scan, MRI or other modality-confirmed progression of disease, 
but continue to collect follow-up data for safety and overall survival as per protocol. 
Subjects must be withdrawn/discontinued from the treatment for the following reasons: 
 The subject has intercurrent illness that prevents further administration of 
treatment. 
 The subject has a confirmed positive serum pregnancy test. 
 The subject is lost to follow-up. 
8.1.6 
Visit Requirements 
Visit requirements are outlined in Section 7.0 − Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 8.1 − Trial Procedures. 


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8.1.6.1 
Screening 
8.1.6.1.1 
Screening Period 
The screening period covers the 90 days prior to Day 1, Cycle 1.  Days −90 through −28 will 
include restaging for Ta and T1 tumors. 
The study screening visit is mandatory and must occur in the 28 days prior to Day 1, Cycle 1 
of treatment.  The study screening visit includes full study informed consent and 
documentation of consent.  No study required procedures (excluding those that are standard 
of care) are to occur prior to informed consent of the subject.  All inclusion/exclusion criteria 
must be reviewed and all of the inclusion and none of the exclusion criteria must be met to 
advance the subject on to the Treatment Period.  The screening period procedures include: 
full study informed consent, review of inclusion/exclusion criteria, documentation of 
demographics and medical history, concomitant medication review, cystoscopy and urine 
cytology, including restaging of tumor for Ta and T1, review of ongoing symptoms for 
documentation of baseline adverse effects, full physical examination, ECOG performance 
status, vital signs, electrocardiogram, chest X-ray, and baseline pulmonary function tests as 
well as laboratory assessments indicated in Section 7−Trial Flow Chart.  Collection of a 
baseline bladder cancer tumor specimen, as well as baseline blood and urine specimens for 
correlative studies, will also occur during the screening period.  Assessment of coagulation 
status will be performed prior to each resection as per standard of care. 
8.1.6.2 
Treatment Period 
8.1.6.2.1 
Dose Escalation 
The first 3 enrolled patients will be treated with 100 mg of MK-3475 every 3 weeks for 6 
cycles.  If one subject of the three requires the dose of MK-3475 to be withheld or 
discontinued, the 100 mg cohort will be expanded to 6 subjects.  If two out of three or two 
out of six subjects develop toxicity that requires the dose to be withheld or discontinued, the 
dose will be not be escalated to 200 mg MK-3475 every 3 weeks.  All remaining subjects 
will be treated at 100 mg MK-3475 every 3 weeks for 6 cycles. 
Physical examination and assessment of toxicity will be performed before each 
administration of MK-3475.  A CBC will be obtained on Day 1 of every 3-week cycle.  
Biochemistry panel examining electrolytes, and liver enzymes will be performed on Day 1, 
Cycle 1 of MK-3475, at Weeks 7, 10 and 13, and at the end of therapy (Week 19).  
Treatment will not proceed unless laboratory values are acceptable.  Urinalysis will occur at 
weeks 7-12 prior to each BCG treatment.  BCG treatment will not proceed unless urinalysis 
results are acceptable.  Collect and record non-serious and serious adverse events and 
assignment of toxicity grade (NCI CTCAE, Version 4) at each visit.  Collect and record any 
changes in concomitant mediation. 


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Subjects will be provided with an oral thermometer and a diary (Appendix H) to document 
twice daily oral temperatures.  The diary will also ask for documentation of other symptoms 
to help monitor for systemic infection of BCG. 
The AUA IPSS and QOL questionnaires are to be administered at Day 1 Cycle 1 and Week 
10 visit prior to any study procedures. 
8.1.6.2.3 
Phone Monitoring 
To monitor for systemic BCG infection, subjects will be called daily on days 2-4 of each 
BCG treatment cycle (Weeks 7-12).  Subjects will be queried on symptoms which may 
indicate systemic infection.  If clinically indicated, subject will be seen and clinically worked 
up for systemic infection and treatment started as indicated. 
8.1.6.3 
Unplanned Visits 
Unplanned visit information will be collected as well.  Information collected will include: 
disease symptoms and assessment/status, laboratory/imaging assessments, and toxicity 
assessments. 
8.1.6.4 
Post-Treatment Visits 
An evaluation under anesthesia with cystoscopy, cytology, and random bladder biopsies (if 
indicated for positive findings on cystoscopy or cytology) will be performed at Week 19 
(approximately 6 weeks after the last dose of BCG) to assess for response.  Physical 
examination, performance status, as well as vital signs, will also be assessed at the Week 19 
visit.  Laboratory assessments will include hematology and chemistry as outlined in Section 7 
– Trial Flow Chart and Table 7.  Coagulation assessment (PT/PTT/INR) will be re-assessed, 
if resection/biopsy is indicated.  Specimens needed for correlative studies will again be 
collected, including blood, urine, saliva and tumor (if biopsy is performed).  The collection, 
storage, and processing of laboratory samples are detailed in the Procedure Manual. 
The AUA IPSS and QOL questionnaires are also to be administered at Week 19 visit prior to 
any study procedures. 
8.1.6.5 
Treatment Discontinuation/Safety Follow-Up Visit 
The Treatment Discontinuation Visit and Safety Follow-Up Visit include identical 
procedures and assessments.  Subjects withdrawn from treatment prior to completion of the 
Treatment Period should undergo a Discontinuation Visit for safety purposes and may occur 
any time within 30 days of the subject discontinuing treatment, but preferably prior to the 
subject initiating a new treatment.  The mandatory Safety Follow-Up Visit should be 
conducted approximately 30 days after the last dose of trial treatment or before the initiation 
of a new anti-cancer treatment, whichever comes first.  All AEs that occur prior to the Safety 
Follow-Up Visit should be recorded.  Subjects with an AE of Grade >1 will be followed until 
the resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, 


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whichever occurs first.  SAEs that occur within 30 days of the end of treatment or before 
initiation of a new anti-cancer treatment should also be followed and recorded. 
Assessments at the Discontinuation/Safety Follow-Up Visit include a full physical 
examination, ECOG Performance Status and vital signs.  Laboratory assessments include 
hematology, chemistry, and urinalysis, as well as evaluation of thyroid function.  
Concomitant medications and toxicity assessment will be recorded as well. 
8.1.6.6 
Follow-up Visits 
Subjects who complete all study treatment or discontinue trial treatment for a reason other 
than disease progression will move into the Follow-Up Phase and should be assessed at 19 
week cystoscopy.  Additional follow up information will be collected at 3, 6, 9, 12, 18, and 
24 months post completion of treatment.  Every effort should be made to collect information 
regarding disease status, start of new anti-neoplastic therapy, disease recurrence, disease 
progression, death, or end of the study.  Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. 
A final set of AUA IPSS and QOL questionnaires are also to be administered at the 3 month 
Follow Up visit. 
9.0 
ASSESSING AND RECORDING ADVERSE EVENTS 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the investigational product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Adverse events may occur during the course of the use of investigational product in clinical 
trials, or as prescribed in clinical practice, from overdose (whether accidental or intentional), 
from abuse and from withdrawal. 
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed, but before treatment 
allocation/randomization, must be reported by the Investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including, but 


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not limited to, washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the Investigator.  Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
9.1.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting. 
9.1.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 20% over the prescribed dose and an overdose of BCG is considered 
more than one vial of BCG administered per instillation, unless a greater number of vials are 
prescribed due to multi-focal disease. 
In the event of an overdose, the event should be reported to the Sponsor and the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided, if clinically indicated.  No specific information is available on the treatment of 
overdose of MK-3475.  If over dosage of BCG occurs, the patient should be closely 
monitored for signs of active local or systemic BCG infection.  For acute local or systemic 
reactions suggesting active infection, an infectious disease specialist experienced in BCG 
complications should be consulted. 
If an adverse event(s) is associated with (“results from”) the overdose of a study drug, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
If a dose of an investigational product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days to the manufacturer’s safety division (For Merck 
products this is Merck Global Safety, Attn: Worldwide Product Safety; FAX 215 993-1220). 
 


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9.1.2 
Reporting of Pregnancy and Lactation to the Sponsor 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
Investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed, but before treatment 
allocation/randomization, must be reported by the Investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including, but 
not limited to, washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days, or 30 days following cessation of treatment if the subject initiates new 
anti-cancer therapy, whichever is earlier, must be reported by the Investigator.  All subjects 
and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
the product’s manufacturer safety division. 
9.1.3 
Immediate Reporting of Adverse Events to the Sponsor  
9.1.3.1 
Serious Adverse Events 
A serious adverse event is any adverse event occurring while the subject is enrolled into the 
study that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is another important medical event  
Note: 
In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in 
the same timeframe as SAEs to meet certain local requirements.  Therefore, 
these events are considered serious by Merck for collection purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
 


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Refer to Table 8 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study, that occurs 
to any subject must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including, but not limited to, washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study, whether or not related to the investigational product, must be reported 
within 24 hours to the Sponsor (and Merck Global Safety if a Merck product.) 
Additionally, any serious adverse event, considered by a qualified physician to be related to 
the investigational product that is brought to the attention of the Investigator at any time also 
must be reported immediately to the Sponsor and to product’s manufacturer. 
SAE reports and any other relevant safety information are to be forwarded to the FDA 
and the drug manufacturer’s safety division, as appropriate (Merck Global Safety 
facsimile number:  +1-215-993-1220). 
A copy of all 15 Day Reports and Annual Progress Reports are to be submitted as required 
by FDA, or other local regulators.  Investigators will cross reference this submission 
according to local regulations to the Merck Investigational Compound Number (IND, CSA, 
etc.) at the time of submission.  Additionally Investigators will submit a copy of these reports 
to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
9.1.3.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to the 
product manufacturer safety division. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 


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intervention, including, but not limited to, washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1. An overdose of study drug, as defined in Section 9.1.1 - Definition of an Overdose for 
this Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin laboratory value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase 
laboratory value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note: 
These criteria are based upon available regulatory guidance documents.  The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology. 
9.1.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 9.1.3- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event.  Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g., transportation issues etc.) will not be considered 
a SAE. 
 


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9.1.4 
Evaluating Adverse Events 
An Investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0.  Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
 
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Table 8: Evaluating Adverse Events 
An Investigator who is a qualified physician will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring while the subject is enrolled into the study: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event, for collection purposes.   
An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and 
to Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship 
Merck Product  
Did the product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an Investigator who is 
a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the Investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.  
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 


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Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an Investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a product relationship). 
Yes, there is a reasonable 
possibility of product relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR the 
AE is more likely explained by another cause than the Merck product.   (Also entered for a subject with overdose without an associated AE.) 


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9.1.5 
Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and Investigators in 
accordance with all applicable global laws and regulations.  If appropriate, adverse events will be 
reported to the drug manufacturer’s safety division. 
10.0 
STATISTICAL ANALYSIS PLAN 
10.1 
Statistical Analysis Plan Summary 
A minimum of 15 subjects will be enrolled.  Seventy percent of bladder tumors are superficial 
[22] indicating to enroll at least 15 patients, approximately 21-25 patients will need to be 
approached to meet eligibility and to allow for patient disinterest. 
Fifty percent of those patients who respond to BCG treatment develop recurrent disease [30; 31] 
generally detected within 6 months of BCG treatment.  Those patients with recurrent disease 
often are sent for radical cystectomy as there are no other acceptable standard treatment options.  
This study, though primarily evaluating maximum tolerated dose, will examine the percent 
response at 19 weeks to determine if MK-3475 has altered the pattern of responders as early as 
19 weeks from the start of treatment.  The results of this study will not only examine the safety 
of combining MK-3475 with BCG for future studies, but will also assist in determining patient 
eligibility (recurrent superficial bladder cancer versus initial diagnosis) and considerations for 
future study design. 
Patient related data will be collected and transferred to an excel spreadsheet for statistical 
analysis.  SAS software version 9.4 will be used for all data analysis.  Descriptive statistics will 
be computed for all study variables.  Continuous variables will be described with measures of 
central tendency (mean, median) and dispersion (range, standard deviation).  Categorical 
variables will be summarized as frequencies and percentages.  Some examples include tumor 
stage (Ta, T1, Cis), age, ECOG Performance Scale (0, 1, 2), sex, and use of tobacco and alcohol. 
For primary objective 1, the proportion of patients with each AE will be reported along with the 
NCI CTCAE Grade of the AE.  The Quality of Life Questionnaire, which includes one question 
with seven categorical responses, will be described with frequencies and percentages.  The 
American Urologic Association Symptoms Index Questionnaire, which includes seven questions 
each with a numerical score between 0 and 5 as well as a final numerical sum of all responses, 
will be described with measures of central tendency and dispersion.  Due to the questionnaires 
being given at three time points (Pre-treatment, Mid-treatment, and Post-treatment), the 
responses may be analyzed to look for longitudinal effects over time for specific variables of 
interest with repeated measures ANOVA to evaluate changes and control for individual 
differences (although this would be very low power due to n=15). 
For the secondary objective, subjects will be assessed at 19 weeks, 3 months, 12 months, and 24 
months post treatment completion for complete response.  The outcome endpoint will be 
complete response status at 19 weeks, 3 months, 12 months, and 24 months post treatment to 
measure complete response, recorded as yes or no and summarized as proportions and a percent.  


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These proportions/percent will be reported, but no statistical analysis will be performed as this is 
a single arm phase I study, and no control group is available for direct comparison. 
For the exploratory objectives, Pearson or Spearman’s rank correlation coefficient will be used to 
estimate correlations between expression level change and treatment outcome, as well as the 
correlations between mutation presence and treatment outcome. 
11.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
11.1 
Standard Treatment 
BCG will be utilized as the product of standard treatment for this protocol for superficial bladder 
cancer.  The Investigator will take appropriate steps to ensure that appropriate records are 
maintained regarding the use of BCG in the study.  BCG will be supplied through commercial 
sources and the supply, storage, handling, distribution, and usage of BCG will be in accordance 
with local practice and any applicable laws and regulations, including this protocol. 
Clinical Supplies will be provided through commercial sources.  The approved package labeling 
will be utilized for the preparation and storage and handling of BCG. 
11.2 
Investigational Product 
The Investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 9. 
Table 9: Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3475 100 mg/ 4mL 
Solution for Injection 
 
11.3 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
11.4 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment.  Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 


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11.5 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
11.6 
Returns and Reconciliation 
The Investigator or designee is responsible for keeping accurate records of the clinical supplies 
received from Merck, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy.  It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local, and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
12.0 
ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 
Confidentiality 
The Investigator and Sponsor of the study must adhere to all applicable data privacy and 
confidentiality laws and regulations (i.e. HIPAA).  Those applicable include institutional, state, 
and Federal Law.  It is the responsibility of the Investigator and Sponsor to ensure the subject 
data as well as sensitive study information is handled according to applicable guidelines and 
laws.  Appropriate authorization and consent for use, disclosure, or transfer of protected health 
information must be obtained. 
Subject names will not be recorded on the CRF.  Only the subject number and subject's initials will 
be recorded, where permitted.  If the subject's name appears on any other document (e.g., pathology 
report), it must be obliterated on the copy of the document as appropriate.  Study data stored on a 
computer will be stored in accordance with local data protection laws.  The subjects will be informed 
that representatives of the sponsor or its designee, IRB, and regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made available 
for inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
12.2 
Compliance with Financial Disclosure Requirements 
All participating Investigators must have on file a completed clinical Investigator Financial 
Disclosure Form.  The form must sufficiently detail any financial interests or arrangements that 
may apply.  For the purposes of this study, the Financial Disclosure Form required by the 


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Springfield Committee for Research Involving Human Subjects will be utilized.  A clinical 
Investigator is defined as any Investigator or Sub-Investigator who is directly involved in the 
treatment or evaluation of research subjects (this includes the spouse and each dependent child of 
the clinical Investigator).  All new study personnel must submit a completed Financial 
Disclosure Form with the IRB application.  Investigators are required to report any changes of 
their financial information/status as previously reported while the study is ongoing and for a 
period of 1 year after the completion of the study. 
12.3 
Compliance with Law, Audit and Debarment 
The Investigator, Sub-Investigator and Sponsor of the study are required to comply with and 
adhere to all local, state, and federal law that is applicable to the study. 
12.3.1 
Sponsor Audits  
At any point throughout the study, the Sponsor may visit the study site to conduct an audit of the 
study.  The purpose of this visit generally will be to determine the Investigator's adherence to the 
Protocol, applicable regulations, and the Sponsor's procedures, as well as assessing the accuracy of 
the study data. 
12.3.2 
Inspection by Regulatory Authorities 
A regulatory authority may visit the Investigator/Sponsor to conduct an inspection of the study and 
the site.  The site Investigator and staff are expected to cooperate with the inspectors and allow 
access to all source documents supporting the CRFs and other study-related documents.  
12.4 
Compliance with Laws and Regulations 
The proposed study is to be conducted according to federal regulation including: 
Please refer to: Code of Federal Regulations, Title 21: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm] 
Coder of Federal Regulations, Title 45 Part 46 
12.4.1 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
 


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12.4.2 
Protocol Adherence 
IRB approval and all materials approved by the IRB for this study, including the subject ICF and 
recruitment materials, must be maintained by the Investigator and made available for inspection.  
Each Investigator must adhere to the Protocol as described in this document and agree that 
changes to the Protocol, with the exception of medical emergencies, must be discussed and 
approved by the IRB.  The Investigator is responsible for enrolling subjects who have met the 
inclusion and exclusion criteria.  The IRB granting approval must be notified of all changes in 
and deviations from the Protocol that may increase risk to the subject, and/or may adversely 
affect the rights of the subject or validity of the investigation. 
12.5 
Quality Management System 
Qualified staff of the Sponsor will monitor the study according to a pre-arranged monitoring 
plan.  Monitoring of the study will include: 
 Evaluation of study progress 
 Verification of CRF accuracy and completeness 
 Resolution of inconsistencies in study records 
 Assurance of protocol requirements and investigator’s obligations are fulfilled 
 Assurance of compliance with applicable laws and regulations 
 Study monitors will periodically review all CRFs and supporting source documentation of 
participating subjects.  The CRFs and supporting documentation must remain up to date and 
available to the study monitor as arranged.  CRF data entry will be verified to correspond with 
source documentation (laboratory, imaging, pathology reports, etc.) and reviewed for 
completeness.  Data discrepancies will be identified and reported to the Investigator and site 
staff. 
Protocol deviations will be identified and recorded on a deviation log. 
12.6 
Data Management 
The Investigator will be provided with a CRF for each subject.  Entries made in the CRF must be 
verifiable against source documents; any discrepancies should be explained and documented.  
The Investigator will be responsible for reviewing all data and CRF entries and will sign and date 
the designated pages in each subject's CRF, verifying that the information is true and correct.  
The Investigator is responsible for the review and approval of all responses. 
Data management will be performed from CRFs. All CRF data will be entered into a validated 
database.  All data entry, verification, and validation will be performed in accordance with the 
current standard operating procedures of the Sponsor. 
12.6.1 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved, 2 years following the 


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termination of the test article for investigation.  State of IL Law requires retention of materials 
for 6 years following completion of study.  If it becomes necessary for a regulatory authority to 
review any documentation relating to the study, the Investigator must permit access to such 
records. 
All CRFs will be maintained or made available at the site in compliance with applicable record 
retention regulations. 
 
 


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13.0 
LIST OF REFERENCES 
1. 
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8. 
2. 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated 
B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 
2002; 8(8):793-800. 
3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
4. 
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66. 
5. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
6. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61. 
7. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400. 
8. 
Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81. 
9. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. Clin 
Cancer Res 2008;14(16):5220-7. 
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. Tumor 
infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. 
BMC Immunol 2010;11:19. 
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94. 
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict clinical 
outcome. Science 2006;313:1960-4. 
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51. 


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14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival 
of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic 
cell infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-
30. 
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53. 
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841.  
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx 
V, et al. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in 
primary cutaneous melanoma. Cancer Immunol Immunother 2008;57:97-106. 
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11. 
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic 
lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-59. 
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7. 
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory 
T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor 
prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6. 
 
22. Jemal, A., et al., Cancer statistics, 2003. CA Cancer J Clin, 2003. 53(1): p. 5-26. 
 
23. Soloway, M.S., Overview of treatment of superficial bladder cancer. Urology, 1985. 26(4 
Suppl): p. 18-26. 
 
24. Redelman-Sidi, G., M.S. Glickman, and B.H. Bochner, The mechanism of action of BCG 
therapy for bladder cancer--a current perspective. Nat Rev Urol, 2014. 11(3): p. 153-62. 
 
25. Hall, M.C., et al., Guideline for the management of nonmuscle invasive bladder cancer 
(stages Ta, T1, and Tis): 2007 update. J Urol, 2007. 178(6): p. 2314-30. 
 
26. Dalbagni, G. and H.W. Herr, Current use and questions concerning intravesical bladder 
cancer group for superficial bladder cancer. Urol Clin North Am, 2000. 27(1): p. 137-46. 
 


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27. Lamm, D.L., et al., A randomized trial of intravesical doxorubicin and immunotherapy 
with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. N Engl J Med, 
1991. 325(17): p. 1205-9. 
 
28. Rintala, E., et al., Intravesical chemotherapy (mitomycin C) versus immunotherapy 
(bacillus Calmette-Guerin) in superficial bladder cancer. Eur Urol, 1991. 20(1): p. 19-25. 
 
29. Vegt, P.D., et al., A randomized study of intravesical mitomycin C, bacillus Calmette-
Guerin Tice and bacillus Calmette-Guerin RIVM treatment in pTa-pT1 papillary carcinoma 
and carcinoma in situ of the bladder. J Urol, 1995. 153(3 Pt 2): p. 929-33. 
 
30. Krege, S., et al., A randomized multicenter trial of adjuvant therapy in superficial bladder 
cancer: transurethral resection only versus transurethral resection plus mitomycin C versus 
transurethral resection plus bacillus Calmette-Guerin. Participating Clinics. J Urol, 1996. 
156(3): p. 962-6. 
 
31. Lundholm, C., et al., A randomized prospective study comparing long-term intravesical 
instillations of mitomycin C and bacillus Calmette-Guerin in patients with superficial 
bladder carcinoma. J Urol, 1996. 156(2 Pt 1): p. 372-6. 
 
32. Hudson, M.A. and H.W. Herr, Carcinoma in situ of the bladder. J Urol, 1995. 153(3 Pt 1): 
p. 564-72. 
 
33. Herr, H.W., et al., Superficial bladder cancer treated with bacillus Calmette-Guerin: a 
multivariate analysis of factors affecting tumor progression. J Urol, 1989. 141(1): p. 22-9. 
 
34. Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with advanced 
cancer. N Engl J Med, 2012. 366(26): p. 2455-65. 
 
35. Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
 
36. Keir, M.E., et al., PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 
2008. 26: p. 677-704. 
 
37. Zhang, P., et al., Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) 
surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. 
Mol Immunol, 2008. 45(5): p. 1470-6. 
 
38. Konishi, J., et al., B7-H1 expression on non-small cell lung cancer cells and its relationship 
with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res, 2004. 
10(15): p. 5094-100. 
 
39. Thompson, R.H., et al., Tumor B7-H1 is associated with poor prognosis in renal cell 
carcinoma patients with long-term follow-up. Cancer Res, 2006. 66(7): p. 3381-5. 


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40. Thompson, R.H., et al., Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of 
tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A, 2004. 
101(49): p. 17174-9. 
 
41. Inman, B.A., et al., PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and 
BCG-induced granulomata: associations with localized stage progression. Cancer, 2007. 
109(8): p. 1499-505. 
 
42. De Libero, G. and L. Mori, The T-Cell Response to Lipid Antigens of Mycobacterium 
tuberculosis. Front Immunol, 2014. 5: p. 219. 
 
43. Stein, J.P., et al., Radical cystectomy in the treatment of invasive bladder cancer: long-term 
results in 1,054 patients. J Clin Oncol, 2001. 19(3): p. 666-75. 
 
44. Skinner, E.C., et al., SWOG S0353: Phase II trial of intravesical gemcitabine in patients 
with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical 
bacillus Calmette-Guérin. J Urol, 2013. 190(4): p. 1200-4. 
 
45. Sylvester, R.J., et al., Predicting recurrence and progression in individual patients with 
stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients 
from seven EORTC trials. Eur Urol, 2006. 49(3): p. 466-5; discussion 475-7. 
 
 


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14.0 
APENDICES: 
Remainder of Page Intentionally Left Blank 
 


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APPENDIX A 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, 
but unable to carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982.  The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
 


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APPENDIX B 
Calculation of CKD-EPI GFR 
http://www.qxmd.com/calculate-online/nephrology/ckd-epi-egfr 
The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation was developed in 
an effort to create a formula more precise than the MDRD formula, especially when actual GFR 
is > 60 mL/min per 1.73 m2.  Researchers pooled data from multiple studies to develop and 
validate this new equation.  They randomly divided 10 studies, which included 8,254 
participants, into separate data sets for development and internal validation.  Sixteen (16) 
additional studies, which included 3,896 participants, were used for external validation.  The 
CKD-EPI equation performed better than the MDRD (Modification of Diet in Renal Disease 
Study) equation, especially at higher GFR, with less bias and greater accuracy.  When looking at 
NHANES (National Health and Nutrition Examination Survey) data, the median estimated GFR 
was 94.5 mL/min per 1.73 m2 vs. 85.0 mL/min per 1.73 m2, and the prevalence of chronic kidney 
disease was 11.5% versus 13.1%.  The CKD-EPI equation, expressed as a single equation, is: 
GFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 1.018 [if female] X 1.159 [if 
black] 
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is –0.329 for 
females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
 
 
 
 
 
 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van 
Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A New 
Equation to Estimate Glomerular Filtration Rate. Ann Intern Med 150(9):604-12. (2009) 
Stevens LA et al. Comparative Performance of the CKD Epidemiology Collaboration (CKD-EPI) and the 
Modification of Diet in Renal Disease (MDRD) Study Equations for Estimating GFR Levels Above 60 
mL/min/1.73 m2. AJKD 56(3):486-495. 


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APPENDIX C 
TICE® BCG Package Insert 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM1630
39.pdf 
 
 
 
 


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Appendix D 
Questionnaire 


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AUA SYMPTOM SCORE 
 
Highlight or bold or change font color of the response correct for you 
and type in your score in the far right box for all SEVEN questions.  
 
1. Incomplete emptying: Over the past month, how often have you had a sensation of not 
emptying your bladder completely after you finished urinating?  
Not at all 
 
Less than 1 
time in 5 
Less than 
half the time 
About half 
the time 
More than 
half the time 
Almost 
always 
Your Score 
0 
1 
2 
3 
4 
5 
 
 
2. Frequency: Over the past month, how often have you had to urinate again less than 2 hours 
after you finished urinating? 
Not at all 
 
Less than 1 
time in 5 
Less than 
half the time 
About half 
the time 
More than 
half the time 
Almost 
always 
Your Score 
0 
1 
2 
3 
4 
5 
 
 
3. Intermittency: Over the past month, how often have you found that you stopped and started 
again several times when you urinated? 
Not at all 
 
Less than 1 
time in 5 
Less than 
half the time 
About half 
the time 
More than 
half the time 
Almost 
always 
Your Score 
0 
1 
2 
3 
4 
5 
 
 
4. Urgency: Over the past month, how often have you found it difficult to postpone urination? 
Not at all 
 
Less than 1 
time in 5 
Less than 
half the time 
About half 
the time 
More than 
half the time 
Almost 
always 
Your Score 
0 
1 
2 
3 
4 
5 
 
 
5. Weak-stream: Over the past month, how often have you had a weak stream? 
Not at all 
 
Less than 1 
time in 5 
Less than 
half the time 
About half 
the time 
More than 
half the time 
Almost 
always 
Your Score 
0 
1 
2 
3 
4 
5 
 
 
6. Straining: Over the past month, how often have you had to push or strain to begin urination? 
Not at all 
 
Less than 1 
time in 5 
Less than 
half the time 
About half 
the time 
More than 
half the time 
Almost 
always 
Your Score 
0 
1 
2 
3 
4 
5 
 
 
7. Nocturia: Over the past month or so, how many times did you get up to urinate from the time 
you went to bed until the time you got up in the morning? 
None 
 
1 time 
2 times 
3 times 
4 times 
5 or more 
times 
Your Score 
0 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
Add up your scores for total AUA score =  _______ 
 
Quality of Life Due to Urinary Symptoms: If you were to spend the rest of your life with your 
urinary condition just the way it is now, how would you feel about that?  (Bold, Highlight or 
Underline) 
 
   Delighted          Pleased          Mostly satisfied         Mixed         Mostly dissatisfied        Unhappy        Terrible 
 
 
 
Last Name 
First Name 
Date 
 


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Appendix E 
CTCAE 4.0 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 


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Appendix F 
Basic Science Correlates 
Objective1.  Staining for PD-1, PDL-1, and CD3 in bladder tissue samples 
obtained at initial tumor resection and on follow up biopsies 
Immunohistochemistry for PD-1, PD-L1, and CD3 in tissue from pretreatment biopsy and tumor 
resection will be performed to investigate the association between tissue expression of these 
markers and response to MK-3475.  When preparing and submitting slides, newly cut sections 
will be utilized to ensure stability of the PD-L1 epitope.  Staining for immunohistochemistry for 
markers of interest will involve baking formalin fixed paraffin embedded tissue sections for 45 
minutes at 60 °C, then deparaffinized and rehydrated with serial passage through changes of 
xylene and graded ethanols.  All slides will be subjected to heat induced epitope retrieval in 
either Envision FLEX Target Retrieval Solution, High pH (cat K8012, Dako, Carpineteria CA) 
or Target Retrieval Solution, pH 6.1 (cat S1699, Dako).  Endogenous peroxidase in tissues will 
be blocked by incubation of slides in 3% hydrogen peroxide solution prior to incubation with 
primary antibody (anti-PD-L1 clone 22C3, Merck Research Laboratories, Palo Alto CA; anti-
PD-1 clone NAT105, Cell Marque, Rocklin CA; or anti-CD3 clone F7.2.38, Dako) for 60 
minutes.  Antigen-antibody binding will be detected using polymer-based methods and 
visualized by application of 3,3' diaminobenzidine (DAB) chromogen (K4368, Dako).   Stained 
slides will be counterstained with hematoxylin and coverslipped for review and scoring by a 
pathologist employing a semiquantitative 0-5 scale. 
Specimens collected from biopsy (formalin fixed tissue blocks and slides) obtained at baseline 
(utilizing the specimen ICF form or the main study ICF) and Week 19 (main study ICF) will be 
utilized for the completion of Basic Science Correlates, Objective 1. 
Objective 2.  Whole exome sequencing of germline DNA and formalin fixed, 
paraffin embedded tissue on all patients.  Correlation will be made to mutations 
and treatment outcomes. 
The study Investigators are submitting a protocol that allows for DNA collection from 
genitourinary cancer patients.  The same protocol will allow for collection of clinical data and 
DNA sequencing using next generation technology from patients who received MK-3475.  
Pathology reports from pre- and post-MK-3475 tumor resections and biopsies will be obtained.  
Response/no response to MK-3475 will be ascertained from the collected clinical data using 
definitions of response agreed on for high risk superficial bladder cancer.  Germline DNA from 
patients with a complete set of data will be sequenced using next generation sequencing (exome 
sequencing at 40x) provided by industrial vendors (such as www.edgebio.com).  Data from next 
generation sequencing will be analyzed using software provided by Ingenuity Inc. 
(www.ingenuity.com).  Variants will be analyzed both in an agnostic and non-agnostic manners.  
Any genes reported in the literature to be associated with response to PDL-1 therapy will be 
examined to agnostically identify variants within these genes shared between responders/no 
responders to MK-3475 at a significant level.  In addition, genetic variants common to 
responders/non responders and unrelated to genes identified previously in the literature as being 


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related to PDL-1 response will be examined (non-agnostic analysis).  Such non-agnostic variants 
will be also considered as important targets for biomarker development if they are significantly 
associated with response/no response to treatment.  Variants associated with response/no 
response will be then validated in the discovery cohort using sequenome analysis 
(www.sequenome.com) as agreed upon in the scientific methodology of such studies to avoid 
replicating variants that do not actually exist in the sampled DNA. 
Specimens (including tumor and surrounding normal tissue, whole blood, serum, and urine) will 
be collected for future unspecified research if the subject agrees to collection and storage for 
future unspecified research.  Specimens may come from subjects fully enrolled in the treatment 
portion of the study at baseline and Week 19.  Specimens may also be obtained from subjects 
who have declined the treatment portion of the study or were ineligible, but gave permission for 
use of specimens despite not being enrolled into the treatment portion of the study.  The 
specimens will be stored until completely utilized or for 50 years, whichever occurs first.  These 
specimens will be utilized for completion of Basic Science Correlatives, Objective 2 if funding is 
secured or for other studies which may become apparent throughout the study, for example, 
development of a urine based assay for response assessment.  Not all studies have been identified 
at this time. 
Objective 3. Immune-profiling of bladder exudate and blood from patients treated 
with combination of BCG and pembrolizumab for high risk transitional cell 
carcinoma of the bladder 
Bladder cancer is the fifth most common cancer in the United States.(1) The majority of 
diagnoses are non-muscle invasive bladder cancer (NMIBC), however a significant proportion of 
these cases will recur and some will ultimately become muscle invasive.(2) Thus, prevention of 
post-transurethral resection of bladder tumor (TURBT) recurrence of intermediate risk NMIBC 
would represent a major step towards reduction of bladder cancer mortality. Intravesical 
instillation of BCG represents first line treatment for NMIBC and is effective in preventing 
recurrence of superficial disease.(3) This is thought to elicit an immune reaction and the release 
of cytokines that active an immune response from neutrophils, macrophages, and T cells.(3)  
Recently, there have been advances in the treatment of advanced bladder tumors with agents 
targeting the programmed cell death protein (PD-1)/programmed cell death ligand (PDL-1) 
checkpoint pathway.(4) By blocking this pathway, a greater antitumor response by T cells is 
created resulting in increased bladder cancer cell immune mediated destruction.(5) We have a 
phase I clinical study examining the results of combining pembrolizumab, a monoclonal anti-
PD1 antibody, with BCG treatments. In these patients, we have collected both urine and blood 
pre- and post-treatment. The urine in these patients contains the bladder inflammatory exudate 
that developed during treatment. We hypothesize that the understanding of how combined 
BCG and pembrolizumab treatment affect the local (bladder exudate in urine) and 
systemic (blood) immune environment could be obtained from immune-profiling bodily 
fluids of our trial patients.  
Our collaborator, Dr Bruce Patterson from IncellDx has developed a high parameter flow 
cytometry assay for immune profiling in solid tumors and urine. In a lung study that combined 
primary tumor immune profiling and Circulating Tumor Cell (CTC) analysis, they were able to 


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identify both drug targets in the primary tumors and factors in the primary tumor that diminished 
immune control of tumor cells that led to detection of CTCs especially CTCs expressing PD-L1. 
We will use the patient samples derived from our phase I study and perform high parameter (>20 
markers) analysis of urine and blood samples, below, both pre- and post-treatment to quantify the 
 
 immune cell sub-populations to create an immune profile. Furthermore, we will analyze serum 
cytokines to further establish immune response in patients. We will also compare the immune 
profiles for treatment responders and non-responders to determine if there are biomarkers for 
predicting response to this combined treatment modality much like we had done previously to 
identify immune control in the lung (below). 
 
 
We will use the patient samples derived from our phase I study and perform FACS analysis to 
sort urine and blood samples, both pre- and post-treatment, into immune cell sub-populations to 
create an immune profile. Furthermore, we will analyze serum cytokines to further establish 
No CTC cluster


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immune response in patients. We will also compare the immune profiles for treatment responders 
and non-responders to determine if there are biomarkers for predicting response to this combined 
treatment modality.  
We will utilize patient samples from a single arm phase I study in which patients with high risk 
bladder cancer are enrolled. Patients will receive TURBT for their bladder tumor as a standard of 
care treatment for their disease, followed by treatment of 200mg IV of pembrolizumab every 3 
weeks. These cycles will overlap with BCG treatment for 6 weeks that were initiated no later 
than 2 weeks after TURBT. Patients will have follow up with cystoscopy every 3 months for one 
year. Response at one year will be decided based on negative cytology and cystoscopy for 
bladder cancer. Pre- and post-treatment urine containing bladder exudate and blood will be spun 
down to isolate immune cells, which will be prepared for flow cytometric analysis. Antibodies to 
markers of T-cells (CD3, CD4, CD8, RORT), B-cells (CD19, CD20, Ig, ĸ), NK cells (CD56, 
CD16), Macrophages (CD14, CD33), and Dendritic Cells (CD11c, CD123, HLA-DR). In 
addition, we will perform Luminex Assays on patient serum samples to determine cytokine 
profiling (IL-1beta, IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, GM-CSF, IFN-gamma, 
TNF-alpha). We will examine immune profiles pre- and post- treatments as well as comparing 
the immune profiles between patients that respond to treatment (ie no tumor recurrence) with 
patients that have tumor recurrence.  
Bladder Circulating Tumor Cell Enumeration 
 
 
 
 
 
 
 
Whole blood (8mL) will be drawn from patients. These samples will be run on the Celsee 
CelSelect enumeration chip to quantify the number of circulating tumor cells (CTCs) from the 
patients’ pre-and post-treatment samples. The captured circulating tumor cells will be stained for 
PD-L1 and CCR5 to identify potential targets to eliminate metastasis. 
 
 
Recover >80-90% of CTCs
Microchambers Size Select
Stain CTCs for Enumeration
y = 0.8006x
R² = 0.9741
0
10
20
30
40
50
0
20
40
60
Number of Cells 
captured
Number of Cells Spiked


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Potential experimental difficulties and alternative approaches 
We do not foresee any technical issues with regard to performing the experimental approaches. 
Our collaborator’s laboratory is experienced in isolating immune cells from patient samples and 
performing FACS analysis. The antibodies we intend to use for staining have all been tested. 
Though the fundamental groundwork for success may be in place, potential pitfalls may always 
arise. 
Even though we plan to spin down samples, this does not necessarily mean cells will be present 
in sufficient numbers to perform our experiments. Given most patient samples were collected 
and frozen prior to analysis, there is risk of cell lysis compromising analysis. If this occurs, we 
may be required to change buffering solutions used prior to freezing. 
1. 
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as 
Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-
26. 
2. 
Pieraerts C, Martin V, Jichlinski P, Nardelli-Haefliger D, Derre L. Detection of 
functional antigen-specific T cells from urine of non-muscle invasive bladder cancer patients. 
Oncoimmunology. 2012;1(5):694-8. 
CT
WB
CD4
5-  
CD4
5+  
PDL-
1+  
PDL-
1+  
Overl
CT
WBC  
CD4
5-  
CD4
5+  
PDL-
1+  
PDL-
1-  
Overl
Bladder Cancer Sample 
19-
0595 
19-
0595 
Sample 19-0595 = 2 
CTC 
Sample 19-0600 = 0 
Assay- IncellDx BioInk (PDL-1-Cy5, PanCK-PE, CD45-GFP) 
on Celsee Cell Select Platform Chips Scanned on BioTek LionHeart Using Celsee ALgorithm 


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3. 
Mehta K, Patel K, Parikh RA. Immunotherapy in genitourinary malignancies. J Hematol 
Oncol. 2017;10(1):95. 
4. 
Aggen DH, Drake CG. Biomarkers for immunotherapy in bladder cancer: a moving 
target. J Immunother Cancer. 2017;5(1):94. 
5. 
Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 
immunotherapy for bladder cancer: The future is now. Cancer Treat Rev. 2017;54:58-67. 
 
 


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Appendix G 
Patient Diary 
 


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Patient BCG Treatment Diary 
 
 Patient ID:____________ 
 
Date of BCG Treatment: _______________ 
WEEK 7 CYCLE 1 BCG TREATMENT 
Temperature 
DAY 1 
DAY 2 DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
Morning ºF 
 
 
 
 
 
 
 
 
Before Bed ºF 
 
 
 
 
 
 
 
 
 
Symptoms:____________________________________________________________________ 
_____________________________________________________________________________ 
Date of BCG Treatment: _______________ 
WEEK 8 CYCLE 2 BCG TREATMENT 
Temperature 
DAY 1 
DAY 2 DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
Morning ºF 
 
 
 
 
 
 
 
 
Before Bed ºF 
 
 
 
 
 
 
 
 
 
Symptoms:____________________________________________________________________ 
_____________________________________________________________________________ 
 
 


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Patient BCG Treatment Diary 
 
 Patient ID:____________ 
Date of BCG Treatment: _______________ 
WEEK 9 CYCLE 3 BCG TREATMENT 
Temperature 
DAY 1 
DAY 2 DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
Morning ºF 
 
 
 
 
 
 
 
 
Before Bed ºF 
 
 
 
 
 
 
 
 
 
Symptoms:____________________________________________________________________ 
_____________________________________________________________________________ 
 
Date of BCG Treatment: _______________ 
WEEK 10 CYCLE 4 BCG TREATMENT 
Temperature 
DAY 1 
DAY 2 DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
Morning ºF 
 
 
 
 
 
 
 
 
Before Bed ºF 
 
 
 
 
 
 
 
 
 
Symptoms:____________________________________________________________________ 
_____________________________________________________________________________ 
 
 
 
 


Product:  MK-3475 
Protocol/Amendment No.:  Amendment 5, 21 October 2019 
 
 
Page 88 of 89 
 
Patient BCG Treatment Diary 
 
 Patient ID:____________ 
Date of BCG Treatment: _______________ 
WEEK 11 CYCLE 5 BCG TREATMENT 
Temperature 
DAY 1 
DAY 2 DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
Morning ºF 
 
 
 
 
 
 
 
 
Before Bed ºF 
 
 
 
 
 
 
 
 
 
Symptoms:____________________________________________________________________ 
_____________________________________________________________________________ 
Date of BCG Treatment: _______________ 
WEEK 12 CYCLE 6 BCG TREATMENT 
Temperature 
DAY 1 
DAY 2 DAY 3 
DAY 4 
DAY 5 
DAY 6 
DAY 7 
Morning ºF 
 
 
 
 
 
 
 
 
Before Bed ºF 
 
 
 
 
 
 
 
 
 
Symptoms:____________________________________________________________________ 
_____________________________________________________________________________ 
 
_______________________________________ 
 
___________________________ 
Patient Signature 
 
 
 
 
 
 
Date 
 
 


Product:  MK-3475 
Protocol/Amendment No.:  Amendment 5, 21 October 2019 
 
 
Page 89 of 89 
 
Appendix H 
 
Summary of Changes 
 
1. 
Updated Version number and date 
 All headers and references to version numbers or dates 
 
2. 
Administrative Corrections 
 Spelling, formatting, and consistency errors corrected 
 Updated participating Investigators 
 
3. 
Appendix F 
 Added Objective 3: Immune-profiling of bladder exudate and blood from patients 
treated with combination of BCG and pembrolizumab for high risk transitional 
cell carcinoma of the bladder 
 
13. 
Appendix H 
 Updated Summary of Changes 

ICF_001.pdf: 
Page 1 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
INFORMED CONSENT FORM
PHASE I STUDY OF MK-3475 IN COMBINATION WITH BCG FOR PATIENTS 
WITH HIGH RISK SUPERFICIAL BLADDER CANCER
You are being asked to be a subject in a 
research study. The main goal of a research 
study is to gain knowledge that may help future 
patients, whereas routine care is based upon 
the best known treatment and is provided with 
the main goal of helping the individual patient.
If you agree to participate in this study, you will 
be asked to sign this informed consent 
document. Informed consent is a written 
agreement that you, or your authorized 
representative, sign indicating willingness to 
participate in this research. This informative 
document will tell you about the purpose, risks, 
and benefits of this research study. You should 
consent only after you have been given all the 
necessary information and have had enough 
time to decide whether you wish to participate.  
Your signature on this form is voluntary and 
does not waive any of your legal rights or make 
any institutions or persons involved in this 
research any less responsible for your well-
being.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 2 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
TITLE:
Phase I Study of MK-3475 in Combination with BCG for Patients with High 
Risk Superficial Bladder Cancer
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. 
Clinical trials include only people who can choose to take part. Please take your time to make your 
decision about taking part. You may discuss your decision with your friends and family. You can also 
discuss it with your health care team. If you have any questions, you can ask your study doctor for 
more explanation.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.
You are being asked to take part in this study because you were diagnosed with superficial bladder 
cancer that has not responded to previous treatment with BCG. Superficial bladder cancer is a type 
of cancer found in the lining of the bladder and that has not invaded the muscle of the bladder wall. 
Typically, superficial bladder cancer is treated with medications that are placed inside the bladder 
through a catheter (tube inserted into the urethra) to decrease the possibility of the cancer returning. 
The urethra is the tube that carries urine from the bladder to the outside of the body.
You may take home an unsigned copy of this consent form to think about or discuss with your 
regular doctor, family, or friends before making your decision. Whether you take part in this study or 
not is entirely your decision. If you decide to take part in the study and sign this form, you may still 
end your participation at any time. In any case, your decision will not affect your regular medical care 
or any benefit to which you are otherwise entitled. If you decide to take part in this study, you will be 
asked to sign the consent form.
WHO IS THE PRINCIPAL INVESTIGATOR FOR THIS STUDY?
Krishna A. Rao, MD
Telephone Number: 217-545-1129
WHY IS THIS STUDY BEING DONE?
This study is being conducted to test the safety of Pembrolizumab, also known as MK-3475 or 
Keytruda®, at different dose levels in combination with the current therapy (BCG) for superficial 
bladder cancer. We want to find out what effects, good and/or bad, it has on you and your bladder 
cancer.
Pembrolizumab (study drug) aids the body’s immune system in fighting cancerous tumors and is 
approved by the Food and Drug Administration (FDA) for the treatment of various cancer types, 
including lung and melanoma. It is considered investigational in this study, which means it is not 
approved by the FDA for the treatment of superficial bladder cancer.
Bacillus Calmette-Guerin (BCG) is used to treat bladder cancer because it stimulates immune 
responses that can destroy cancer cells within the bladder. It is most often used after the cancer has 
been removed from the bladder using transurethral resection (TUR) surgery to prevent the 
recurrence of the cancer. This is an FDA approved and routine treatment for superficial bladder 
cancer and may occur even if you choose not to participate in this study.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 3 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
BCG is also used in some countries as a vaccine to provide protection against tuberculosis (TB).
When it is used to treat bladder cancer, BCG is given through a urinary catheter (intravesically) into 
the bladder.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 15-24 people will take part in this study. This is a multi-site study which means there are other 
clinics, including the Simmons Cancer Institute, that will be enrolling these patients.
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?
Before you begin the study...
You will need to have the following exams, tests or procedures to find out if you can be in the study. 
These exams, tests or procedures are part of regular care and may be done even if you do not join 
the study. If you have had some of them recently, they may not need to be repeated. This will be up 
to your study doctor.

Obtain informed consent for participation in the treatment study.

Obtain some of your personal and background information, such as your name, date of 
birth, race, etc.

Review of your medical conditions and all medications you have taken recently or are 
currently taking.

A review of your current symptoms and general activity level; how well you are doing in your 
daily life.

A complete physical examination, including assessment of vital signs (temperature, height, 
weight, heart rate, blood pressure, and respirations or breathing rate).

Cystoscopy - a procedure used to see inside your bladder. During a cystoscopy procedure, 
your doctor uses a hollow tube (cystoscope) equipped with a lens to carefully examine the 
lining of your bladder and your urethra. The cystoscope is inserted into your urethra and 
slowly advanced into your bladder.

Trans-urethral removal of bladder tumor with a diagnosis of superficial bladder cancer 
(surgical removal of the tumor through the urethra rather than an incision on the abdomen). 
If you have had removal of your tumor at another institution and it is unclear if the tumor has 
advanced from the lining of your bladder into the muscle of the bladder you may need to 
have a second surgical procedure to ensure that you do not have more advanced disease. 
Bladder cancer that has crossed into the bladder muscle is treated differently than cancer 
that only remains in the lining of the bladder.

Biopsy - A small amount of tissue will be removed from your bladder to determine if you 
have cancer. The biopsy may have been performed previously and, if so, will only be 
repeated if it is required to confirm that your cancer has not crossed into the bladder muscle.
In order to participate in the treatment portion of the study, a sample of your tumor is required in 
either the form of previously collected specimens or slides OR a new specimen or slides from a 
current biopsy.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 4 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
Additional specimens, including blood, saliva and urine are requested at various time points 
throughout the study. These specimens are optional and you may decline them and still participate 
in the treatment study. You will be given the option to decline or accept these additional specimens 
later in this consent.
If these tests and procedures show that you have superficial bladder cancer, then you will need the 
following tests and procedures required by the study before you begin treatment:

Electrocardiogram (ECG) - a tracing of the electrical activity of the heart. This procedure 
may be done at other times during the study, if deemed appropriate by your study doctor.

Chest X-ray - a painless test that creates pictures of the structures inside your chest, such 
as your heart, lungs, and blood vessels.

Pulmonary function tests - a group of tests that measure how well the lungs take in and 
release air and how well they move gases, such as oxygen from the air into the body's blood 
stream.
If you currently have, or have had in the past, an inflammation of the lungs not 
caused by an infection that required treatment with steroids you may not be eligible 
to participate in this study. Please inform the study team if you have any lung related 
conditions.

Blood tests to determine your blood count and chemistry, to check your overall health, and 
to see how well your blood clots.

Urine analysis - an examination of your urine to check for disease and kidney health.

Thyroid function - a blood test to determine the levels of hormones produced by the thyroid 
gland.

Hepatitis Panel - a blood test for viral infections of the liver.

Pregnancy test, if you are a woman of child bearing potential.

Blood, saliva, urine and tissue samples collected for additional research.

American Urologic Association symptom index and quality of life questionnaire.
During the study...
If the exams, tests and procedures show you can be in the study, and you choose to take part, you 
will then receive the following treatment.
BCG
BCG is a bacterial strain called Bacillus Calmette-Guerin. It contains live, attenuated (weak) 
bacteria. In order for BCG to work it must come in direct contact with the tumor cells. In order to do 
so the BCG is instilled (administered directly into the bladder). You will receive treatment once a 
week for 6 weeks as part of this study treatment. BCG treatment will begin on Day 1 of Week 7. 
Depending on your response after Week 19, you may have additional treatments beyond the 6 
scheduled, but they will be outside of your participation in this study.
Below is a description of the procedure:
It is suggested that you limit your fluid intake for 4 hours before the procedure, so you will be able to 
hold the medicine in your bladder during the treatment. Upon arrival, you will be asked to provide a 
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 5 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
urine specimen to ensure that it is safe to administer your BCG treatment. It is important that you be 
on time to your appointment as your BCG is mixed specifically for you and can only be kept for a 
short time.
BCG is given through a urinary catheter (a tube inserted through your urethra). Treatment may be 
uncomfortable, but generally is not painful. The actual placement of the BCG into your bladder only 
takes a few minutes. The BCG will be instilled into the bladder according to this site’s institutional 
standards based on FDA approved indications for treatment of bladder cancer. If you have any 
questions, please ask the study staff.
Once outside the body, BCG fluid may be unsafe for you and others to come in contact with it. 
Simple safety measures will help keep you and others safe. This includes sitting down while 
urinating, adding bleach to the toilet, closing the toilet lid before flushing, and washing your hands 
and genital areas carefully with soap after every urination.
You will also be asked to drink plenty of fluids to help wash out the BCG from your bladder after 
treatment has finished.
You should report any unusual symptoms to your study doctor while undergoing BCG treatment. 
This includes: noticing blood in your urine, urgent or frequent need to urinate, flu-like symptoms or a 
fever of 101.3ºF or higher.
Pembrolizumab (study drug)
Pembrolizumab will be given to you through intravenous (needle inserted into your vein) infusion. 
You will be given study drug once every 21 days (one cycle) for a total of 6 cycles. It will take 30 
minutes for the infusion of the study drug. If you develop side effects as a result of the study drug or 
its infusion you may be given pre-medications prior to your treatment to lessen the side effects. This 
may lengthen your treatment time.
Pembrolizumab will be given on Day 1 of weeks 1, 4, 7, 10, 13, and 16 while BCG will be given on 
Day 1 of weeks 7-12.
The first three patients enrolled in the study were given a dose of 100mg of pembrolizumab. The 
data safety committee approved the escalation of the dose to 200mg of pembrolizumab in 
combination with BCG. You will be in the group treated with 200mg of pembrolizumab in 
combination with BCG.
While being treated…
You will need these tests and procedures that are part of regular care, but may be done more often 
because you are in this study. Additional tests may also be done as part of your regular care, if your 
doctor requests them.

Physical examination and reporting of adverse events (side effects) will be performed before 
each administration of study drug.

Review of your medications and any changes that may have occurred.

Review of how you are performing in your daily activities.

Urinalysis will occur at weeks 7-12 prior to each BCG treatment.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 6 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
You will need these tests and procedures that are being done to see how the study is affecting your 
body.

You will be asked to complete questionnaires about your urination habits (frequency, 
urgency, etc.) and quality of life on Day 1 of weeks 1, 10 and 19.

Blood counts will be obtained on Day 1 of every 21 day cycle.

Blood chemistries will be performed on Day 1 of weeks 1, 7, 10, 13 and at the end of 
therapy (Week 19).

Blood tests will be performed to evaluate your blood clotting function (may be done more 
frequently when clinically indicated).

You will be called on Days 2 through 4 of each BCG treatment (Weeks 7-12) to inquire 
about any symptoms you may be having and to see if you have a fever.

You will be given a thermometer and a diary to fill out during the weeks of your BCG 
treatment. You will be asked to take your temperature in the morning and evening every day 
and record it on the diary as well as any symptoms you are having. This will occur every day 
for the full 6 weeks of BCG treatment or a total of 42 days.

Blood, urine and tissue samples will be collected for additional research.
When you finish your treatment (Week 19)...
You will need the following tests and procedures. They are part of regular care.

Physical examination with vital signs and weight.

Review of your medications, symptoms and any adverse effects you may be having.

Review of how you are performing in your daily activities.

Blood tests to evaluate your blood clotting function.

Tests for blood counts and chemistries.

Urine analysis, cystoscopy and possible bladder biopsy.
You will need these tests and procedures that are being done to see how the study is affecting your 
body. (All done once at the 30 day follow up after the end of treatment, unless otherwise indicated.)

Collection of blood and urine samples for additional research studies (Week 19 only), if you 
agree to the optional collection for future research.

Collection of bladder tissue taken (required), only if you have a biopsy during your 
cystoscopy at Week 19.

You will be asked to answer the American Urologic Association symptom index and quality 
of life questionnaire (and also at 90 days after your cystoscopy).

Review of your medications, symptoms and any adverse effects you may be having.

Tests for blood counts and chemistries, as well as thyroid function.

Review of the status of your disease (has it recurred and if any new therapies have 
occurred) at 90 days after your cystoscopy.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 7 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
WHAT HAPPENS DURING LONG TERM FOLLOW UP?
The study wants to monitor your cancer status following your treatment. Subjects who complete all 
study treatment or discontinue study treatment for any reason other than disease progression will 
move into the Follow-Up Phase of the study.
Information about your cancer (if it has returned) and any new treatments will be monitored at about 
3, 6, 9, 12, 18 and 24 months after completion of study treatment/cystoscopy. We expect this to 
somewhat follow your usual routine care. Usual care will include cystoscopy and possible biopsy or 
resection, if indicated by your urologist. We will collect information through routine visits, calls or 
from public sources, such as obituaries. If a clinic visit is required, it may be done at another clinic if 
you do not live locally.
If you agreed to the collection of research specimens, you will also be asked to provide urine, blood 
and tissue (only if a biopsy or resection is required medically) at these visits if you are being seen at 
the study site.
You will also be asked to complete a set of final questionnaires about your urination habits 
(frequency, urgency, etc.) and quality of life during the study Follow-up Phase. These questionnaires 
can be completed at a clinic visit, by mail or at the time of a telephone contact.
HOW LONG WILL I BE IN THIS STUDY?
You will be in this study for approximately 28 months from the time of consent until final follow up 
for the study.
CAN I STOP BEING IN THIS STUDY?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or 
decide to stop. He or she will tell you how to stop safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
Pembrolizumab can be evaluated by your study doctor. Another reason to tell your study doctor that 
you are thinking about stopping is to discuss what follow-up care and testing could be most helpful 
for you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow study instructions; or if the study is stopped.
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THIS STUDY?
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors do not know all the side effects that may happen.  
Side effects may be mild to very serious. Your health care team may give you medicines to help 
lessen side effects.
Many side effects go away after you stop taking the Pembrolizumab. In some cases, side effects can 
be serious or long-lasting or may never go away. Serious side effects are those that may require 
hospitalization or may be irreversible, long-term, life threatening or fatal. To identify the “serious” 
risks, a double asterisk (**) has been placed next to the risk below.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 8 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
Pembrolizumab works by helping your immune system fight your cancer. However, pembrolizumab 
can also cause your immune system to attack normal organs and tissues in your body and can 
affect the way they work, which can result in side effects. These side effects may be serious (i.e. 
causing hospitalization or be life-threatening), may result in death, and/or may occur after you stop 
taking pembrolizumab. These side effects can affect more than one of your normal organs and 
tissues at the same time.
It is also possible to experience a serious allergic reaction, which could become life-
threatening or fatal. Symptoms of an allergic reaction include rash, hives, itching, swelling of the 
mouth, face, lips, tongue or throat, dizziness, tightness in the chest, coughing or trouble breathing. If 
you believe you are having a serious allergic reaction, you should seek emergency medical 
assistance immediately.
You should talk to your study doctor about any side effects that you have while taking part in the 
study.
Risks and side effects related to the Pembrolizumab include the following:
VERY COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening or where 
noted, may cause death)
Out of 100 people who receive pembrolizumab, 20 or more people may have the following:

Itching of the skin

Loose or watery stools

Cough
COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening or where noted, 
may cause death)
Out of 100 people who receive pembrolizumab, at least 5, but less than 20 people, may have the 
following:

Joint pain

Rash

Fever

Back pain

Pain in your belly

Loss of skin color

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have infrequent or 
hard stools

Low levels of salt in the blood that may cause you to feel tired, confused, have a headache, 
muscle cramps and/or feel sick to your stomach
LIKELY CHANGES IN LABORATORY RESULTS

Hyperglycemia (increase in glucose levels in blood)

Hyponatremia (low sodium levels in blood)
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 9 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019

Hypoalbuminemia (low levels of albumin in blood)

Hypertriglyceridemia (high triglyceride levels in blood)

Increased liver enzymes

Hypocalcemia (low levels of calcium in the blood)
UNCOMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening, or where 
noted, may cause death)
Out of 100 people who receive pembrolizumab, at least 1, but less than 5 people, may have the 
following:

**Inflammation of the lungs so you may feel short of breath and cough. Sometimes this 
might lead to death.

Too much thyroid hormone so you may feel anxious, angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, have loose and watery stools.

**Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a fever, feel 
short of breath, experience a decrease in blood pressure at the time of receiving your 
infusion (IV) or just after, or pain at the site of infusion.

**Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools, and black, tarry, sticky stools or stools with blood or mucus.

**Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin 
redness. The skin inflammation (i.e. peeling, itching and redness) could also be widespread 
throughout your body. More severe skin reactions may involve the inside of your mouth, the 
surface of your eye and genital areas, and/or may cause the top layer of your skin to peel 
from all over your body which can cause severe infection. These severe conditions can 
sometimes lead to death.
RARE, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening, or where noted, may 
cause death)
Out of 100 people who receive pembrolizumab, less than 1 person may have the following:

**Inflammation of the nerves that may cause pain, weakness or tingling in your hands and 
feet, and may spread to your legs, arms and upper body leading to severe muscle 
weakness and possible temporary paralysis.

**Inflammation of the muscles so you may feel weak or have pain in your muscles.

**Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you 
may have severe pain in the top part of your belly that may move to your back, feel sick to 
your stomach, and vomiting that gets worse when you eat.

**Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to light, 
eye pain, see floaters or have headaches.

**Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like 
not eating, feel tired, have a mild fever, have a pain in the right side of your belly, yellow 
eyes and skin, and dark urine.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


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Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
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
**Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick 
to your stomach or have headaches, changes in your behavior, double vision, few to no 
menstrual cycles, weakness, vomiting and dizziness or fainting.

**Adrenal glands (glands on top of the kidneys) that may not make enough hormone 
(secondary adrenal insufficiency), which could cause tiredness, weight loss, muscle 
weakness, feeling faint, joint, muscle and belly aches, nausea, vomiting, loose or watery 
stools, fever, salt craving, and sometimes darkening of the skin like a suntan.
**A more serious form of adrenal insufficiency (primary adrenal insufficiency, also 
called Addison’s disease) has been identified with the use of pembrolizumab. 
Primary adrenal insufficiency has similar side effects as secondary adrenal 
insufficiency, but can be life-threatening. Primary adrenal insufficiency is an 
irreversible condition.

**Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling thirstier 
than usual, frequent urination and weight loss. You are likely to need regular insulin shots.

**Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, 
swelling and low back pain.

**Inflammation of the middle layer of your heart wall that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of 
breath and swelling of the legs. You may experience a fast or irregular heartbeat that may 
cause dizziness or fainting. Sometimes this condition can lead to death.

**Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones.  This 
condition may lead to a change in your heart rate, blood pressure, body temperature, and 
the rate at which food is converted into energy.

**A condition that may make you feel weak and tired and might have drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and 
legs, or difficulty breathing.

**The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin, or lungs.

**Inflammation of the brain with confusion and fever. This may also include: disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, 
weakness or loss of movement in some parts of your body, and loss of consciousness.

**Pulmonary Embolism (blood clot in the lung that presents with symptoms of chest 
pain/discomfort and shortness of breath)
Additionally, since pembrolizumab was approved in September 2014, side effects have been 
reported by people receiving pembrolizumab. These side effects were voluntarily reported from a 
group of people of unknown size. It is not possible to estimate the frequency of these side effects:

Inflammation of the joints (arthritis) which may include joint pain, stiffness and/or swelling.

**Severe responses of the immune system that cause the body to attack its own blood 
cells, spleen, liver, lymph nodes, skin and brain. This may include fever, rash, 
inflammation of the liver, yellowing of the skin, an enlarged liver and spleen, low blood 
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


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Protocol No.: 014-001SBC
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Site’s FINAL ICF, Version Dated 13 November 2019
counts, and enlarged lymph nodes. The nervous system may also be affected and 
cause confusion, seizures, and even coma.

**If you have had an allogeneic stem cell transplant (a procedure in which a person 
receives blood-forming stem cells from a donor), you may experience graft versus host 
disease (GvHD), which may include diarrhea, skin rashes, and liver damage, after 
receiving pembrolizumab. Sometimes this condition can lead to death.

**If you have had a solid organ transplant (for example, if you received a kidney or heart 
transplant), you may experience rejection of the transplanted organ. Your doctor will monitor 
you and should tell you what signs and symptoms you should report depending on the type 
of organ transplant you have had.
Risks and side effects related to the BCG treatment include the following:
Likely (Greater than 20 out of 100 patients experienced these side effects)

Painful urination

Urinary frequency

Flu-like symptoms

Hematuria (blood in urine)

Fever
Less Likely (Between 4 and 20 out of every 100 patients experienced these side effects)

Malaise/fatigue

**Cystitis (inflammation of the bladder)

Urgency (the feeling of the need to urinate)

Nocturia (frequent urination throughout nighttime)

Cramping or pain in bladder

Chills

Nausea

Incontinence (loss of bladder control)
Rare, but serious (Less than 4 out of every 100 patients experienced these side effects)

**Anemia - decrease in the number of red blood cells which may cause tiredness

**BCG sepsis – whole body inflammation caused by severe infection

**BCG infection in other organs

**Coagulopathy - impaired clotting of blood

**Contracted Bladder (spasms of the bladder)

**Epididymitis/prostatitis - inflammation of the prostate or epididymis, the tube which carries 
sperm from the testicle

**Hepatic Granuloma –a collection of immune cells in the liver

**Hepatitis-Inflammation of the liver

**Leukopenia - decreased number of blood cells which help fight infection
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


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Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019

**Orchitis - inflammation of the testis

**Pneumonitis - inflammation of the lung

**Urinary obstruction-blockage of the flow of urine from the body
REPRODUCTIVE RISKS
The effects of the investigational drug on an unborn child are unknown. You should not become 
pregnant or father a baby while on this study. It is very important that you practice birth control to 
prevent pregnancy during this study.
If you are sexually active, you and your partner must use adequate and acceptable methods of birth 
control to avoid pregnancy from the time the consent form is signed and for 120 days after your last 
dose of study drug. Acceptable methods include use of an IUD, contraceptive rod implant, 
vasectomy of the male partner or a combination of two of any of the following: diaphragm with 
spermicide, cervical cap with spermicide, contraceptive sponge, male or female condom (cannot be 
used together), and hormonal contraceptive pill/patch/subcutaneous injection. If you or your partner 
do become pregnant, you should notify the study doctor as soon as possible.
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is 
consistently employed as the subject’s preferred and usual lifestyle.
Female participants must not be pregnant at the time of study entry. This must be confirmed by a 
pregnancy test taken within 96 hours before the first dose of the study drugs. Women should not 
breast feed a baby while on this study because the study drugs may affect an infant.
If you do become pregnant, you will stop taking study drugs, but will be followed for safety reasons. 
You will be followed by the study doctor until completion of the pregnancy. If the pregnancy ends for 
any reason before the anticipated date, the study doctor will notify the sponsor of the research. At 
the completion of the pregnancy, the study doctor will document the outcome of the pregnancy.
For men, if your spouse or partner thinks she is pregnant during the study, tell your study doctor 
immediately. The study doctor will ask to follow the pregnancy until completion. If the pregnancy 
ends for any reason before the anticipated date, the study doctor will notify the sponsor of the 
research. At the completion of the pregnancy, the study doctor will document the outcome of the 
pregnancy.
The effects of the study drugs on male fertility are unknown.
If you are a patient at St. John’s Hospital, you should be aware that St. John’s (an Affiliate of 
Hospital Sisters Health System), a Catholic health care facility, adheres to the Ethical and Religious 
Directives for Catholic Health Care Services. St. John’s is not endorsing birth control; however, in 
order to maintain compliance with the study, we are required to provide this information to 
participants, as a matter of public safety. Please note that no method of birth control besides 
complete abstinence provides 100% protection from pregnancy. If you are concerned about the 
morality of methods of birth control, please consult your religious advisor before agreeing to 
participate in this study.
For more information about risks and side effects, ask the study doctor.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


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Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
There are risks to taking part in any research study. Participation in this study may involve some 
risks or discomforts. These may be related to the procedure itself or to the study drugs. There may 
be some unanticipated risks.
The anticipated risks and discomforts related to the procedures include, but are not limited to, the 
following:
Intravenous (IV) Infusions: A method of delivering drugs directly into a vein (intravenous) using a 
needle or tube. A thin plastic tube called an IV catheter is inserted into the vein. While delivery of 
drugs by IV is generally safe, it can cause side effects. Examples of IV side effects include:

Infection at the infusion site which can also travel into the bloodstream causing a severe 
infection throughout the body; symptoms can include fever and chills, as well as redness, 
pain, and swelling at the infusion site.

Damage to blood vessels and infusion site which can cause infiltration (causing the drug to 
leak into surrounding tissue instead of going into the bloodstream). Infiltration can cause 
tissue damage. Phlebitis, or inflammation of the veins is also possible; symptoms of both 
infiltration and phlebitis include warmth, pain, and swelling at the infusion site.

Air embolism which can cause air bubbles to travel to the heart or lungs and block blood 
flow; an air embolism can cause severe problems, such as heart attack or stroke.

Blood clots can form which can block important blood vessels and cause problems such as 
tissue damage or death; deep vein thrombosis (DVT) is a type of dangerous blood clot that 
IV treatment can cause.
Urinary Catheter Insertion: A procedure using a thin plastic tube inserted through the urethra to 
deliver BCG to the bladder. Side effects include:

Discomfort and/or pain during the catheter insertion; numbing medication may be used to 
reduce the discomfort.

Infection in the urethra, bladder or, less commonly, kidneys; symptoms include pain in the 
bladder or urethra, offensive-smelling discharge from the urethra, passing foul-smelling, 
cloudy urine, general symptoms of an infection, such as a high temperature (100.4°F or 
above), a feeling of being generally unwell, tired and lethargic (lacking in energy).

Bladder spasm, which feels like abdominal cramps.

Leakage around the catheter causing incomplete delivery of the BCG dose.

Injury to the urethra caused by inserting the catheter.

Injury to the bladder or rectum (back passage) caused by incorrectly inserting the catheter.
Blood Sampling: Obtaining blood may sometimes cause local pain or discomfort at the site where 
the blood is drawn, bruising, occasional light headedness and, rarely, fainting.
Approximately 30 - 45 ml (2 - 3 tablespoons) of blood will be collected during your screening visit 
and then approximately 10 ml (2 teaspoons) each cycle of treatment.
ECG: You may experience some discomfort, skin redness or irritation when the ECG electrodes are 
removed from the skin.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


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Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
Chest X-ray: There is low radiation exposure. X-rays are monitored and regulated to provide the 
minimum amount of radiation exposure needed to produce the image. Most experts feel that the risk 
is very low compared with the benefits. Pregnant women and children are more sensitive to the risks 
of X-rays.
Transurethral Bladder Resection: There is a risk of bleeding, infection of the bladder, perforation 
(or hole) of the bladder wall, blood in the urine or blockage of the urethra by blood clots in the 
bladder.
Cystoscopy: There is a risk of bleeding, infection of the bladder, and complications from the 
anesthesia. There are also risks of perforation of the bladder or anywhere along the urinary tract, 
development of scar tissue which can cause difficulties in urination, and the inability to urinate or 
obstruction of the flow of urine. The bladder can also become distended during the procedure, which 
temporarily weakens the voiding muscles.

Men can sometimes experience pain and swelling in the testicles after an extensive 
procedure.
Biopsy: All medical procedures that involve removing tissue run the risk of bleeding and infection. 
There is also a risk of blood or blood clots in your urine, as well as a burning sensation when you 
urinate.
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY?
If you agree to take part in this study, there may or may not be medical benefit to you. We hope the 
information learned from this study will benefit other patients with superficial bladder cancer in the 
future.
WHAT OTHER OPTIONS ARE THERE?
Instead of being in this study, you have these options:

You could choose not to participate in this study.

You could choose to receive only treatment with BCG and follow up with cystoscopy to treat 
recurrence if it happens.
Please talk to your regular doctor or the study doctor about these and other options.
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE?
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Your personal information may be given out if 
required by law. If information from this study is published or presented at scientific meetings, your 
name and other personal information will not be used.
A federal law called the Genetic Information Nondiscrimination Act (GINA) generally makes it illegal 
for health insurance companies, group health plans, and employers with 15 or more employees to 
discriminate against you based on your genetic information. GINA does not protect you against 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
genetic condition or disease.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 15 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
State law may require that you sign a separate consent form for HIV, Sexually Transmitted Diseases 
(STD) or communicable diseases testing. Test results may be reportable to the Illinois Department 
of Public Health (IDPH). For more information please visit http://www.idph.state.il.us/.
WHAT ARE THE COSTS?
The following tests and/or procedures are required solely for the purposes of this research study and 
will be paid for by the sponsor of the study. (They will be provided at no cost to you or your 
insurance company.):

All blood tests (blood counts and chemistries, thyroid function tests, hepatitis panel, sample 
collection), pulmonary function tests, electrocardiogram, and chest X-ray required to make 
sure you could enter the study, and that are performed to monitor for side effects of the 
investigational therapy.

The pembrolizumab will be provided at no cost as well as the cost for intravenous treatment 
once every 3 weeks for the total of 6 treatments.

The BCG will be provided at no cost. However, you or your insurance company will be 
charged the cost associated with the BCG instillation (delivery through a urinary catheter).
You or your insurance company will be charged for routine care (i.e., cystoscopy, urinalysis, 
resection) and continuing medical care and/or hospitalization at the usual rate.
You will not be paid for taking part in this this study.
INSTITUTION AND INVESTIGATOR INTERESTS
SIU School of Medicine and the Principal Investigator, Krishna A. Rao, MD, received a grant from 
Merck & Co. to support the costs of conducting this clinical trial. Merck & Co. is the manufacturer of 
the drug (Keytruda®/MK-3475/pembrolizumab) being used in this study. Merck & Co. is also 
providing the drug free of charge to subjects while participating in this study.
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?
If you are injured during your participation in this study, you should contact the study doctor as soon 
as possible in person or at the telephone number listed on page 2 of this consent form. If you have a 
medical emergency during the study, you should go to the nearest hospital emergency room. Be 
sure to tell the hospital staff that you are in a research study being conducted at this study clinic. Ask 
them to call the study doctor at the telephone number on the second page of this consent form for 
further instructions or information about your care.
In the event of any injury resulting from study procedures, immediate medical treatment for injuries is 
available at usual and customary fees at Memorial Medical Center or St. John’s Hospital, 
Springfield, Illinois or your local hospital.
Your medical expenses will be your responsibility or that of your third-party payer, although you are 
not precluded from seeking compensation for injury related to your participation in the research 
study.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 16 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
If you suffer any physical injury as a result of participation in this study, you should contact the 
Chairperson of the Springfield Committee for Research Involving Human Subjects (which is a group 
of people who review the study to protect your rights) at:
Southern Illinois University School of Medicine
201 East Madison
P.O. 19664
Springfield, IL  62794-9664
Telephone number: (217) 545-7602
WHAT ARE MY RIGHTS AS A PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or may leave this study at any 
time. Leaving this study will not result in any penalty or loss of benefits to which you are entitled.
We will tell you about new information that may affect your willingness to stay in this study.
WHO WILL USE AND SHARE INFORMATION ABOUT MY PARTICIPATION IN THE STUDY?
This section explains who will use and share your study-related health information if you agree to 
participate in this study.
A federal privacy law, the Health Insurance Portability & Accountability Act (HIPAA), protects your 
individually identifiable health information (protected health information). The privacy law requires 
the researchers to get your agreement to allow them to use and/or disclose your protected health 
information for research purposes in this study. Your agreement will be documented when you sign 
this consent. This authorization to use and share your information expires in 50 years.
During the study, the researchers will use, collect, and record health information about you. This can 
include any information about you that the study doctor needs to conduct this study.
The protected health information that may be used and/or disclosed includes: 

Name

Address

Telephone number

Social security number

Medical record number

Race

Gender

Date of birth

History and diagnosis of allergies

Family medical history

Current and past medical records

Prior medical history

Current and past medications

Current and past therapies

Information from a physical examination that generally also includes blood pressure reading, 
heart rate, breathing rate, temperature, height and weight
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 17 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019

Medical data, including blood and urine test results, pathology reports, and scan results 
(MRI, CT, ECHO, MUGA, EKG, etc.)

Information on side effects (adverse events) you may experience, and how these were 
treated.
If you sign this consent, you agree to allow the study doctor and research team to use and/or 
disclose your protected health information described above with:

SIU HealthCare

SIU School of Medicine

Memorial Medical Center

St. John’s Hospital

Merck Sharp, & Dohme Corporation, any laboratories, individuals, and organizations that 
use your health information in connection with this study, including the researchers at other 
sites.

The study sponsor, SIU School of Medicine, including representatives, collaborators, 
assignees, licensees or designees and their affiliates, agents, employees, its current or 
future research partners, collaborators and other individual organizations that analyze or use 
the information for research activities (e.g. laboratories, etc.)

Southern Illinois University School of Medicine’s Institutional Review Board: The Springfield 
Committee for Research Involving Human Subjects (SCRIHS)

Government representatives, when required by law

U.S. Food and Drug Administration (If an FDA regulated clinical trial) 

Office for Human Research Protections (OHRP)
There are national and state laws that require the study doctor to protect the privacy of your records. 
However, you do not have a guarantee of absolute privacy. Some information may be subject to re-
disclosure. If this should occur, your information may no longer be covered/protected by the federal 
privacy protections.
If you would like to know how the sponsor would protect the privacy of your records, ask the study 
doctor how to get this information.
You have the right to see and copy your records. However, if you sign this consent form, you may 
not be able to see or copy some records until all subjects complete the study. Once the study has 
ended, you will be able to see and copy your records.
You can withdraw your consent to use and share your records at any time. If you choose to 
withdraw your authorization, you must submit this request in writing to Dr. Krishna A. Rao to 
inform him of your decision at the following address:
Krishna A. Rao, MD
Associate Professor of Clinical Medicine
Department of Internal Medicine, Division of Hematology/Oncology
Southern Illinois University School of Medicine
Attention: Clinical Trials Office, Room 3000
315 West Carpenter Street, Springfield, Illinois 62702
Telephone: 217-545-1129
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 18 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
If you decide to withdraw from this study, federal regulations may allow the data collected about you 
to continue to be used for the purposes of the study. Please be sure to ask the study doctor about 
your options for removing your data should you withdraw from this study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about this study or a study-related injury, contact the study doctor Krishna A. Rao, MD 
at 217-545-1129.
For questions about your rights as a study participant, contact the Springfield Committee for 
Research Involving Human Subjects (which is a group of people who review the study to protect 
your rights) at:
Southern Illinois University School of Medicine
201 East Madison
P.O. 19664
Springfield, IL  62794-9664
Telephone number: (217) 545-7602
The Chairperson of this committee will review the matter with you.
THE REMAINDER OF THIS PAGE IS INTENTIONALLY LEFT BLANK.
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 19 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
Permission for Future Research
SIU School of Medicine, the study sponsor, would like to keep any unused portion of your tumor and 
saliva, blood and urine samples in a tissue bank for future research. The main goal of a Tissue Bank is 
to collect biological specimens (tissue, hair, blood, etc.) for use by researchers to gain knowledge about 
human disease that may help other people in the future. The specimens will be stored until your 
specimens are used up or for 50 years, whichever occurs first.
At this time, it is impossible to name all the different types of studies that researchers may want to 
perform using your specimens, including studies on the genetics of your disease. However, studies 
performed using these specimens can help researchers understand how the human body works and 
can be helpful in the development of new tests and treatments for diseases. In the future, this research 
may help to develop new products, such as drugs or tests to detect disease. Some of the possible 
goals of the research involving human specimens might include determining whether a particular gene 
(material that is passed from parents to child that determines the makeup of the body) is associated 
with a certain type of disease. You should be aware that new products might be developed and 
commercially sold as a result of research done on your specimens. You should understand that you will 
receive no economic benefit from this commercial development. You will not be offered any 
compensation for your tumor, saliva, blood and urine samples.
The research that may be conducted with your specimens is not designed to provide direct benefit to 
you. You will not be notified of any results of the research conducted using your specimens. However, 
others may be helped through the knowledge gained from these studies regarding diseases or 
conditions and how to detect, prevent or treat them.
Information from your medical records may be stored along with your specimens. The results of 
research, including genetic testing, not described in this informed consent document will not be 
provided to you or your healthcare provider. Any information obtained for the Tissue Bank that may 
identify you will remain confidential within the limits of the law or will be disclosed only with your 
permission and the approval of the Springfield Committee for Research Involving Human Subjects.
A federal law called the Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for 
health insurance companies, group health plans, and employers with 15 or more employees to 
discriminate against you based on your genetic information. GINA does not protect you against genetic 
discrimination by companies that sell life insurance, disability insurance, or long-term care insurance. 
GINA also does not protect you against discrimination based on an already-diagnosed genetic 
condition or disease.
The study sponsor may share your specimens with researchers or collaborators at other institutions.  
Information that could be linked to you or allow your specimens to be identified will not be released with 
your specimens. Should any publication or public presentation result from this research, your identity 
will not be revealed.
CONSENT/AUTHORIZATION FOR ADDITONAL RESEARCH ON SPECIMENS
We would like to request your consent to use your tumor tissue samples, and saliva, blood and urine 
samples collected during the study to perform additional research on superficial bladder cancer. You 
are free to change your mind at any time. If you wish to withdraw consent for use of the samples, you 
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 20 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
will need to contact the study center and inform them of your decision. The sponsor can keep and use 
any information from the samples which is obtained prior to your decision to withdraw consent.
Please indicate below whether you agree to allow for the following:
1.
If I am unable to participate in the TREATMENT STUDY, I would like my specimens 
destroyed.
 YES
  NO    (If no, please see question 2 below)
Participant's Initials ________
2.
I agree to the storage of and additional analysis of the sample taken from the tumor and 
surrounding tissue after my trans-urethral resection of my bladder:

YES, I give permission for my tumor and surrounding tissue sample to be stored and used 
for additional research.

NO, I do not give my permission for my tumor tissue and surrounding tissue sample to be 
stored and used for additional research.
Participant's Initials ________
3.
Collection of blood for storage and analysis for future research.

YES, I give permission for the collection of about 13 tablespoons, over the course of the 
study, of blood to be collected for additional research, including that related to bladder 
cancer and its treatment.

NO, I do not give permission for the collection of about 13 tablespoons, over the course of 
the study, of blood to be collected for additional research, including that related to bladder 
cancer and its treatment.
Participant's Initials ________
4.
Collection of urine for storage and analysis for future research.

YES, I give permission for the collection of urine specimens to be collected for additional 
research, including that related to bladder cancer and its treatment.

NO, I do not give permission for the collection of urine specimens to be collected for 
additional research, including that related to bladder cancer and its treatment.
Participant's Initials ________
5.
Collection of saliva for storage and analysis for future research.

YES, I give permission for the collection of a saliva specimen at baseline to be collected 
for additional research, including that related to bladder cancer and its treatment.

NO, I do not give permission for the collection of a saliva specimen at baseline to be 
collected for additional research, including that related to bladder cancer and its treatment.
Participant's Initials ________
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021


Page 21 of 21
Protocol No.: 014-001SBC
Amendment 5, dated 21 October 2019
Site’s FINAL ICF, Version Dated 13 November 2019
DOCUMENTATION OF INFORMED CONSENT
AFTER SIGNATURES ARE OBTAINED FROM YOU AND AUTHORIZED STUDY PERSONNEL 
LISTED BELOW, A SIGNED COPY OF THIS CONSENT WILL BE GIVEN TO YOU.
You are voluntarily making a decision whether to participate in this study. Your signature means that 
you have read and understood the information presented and have decided to participate. Your 
signature also means that the information on this consent form has been fully explained to you and all 
your questions have been answered to your satisfaction. If you think of any additional questions during 
this study, you should contact the study doctor(s).
I agree to take part in this study.
Signature of Participant, Legal Guardian, or Power of Attorney
Date
Printed Name
I certify that all the elements of informed consent described on this consent form have been explained 
fully to the participant. In my judgment, the participant has voluntarily and knowingly given informed 
consent and possesses the legal capacity to give informed consent to participate in this study.
Signature of Authorized Study Personnel
Date
Printed Name
AUTHORIZED STUDY PERSONNEL CAPABLE OF OBTAINING INFORMED CONSENT FROM PARTICIPANTS
Participating Physician(s) and Participating Health Care Personnel
Principal Investigator
Krishna A. Rao, MD
(217) 545-1129
Co-Investigator(s)
Bradley Schwartz, DO
(217) 545-7362
Aziz-Ur-Rehman Khan, MD
(217) 545-1129
Swati Pathak, MD
(217) 545-1129
Edem Agamah, MD
(217) 545-1129
Dodie Gazda, ANP-BC
(217) 545-8124
Participating Health Care Personnel
Smitha Abraham, RN, BSN
(217) 545-7929
Rebecca Wolf, RN, BSN
(217) 545-7489
Kathy Robinson, PhD
(217) 545-1946
IRB NUMBER: 14-208-B
IRB APPROVAL DATE: 03/11/2020
IRB EXPIRATION DATE: 03/11/2021