A Phase 1 Dose-Escalation Study of Intravesical MK-3475 and Bacillus Calmette-Guerin (BCG) in Subjects With High Risk and BCG-Refractory Non-Muscle-Invasive Bladder Cancer
Phase: PHASE1
Conditions: Recurrent Bladder Carcinoma, Stage 0a Bladder Urothelial Carcinoma, Stage 0is Bladder Urothelial Carcinoma, Stage I Bladder Cancer
Sponsor: Northwestern University

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
i
A Phase 1 Dose-Escalation Study of Intravesical Pembrolizumab and 
Bacillus Calmette-Guerin (BCG) in Subjects with High Risk and BCG-
Refractory Non-Muscle-Invasive Bladder Cancer
Principal Investigator:
Joshua Meeks, MD, PhD
Assistant Professor of Urology
Northwestern University Feinberg School of Medicine
676 N. St. Clair St., Galter 20-150 
Chicago, IL 60611
Phone:  312-363-8959
Joshua.meeks@northwestern.edu 
Sub-Investigator(s):
Maha Hussain, MD, FACP, FASCO
Biostatistician:
Masha Kocherginsky, PhD
Northwestern University
mkocherg@northwestern.edu
Study Intervention(s):
Pembrolizumab
IND Number:
130135
IND Holder:
Joshua Meeks, MD, PhD
Funding Source: 
Northwestern University
Version Date:
November 6, 2020 (Amendment 11)
Coordinating Center:
Clinical Trials Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
http://cancer.northwestern.edu/research/clinical-trials-office/index.html 
IRB #: STU00202754-CR0006 Approved by NU IRB for use on or after 1/26/2022 through 1/23/2023.

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................................5
STUDY SCHEMA ............................................................................................................................6
STUDY SUMMARY .........................................................................................................................8
1
INTRODUCTION – BACKGROUND & RATIONALE........................................................10
1.1
Disease Background .....................................................................................................10
1.2
PD-1 Checkpoint Pathway Background and Pembrolizumab Ongoing Clinical Trials ..11
1.3
Rationale for the Current Study.....................................................................................14
2
OBJECTIVES & ENDPOINTS...........................................................................................17
2.1
Primary Objective & Endpoint........................................................................................17
2.2
Secondary Objectives & Endpoints ...............................................................................17
2.3
Exploratory Objectives & Endpoints ..............................................................................17
3
PATIENT ELIGIBILITY......................................................................................................18
3.1
Inclusion Criteria............................................................................................................19
3.2
Exclusion Criteria...........................................................................................................21
4
TREATMENT PLAN ..........................................................................................................23
4.1
Overview........................................................................................................................23
4.2
Treatment Administration ..............................................................................................25
4.3
Dose Escalation Scheme ..............................................................................................26
4.4
Dose Delays/Modifications ............................................................................................28
4.5
Toxicity Management ....................................................................................................29
4.6
Concomitant Medications/Treatments ...........................................................................36
4.7
Other Modalities or Procedures.....................................................................................36
4.8
Duration of Therapy.......................................................................................................37
4.9
Duration of Follow Up....................................................................................................37
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NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
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4.10
Removal of Patients from Protocol Therapy and/or Study as a Whole .........................37
4.11
Study Subject Replacement ..........................................................................................38
5
STUDY PROCEDURES.....................................................................................................39
6
ADVERSE EVENTS ..........................................................................................................42
6.1
Definition of Adverse Event ...........................................................................................42
6.2
Severity of Adverse Events ...........................................................................................42
6.3
Serious Adverse Events ................................................................................................43
6.4
Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) .....................44
6.5
Events of Clinical Interest..............................................................................................44
6.6
Reporting of Pregnancy and Lactation ..........................................................................45
6.7
Reporting Requirements for Adverse Events ................................................................45
7
DRUG INFORMATION ......................................................................................................46
7.1
Pembrolizumab..............................................................................................................46
7.2
BCG...............................................................................................................................47
8
CORRELATIVES/SPECIAL STUDIES..............................................................................49
8.1
PK Studies.....................................................................................................................49
8.2
Tissue Immunohistochemistry Studies..........................................................................50
8.3
Urinary cytokines and lymphocyte phenotypes .............................................................50
8.4
Peripheral blood cytokine assays and lymphocyte phenotypes ....................................51
8.5
NGS...............................................................................................................................50
8.6
Specimen Banking.........................................................................................................51
9
STATISTICAL CONSIDERATIONS ..................................................................................51
10
STUDY MANAGEMENT....................................................................................................52
10.1
Institutional Review Board (IRB) Approval and Consent...............................................52
10.2
Amendments .................................................................................................................52
10.3
Registration Procedures................................................................................................53
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NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
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10.4
Data Management and Monitoring/Auditing ..................................................................53
10.5
Adherence to the Protocol.............................................................................................53
10.6
Investigator Obligations.................................................................................................54
10.7
Publication Policy ..........................................................................................................54
11
APPENDICES....................................................................................................................55
11.1
Appendix A ....................................................................................................................55
11.2
Appendix B ....................................................................................................................56
11.3
Appendix C....................................................................................................................57
12
References........................................................................................................................72
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NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
BCG
Bacillus Calmette-Guerin live attenuated Mycobacterium bovis
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
H&PE
History & Physical Exam
IV (or iv)
Intravenously
MTD
Maximum Tolerated Dose
NMIBC
Non-Muscle-Invasive Bladder Cancer
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PK
Pharmacokinetic
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
reTUR
Repeat transurethral resection
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells
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NU Study Number: NU 15U06
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Protocol Amendment 11 Version Date: November 6, 2020
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STUDY SCHEMA
1 Clinical follow-up for disease recurrence and survival will occur according to this schedule: every 3 months x 
2 years, then every 4 months x 2 years, then every 6 months x 2 years, then yearly. Patients will remain on 
study follow-up until end of trial, withdrawal, or death (whichever occurs first).
High Risk and BCG-Refractory Non-Muscle-Invasive Bladder Cancer
Induction Phase (6 weeks total)
Intravesical BCG at a dose of 50 mg (weeks 0, 1, 2, 3, 4, 5)
+ 
Intravesical pembrolizumab at assigned cohort dose (weeks 0, 2, 4)
Maintenance Phase (begins 2 weeks after last induction BCG dose):
Intravesical BCG and intravesical pembrolizumab 
at assigned cohort dose every 2 weeks for 12 weeks 
(weeks 7, 9, 11, 13, 15 and 17) 
then every 4 weeks up to 1 year (last dose at week 49)
Continue Maintenance treatment up 
to 1 year (last dose at week 49)
Cystoscopy at week 17 and then every 2 months
(final assessment at week 49)
Bladder cancer recurrence during treatment period
Continue follow-up clinically until disease recurrence1
No
Pre-induction Phase (2 weeks total): Intravesical pembrolizumab at assigned cohort dose 
Yes
Discontinue treatment
Follow all patients for survival1
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NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
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Phase
Pre-
induction
Induction Phase
Maintenance Phase
Week
-2
0
1
2
3
4
5
7
9
11
13
15
17
21
25
29
33
37
41
45
49
Treatment
MK
BCG
+MK
BCG
BCG
+MK
BCG
BCG
+MK
BCG
BCG
+MK
BCG
+MK
BCG
+MK
BCG
+MK
BCG
+MK
BCG+
MK+
Cysto
BCG
+MK
BCG+
MK+
Cysto
BCG
+MK
BCG+
MK+
Cysto
BCG
+MK
BCG+
MK+
Cysto
BCG
+MK
BCG+
MK+
Cysto
PKs
(blood & 
urine*)
X
X
Creatinine
Urine
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokines 
& Flow 
Studies#
Blood
X
X
X
IHC
(tissue)
X
MK = Pembrolizumab (MK-4575) given at the assigned dose for the cohort, intravesically
Cysto = cystoscopy
BCG = bacillus Calmette-Guérin (BCG) immunotherapy given at a dose of 50 mg intravesically
PKs = PK testing as described here will be performed on the first 3 patients only; a limited amount of plasma PK testing may be performed on additional 
patients as described in footnote ‘#’ below. Blood samples for serum pharmacokinetics will be collected prior to dosing (time 0 = at the time of required 
standard labs), and again at 15, 30, and 60 min (+/- 2 minutes allowed per time point) after dosing. 
*In addition, urine samples will be collected and banked for future PK analysis at the same weeks as the serum PK samples; urine samples will be 
collected prior to dosing and at 2 hours post-dosing at the time of post-treatment void (+/- 5 minutes is allowed). 
IHC = Tissue for PD-L1, PD-L2, and PD-1 will be requested at baseline and again at the time of any follow-up biopsies performed during treatment.
# Urine samples will be collected prior to dosing and an optional sample at the third void approximately 4-6 hours after dosing. NOTE: The first void will be 2 hours 
post-dosing as part of the treatment (may be used for PK sampling if participating in that component), the second void after dosing will not be used for any 
correlative studies and should be discarded. Samples will be transported to the Pathology Core Facility for processing before distribution to the Flow 
Cytometry Core (cell pellets) and Myriad Laboratories (supernatant). Blood samples will be collected at the time of other labs as noted above. A portion of 
the blood specimens that have been collected for cytokine analysis (time-points week -2, week 0, and week 17) may be used in plasma PK assays, per 
principal investigator discretion. 

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
8
STUDY SUMMARY
Title
A Phase 1 Dose-Escalation Study of Intravesical Pembrolizumab and 
Bacillus Calmette-Guerin (BCG) in Subjects with High Risk and BCG-
Refractory Non-Muscle-Invasive Bladder Cancer 
Version
November 6, 2020 (Amendment 11)
Study Design
Open-label, phase I, dose escalation study, single-center
Study Center(s)
Northwestern University
Objectives
Primary:

To determine the maximum tolerated dose (MTD) up to the 
individual maximum of each of the study drug (pembrolizumab) 
when administered intravesically in combination with BCG in 
subjects with high risk or BCG-refractory non-muscle-invasive 
bladder cancer.
Secondary:

To describe the dose-limiting toxicities (DLTs) of pembrolizumab 
in combination with BCG in this population. 

To assess the safety and tolerability of the combination of 
pembrolizumab and BCG in subjects with high risk or BCG-
refractory non-muscle-invasive bladder cancer.
Exploratory:

To characterize the pharmacokinetics (PK) of pembrolizumab in 
both blood and urine samples when administered intravesically in 
combination with BCG .

To measure cellular and cytokine changes in serum and urine 
samples.

To determine the response rate in terms of complete pathologic 
response in this population.

To document the progression rate associated with the 
combination of intravesical pembrolizumab and BCG in subjects 
with high risk or BCG-refractory non-muscle-invasive bladder 
cancer.

To evaluate the relationship between tumor biomarkers PD-L1, 
PD-L2 and adverse effects and tumor response rate.

To evaluate changes in genetic data using targeted whole exome 
sequencing of DNA and RNA-sequencing from the tumors pre 
and post-treatment

To bank any leftover blood, urine, and tissue samples that remain 
after other studies are complete for future, unspecified use.

To determine the progression free survival rate.

To determine the overall survival rate.

To investigate immune markers collected as standard of care. 
Sample Size
A total of up to 27 subjects may be enrolled (in order to up to 24 
evaluable subjects, based on dose escalations) 
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NU Study Number: NU 15U06
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Diagnosis & Key 
Eligibility Criteria
The patient population will consist of adults diagnosed with 
recurrence of non-muscle-invasive bladder cancer following treatment 
with BCG.
Treatment Plan
The study will have three phases: pre-induction, induction and 
maintenance. Two weeks prior to induction (at week -2), subjects will 
receive the first intravesical instillation of pembrolizumab. During the 6 
week induction phase, intravesical BCG will be administered weekly 
for a total of 6 doses at the standard dose of 50 mg. Concomitant 
pembrolizumab will be administered intravesically every two weeks 
for a total of 3 doses (weeks 0, 2, and 4); the starting dose for the first 
cohort will be 1 mg/kg. The maintenance phase starts on week 7 and 
continues up to 1 year (last dose and cystoscopy at week 49). 
Subjects may remain on maintenance treatment up to week 49 or 
until progression of disease or intolerable adverse effects. Intravesical 
BCG and intravesical pembrolizumab will be given every 2 weeks for 
the first 12 weeks of maintenance therapy (weeks 7, 9, 11, 13, 15, 
and 17 for a total of 6 maintenance doses) and then every 4 weeks 
thereafter (weeks 21, 25, 29, 33, 37, 41, 45, 49 for a total of 8 doses). 
Dose escalation for cohorts will follow a standard 3+3 escalation 
scheme and the additional dose levels are 1mg/kg, 2mg/kg, 5mg/kg 
and 10mg/kg. BCG dose will remain constant for all patients on all 
dose levels. Intrapatient dose escalation is not allowed in this 
protocol. 
Statistical Methodology
This is a phase I dose escalation study using the 3+3 design with 4 
doses. The dose escalation scheme and rules for determining the 
primary outcome, the maximum tolerated dose, are described in 
Section 4.3.  It is expected that up to 24 patients evaluable for dose 
limiting toxicities will be accrued to the study. This 3+3 design has a 
91% chance (49%, 17%) of dose escalating when the true toxicity 
rate for that dose is 10% (30%, 50%).  
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NU Study Number: NU 15U06
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1
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
In the US, 73,000 patients are diagnosed with bladder cancer each year with 80% of 
tumors classified as non-muscle-invasive bladder cancer (NMIBC). This group of 
tumors can be restricted to the bladder mucosa (stage Ta or carcinoma in situ [Tis]) 
or invade the lamina propria (i.e., subepithelial connective tissue; stage T1). They 
are optimally treated with curative intent by transurethral resection (TUR). However, 
approximately 30-80% of these patients will present with tumor recurrences or 
progression to muscle-invasive disease at five years that contribute to the high 
prevalence of this malignancy 1. In 2011, there were an estimated 571,000 people 
with a history of bladder cancer in the United States 2. This wide range of risk of 
recurrence and progression reflects the biologic heterogeneity of these tumors and 
the limited risk stratification tools available for the practicing urologist. As a 
consequence, patients diagnosed with NMIBC are committed to long-term 
surveillance programs that include office visits, cystoscopies and radiological tests 
making NMIBC one of the most expensive malignancies to manage 3,4. This 
elevated risk of recurrence provided the impetus to develop adjuvant treatments 
following tumor resection with the goals to reduce recurrence and progression to 
muscle-invasive disease. Adjuvant treatments include intravesical instillation of 
bacillus Calmette-Guérin (BCG) immunotherapy and intravesical chemotherapy. 
Despite adequate induction with 6 weekly instillations with BCG followed by 
maintenance, 38% of patients still developed recurrence, 7% progressed to muscle-
invasive disease, 5% presented distant metastatic disease, and 3% died from 
bladder cancer 5. Although serious adverse effects occurs in <5% of patients, BCG 
frequently causes cystitis, hematuria, malaise, and fever that results in treatment 
discontinuation in approximately 20% of patients 6. The experience with these side 
effects might also contribute to the dismal adherence of 40% to cystoscopic 
surveillance among NMIBC survivors 7. These results highlight the need to improve 
the outcomes and treatment of patients diagnosed with NMIBC. 
Patients presenting with recurrences after BCG have limited therapeutic options. 
Radical cystectomy or bladder-preserving strategies are generally recommended 
especially for high-grade recurrent tumors. These surgical options have significant 
long-term morbidity, impact on quality of life and the majority of these patients have 
multiple comorbid conditions (i.e., cardiovascular disease, renal insufficiency) 
making them high-risk surgical candidates. It is acceptable to repeat BCG treatment 
for low-grade and selected high-grade tumors especially if the recurrence develops 
more than 1 year after treatment. Limited experience with BCG plus interferon- 
suggests that it can be used for recurrent tumors after 1 or more BCG courses 
resulting in disease free rate of approximately 54-66% at 24 months 8,9. A phase III 
trial compared gemcitabine and mitomycin C for patients with unsuccessful BCG 
treatment 10. Intravesical gemcitabine was better tolerated but 28% of patients still 
developed a recurrence during the 36 months follow up compared to 39% among 
those receiving mitomycin C 10. These results suggest alternative treatments for 
BCG –refractory patients have limited long-term efficacy. Therefore, a radical 
cystectomy and its associated 28% morbidity and 2.5% mortality risks continues to 
offer the highest cure rate in this setting 11.
While the mechanism of action of BCG is not understood, recognition of the tumor 
by an intact immune system is critical to the anti-tumor response elicited by BCG. In 
fact, patient inability to mount an immunogenic tumoricidal response when treated 
with BCG has been proposed as one of the mechanisms of recurrences or residual 
disease. This hypothesis might reflect the immune suppression induced by tumor 
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NU Study Number: NU 15U06
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cells through immune checkpoint proteins such as programmed death-ligand 1 (PD-
L1). PD-L1 binding to T-cell receptors PD-1 and/or B7-H1 causes immune 
suppression and tumor escape. PD-L1 is expressed by 12% bladder tumor cells and 
by 27% of tumor infiltrating immune cells and up to 50% of tumors that are 
carcinoma in situ 12,13. In addition, 95% of lymphocytes that invade bladder tumors 
express the PD-1 receptor.  Expression of PD-1 is correlated with prior intravesical 
BCG therapy and B7-H1 expression predicts death after cystectomy in patients with 
organ-confined bladder cancers. These results made the PD-1 pathway an 
attractive therapeutic target for bladder cancer and other epithelial tumors such as 
lung cancer and melanoma 14. In fact, clinically meaningful efficacy of anti-PD-L1 
and anti-PD-1 antibodies has been demonstrated in clinical trials with patients with 
non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and melanoma 
15,16. In patients that develop BCG-refractory bladder tumors, bladder granuloma 
often over-express PD-L1 after induction of BCG suggesting tumor PD-L1 
expression may dampen the response to BCG 13.
The relevance of PD-1 blockade for bladder cancer treatment was recently 
confirmed by a phase I study evaluating a human monoclonal antibody directed 
against the PD-L1 (MPDL3280A) in sixty-seven patients with metastatic bladder 
cancer. The treatment was well tolerated among this heavily pretreated patient 
population (79% of patients had received cisplatin and 34% had received 
carboplatin; 48% had undergone cystectomy) including patients with renal 
insufficiency. There were no treatment related grade 4 or 5 adverse events or 
immune-related toxicities. Grade 3-4 adverse events occurred in three patients and 
included asthenia, thrombocytopenia and hypophosphatemia. Other frequent grade 
1 and 2 adverse events were decreased appetite, fatigue, and nausea. An overall 
response rate of 55% was documented and included 2 complete responses. There 
was also a higher response rate among patients with tumor-infiltrating immune cells 
positive for PD-L1 by immunohistochemistry (43% vs. 11%). Median time to first 
response was 42 days and median duration of response had not been reached at 
the presentation of the results 12. Taken together, these results validate the 
checkpoint PD-1 pathway as a promising therapeutic target in bladder cancer. The 
present study proposes to evaluate the safety and determine the maximum tolerated 
dose of pembrolizumab (a humanized IgG4 monoclonal antibody with high 
specificity of binding to the PD-1 receptor) when administered intravesically in 
combination with BCG for patients with BCG-refractory non-muscle invasive bladder 
cancer. Pembrolizumab is undergoing clinical development as an intravenous 
immunotherapy for advanced malignancies.   
1.2
PD-1 Checkpoint Pathway Background and Pembrolizumab Ongoing Clinical 
Trials
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades 17. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies 18-22. 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 solid 
malignancies such as ovarian, colorectal and pancreatic cancer, hepatocellular 
carcinoma, malignant melanoma and renal cell carcinoma (RCC). Furthermore, TILs 
can be expanded ex vivo and re-infused, inducing durable objective tumor 
responses in cancers such as melanoma 23,24.
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 
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by the gene PDCD1) is an Ig superfamily member related to CD28 and CTLA-4 that 
has been shown to negatively regulate antigen receptor signaling upon engagement 
of its ligands (PD -L1 and/or PD-L2) 25,26. The structure of murine PD-1 has been 
resolved 21. 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 de-phosphorylation of effector molecules such as CD3ζ, PKCθ 
and ZAP70, which are involved in the CD3 T-cell signaling cascade 25,27-29. 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 30,31. 
PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T -cells, B-cells, Tregs and Natural Killer cells 32,33. Expression has 
also been shown during thymic development on CD4-CD8- (double negative) T-cells 
as well as subsets of macrophages and dendritic cells 22. 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 including 
bladder carcinoma 30,34-38. 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-1 
ligand 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 34. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T-cell inhibitor. High 
expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been 
found to correlate with poor prognosis and survival in various cancer types, 
including RCC 39, pancreatic carcinoma 40, hepatocellular carcinoma 41, ovarian 
carcinoma 42, and localized bladder carcinoma 37,38. The observed correlation of 
clinical prognosis with PD-L1 expression in multiple cancers 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. 
Studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have 
demonstrated anti-tumor responses as a monotherapy in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma and colorectal carcinoma. Blockade of 
the PD-1 pathway effectively promoted CD8+ T-cell infiltration into the tumor and 
the presence of IFN-, granzyme B and perforin, indicating that the mechanism of 
action involved local infiltration and activation of effector T-cell function in vivo 40,43-
47. In addition, the combination of gemcitabine and anti-PD-L1 mAb therapy 
demonstrated synergy in the reduction of pancreatic mouse tumors 40. 
1.2.1
Clinical Experience with Pembrolizumab 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate 
the safety and clinical activity of single agent pembrolizumab. The dose 
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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. Based on PK data showing a half-life 
of 21 days, the protocol was amended to change the dosing frequency in 
the expansion cohort to every 3 weeks (Q3W). Two subjects with melanoma 
from the initial cohort of subjects treated in Protocol 001 showed confirmed 
objective responses based on RECIST 1.1. The ongoing expansion cohort 
in Protocol 001 is enrolling melanoma subjects and promising preliminary 
anti-cancer activity has been observed (37% objective responses; 44% best 
objective response by RECIST 1.1). Of further note, those patients with 
melanoma who were treated with pembrolizumab 10 mg/kg Q2W had a best 
objective response rate of 56% by RECIST 1.1, and those treated at 10 
mg/kg Q3W had a best objective response rate of 36%. None of these 
patients were randomized between the two treatment schedules. Amongst 
approximately 130 subjects with melanoma treated with pembrolizumab at 
Q2W and Q3W the most common AEs were fatigue, nausea, rash, diarrhea, 
cough, pruritus, arthralgia, headache, abdominal pain, increased AST, 
pyrexia, and decreased appetite. The most common drug-related adverse 
events (AEs) included fatigue, rash, pruritus, diarrhea, and arthralgia. The 
incidence of Grade 3-5 AEs was 27%. Potentially immune-related AEs have 
been observed, including pneumonitis in both the melanoma and NSCLC 
cohorts. Although most cases do not result in death, in one instance, a 96-
year old man with melanoma who experienced Grade 2 
pneumonia/pneumonitis suffered a fatal myocardial infarction while being 
treated for the pneumonia/pneumonitis.
Pembrolizumab Protocol 001 (PN001) Part C enrolled 38 subjects with 
NSCLC who experienced progression of cancer after initiation of their 
second line of systemic therapy to receive monotherapy pembrolizumab. 
The preliminary objective response rate was 24% by investigator assessed 
immune-related response criteria (irRC). Clinical responses have been 
observed in subjects with adenocarcinoma, squamous cell carcinoma, and 
large cell carcinoma when assessed by irRC. The median duration of 
treatment amongst responders is a minimum of 34 weeks. Most responders 
continue on therapy. Subjects were required to submit a newly obtained 
tumor biopsy prior to initiating therapy with pembrolizumab to evaluate the 
tumors for expression of PD-L1, the presumptive predictive biomarker of 
pembrolizumab, using an immunohistochemistry assay. A modified H-score 
scoring system of PD-L1 expression was established for NSCLC by 
analyzing tumor specimens from resected NSCLC specimens. This scoring 
system was then applied to the samples from PN001 Part C. A total of 35 
patients from PN001 had tumor samples evaluable and a clinical response 
assessed. All but 3 patients were from Part C; 3 patients from Part A had 
NSCLC, submitted tumor tissue, and had a clinical response assessment. 
Seven of the 35 patients had a clinical response (20%) by investigator 
assessed irRC. Six responders (26%) were observed amongst the twenty-
three patients whose tumors expressed PD-L1. Of note, these six 
responders clustered at the higher end of the modified H-score. Six of nine 
(67%) patients whose tumors expressed PD-L1 to an extent above the 
preliminary cut point had a clinical response. Only one response was noted 
amongst the twelve patients whose tumors did not express PD-L1. Given 
these results, the use of PD-L1 as a predictive biomarker is being further 
explored in subsequent NSCLC studies.
The combined effect of BCG and pembrolizumab may increase the urgency 
and frequency of BCG, resulting in systemic steroid administration which 
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could potentially increase the rate of systemic BCG infection. However, 
such local side effects are usually treated with anti-cholinergic medication 
rather than systemic steroids. BCG-sepsis occurs at a rate of 0.4% when 
given without PD-1 inhibitor.
1.2.2
Intravesical Administration of Pembrolizumab
There are now numerous papers demonstrating activity of PD-1 based 
therapy for bladder cancer. PDL-1 is expressed by bladder cancers. 
Importantly, these expression studies demonstrate that expression of PD-L1 
increases in patients treated with BCG and is localized around the 
granulomas57.  This may be a mechanism of resistance to BCG, allowing 
tumor cells to evade treatment. . Preclinical studies have demonstrated that 
treatment of mice with non-muscle invasive bladder with PD-1 inhibitors can 
block tumor progression60. In our data, we have seen a 17X increase in 
immune cells infiltrating the bladder of mice receiving the bladder cancer 
carcinogen BBN.  These immune cells (CD45+) are primary localized to the 
bladder, confirming that local delivery of the PD-1 inhibitor is an actionable 
target. 
Multiple trials are now underway for NMIBC (NCT02324582, 
NCT02625961).  Our trial is unique providing intravesical delivery. While we 
have no pre-clinical data demonstrating increased bio-delivery, multiple 
other antibody based therapies have been utilized in bladder cancer.  These 
monoclonal antibodies bind the bladder epithelium and can demonstrate 
activity58, 59, 61. The benefit of this approach is reduced exposure to potential 
systemic administration. While these medications have been well-tolerated, 
the NMIBC population has only localized, superficial disease and long-term 
side effects of intravenous checkpoint inhibitors are unknown.
1.3
Rationale for the Current Study
1.3.1
Rationale for testing pembrolizumab in non-muscle invasive bladder 
cancer
To date, immune modulation regimens for patients with BCG-refractory 
NMIBC are restricted to the addition of intravesical interferon- to BCG with 
limited efficacy. No studies have addressed the safety or efficacy of a 
monoclonal antibody against PD-1 given intravesically. The intravesical 
delivery of pembrolizumab has the advantage of greater exposure of 
bladder tissue to the drug that can possibly enhance its efficacy while 
minimizing systemic side effects including fatigue, diarrhea, decreased 
appetite, pruritus and nausea. On the other hand, the low permeability of 
the urothelium might represent a limitation to the intravesical delivery. The 
urothelium is unlikely to be permeable to the drug as the chemotherapeutic 
mitomycin c (which is used as standard of care by placement into the 
bladder immediately after surgery) has a molecular weight of 54 kd and the 
drug has a molecular weight of 146 kd. However, the inflammation induced 
by BCG can potentially enhance the permeability of the bladder mucosa 
facilitating pembrolizumab reaching the target on possible remaining tumor 
cells at the bladder wall 48. Therefore, the main goal of the present phase I 
dose-escalation study is to determine the maximum tolerated dose (MTD) of 
pembrolizumab that can be given intravesically in combination with BCG for 
patients with BCG-refractory NMIBC (up to the individual maximum 
tolerated dosages of each drug). Secondary goals include describing the 
dose limiting toxicities and assessing safety of the combination of 
pembrolizumab and BCG. The determination of the pembrolizumab MTD 
will be critical to design future trials to investigate the efficacy of this novel 
treatment for patients with BCG-refractory NMIBC. 
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Several lines of evidence documenting the immune dysfunction associated 
with bladder cancer supports the hypothesis that immunotherapy can alter 
the process of carcinogenesis. Earlier studies investigating the 
immunological profile of patients with bladder cancer showed significant 
impairment of lymphocytes function and a predominance of T-regulatory 
cells and Th1 inhibitory cytokines in the tumor environment, some of the 
immune dysfunction was reversed after cystectomy 49,50.  The number of 
CD8 tumor infiltrating T lymphocytes is correlated with bladder cancer-
specific survival supports the critical role of immune response on this 
disease. One of the critical mediators of immune response is the B7 family 
of immune co-regulatory proteins (B7-H1 or PD-L1, B7-H3, PD-1), which 
have been demonstrated to result in immune evasion of urothelial cancer 51. 
B7 homolog 3 (B7-H3) molecule displays higher expression in bladder 
cancer cells compared to normal urothelium (70% vs. 20%) irrespective of 
tumor stage suggesting its involvement in early stages of carcinogenesis 37. 
Expression of PD-1 in infiltrating lymphocytes and its ligand B7-H1 (also 
known as PD-1 ligand 1) in tumor cells were associated with advanced 
tumor stage. Urothelial expression of PD-L1 was also predictive of mortality 
following cystectomy in patients with organ-limited disease (i.e., pTa, pT1, 
CIS, pT2Nx/N0M0). Relevant to the current protocol, patients previously 
treated with BCG showed a distinct profile of T-cell co-regulators expression 
at cystectomy. These tumors showed reduced expression of PD-L1 and 
increased expression of B7-H3 and PD-1 37. Together, these findings 
provided the impetus to explore the activity of PD-1 blockade in non-muscle 
invasive bladder cancer using the humanized antibody against PD-1 
(pembrolizumab). 
1.3.2
Rationale for Dose Selection
In the first in human study (Protocol number 001, refer to IB), which 
treated a variety of tumor types, 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 every 2 weeks). No DLT was 
observed and no MTD reached at these dose levels. Dose level 10 mg/kg 
every 3 weeks was evaluated in previously treated patients with NSCLC in 
Part C of Protocol 001. Pembrolizumab has also shown signs of efficacy 
and acceptable PK and PD results when administered both every 2 weeks 
and every 3 weeks. PK data analysis of pembrolizumab administered 
intravenously every 2 weeks showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB). 
Pharmacodynamic data (IL-2 release assay) suggested that peripheral 
target engagement is durable (>21 days). Previously treated patients with 
NSCLC in PN001 Part C have experienced durable objective responses 
with acceptable toxicity when treated with pembrolizumab at 10 mg/kg 
every 3 weeks. Preliminary data in patients with melanoma and NSCLC 
demonstrates objective responses by pembrolizumab when administered at 
the 2 mg/kg every 3 weeks dose and schedule. These results document 
efficacy results with both 2 mg/kg and 10 mg/kg doses. The additional dose 
level of 1 mg/kg was selected based on efficacy estimated by PK-PD 
modeling studies (discussed below) and concerns with safety given multiple 
intravesical administrations.  
A syngeneic mouse tumor efficacy experiment, that included PK sampling 
and tissue receptor occupancy was conducted with a surrogate antibody 
and analyzed by translational PK-PD modeling. Results were 
extrapolated to man with inclusion of human relevant parameters for 
PK, pembrolizumab binding properties to PD-1 and the FcRN receptor, and 
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clinical NSCLC growth patterns, effectively normalizing dosing for 
humans in this model. This analysis led to the conclusion that the 
lowest dose of pembrolizumab with the potential to be equivalent to 10 
mg/kg of pembrolizumab was 1-2 mg/kg. Considering the lack of clinical 
experience with intravesical administration of pembrolizumab and the need 
for multiple administrations, the dose 1 mg/kg was selected as the start 
dose in this study and will be used in first cohort of three evaluable subjects. 
Additional dose levels will include 2 mg/kg and 10mg/kg (see details of 
doses escalation on Section 4.3). 
Because of uncertainty as to which dose schedule will have the better 
efficacy and safety profile in patients with BCG-refractory NMIBC, two 
dosing intervals of pembrolizumab will be utilized in this trial, every 2 
weeks during induction therapy until week 17 (first cystoscopy) and every 6 
weeks for the remaining period of maintenance phase (weeks 23, 29, 35, 41, 
47). The shorter interval during induction therapy is based on the hypothesis 
that maximizing the PD-1 blockade during the BCG instillation might 
enhance the anti-tumor effect. 
There is a possibility of adding an expansion cohort of up to 10 subjects to 
further define safety and efficacy of pembrolizumab. This will be determined 
by Merck after completion of the dose escalation phase.
1.3.3
Rationale for Exploratory Studies 
Pembrolizumab has been shown to modulate the levels of several cytokines 
during studies using cultured blood cells from healthy donors, cancer 
patients, and primates (refer to IB). The correlative studies on this trial will 
explore humoral and cellular responses to pembrolizumab and BCG 
treatments by measuring cytokines (i.e., IL-2, IL-6, IL-8, IL-10, IL-18, IFN 
and TNF-) in urine and serum samples and analyzing peripheral blood 
lymphocyte phenotypes. 
Prior experiments with tumor response to BCG suggested that up-regulation 
of Th1 cytokines (i.e., IFN, IL-2, IL-12) is associated with BCG response 
and increased levels of Th2 cytokines (i.e., IL-6 and IL-10) correlate with 
recurrence 53-55. Induction of IL-2 mRNA in peripheral-blood mononuclear 
cells also predicted antitumor response during BCG treatment of non-
muscle invasive bladder cancer. Urinary IL-2 measured 6 and 8 hrs after 
BCG administration correlated with higher risk of recurrence, whereas 
urinary IL-10 and IFN did not present significant correlation with BCG 
failure 55. Therefore, correlative studies will evaluate the profile of cytokine 
production in urine and serum samples of patients receiving BCG and 
pembrolizumab and correlate with toxicity and risk of progression of non-
muscle invasive bladder cancer. Peripheral blood lymphocyte phenotype 
determination by flow cytometry will also be performed to explore possible 
correlations with therapeutic benefit and/or toxicity.
Tumor specimens collected prior to study entry and those obtained during 
the study will be tested for the expression of PD-1, PD-L1, PD-L2 and 
profile of immune cell infiltration by immunohistochemistry. This analysis will 
evaluate the effect of treatment on tumor expression of these molecules and 
to explore possible correlations with toxicity and risk of recurrence. Clinical 
studies with anti-PD1 and anti-PD-L1 antibodies have suggested a 
correlation between clinical response and expression of PD-L1 in tumors 
15,56. QualTek has developed and validated a PD-L1 IHC assay using 
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Merck's proprietary 22C3 antibody. This assay has served as the prototype 
companion diagnostic assay and has been used by QualTek to test 
thousands of clinical samples, including those for prospective enrollment.  
The PD-L1 IHC assay has been validated and tested in over 20 different 
tumor indications in various clinical studies and on thousands of archived 
FFPE samples. Use of the assay has resulted in numerous recent abstracts 
(ASCO 2014, 2015) and has also been cited in the April NEJM publication 
in NSCLC. The exploratory testing in this study will be conducted using the 
same assay, with Merck’s proprietary antibody, that was developed for 
MK3475 clinical trials, and analyzed by the same seasoned pathologists 
who have been reviewing PD-L1 expression for Merck clinical samples.
 
2
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
The primary objective of this phase I dose-escalation study will be to determine the 
maximum tolerated dose (MTD) of the study drug (pembrolizumab) when 
administered intravesically in combination with BCG in patients with high risk or 
BCG-refractory non-muscle-invasive bladder cancer (up to the individual maximum 
tolerated dose of each drug alone). The MTD will be defined as the highest dose 
that causes dose limiting toxicities (DLTs) in <2 of 6 patients.
2.2
Secondary Objectives & Endpoints
Secondary objectives and endpoints will include the following:
2.2.1
To describe the DLTs of pembrolizumab in combination with BCG in this 
population. DLTs will be defined as described in Section 4.3.1 and the 
period for assessing DLTs will be during the 2 week pre-induction phase 
and the seven weeks of induction phase.
2.2.2
To assess the safety and tolerability of the combination of pembrolizumab 
and BCG in subjects with high risk or BCG-refractory non-muscle-invasive 
bladder cancer. The number, frequency, and severity of adverse events (as 
defined by the NCI Common Terminology Criteria for Adverse Events or 
CTCAE v 4.03) will be recorded.
2.3
Exploratory Objectives & Endpoints
2.3.1
To characterize the pharmacokinetics (PK) of pembrolizumab in both blood 
and urine when administered intravesically in combination with BCG. This 
will be done on the first 3 patients only to provide exploratory data. (A 
limited amount of plasma PK testing may be performed on additional 
patients as described below.*) PK will be evaluated by serial blood and 
urine sampling at specified time points before and after treatment 
(described in Section 5) during weeks -2 and 4 for determination of plasma 
and urine concentration-time profiles and PK parameters of pembrolizumab. 
Blood PKs will be performed by an outside vendor; urine will be collected 
and stored in the Meeks Lab for later analysis.
*A portion of the blood specimens that have been collected for cytokine 
analysis (time-points week -2, week 0, and week 17) may be used in 
plasma PK assays, per Principal Investigator discretion.
2.3.2
To measure humoral and cellular responses to tumor antigens on serum 
and urine samples by measuring the levels of cytokines (i.e., IL-2, IL-6, IL-8, 
IL-10, IL-18, IFN and TNF-) and peripheral blood lymphocyte phenotype 
throughout treatment. Urine and blood samples will be collected before and 
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after dosing throughout treatment (as described in the study schema). 
Cytokines will be measured using ELISA assays. Lymphocyte profiles will 
be analyzed using automated flow cytometric techniques. 
2.3.3
To determine the response rate in terms of complete pathologic response in 
this population assessed when patient undergoes cystoscopies (weeks 17, 
25, 33, 41, and 49 if applicable). Patients will be examined via bladder 
cystoscopy and may undergo biopsy for pathological confirmation if needed. 
Responses will be categorized as yes or no for bladder recurrence.
2.3.4
To document the progression rate associated with the combination of 
intravesical pembrolizumab and BCG in patients with high risk or BCG-
refractory non-muscle-invasive bladder cancer. Tumor progression will be 
defined as positive transurethral resection and/or biopsy. 
2.3.5
To evaluate the relationship between tumor biomarkers PD-L1, PD-L2, PD-
1 as defined by immunohistochemistry (IHC) and adverse effects and 
recurrence rate. This evaluation will be performed on archived tissue 
samples obtained at baseline and on fresh tissue from any subsequent 
biopsies performed during cystoscopies scheduled for weeks 17, 25, 33, 41, 
and 49. Expression of PD-1, PD-L1, PD-L2 and immune cell infiltration by 
IHC will be assessed and results will be correlated with adverse effects and 
recurrence rate. 
2.3.6
To evaluate changes in genetic data using targeted whole exome 
sequencing of DNA and RNA-sequencing from the tumors pre and post-
treatment. This evaluation will be performed on archived tissue samples 
obtained at baseline and on fresh tissue or FFPE tissue samples from any 
subsequent biopsies performed during cystoscopies scheduled for weeks 
17, 25, 33, 41, 49 and at progression.
2.3.7
To bank any leftover blood, urine, and tissue samples that remain after 
other studies are complete for future, unspecified use.
2.3.8
To document the progression free survival rate associated with the 
combination of intravesical pembrolizumab and BCG in patients with high 
risk or BCG-refractory non-muscle-invasive bladder cancer. Progression 
free survival will capture disease progression and all-cause death. 
2.3.9
To document the overall survival rate associated with the combination of 
intravesical pembrolizumab and BCG in patients with high risk or BCG-
refractory non-muscle-invasive bladder cancer. Overall survival will capture 
all-cause death. 
2.3.10
To investigate immune markers associated with the combination of 
intravesical pembrolizumab and BCG in patients with high risk or BCG-
refractory non-muscle-invasive bladder cancer. Immune marker data that 
are assessed as standard of care at any time during trial participation will be 
analyzed and correlated with trial therapy and response. 
3
PATIENT ELIGIBILITY
The target population for this study is patients with high risk or BCG-refractory non-muscle 
invasive bladder cancer. This will be a single-center trial conducted in the Northwestern 
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Medicine Developmental Therapeutics Institute in conjunction with the Department of Urology 
of Northwestern University at Northwestern Medicine. 
Up to 24 evaluable subjects will be needed for this trial, therefore up to a total of 27 may be 
enrolled in order to achieve the necessary number of evaluable subjects. BCG-refractory is 
defined as tumor recurrence within 6 months of receiving at least 2 courses of intravesical BCG 
(at least 5 or 6 inductions and at least 2 or 3 maintenance doses) or T1 high grade disease at 
the first evaluation following induction BCG alone (at least 5 or 6 induction doses).  Therefore, 
patients who develop a recurrence of bladder cancer during maintenance treatment period with 
BCG will be also eligible to the present study. However, patients who were not able to complete 
prior induction BCG treatment because of intolerable toxicities and developed a recurrence will 
not be eligible for this trial given increased risk of adverse events with repeated exposure. 
On average, 1-2 high risk or BCG-refractory potentially eligible patients are seen per month in 
the Urology clinic, and it is anticipated that one patient will be accrued every 2-3 months. 
Potential patients may be referred to the Principal Investigator (PI) at Northwestern University, 
Dr. Joshua Meeks, at 312-363-8959. In addition, the sub-investigators have significant 
experience and collaborations with nearby university and community urology groups to help 
provide additional referrals for this high priority study when activated. 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and none of the exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is registered. 
Please refer to Section 10.3 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a histologically documented recurrence of non-muscle-
invasive bladder carcinoma (T1HG, T1HG after reTUR or BCG refractory; if 
patient has received BCG they can be Ta, Tis, or T1) 
Note: Gross disease is not allowed, however positive urine cytology and 
carcinoma in situ is permitted.
3.1.2
Patients must be BCG-unresponsive. A patient is BCG-unresponsive if they 
meet one or more of the following criteria:

Patient has persistent or recurrent high-grade Ta/CIS/ urothelial 
carcinoma after completing therapy with at least induction BCG (≥5 
doses) and first round maintenance or second induction BCG (≥2 
doses). Patient has high grade T1 urothelial carcinoma after induction 
BCG (≥5 doses) only or after induction BCG (≥5 doses) and first round 
maintenance or second induction BCG (≥2 doses). 

Patient is disease-free at completion of BCG (i.e., complete response) 
but then experiences a high-grade recurrence before or at the 6 month 
follow-up cystoscopy.  

Recurrence after treatment with at least 3 doses of a BCG refractory 
agent (for example, though not limited to, gemcitabine, docetaxel, 
valrubicin or an interferon adenovirus).
3.1.3
Patients must have received one course of induction treatment with BCG (4-
6 weekly doses), irrespective of the interval since last treatment. Patients 
are allowed to have received any number of prior chemotherapy 
instillations. 
NOTE: Patients may have received prior intravesical interferon. 
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3.1.4
Patients must be age ≥ 18 years. 
3.1.5
All patients positive for invasion must have imaging (CT scan or MRI) 
documenting normal upper urinary tracts and absence of locally advanced 
bladder cancer within 60 days prior to study registration. 
3.1.6
Have a performance status of 0-1 on the ECOG Performance Scale
3.1.7
Patients must have adequate organ and bone marrow function within 14 
days prior to registration, as defined below: 
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥7 g/dL or ≥5.6 mmol/L 
Renal
Serum creatinine OR
Measured or calculateda creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
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)
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
≤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 institutional standard.
3.1.8
Females of child-bearing potential (FOCBP) and males must agree to use 
adequate contraception (e.g. hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and 
for 120 days following completion of therapy. Should a female patient 
become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately.
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy

Has had menses at any time in the preceding 12 consecutive months 
(and therefore has not been naturally postmenopausal for > 12 months)
3.1.9
FOCBP must have a negative urine or serum pregnancy test within 7 days 
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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3.1.10
Patients must have the ability to understand and the willingness to sign a 
written informed consent prior to registration on study.
3.1.11
Patients must be willing and able to comply with scheduled visits, treatment 
and assessments.
3.2
Exclusion Criteria
3.2.1
Patients who have had chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to study Day -14 or who have not 
recovered (to ≤ Grade 1 or baseline) from adverse events due to a 
previously administered agent are not eligible.
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and do qualify for the study.
Note:  If subject received major surgery within 4 weeks prior to Day -14, 
they must have recovered adequately from the toxicity and/or complications 
per PI discretion. 
3.2.2
Patients who have received any other investigational agent ≤ 28 days prior 
to registration are not eligible. 
3.2.3
Patients who have received a prior monoclonal antibody ≤ 28 days prior to 
study Day -14 are not eligible.
3.2.4
Patients who have not recovered (to ≤ Grade 1 or baseline) from adverse 
events due to agents administered ≥ 28 days earlier are not eligible.
3.2.5
Patients who have a diagnosis of immunodeficiency (per PI discretion) or 
who have received treatment with systemic immunosuppressive 
medications (including but not limited to prednisone, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor 
[anti-TNF] agents) ≤ 14 days prior to study registration are not eligible. 
NOTE: Patients who have received acute, low-dose, systemic 
immunosuppressant medications (e.g., one-time dose of dexamethasone 
for nausea) may be enrolled in the study. The use of inhaled corticosteroids 
and mineralocorticoids (e.g., fludrocortisone) is allowed. 
3.2.6
Patients who have a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to pembrolizumab are not eligible.
AND/OR
Patients who have had prior exposure to compounds of similar chemical or 
biologic composition to pembrolizumab are not eligible. 
3.2.7
Patients who have documentation of an uncontrolled intercurrent illness (as 
noted in their medical records) including, but not limited to any of the 
following, are not eligible: 

Ongoing or active infection requiring systemic treatment

Symptomatic congestive heart failure (New York Heart Association 
cardiac disease Class III or IV)

Unstable angina pectoris

Myocardial infarction within the previous 3 months

Unstable cardiac arrhythmias
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
Psychiatric illness/social situations that would limit compliance with 
study requirements

Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s 
safety or study endpoints
3.2.8
Female patients who are pregnant or nursing are not eligible.
3.2.9
Patients who have a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to BCG are not eligible.
3.2.10
Patients who have had an active infection requiring systemic therapy ≤ 7 
days prior to Day -14 are not eligible UNLESS they are symptom-free and 
have a negative culture at the time of dosing on Day -14. 
3.2.11
Patients who received a live, attenuated vaccine ≤ 28 days before study 
registration or are anticipated to require such a live attenuated vaccine are 
not eligible. 
NOTE: Influenza vaccination should be given during influenza season only 
(approximately October to March). Patients must not receive live, 
attenuated influenza vaccine (e.g., FluMist) ≤ 28 days prior to study 
registration or at any time during the study. 
3.2.12
Patients who are known to be (i.e. documented in medical records) human 
immunodeficiency virus (HIV) positive are not eligible.
3.2.13
Patients with active tuberculosis are not eligible.
3.2.14
Patients with known active hepatitis B (chronic or acute; defined as having a 
positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C 
are not eligible. 
NOTE: Patients with past hepatitis B virus (HBV) infection or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [HBc Ab] and 
absence of HBsAg) are eligible. HBV DNA must be obtained in these 
patients 14 days prior to study registration.
NOTE: Patients positive for hepatitis C virus (HCV) antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA.
3.2.15
Patients who have a history of severe allergic, anaphylactic, or other 
hypersensitivity reactions to chimeric or humanized antibodies or fusion 
proteins are not eligible.
3.2.16
Patients with an active autoimmune disease requiring ongoing systemic 
treatment (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs) are not eligible. 
NOTE: A minimum 14 day washout period is required for eligibility.
NOTE: 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. 
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3.2.17
Patients with history of interstitial lung disease or active, non-infectious 
pneumonitis are not eligible. 
NOTE: History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted. 
3.2.18
Patients who receive treatment with systemic immunostimulatory agents 
(including but not limited to IFNs, IL-2) within 6 weeks or five half-lives of the 
drug, whichever is shorter, prior to study registration are not eligible.
3.2.19
Patients who received prior treatment 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) are not 
eligible. 
3.2.20
Patients who have a history of another malignancy within the previous 12 
months are not eligible.  
  
Note: Exclusions include: 

Patients with a disease-free interval of > 12 months and/or have not 
received systemic therapy for > 12 months for another malignancy 
are eligible. 

Basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially 
curative therapy are eligible.

If another malignancy is incidentally found during study eligibility 
work up and does not require treatment the patient will be eligible. 
This should be clearly documented in the medical record at the time 
of study registration.
3.2.21
Patients who have a history of an allogeneic tissue/solid organ transplant 
are not eligible.
4
TREATMENT PLAN
4.1
Overview
Treatment will be administered on an outpatient basis. Treatment will be divided into 
pre-induction, induction and maintenance therapy phases. Two weeks prior to 
induction, subjects will receive the first intravesical instillation of pembrolizumab 
(week -2). During induction therapy, patients will receive standard intravesical 
instillation with BCG once weekly for 6 weeks (total of 6 BCG instillations). Patients 
will also be treated with concomitant pembrolizumab, given intravesically every 2 
weeks during the induction period (total of 3 pembrolizumab instillations; weeks 0, 2, 
and 4). The maintenance phase starts at week 7 and continues up to 1 year (last 
dose and cystoscopy at week 49). Intravesical BCG and intravesical pembrolizumab 
will be given every 2 weeks for the first 12 weeks of maintenance therapy (weeks 7, 
9, 11, 13, 15, 17 for a total of 6 doses) and then every 4 weeks thereafter (weeks 
21, 25, 29, 33, 37, 41, 45 and 49 for a total of 8 doses) until completion of treatment 
or early discontinuation for any reason. 
Cystoscopies will be performed 8 weeks (approximately 2 months) from the end of 
the induction period (week 17) and will be repeated at 8-week intervals until week 
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49. If ambulatory cystoscopy reveals any abnormal finding requiring further 
investigation, BCG and/or pembrolizumab administration will be suspended until 
clinical investigation is completed. Tumor progression will be defined as positive 
transurethral resection and/or biopsy including tumor stage progression, muscle 
infiltration or metastasis. Should a bladder cancer progression be confirmed, the 
subject will be off treatment and off-study. Otherwise, subject will be able to resume 
study treatments approximately 4 weeks (per PI discretion) after any bladder biopsy 
to allow appropriate healing. NOTE: the PI will review and confirm when appropriate 
healing has occurred to allow resumption of treatment. Any patient who has a high-
risk lesion resected on a follow-up cystoscopy must be removed from study 
treatment. 
This phase I study will utilize a 3+3 dose escalation scheme for the study drug 
pembrolizumab with an initial dose of 1 mg/kg given intravesically to the first cohort 
of three subjects. Details regarding dose escalation can be found in section 4.3. 
This study will enroll a maximum of 18 evaluable subjects. Evaluable subjects for 
toxicity will be those who receive at least one dose of the study drug. Evaluable 
subjects for response are those who meet the minimum treatment and safety 
evaluation requirements of the study: i. the subject has received the six doses of 
BCG and three doses of pembrolizumab planned for the induction phase and has 
sufficient safety data available to assess the occurrence of dose limiting toxicities; ii. 
the subject has received at least 1 dose of pembrolizumab out of the total 11 doses 
planned during the maintenance period.
There is a possibility of adding an expansion cohort of up to 10 subjects to further 
define safety and efficacy of pembrolizumab. This will be determined by Merck after 
completion of the dose escalation phase.
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4.2
Treatment Administration
Table 4-1: Treatment Summary
Agent
Dose *
Route
Schedule
Pre-induction 
Phase
Pembrolizumab
Variable 
depending 
on cohort
Intravesically
Once at week -2 (Day -14)
BCG
50mg
Intravesically
Once per week, weeks 0-5^
Induction 
Phase
Pembrolizumab
Variable 
depending 
on cohort
Intravesically
Once at weeks 0, 2, 4 
BCG
50mg
Intravesically
Maintenance 
Phase
Pembrolizumab
Variable 
depending 
on cohort
Intravesically
Weeks 7, 9, 11, 13, 15, 17, 
21, 25, 29, 33, 37, 41, 45, 49
* Pembrolizumab dose cohorts: 1 mg/kg, 2 mg/kg, 5mg/kg and 10 mg/kg. 
^ Treatments should occur +/- 2 days from the same day each week.
4.2.1
BCG 
BCG will be administered weekly during the Induction phase of treatment, 
followed by maintenance BCG (see duration of therapy; section 4.8). Every 
effort should be made to administer treatments on the same day each week, 
however a window of +/- 2 days is allowed to accommodate scheduling 
issues. BCG administration should begin at least 2 weeks after any prior 
cystoscopies or intravesical procedures to allow healing of bladder 
epithelium. Each BCG dose will consist of 50mg BCG (TICE® BCG) diluted 
in 50ml of sterile normal saline that will be injected into the bladder through 
sterile urethral catheterization. There will be no dose escalation planned for 
BCG, however the dose may be reduced based on toxicity criteria in section 
4.4. After emptying the bladder, the BCG solution will be injected 
intravesically over 1 or 2 minutes and retained for 2 hours. Following the 
administration, patients will receive instructions to drink large amounts of 
fluids and monitor for symptoms that can develop and be related to the BCG 
instillation: dysuria, urgency, frequency, hematuria, persistent fever 
(temperature above 101oF for more than 2 days), chills, night sweats, 
malaise, arthralgia, cough, or skin rash. 
4.2.2
Pembrolizumab 
Pembrolizumab treatment will start two weeks prior to BCG administration 
(week -2). Patients will receive three instillations of pembrolizumab 
concomitant with BCG (weeks 0, 2, and 4; induction period), followed by 
maintenance pembrolizumab (see duration of therapy; section 4.7). The 
dose that subjects receive will depend upon the cohort to which they are 
enrolled; the starting dose will be 1 mg/kg. Each pembrolizumab dose will 
be diluted in 50ml of sterile normal saline and injected into the bladder 
through sterile urethral catheterization during 1 or 2 minutes and retained 
for 2 hours. During the days that BCG and pembrolizumab are given 
concomitantly, BCG will be administered and immediately followed by 
pembrolizumab administration; each medication will be diluted in 50ml and 
the total volume of 100ml will be retained for 2 hours. If pembrolizumab 
administration is scheduled on the same day as the cystoscopy (weeks 17, 
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25, 33, 41, and 49), pembrolizumab may be injected through the cystoscope 
provided no abnormal findings were noted.
4.3
Dose Escalation Scheme
There will be no dose escalation for BCG (patients on all cohorts will receive the 
same dose). The table below summarizes the pembrolizumab dose levels; subjects 
will receive the same dose of pembrolizumab during pre-induction, induction and 
maintenance phases. No dose reductions are permitted for pembrolizumab. BCG 
may be reduced for toxicity as described in section 4.4. A standard “3+3” dose 
escalation design will be utilized. Initially, the study will enroll 3 subjects at the 
starting dose (level 1), after which enrollment will be temporarily suspended until all 
3 patients complete the DLT evaluation period (defined as the 2 week pre-induction 
phase and the seven weeks of induction phase). Once all 3 subjects complete the 
DLT period and toxicity data has been reviewed by the Northwestern University 
Data Monitoring Committee, a decision will be made to proceed with escalation 
accordingly the rules below. 
Table 4-2: Escalation Dose Levels
Dose Level
Pembrolizumab
BCG
Number of patients
1
1 mg/kg
50mg
3-6
2
2 mg/kg
50mg
3-6
3
5 mg/kg
50mg
3-6
4
10 mg/kg
50mg
3-6
The following rules will be used at each dose level to determine whether or not to 
proceed to the next dose level:

If 0 of 3 subjects at a given dose level experience a DLT (defined below), 
then escalation will proceed to the next dose level.

If 2 or 3 of 3 subjects at a given dose level experience a DLT, then one of 
the following must occur:
o
If this happens at level 1, the study will be closed to further accrual 
and the regimen of pembrolizumab + BCG will be considered too 
toxic at any dose.
o
If this happens at level 2 or beyond, the previous level will be 
declared the maximum tolerated dose (MTD).

If 1 of 3 subjects at a given dose level experiences a DLT, then an 
additional 3 slots will be added (for a total of 6 patients at that level):
o
If 1 of 6 total experiences a DLT, then escalation will proceed to the 
next level.
o
If ≥ 2 of 6 total experience a DLT, the previous level will be declared 
the MTD. 
NOTE: Whichever dose level is declared the MTD must have 6 total subjects treated 
at that level. For example, if 3 subjects are treated at level 2 and 0 subjects 
experience DLT, escalation would then proceed to level 3. However, if ≥ 2 subjects 
at level 3 experience DLT, enrollment to level 2 would need to be re-opened to 
enroll an additional 3 subjects at that level (with 0 or 1 DLT observed in 6 total 
subjects) in order to declare level 2 the MTD. If dose level 3 is achieved without 
MTD-defining DLT, dose level 3 will be considered the recommended phase II dose 
for future trials. 
4.3.1
Definitions
DLT is defined as a significant adverse events (detailed below) occurring 
during the DLT observation period (consisting of the 2 week pre-induction 
phase and the 7 weeks of induction phase) that is related to either drug or 
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the combination. DLT will be evaluated according to CTCAE v 4.03 criteria. 
Delay in starting BCG or pembrolizumab therapy by more than 2 weeks due 
to toxicity during either the pre-induction or induction phases, regardless of 
attribution or grade, will be considered a DLT. 
Significant adverse events qualifying as a DLT are as defined in the table 
below:
Table 4-3: DLT Definitions
Local, Bladder-Related Toxicities – Considered to Be DLTs**
Toxicity
Grade
Including/Requiring
Not Included/Not DLT
Bladder perforation
≥ 2
extra peritoneal perforation
Bladder spasm
≥ 3
Hospitalization
Cystitis, noninfective
≥ 3
Transfusion, IV medications, 
and/or operative intervention
Grade 3 with gross 
hematuria or requiring 
elective endoscopic 
intervention and/or 
radiologic intervention 
Hematuria
≥ 3
Transfusion, operative 
intervention, limiting self-
care ADL
Gross hematuria, IV 
medication, elective 
endoscopic procedures, 
radiologic intervention
Urinary incontinence
≥ 3
Intervention required, 
limiting self-care ADL
Urinary retention
≥ 3
Substantial loss of affected 
kidney function or mass
Urinary tract 
obstruction
≥ 3
Symptomatic and altered 
organ function, endoscopic 
intervention
Urinary tract pain
≥ 3
Severe pain, limiting self-
care ADL
Bladder infection
3
≥ 4
Will be DLT only if invasive 
procedure is required (e.g. 
draining an abscess). 
All 
Antibiotics or other non-
invasive procedures 
required.
Urinary tract 
infection
3
≥ 4
Will be DLT only if invasive 
procedure is required (e.g. 
draining an abscess). 
All
Antibiotics or other non-
invasive procedures 
required.
Local, Bladder-Related Toxicities – Will NOT Be DLTs
Toxicity
Grade
Including/Requiring
Not Included/Not DLT
Urinary frequency
Any
n/a
n/a
Urinary urgency
Any
n/a
n/a
Other, Non-Hematologic Toxicities**
Toxicity
Grade
DLT or Not?
All other aside from 
those listed above.
≥ 3
Will be considered DLT if felt to be related to either drug 
or the combination, except as noted below.
3
Will be considered DLT if refractory to treatment as 
outlined in Supportive Care Guidelines (Section 4.4.3)
Will be considered DLT if lasting >72 hours in the 
absence of maximal medical therapy
Diarrhea
4
Bloody or Grade 4 diarrhea will be DLT
Nausea & vomiting
3
Will only be considered DLT if it is refractory to anti-
emetic therapy and unable to be corrected to ≤ Grade 1 
within 24 hours.
Will be considered DLT if lasting >72 hours in the 
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absence of maximal medical therapy
Creatinine, elevated
Rise to Grade 3
Will be considered DLT if not corrected to ≤ Grade 1 
within 24 hours with IV fluids.
≥ 3
Will be considered DLT if unable to be corrected to ≤ 
Grade 2 within 24 hours.
Metabolic toxicities 
(e.g. glucose, 
hypokalemia, 
hypomagnesemia, 
hyperuricemia, 
hypophosphatemia, 
and hyponatremia)
4 – symptomatic
Will be considered dose-limiting regardless of duration or 
ability to correct
Drug-induced liver 
injury
Concurrent AST 
or ALT > 3x ULN 
and total bilirubin 
> 2x ULN
Will be considered DLT. Requires permanent study 
discontinuation.
Hematologic Toxicities**
3 (<50,000/L)
Will be considered DLT if associated with hemorrhage
Thrombocytopenia 
4 (<25,000/L)
Will be considered DLT
4 (<500/L)
Will be considered DLT
Neutropenia
3 (<1000/L) with 
associated fever 
(febrile 
neutropenia)
Will be considered DLT
**Any Grade 2 adverse event lasting greater than 10 days will be considered a DLT.
4.4
Dose Delays/Modifications
Symptoms of local toxicity will be monitored throughout treatment. Treatment will be 
delayed for up to 2 weeks (14 days) if grade 2 local toxicity (not considered DLT) 
develops during pre-induction, induction, or maintenance phases. In addition, BCG 
dose modifications will be managed according to standard of care procedures; 
specifically, in the case of a grade 2 local bladder toxicity, the dose should be 
delayed, and BCG may be re-challenged at half the dose (25mg) per the treating 
physician’s discretion within 2 weeks (14 days) of the last administration. Local 
toxicities related to the treatment with BCG and/or pembrolizumab include bladder 
spasm, cystitis noninfective, hematuria, urinary frequency, urinary retention, urinary 
tract pain, urgency. In addition, for grade 2 bladder or urinary tract infection, 
treatment may be delayed up to 2 weeks at the discretion of the treating physician; 
for grade 3 bladder or urinary tract infection, antibiotics are allowed with a 2 week 
delay of treatment as long as the infection has been cleared symptomatically. 
Treatment may resume when the toxicity resolves or improves to grade 1. If toxicity 
does not resolve to Grade 0-1 within 2 weeks (14 days) after scheduled dose, trial 
treatment should be discontinued after consultation with the PI and DSMC. 
The patients will be allowed to delay treatment during induction or maintenance by 
up to 2 weeks (14 days) due to scheduling difficulties. When BCG is delayed due to 
local bladder toxicities, pembrolizumab will be delayed as well.   Doses of 
pembrolizumab will not be reduced due to toxicities. BCG doses may be reduced 
following standard of care as described above. If the patient needs to undergo a 
transurethral biopsy or resection during the study, there will be a delay of 
approximately 4 weeks (per PI discretion) until the next treatment of BCG or 
pembrolizumab to allow healing of biopsy/resection site. 
In addition, pembrolizumab will be withheld for drug-related Grade 4 hematologic 
toxicities, non-hematological toxicity ≥ Grade 3 including laboratory abnormalities, 
and severe or life-threatening AEs. Delay by up to 2 weeks (14 days) is permitted. 
Treatment may resume when the toxicity resolves or improves to grade 1. If toxicity 
does not resolve to Grade 0-1 within 2 weeks (14 days) after the scheduled dose 
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administration, trial treatment should be discontinued after consultation with the PI 
and DSMC. With PI and DSMC agreement, subjects with a laboratory adverse event 
still at Grade 2 after 2 weeks may continue treatment in the trial only if 
asymptomatic and controlled. 
4.5
Toxicity Management  
Any patient who receives at least one dose of study drug will be evaluable for 
toxicity endpoints. Toxicity will be assessed according to CTCAE v 4.03 criteria
4.5.1
Immune-Related Adverse Events
The limited systemic absorption of chemotherapy agents and cytokines (i.e., 
IFN) when administered intravesically predicts that immune-related adverse 
events (irAEs) observed in patients receiving intravenous pembrolizumab 
will be rare. Nevertheless, all measures will be in place for careful 
monitoring and management should these occur
Table 4-4. Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued 
if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 
2
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs 
and symptoms of 
pneumonitis

Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment

Add prophylactic antibiotics 
for opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / 
Colitis 
Grade 4
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs 
and symptoms of 
enterocolitis (i.e., diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of bowel 
perforation (i.e., peritoneal 
signs and ileus).

Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis. 

Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is 
not feasible, fluid and 
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electrolytes should be 
substituted via IV infusion.
Grade 2
Withhold

Administer corticosteroids 
(initial dose of 0.5- 1 
mg/kg prednisone or 
equivalent) followed by 
taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure
Withhold

Initiate insulin replacement 
therapy for participants 
with T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.  

Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-selective 
beta-blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement hormones 
(e.g., levothyroxine or 
liothyroinine) per standard 
of care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper.

Monitor changes of renal 
function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
Intolerable/ 
persistent 
Grade 2
Withhold
All other 
immune-related 
AEs
Grade 3
Withhold or 
discontinue 
based on the 
type of event.  
Events that 

Based on type and 
severity of AE administer 
corticosteroids 

Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes
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require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 
3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy 
or achieved metabolic control (in case of T1DM).  
 
4.5.2
Management of Specific Adverse Events
In addition to the table above, subjects should receive appropriate 
supportive care measures as deemed necessary by the treating investigator 
including but not limited to the items outlined below:

Anti-infectives: Subjects with a documented infectious complication 
should receive oral or IV antibiotics or other anti-infective agents as 
considered appropriate by the treating investigator for a given infectious 
condition, according to standard institutional practice. Please refer to 
section 4.4 for guidance regarding delay of treatment up to 2 weeks (14 
days) for local, treatment-related, bladder and urinary tract infections. 

Management of Infusion Reactions: NOTE: intravenous infusion is no 
the route of administration that will be employed in this protocol. The 
risk of these reactions is relevant with intravenous administration of 
pembrolizumab and it is not expected to be clinically significant with 
intravesical administration. However, all measures will be in place for 
careful monitoring and management should these occur. Acute infusion 
reactions (which can include cytokine release syndrome, angioedema, 
or anaphylaxis) are different from allergic/hypersensitive reactions, 
although some of the manifestations are common to both AEs. Signs 
and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity 
(including drug fever); Arthralgia (joint pain); Bronchospasm; Cough; 
Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, 
malaise); Headache; Hypertension; Hypotension; Myalgia (muscle 
pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; 
Sweating (diaphoresis); Tachycardia; Tumor pain (onset or 
exacerbation of tumor pain due to treatment); Urticaria (hives, welts, 
wheals); Vomiting. 
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Table below shows treatment guidelines for subjects who experience an infusion reaction associated with intravenous 
administration of pembrolizumab. In the event that an infusion-like reaction does occur with intravesical administration of a 
patient on this study, the guidelines below should be followed.
Table 4-5: Management of Infusion Reactions
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 hrs
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 and 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 pembrolizumab 
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); 
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
No subsequent dosing

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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
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.
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 v4.03 (CTCAE) at http://ctep.cancer.gov

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4.5.3
Overview of Guidelines for Managing Suspected Pneumonitis from 
pembrolizumab 
Subjects with symptomatic pneumonitis should immediately stop receiving 
pembrolizumab and have an evaluation. The evaluation may include 
bronchoscopy and pulmonary function tests to rule out other causes such 
as infection.  If the subject is determined to have study drug associated 
pneumonitis, the suggested treatment plan is detailed in the table below.
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 2 weeks, the 
following rules should apply:
First episode of pneumonitis

May increase dosing interval by one week in subsequent cycles

Second episode of pneumonitis – permanently discontinue 
pembrolizumab if upon rechallenge subject develops pneumonitis  
Grade 2
4.5.4
Supportive Care Guidelines for Events of Clinical Interest and 
Immune-related Adverse Events (irAEs)
Events of clinical interest of a potential immunologic etiology (irECIs) may 
be defined as an adverse event of unknown etiology, associated with drug 
exposure and is consistent with an immune phenomenon.  irAEs may be 
predicted based on the nature of the pembrolizumab compound, its 
mechanism of action, and reported experience with immunotherapies that 
have a similar mechanism of action. Special attention should be paid to AEs 
that may be suggestive of potential irAEs.  An irAE can occur shortly after 
the first dose or several months after the last dose of treatment.  
If an irAE is suspected, efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin or other etiologic causes prior to labeling an 
adverse event as an irAE.  Information on how to identify and evaluate 
irAEs has been developed and is included in the Event of Clinical Interest 
and Immune-Related Adverse Event Guidance Document located in the 
Administrative Binder.  Subjects who develop a Grade 2 or higher irAE 
should be discussed immediately with the Sponsor.  
Table 4-6: Management of Pneumonitis
Study drug 
associated 
pneumonitis
Withhold/Discontinue 
pembrolizumab?
Supportive Care
Grade 1 
(asymptomatic)
No action
Intervention not indicated
Grade 2
Withhold pembrolizumab, 
may return to treatment if 
improves to Grade 1 or 
resolves within 2 weeks
Systemic corticosteroids are indicated.  
Taper if necessary.
Grade 3 and Grade 4
Discontinue 
pembrolizumab
Systemic corticosteroids are indicated. The 
use of infliximab may be indicated as 
appropriate.  Refer to the Event of Clinical 
Interest and Immune-related Adverse Event 
Guidance Document for additional 
recommendations.
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Recommendations to managing irAEs not detailed elsewhere in the protocol 
are detailed in the table below.
Table 4-7: Management of irAEs
irAE
Withhold/Discontinue 
pembrolizumab
Supportive Care
Grade 1
No action
Provide symptomatic treatment
Grade 2
May withhold 
pembrolizumab
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment
Grade 3 and Grade 4
Withhold pembrolizumab
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg per day 
prednisone equivalent 
within 2 weeks of toxicity
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic 
treatment.  May utilize 1 to 2 mg/kg 
prednisone or equivalent per day.
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks.
4.5.4.1 Severe skin reactions
Immune-mediated severe skin reactions have been reported in 
patients treated with pembrolizumab. Monitor patients for suspected 
severe skin reactions and exclude other causes. Based on the 
severity of the adverse reaction, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal 
necrolysis (TEN), some with fatal outcome, have been reported in 
patients treated with pembrolizumab. For signs or symptoms of SJS 
or TEN, withhold pembrolizumab and refer the patient for 
specialized care for assessment and treatment. If SJS or TEN is 
confirmed, permanently discontinue pembrolizumab.
4.5.4.2 Other Immune-Mediated Adverse Reactions
The following additional clinically significant, immune-mediated 
adverse reactions were reported in less than 1% of patients treated 
with pembrolizumab in KEYNOTE-001, KEYNOTE-002, KEYNOTE-
006, and KEYNOTE-010: uveitis, myositis, Guillain-Barré 
syndrome, and pancreatitis. The following was reported in other 
clinical studies with pembrolizumab or in post-marketing use: 
myocarditis. 
Cases of these immune-mediated adverse reactions, some of which 
were severe, have been reported in clinical trials or in post-
marketing use.
Solid organ transplant rejection has been reported in the post-
marketing setting in patients treated with pembrolizumab. 
Treatment with pembrolizumab may increase the risk of rejection in 
solid organ transplant recipients. Consider the benefit of treatment 
with pembrolizumab versus the risk of possible organ rejection in 
these patients.
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4.6
Concomitant Medications/Treatments
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 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. 
4.6.1
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 may 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. 
4.6.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase of this trial:

Anti-cancer systemic chemotherapy or biological therapy 

Anti-cancer immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 

Live vaccines within 4 weeks prior to study registration 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, 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 at any time during the study. 

Glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology. 
However, patients are allowed to use bronchodilators or local steroid 
injections if clinically necessary. 
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.  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 follow-up phase. 
4.7
Other Modalities or Procedures
Flexible cystoscopy will be performed in the office at weeks 17, 25, 33, 41, and 49. 
The patient is placed supine, and their legs are flexed at the hips. The urethra is 
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prepped with iodine and draped to create a sterile environment. A 16 F Storz 
cystoscope is placed via urethra into the bladder. The entire urothelium is inspected 
(including the prostate in men). Retroflexion of the scope is performed to evaluate 
the base of the bladder. The bladder is then barbatoged with 60 cc of normal saline 
for cytology. The scope is removed. 
4.8
Duration of Therapy
The study therapy will include a 2 week pre-induction phase, 6 week induction 
phase, followed by maintenance therapy which may continue up to 1 year (last dose 
at week 47) or until:

Disease progression

Inter-current illness that prevents further administration of treatment

Resection of a high risk lesion during a study cystoscopy

Unacceptable adverse event(s)

Patient decides to withdraw from treatment or the study as a whole

General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator.
4.9
Duration of Follow Up
4.9.1
Safety Follow-Up Visit
The end-of-treatment visit will be conducted approximately 30 days (± 7 
days) after the last dose of trial treatment, OR at the time of the week 53 
cystoscopy (if the patient completes all of the maintenance phase), OR 
before the initiation of a new anti-cancer treatment, whichever comes first. 
All AEs that occur prior to this 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, whichever occurs first. 
SAEs that occur within 90 days of the end of treatment or before initiation of 
a new anti-cancer treatment should also be followed and recorded.
4.9.2
Follow-Up Visits
After discontinuing trial therapy, patients will be followed clinically for 
disease recurrence and survival according to the below schedule. There is 
no specific limit on the length of follow-up, as it is intended to follow all 
patients for survival.
After the last dose of trial therapy, follow patients:

Every 3 months (± 30 days) during years 1 and 2;

Every 4 months (± 60 days) during years 3 and 4;

Every 6 months (± 60 days) during years 5 and 6;

Every 12 months (± 90 days) thereafter; 

Or until death, withdrawal, or end of study (whichever occurs first).
Information regarding post-study anti-neoplastic treatment will be collected if 
new treatment is initiated.
4.10
Removal of Patients from Protocol Therapy and/or Study as a Whole
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include:

Patient voluntarily withdraws from treatment (follow-up permitted); 

Patient withdraws consent (termination of treatment with no follow-up);

Patient is unable to comply with protocol requirements (follow-up permitted);

Patient demonstrates disease progression (follow-up permitted);

Patient undergoes resection of a high risk lesion on a study cystoscopy
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
Patient experiences toxicity that makes continuation in the protocol unsafe 
(follow-up permitted);

Treating physician concludes that continuation on the study would not be in the 
patient’s best interest (follow-up permitted);

Patient becomes pregnant;

Development of second malignancy that requires treatment, which would 
interfere with this study (follow-up permitted);

Lost to follow-up. 
4.11
Study Subject Replacement
Three subjects within a dose level must be observed during DLT evaluation period 
(defined as the 2 week pre-induction phase and the 7 weeks of induction phase) 
before accrual to the next higher dose level may begin. Evaluable subjects for DLT 
will be those who receive the pre-induction (week -2) dose of pembrolizumab. 
Inevaluable subjects (those who are registered but never receive the pre-induction 
dose of pembrolizumab) will be replaced.
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5
STUDY PROCEDURES
Table 5: Study Procedures
Baseline
Treatment Period
Off Treatment
Timeline
Screening2
Pre-induction 
Phase 
(Day -14)
Induction 
Phase
(weeks 0 thru 
5)
Maintenance Phase: 
(weeks 7 thru 53)
End of 
Treatment 
Visit20
Follow-up21
Assessments/Procedures
X
X
X
Informed Consent
X
History
X
Physical exam1
X
X
X
X
Concomitant meds
X
X
X
X
X
ECOG Status
X
X
X
X
X
Adverse events3
X
X
X
X
X
Cystoscopy4
X
X4, 5
Urine cytology4
X
X4
Imaging studies6
X
CBC with diff7
X
X
X7
X7
Chemistry labs8 
X
X
X
X8
Coagulation labs9
X
Thyroid tests10
X
X10
Urinalysis
X
X
X
X
Pregnancy test11
X
Urine creatinine12
X
X
X
Urine PK sample13
X
X
Serum PK sample14
X
X
Research blood sample15
X15
X15
X15
Research urine sample16
X16
X16
X16
Tissue for research17
X
X
Pembrolizumab18
X
X
X
BCG19
X
X
Survival/disease status
X
1.
Physical exam will include weight and vital signs (temperature, pulse, and blood pressure). Height will be measured at baseline only. A 
full physical exam should be performed at baseline; thereafter, a directed physical may be performed prior to each treatment 
administration.

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2.
Screening labs should be completed within 14 days prior to registration (except for pregnancy test). All other screening assessments 
should be performed with 28 days prior to registration unless otherwise noted. Screening and pre-induction procedures may be 
performed on the same day, if desired.
3.
Baseline symptoms should be recorded at screening. 
4.
Cystoscopies will be performed at baseline and then to check for recurrence at weeks 17, 25, 33, 41, and 49; these may be performed 
more often if clinically indicated. A urine cytology will be performed at the same time as each cystoscopy.
5.
Treatment of patients who undergo biopsy for pathogenic response at weeks 17, 25, 33, 41, and 49 may be held for the outcome at 
discretion of the treating surgeon. 
6.
Only required for patients who are positive for invasion.  Baseline imaging will consist of CT or MRI. Studies showing normal upper 
tracts and absence of locally advanced bladder cancer required within 60 days before study registration. Follow-up imaging is not 
required but may be performed if clinically indicated.
7.
CBC will be performed at baseline pre-dose at each treatment visit, within 48 hours if necessary. CBC may be performed more often if 
clinically indicated. 
8.
Chemistry labs will be done at baseline and pre-dose at each treatment visit and should include albumin, alkaline phosphatase, 
ALT/AST, lactate dehydrogenase, bicarbonate, creatinine (or calculated creatinine clearance), uric acid, calcium, chloride, glucose, 
phosphorus, potassium, sodium, magnesium, bilirubin, total protein, BUN. Chemistry labs may be completed within 48 hours prior to 
dosing.
9.
Includes PT/INR, PTT 
10. Includes T3, FT4, and TSH and will be performed at screening and week 17 only (unless otherwise clinically indicated).
11. Serum or urine pregnancy test required within 7 days prior to Day -14 for all females of child-bearing potential.
12. A portion of each urine sample will be sent to the NMH Labs for urine creatinine measurement
13. For first 3 patients only: A urine sample for PKs will be collected prior to dosing and 2 hours (+/- 5 minutes allowed for collections) 
after dosing at weeks -2 and 4. Urine samples for PK testing will be banked and stored in the Meeks Lab for future analysis. See 
Section 8 and the Lab Manual for details.
14. For first 3 patients only: Serum concentrations of MK-3475 will be evaluated during pre-induction (week -2) and during induction 
(week 4). For each sample 3 mL of whole blood will be collected in a red top tube (containing now anti-coagulant or serum separator 
gel) just prior to dosing (time 0) and at 15, 30, and 60 minutes (+/- 2 minutes) post-dosing. See Section 8 and Lab Manual for 
processing and shipping details.
15. A separate blood sample for measurement of cytokines and cellular profiling by flow cytometry will be collected at weeks -2, 0, and 17. 
Two 3 ml lavender EDTA tubes should be collected pre-dose at each time-point. Tubes will be transported to the Pathology Core 
Facility for processing and distribution to the Flow Cytometry Core Laboratory of the Lurie Cancer Center (for flow studies) and Myriad 
Laboratories (for cytokine assays). Please refer to Section 8.0 and the corresponding lab manual for additional instructions. A portion of 
the blood specimens that have been collected for cytokine analysis may be used in plasma PK assays, per Principal Investigator 
discretion.
16. Urine for sample (approximately 40-50 ml) for measurement of cytokines and cellular profiling by flow cytometry will be also be 
collected in a sterile cup throughout treatment, prior to dosing and an optional collection at the third void approximately 4-6 hours after 
each dose (weeks -2, 0, 1, 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 21, 25, 29, 33, 37, 41, 45, and 49). NOTE: The first void will be 2 hours post-
dosing as part of the treatment (may be used for PK sampling if participating in that component), the second void after dosing will not 
be used for any correlative studies and should be discarded. An optional urine for research will be obtained at the third void, which is 
typically 4-6 hours after dosing; however the time does not need to be exact and may be adjusted depending on patient needs/urgency. 

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Urine will be collected in a sterile plastic container and transported to the Pathology Core Facility for processing. The cell pellets will 
then be sent to the Flow Cytometry lab for flow studies; the supernatant will be sent to Myriad Laboratories for cytokine analysis. See 
section 8.0 and the Lab Manual for additional details.
17. Archived tumor tissue for biomarker analysis and NGS is requested for all patients. A formalin fixed paraffin embedded tumor tissue 
sample (or newly obtained formalin fixed biopsy of a tumor lesion not previously irradiated) may be provided in the form of at least 
fifteen unstained slides (5 slides for IHC analysis and 10 slides for whole exome sequencing). A cytologic specimen will not be 
acceptable. In addition, if biopsies are performed during scheduled cystoscopies throughout the study, an additional 15 unstained 
slides from each will also be obtained for study purposes only if the samples contain tumor tissue. See section 8.0 and the Lab Manual 
for details.
18. Pembrolizumab will be administered intravesically at the assigned dose for the cohort at the following weeks: -2, 0, 2, 4, 7, 9, 11, 13, 
15, 17, 21, 25 29, 33, 37, 41, 45 and 49.
19. BCG 50 mg will be administered intravesically during induction (6 weekly doses) and maintenance (weeks 7, 9, 11, 13, 15, 17, 21, 25 
29, 33, 37, 41, 45 and 49); every effort should be made to administer doses on the same day each week, however a window of +/-2 
days is permitted for each dose.
20. Whether a patient completes the full year of therapy or discontinues early for any reason, an end-of-treatment visit should be conducted 
approximately 30 days (± 7 days) from the last dose of study drug.
21. Once off treatment, patients will be followed clinically for disease recurrence and survival according to the following schedule. After the 
last dose of trial therapy, follow patients every 3 months (± 30 days) during years 1 and 2, every 4 months (± 60 days) during years 3 
and 4, every 6 months (± 60 days) during years 5 and 6, and every 12 months (± 90 days) thereafter, or until death, withdrawal, or end 
of study (whichever occurs first). If a patient discontinues treatment (for any reason other than disease recurrence) prior to completing 
the full year of therapy, they will immediately enter into the clinical follow-up phase.

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6
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The level of risk 
attributed to this study requires High Intensity Monitoring, as outlined in the DSMP. In addition, the 
study will abide by all safety reporting regulations, as set forth in the Code of Federal Regulations.  
6.1
Definition of Adverse Event 
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 Merck’s 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.
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
placebo or active comparator medication) or marketed, manufactured by, licensed by, 
provided by or distributed by Merck for human use.
Adverse events may occur during the course of the use of Merck product in clinical trials 
or within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
All adverse events will be recorded from the time the consent form is signed through 30 
days following cessation of treatment and 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 6.3.
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.
6.2
Severity of Adverse Events
All adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.
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
Moderate (grade 2): the event causes discomfort that affects normal daily activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the event.

Fatal (grade 5): the event caused death.
6.3
Serious Adverse Events
All SAEs, regardless of attribution, occurring from time of signed informed consent, 
through 30 days after the last administration of study drug, must be reported upon 
discovery or occurrence and within 2 working days to Merck Global Safety as outlined in 
6.7.5. 
 
An SAE is defined in regulatory terminology as any untoward medical occurrence that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is associated with an overdose.
For purposes of this trial, an overdose will be defined as any dose 
exceeding the prescribed dose for pembrolizumab by 20% over the 
prescribed dose. No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, pembrolizumab 
should be discontinued and the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a 
Merck product, the adverse event(s) is reported as a serious adverse event, 
even if no other seriousness criteria are met.
If a dose of Merck’s 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 hours to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as 
a serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of 
“Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
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Progression of the cancer under study is not considered an adverse event unless it 
results in hospitalization or death.
6.4
Unanticipated Problems Involving Risks to Subject or Others (UPIRSO)
A UPIRSO is a type of SAE that includes events that meet ALL of the following criteria:
•
Is unexpected (in terms of nature, severity, or frequency) given the procedures 
described in the research protocol documents (e.g., the IRB-approved research 
protocol and informed consent document) and the characteristics of the human 
subject population being studied
•
Is related or possibly related to participation in the research ("possibly related" 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
•
Suggests that the research places human subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized, even if no harm has actually occurred.
6.5
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the QAM within 2 working days to 
Merck Global Safety (as outlined in 6.7.5).
Events of clinical interest for this trial include:
1.
an overdose of Merck product. 
2.
an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab 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.  .
3.
In the event a subject develops any of the following AEs, a detailed narrative of the 
event should be reported as an ECI to the Sponsor within 24 hours and to Merck 
Global Safety within 2 working days of the event:
a.  Grade ≥ 3 diarrhea
b.  Grade ≥ 3 colitis
c.  Grade ≥ 2 pneumonitis
d.  Grade ≥ 3 hypo- or hyperthyroidism
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document provides 
guidance regarding identification, evaluation and management of ECIs and irAEs.  
Additional ECIs are identified in this guidance document and also need to be reported to 
the QAM within 24 hours and to Merck Global Safety within 2 working days of the event.  
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event.  Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
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performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune-related. 
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck’s product, must be reported within 24 hours to the 
QAM and to Merck Global Safety within 2 working days.
6.6
Reporting of Pregnancy and Lactation 
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), including the pregnancy of a male subject's 
female partner that occurs during the trial or within 120 days of completing the trial 
completing the trial, or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier.  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.
6.7
Reporting Requirements for Adverse Events
6.7.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data and Safety Monitoring Committee (DSMC) according to 
the study’s phase and risk level, as outlined in the DSMP. 
6.7.2
Expedited Reporting to the NU QA/DSMC
All SAEs must be reported to the assigned QAM within 24 hours of becoming 
aware of the event (and to Merck within 2 working days as in section 6.7.5). 
Completion of the NU CTO SAE Form is required.
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)

Country of incidence
All SAEs will be reported to, and reviewed by, the DSMC per the DSMC.
6.7.3
Expedited Reporting to the Northwestern IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their local 
IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the NU 
IRB within 24 hours of notification. 

Any death of a non-NU subject that is unanticipated and at least possibly 
related and any other UPIRSOs will be reported to Northwestern University 
and to the NU IRB within 5 working days of notification.
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
Information pertaining to an NU subject that fits into any of the categories 
listed on the Reportable New Information page will be reported to the NU 
IRB within 5 business days of knowledge or notification.
6.7.4
Reporting to the FDA (completed by the NU QA/DSMC)
The FDA will be notified within 7 calendar days of any SAE that is associated 
with study treatment, is unexpected, and is fatal or life-threatening.
The FDA will be notified within 15 calendar days of any SAE that is associated 
with the study treatment, unexpected, and serious but not fatal or life-
threatening. This includes any previous SAEs that were not initially deemed 
reportable, but are later determined to meet the criteria for reporting (i.e. by the 
DSMC).
All other SAEs will be reported on an annual basis as part of the annual FDA 
report.
6.7.5
Reporting to Merck
SAE and ECI reports and any other relevant safety information are to be 
reported to Merck within 2 business days (using the NU CTO SAE Form) to the 
Merck Global Safety facsimile number:  +1-215-993-1220
7
DRUG INFORMATION
7.1
Pembrolizumab
7.1.1
Other names: 
Pembrolizumab; Keytruda; lambrolizumab; SCH 900475 (Anti-PD-1). Chemical 
name: humanized X PD-1_mAb (H409A11) IgG4
7.1.2
Classification - type of agent: 
monoclonal antibody
7.1.3
Mode of action: 
anti-PD1
7.1.4
Storage and stability: 
Clinical supplies must be stored in a secure, limited-access location under 
the storage conditions specified on the label. Pembrolizumab should be stored 
under refrigerated conditions (2°C - 8°C). The product after reconstitution with 
sterile water for injection is a clear to opalescent solution, which may contain 
proteinaceous and extraneous particulates. The reconstituted DP solution can 
be further diluted with normal saline in IV containers made of polyvinyl chloride 
(PVC) or non-PVC material. Reconstituted vials should be immediately used to 
prepare the intravesical solution in the IV bag and the 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. Pembrolizumab solutions may be stored at room temperature 
for a cumulative time of up to 4 hours. This includes room temperature storage 
of reconstituted solution in vials, room temperature storage of infusion solution 
in the IV bag and the duration of infusion.
7.1.5
Protocol dose: 
Depending on the cohort, doses will be 1 mg/kg; 2 mg/kg; 5 mg/kg or 10 mg/kg
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7.1.6
Preparation: 
Pembrolizumab is provided as a white to off-white lyophilized powder (50 
mg/vial) or as a liquid solution (100 mg/vial) in Type I glass vials intended for 
single use only. Pembrolizumab is formulated with L-histidine as buffering agent, 
polysorbate 80 as surfactant, sucrose as stabilizer/tonicity modifier, and 
hydrochloric acid (HCl) and/or sodium hydroxide (NaOH) for pH adjustment (if 
necessary).
Pembrolizumab Powder for Solution for Infusion is reconstituted with 2.3 mL 
sterile water for injection (SWFI) to yield a 2.4 mL solution containing 25 mg/mL 
of pembrolizumab prior to further dilution. The solution will be injected into the 
bladder through sterile urethral catheterization using a separate syringe than 
was used for the BCG.
7.1.7
Route of administration for this study: 
Intravesical
7.1.8
Availability: 
Not commercially available. Provided by Merck free of charge. The contact for 
drug ordering will be Sloan Stribling (sloan_stribling@merk.com) or Tammy Moll 
(tammy.moll@merck.com). The Merck Drug Request Form should be completed 
and emailed to these contacts.
7.1.9
Side effects: 
Local bladder toxicities including but not limited to dysuria, urinary urgency, 
frequency and hematuria. Immune-related adverse events have been 
associated with pembrolizumab is administered intravenously. For the most 
recent safety update, please refer to the current Investigator’s Brochure or Study 
Agent Prescribing Information.
7.1.10
Return and Retention of Study Drug
The clinical study team will be responsible for keeping accurate records of the 
clinical supplies received from Merck or designee, 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.
7.2
BCG
7.2.1
Other names: 
TICE® BCG; Bacillus Calmette-Guerin
7.2.2
Classification: 
BCG is an attenuated, live culture preparation of the Bacillus of Calmette and 
Guerin (BCG) strain of Mycobacterium bovis.
7.2.3
Mode of action: 
The precise mechanism of action is unknown.
7.2.3
Storage and stability: 
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The intact vials of BCG should be stored refrigerated, at 2-8°C (36-46°F). This 
agent contains live bacteria and should be protected from direct sunlight. The 
product should not be used after the expiration date printed on the label.
7.2.4
Protocol dose: 
Each BCG dose will consist of 50mg BCG (TICE® BCG) diluted in 50ml of 
sterile normal saline that will be injected into the bladder through sterile urethral 
catheterization. Refer to package insert for detailed reconstitution and 
preparation procedures.
7.2.5
Preparation: 
The preparation of the BCG suspension should be done using aseptic 
technique. To avoid cross-contamination, parenteral drugs should not be 
prepared in areas where BCG has been prepared. A separate area for the 
preparation of the BCG suspension is recommended. All equipment, supplies, 
and receptacles in contact with BCG should be handled and disposed of as 
biohazardous. The pharmacist or individual responsible for mixing the agents 
should wear gloves and take precautions to avoid contact of BCG with broken 
skin. If preparation cannot be performed in a biocontainment hood, then a mask 
and gown should be worn to avoid inhalation of BCG organisms and inadvertent 
exposure to broken skin.
Option 1 (Using Syringe method): Draw 1 mL of sterile, preservative-free saline 
(0.9% Sodium Chloride Injection USP) at 4-25°C into a small syringe (e.g., 3 
mL) and add to 1 vial of BCG to resuspend. Gently swirl the vial until a 
homogenous suspension is obtained. Avoid forceful agitation which may cause 
clumping of the mycobacteria. Dispense the cloudy BCG suspension into the top 
end of a syringe (per institutional guideline) which contains 49 mL of saline 
diluent, bringing the total volume to 50 mL. To mix, gently rotate the syringe.
Option 2 (Using Reconstitution Accessories):
Reconstitution Accessories may be provided with each BCG product order. 
Please refer to the Reconstitution Accessories Instructions provided with the 
accessories for a full description of the product reconstitution procedures using 
these accessories. The reconstituted BCG should be kept refrigerated (2-8°C), 
protected from exposure to direct sunlight, and used within 2 hours. Unused 
solution should be discarded after 2 hours.
Note: DO NOT filter the contents of the BCG vial. Precautions should be taken 
to avoid exposing the BCG to direct sunlight. Bacteriostatic solutions must be 
avoided. In addition, use only sterile, preservative-free saline, 0.9% Sodium 
Chloride Injection USP as diluent.
7.2.6
Route of administration for this study: 
Intravesical treatment
7.2.7
Availability: 
BCG is commercially available and will not be provided by the study.
7.2.8
Side effects: 
Symptoms of bladder irritability, related to the inflammatory response induced, 
are reported in approximately 60% of patients receiving BCG. The symptoms 
typically begin 4 to 6 hours after instillation and last 24 to 72 hours. The irritative 
side effects are usually seen following the third instillation, and tend to increase 
in severity after each administration.
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The irritative bladder adverse effects can usually be managed symptomatically 
with products such as pyridium, propantheline bromide, oxybutynin chloride, and 
acetaminophen. The mechanism of action of the irritative side effects has not 
been firmly established, but is most consistent with an immunological 
mechanism. There is no evidence that dose reduction or antituberculous drug 
therapy can prevent or lessen the irritative toxicity of BCG.
“Flu-like” symptoms (malaise, fever, and chills) which may accompany the 
localized, irritative toxicities often reflect hypersensitivity reactions which can be 
treated symptomatically. Antihistamines have also been used.
Adverse reactions to BCG tend to be progressive in frequency and severity with 
subsequent instillation. Delay or postponement of subsequent treatment may or 
may not reduce the severity of a reaction during subsequent instillation.
Although uncommon, serious infectious complications of intravesical BCG have 
been reported. The most serious infectious complication of BCG is disseminated 
sepsis with associated mortality. In addition, M. bovis 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 antituberculous therapy and required orchiectomy.
If a patient develops persistent fever or experiences an acute febrile illness 
consistent with BCG infection, BCG treatment should be discontinued and the 
patient immediately evaluated and treated for systemic infection (see 
WARNINGS).
7.2.9
Return and Retention of Study Drug: 
Not applicable
8
CORRELATIVES/SPECIAL STUDIES
The goal of the planned laboratory correlative studies is to identify biomarkers that help predict 
benefit and/or toxicities from the study regimen. The Pathology Core Facility – Clinical Trials Unit 
(PCF-CTU) of the Robert H. Lurie Comprehensive Cancer Center will coordinate the 
procurement and distribution of all samples to the respective labs where testing will be 
conducted. Please refer to the accompanying Lab Manual for more detailed instructions and 
complete contact information for each lab. In addition, questions may be directed to:
Pathology Core Facility – Clinical Trials Unit
PCF-CTU@northwestern.edu 
8.1
PK Studies
Peripheral blood and urine samples will be collected from the first 3 patients only to 
determine plasma and urine concentration-time profiles and PK parameters of 
pembrolizumab. Samples will be labeled in the clinic with the subject’s de-identified 
study number and collection date. PK analysis will be done through an external vendor. 
Urine PK samples will be stored in the Meeks lab for future analysis.
For PK studies, 3 ml of whole blood will be collected in a red top tube (containing no 
anti-coagulant or serum separator gel) for the first 3 patients during pre-induction (week 
-2) and induction (week 4) at each of the following time points: 0 (pre-dose), 15, 30, and 
60 minutes post-dose (+/- 2 minutes). An aliquot of urine will also be obtained for PK 
analysis from urine samples given at pre-dose and 2 hours (+/- 5 minutes) after dosing. 
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See also Section 8.5 for limited PK analysis on additional patients.
8.2
Tissue Immunohistochemistry Studies
8.2.1
Tissue Procurement 
Tumor samples will be requested from all patients. A formalin fixed paraffin 
embedded tumor tissue sample (or newly obtained formalin fixed biopsy of a 
tumor lesion not previously irradiated) will be procured in the form of at least five 
unstained slides. Cytologic specimens will not be acceptable. If additional 
biopsies are performed during scheduled cystoscopies throughout the study, an 
additional 5 unstained slides from each will also be obtained for IHC studies only 
if the sample contains tumor tissue. See separate lab manual for details on 
processing and shipping.
8.2.2
Assay Methodology
Briefly, paraffin-embedded tumor specimens will be deparaffinized in xylene and 
rehydrated in a graded series of alcohols. Slides will be unmasked in Target 
Retrieval Solution (DakoCytomation, Glostrup, Denmark) using a Decloaking 
Chamber (Biocare Medical, Walnut Creek, Calif) and then blocked for 
endogenous peroxidase for 5 minutes with a peroxidase blocking solution. 
Slides will be rinsed in TRIS-buffered saline with 0.1% Tween-20 (TBST), 
incubated for 30 minutes with 1.5% normal horse serum in TBST, rinsed in 
TBST, and blocked for endogenous avidin and biotin. Slides will then be 
incubated overnight at 48C with an anti-PD1, anti-PD-L1 and anti-PD-L2 
antibodies (BD Biosciences). Tissue slides will be incubated with respective 
antibodies at a concentration of 1:100. This step will be followed by 30 minutes 
of incubation with biotinylated horse antimouse IgG and avidin/biotin complex 
reagent. Slides will be amplified using a Tyramide Signal Amplification Biotin 
System (Perkin-Elmer, Boston, Mass) and incubated in 3-amino-9-
ethylcarbazole chromogen. Isotype-matched antibodies were used to control for 
nonspecific staining. 
Hematoxylin/eosin and PD-1, PD-L1 and PD-L2-stained sections will be 
reviewed by a urologic pathologist. Criteria to be evaluated include: World 
Health Organization/International Society of Urologic Pathology (WHO/ISUP) 
histologic subtype and grade, TNM 2002 pathologic tumor stage, the presence 
and type of intratumoral lymphocytic infiltration, and the quantity and location of 
PD-L1 staining. The tumor will be considered positive for PD-1, PD- L1, PD-L2 if 
>5% of tumor cells had histologic evidence of plasma membrane staining.
8.3
NGS
Ten FFPE unstained slides, 5μm sections on positively charged, unbaked slides and a 
terminal H&E slide and matched normal sample (blood) will be stored in the Meeks Lab 
until analysis.  Analysis will be performed on archived tissue samples obtained at 
baseline and on fresh tissue from any subsequent biopsies performed during 
cystoscopies scheduled for weeks 17, 25, 33, 41, 49 and at progression.
8.4
Urinary cytokines and lymphocyte phenotypes
Urine samples will be collected in a sterile plastic cup from each patient 30 min before 
and an optional sample at the third void approximately 4-6 hours after BCG and/or 
pembrolizumab administration throughout treatment (weeks -2, 0, 1, 2, 3, 4, 5, 7, 9, 11, 
13, 15, 17, 21, 25, 29, 33, 37, 41, 45, and 49. NOTE: The first void will be 2 hours post-
dosing as part of the treatment and the second void after dosing will not be used for any 
correlative studies and should be discarded. An optional urine for research will be 
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obtained at the third void, which is typically 4-6 hours after dosing; however the time 
does not need to be exact and may be adjusted depending on patient needs/urgency. 
Samples will be transported to the Pathology Core Facility for processing. See separate 
lab manual for processing details. 
8.5
Peripheral blood cytokine assays and lymphocyte phenotypes
Two 3 mL lavender EDTA tubes will be collected from patients prior to dosing at weeks -
2, 0, and 17 at the time of other lab collection. One tube of blood will be transported 
immediately to the Flow Cytometry Core Laboratory for processing.  Lymphocyte 
subsets (CD3, CD4, CD8, CD11c, CD19, and CD 45, CD56, Gr-1) will be analyzed 
according to absolute cell numbers per microliter of whole blood, percent representation 
among all lymphocytes, and coexpression of the activation markers CD25, HLA-DR, and 
CD45RO using automated flow cytometric techniques at the Flow Cytometry Core 
Laboratory, Robert H Lurie Cancer Center of Northwestern University under the 
supervision of Suchitra Swaminathan, PhD. 
The second tube of blood will be processed in the Pathology Core Facility prior to 
shipment to Myriad Laboratories for cytokine analysis. A portion of the blood specimens 
that have been collected for cytokine analysis (time-points week -2, week 0, and week 
17) may be used in plasma PK assays, per Principal Investigator discretion.
8.6
Specimen Banking
Patient samples collected for this study and not entirely exhausted by the studies 
described above will be retained in the Meeks Lab (see separate lab manual for location 
details). Specimens will be stored indefinitely and may be used for future, unspecified 
testing. If future use is denied or withdrawn by the patient, best efforts will be made to 
stop any additional studies and to destroy the specimens.
Joshua Meeks, MD, PhD will be responsible for reviewing and approving requests for 
clinical specimen from potential research collaborators outside of Northwestern 
University. Collaborators will be required to complete an agreement (a Material Transfer 
Agreement or recharge agreement) that states specimens will only be released for use 
in disclosed research. Any data obtained from the use of clinical specimen will be the 
property of Northwestern University for publication and any licensing agreement will be 
strictly adhered to. 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available: 

Diagnosis 

Collection time in relation to study treatment

Clinical outcome – if available

Demographic data
9
STATISTICAL CONSIDERATIONS
This is a Phase I dose escalation study using the 3+3 design with 4 doses.  The dose escalation 
scheme and rules for determining the primary outcome, the maximum tolerated dose, are described 
in Section 4.3. In order to achieve up to 24 evaluable patients for dose limiting toxicity and MTD 
determination, up to 27 patients may be accrued to the study. This 3+3 design has a 91% chance 
(49%, 17%) of dose escalating when the true toxicity rate for that dose is 10% (30%, 50%).  
To achieve the secondary objectives, the dose limiting toxicities and adverse events will be 
presented as descriptive frequencies and proportions.  Serious adverse events will be summarized 
by type, frequency, timing, severity and attribution.
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Exploratory objectives (PK, response, progression, immune markers) will be summarized with 
descriptive statistics due to the anticipated small study sample size. Progression free survival (PFS) 
and overall survival (OS) will be analyzed using the Kaplan-Meier method. The median PFS and 
OS estimates will be reported along with confidence intervals.
Progression free survival (PFS) time is calculated as the time that elapses between the initiation of 
trial therapy and the day of first documented disease progression or death from any cause 
(whichever is sooner) for all eligible subjects who receive at least one dose of trial therapy. If 
subsequent anti-cancer therapy is initiated without a preceding disease progression, PFS will be 
censored at the time of initiation of the subsequent anti-cancer therapy. If disease progression or 
death from any cause is not observed prior to completion of study participation or initiation of 
subsequent anti-cancer therapy, the PFS will be censored as the last available disease 
assessment.
Overall survival (OS) time is calculated as the time that elapses between the initiation of trial 
therapy and the date of death from any cause, date of completion of study participation, or date the 
subject is lost to follow up (whichever is sooner) for all eligible subjects who receive at least one 
dose of trial therapy. If death from any cause is not observed prior to completing study participation, 
the OS will be censored as the time of the last available documentation of survival status. 
10 STUDY MANAGEMENT
10.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the consent 
form and protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
10.2
Amendments
Amendments to the protocol will be initiated and maintained by the assigned Medical 
Writer. Requests for revisions may come from multiple sources, including but not limited 
to the Principal Investigator, study team, drug company, or FDA. All amendments will be 
subject to the review and approval of the appropriate local, institutional, and 
governmental regulatory bodies, as well as by Janssen Scientific Affairs. Amendments 
will be distributed by the lead institution (Northwestern) to all affiliate sites upon approval 
by the Northwestern University IRB.
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10.3
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations 
will be registered centrally through the Clinical Research Office at Northwestern 
University before enrollment to study. Please contact the assigned Quality Assurance 
Monitor (QAM) or email the QA Department (croqualityassurance@northwestern.edu) 
for questions regarding patient registration.  
For potential patients for this phase I study, study teams are asked to inform the QAM of 
the date and time that the patient will need to be registered 
(croqualityassurance@northwestern.edu).  
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original wet ink consent in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
The QAM will review all source documentation required to confirm eligibility that is 
readily available in the patient’s electronic medical record (EMR). Any information that is 
not available in the EMR must be de-identified and uploaded in source document section 
of NOTIS. Once the QAM confirms the patient is eligible, he or she will register the 
patient, assign a subject identification number, provide a cohort assignment, and send a 
confirmation of registration to involved personnel. Registration will then be complete and 
the patient may begin study treatment. 
10.4
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University The 
level of risk attributed to this study requires High Intensity Monitoring as outlined in the 
DSMP. The assigned QAM, with oversight from the Data Monitoring Committee, will 
monitor this study in accordance with the study phase and risk level. Please refer to the 
study-specific data submission guidelines.
10.5
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
10.5.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change. 
10.5.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that is under the investigator's control and that has 
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not been approved by the Institutional Review Board (IRB). Protocol deviations must be 
reported according to the policies and procedures of the IRB of record.
A protocol deviation may be considered an instance of Promptly Reportable 
Non-Compliance (PRNC) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has compromised the rights and welfare of the research subject

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
10.6
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators 
and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study 
completion.
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected, entered onto the appropriate eCRFs, and 
submitted within the study-specific timeframes. Periodically, monitoring visits may be 
conducted and the Principal Investigator will provide access to his/her original records to 
permit verification of proper entry of data. The study may also be subject to routine 
audits by the Audit Committee, as outlined in the DSMP. 
10.7
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study reaches 
its primary completion date, as defined by ClinicalTrials.gov. This is the date that the 
final patient was examined or received an intervention for the purposes of final collection 
of data for the primary outcome, whether the clinical trial concluded according to the pre-
specified protocol or was terminated. If the investigator would like data release to be 
approved by the DSMC prior to when study design specifies, and/or prior to three 
months after a study’s primary completion date, the PI must send a written request for 
data approval to the QAM which includes justification. Requests must be made a 
minimum of six to eight weeks in advance of the expected deadline. The request will be 
presented to the DSMC at their next available meeting. Any DSMC decisions regarding 
data release will be provided to the PI. If the request is approved, the QAM will present 
the data set to the DSMC for approval. A final, DSMC-approved dataset, as applicable, 
will then be released 6-8 weeks after the request was made. The investigators are 
expected to use only DSMC-approved data and statistical analyses any time they are 
disseminating trial data. The investigators must send a copy of the draft 
abstract/poster/manuscript to the study’s biostatistician and assigned QAM to confirm 
that the DSMC-approved data and statistical analyses are used appropriately. Once the 
biostatistician and QAM gives final approval, the publication may be submitted to 
external publisher.
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11 APPENDICES
11.1
Appendix A
Common Terminology Criteria for Adverse Events V 4.03 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
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11.2
Appendix B
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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Protocol Amendment 11 Version Date: November 6, 2020
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11.3
Appendix C 
Protocol History of Changes
Amendment 1 – April 12, 2016
Section(s) Affected
Prior Version
Amendment 1 Changes
Rationale
Cover page, Schema, Study 
Summary, 2.0 (Objectives 
and Endpoints), 3.0 (Patient 
eligibility), 3.1.1/3.1.2 
(Inclusion Criteria)
Included only BCG-refractory 
NMIBC patients
Now includes both BCG-
refractory and high risk NMIBC 
patients
FDA request
Cover page
Listed IND Number and Holder 
as TBD
Lists IND Number (130135) and 
IND Holder (Joshua Meeks, 
MD, PhD)
Administrative – new 
information available
List of Abbreviations
n/a
Adds “reTUR = Repeat 
transurethral resection”
Abbreviation included in 
new eligibility language 
(3.1.1)
Schema, Study Summary, 
2.3 (Exploratory Objectives 
& Endpoints), 
4.0 (Treatment Plan), 
5.0 (Study Procedures #9, 
15, 16), 
8.3 (Urinary cytokines and 
lymphocyte phenotypes)
Treatment with pembrolizumab 
during maintenance was to take 
place every 6 weeks with 
cystoscopies occurring every 12 
weeks starting at Week 17.
Maintenance treatment past 
Week 17 will now include 
pembrolizumab every 4 weeks 
(Week 17, 21, 25, 29, 33, 37, 
41, 45, and 49) and 
cystoscopies every 8 weeks. 
The last treatment and 
cystoscopy will occur at week 
49. Correlative urine samples 
will be collected at all new 
treatment time points. 
FDA requested an 
increase in 
cystoscopies to every 8 
weeks; the dosing 
schedule was also 
amended to align with 
this suggestion
Study Summary, 
4.2 (Treatment 
Administration), 
4.3 (Dose Escalation 
Scheme), 
7.1.5 (Protocol Dose), 9.0 
(Statistical Considerations)
Dose levels for pembrolizumab 
include 1mg/kg, 2mg/kg, and 
10mg/kg
Adds a fourth dose level: 
5mg/kg
FDA request for more 
robust safety analysis
Study Summary, 
3.0 (Patient Eligibility), 
9.0 (Statistical 
Considerations)
The sample size was up to 20 
subjects for 12-18 evaluable.
The sample size is increased to 
up to 27 subjects for up to 24 
evaluable.
Aligns with FDA 
suggestion of adding 
another dose level 
(5mg/kg) for 
pembrolizumab
1.0 (Introduction), 
References
n/a
Adds section 1.2.2 to provide 
non-clinical data (and 
corresponding references) on 
intravesical administration of 
pembrolizumab. 
FDA request
3.0 (Patient eligibility), 3.1.1 
(Inclusion Criteria)
Allowed patients with NMIBC 
categorized as Ta, Tis, or T1
Restricts population to patients 
with high risk tumors listed as:
“T1HG, T1HG after reTUR or 
BCG refractory; if patient has 
received BCG they can be Ta, 
Tis, or T1”
FDA request
3.0 (Patient eligibility), 3.1.2 
(Inclusion Criteria)
Lists BCG refractory as “having 
received at least one 6-week 
course of BCG induction plus 1 
maintenance dose, OR 2 full 6-
weeks courses of induction BCG 
treatment”
Changes definition of BCG 
refractory to:
“recurrence within 6 months of 
receiving at least 2 courses of 
intravesical BCG (at least 5 or 6 
inductions and at least 2 or 3 
maintenance doses) or T1 high 
grade disease at the first 
evaluation following induction 
FDA request
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BCG alone (at least 5 or 6 
induction doses).
3.1.4 (Inclusion Criteria)
n/a
Adds a note that patients who 
have received prior intravesical 
interferon are eligible
Clarification based on 
FDA request
3.1.6 (Inclusion Criteria)
Stated “Patients with T1, high-
grade Ta or multifocal Ta must 
have imaging (CT scan or MRI) 
documenting normal upper 
urinary tracts…”
Changes this to state that “All 
patients must have imaging…”
Clarification based on 
FDA request to align 
with requirements in the 
study table – all patients 
should have scans
4.1 (Treatment Overview), 
4.8 (Duration of Therapy), 
4.10 (Removal of Patients 
from Protocol Therapy)
n/a
Adds language that “Any patient 
who has a high-risk lesion 
resected on a follow-up 
cystoscopy must be removed 
from study treatment”
FDA request
4.3.1 (Definitions for Dose 
Escalation)
n/a
Adds the following DLTs:
-Grade 3 nausea, vomiting, and 
diarrhea lasting >72 hours in 
the absence of maximal medical 
therapy
-Grade 3 thrombocytopenia with 
hemorrhage
-Grade 2 AE’s lasting greater 
than 10 days
FDA request for more 
robust safety criteria
4.3.1 (Definitions for Dose 
Escalation), 
4.5.2 (Management of 
Specific AE’s)
n/a
Adds Hy’s law criteria, or drug-
induced liver injury, as criteria 
for permanent study 
discontinuation (“concurrent  
AST or ALT > 3x ULN and total 
bilirubin > 2x ULN”)
FDA request
4.5.3 (Managing Suspected 
Pneumonitis from 
pembrolizumab), 
4.5.4 (Supportive Care 
Guidelines for ECI’s and 
irAE’s)
Pembrolizumab could be held for 
a maximum of 12 weeks for 
Grade 2 pneumonitis 
Pembrolizumab can only be 
held for a maximum of 2 weeks
FDA request to align 
with prior language that 
drug can only be held 
for 2 weeks
5.0 (Study Procedures)
CBC and chemistry labs were 
only required at ___ 
CBC and chemistry labs will be 
done prior to each study 
treatment dose.
FDA request
Amendment 2 – November 30, 2016
Section(s) Affected
Prior Version
Amendment 2 Changes
Rationale
Title Page; 
Study Schema; 
Study Summary; 
1.0 (Introduction); 
2.0 (Objectives & 
Endpoints); 3.2.6 (Exclusion 
Criteria); 
4.0 (Treatment Plan); 5.0 
(Study Procedures); 6.3 
(SAE’s); 
7.1 (Pembrolizumab); 8.1 
(PK Studies); 8.3 (Urinary 
cytokines and lymphocyte 
phenotypes); 
Appendix C (Protocol 
History of Changes)
Study drug referred to as MK-
3475
Updates name of study drug to 
pembrolizumab
Administrative update to 
align with most current 
IB
Title Page
n/a
Adds Maha Hussain as sub-
investigator
Administrative update; 
new faculty
Study Schema; Study 
BCG dose listed as 81mg
BCG dose updated to 50mg
Correction of 
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Summary; 
4.2 (Treatment 
Administration);
4.2.1 (BCG); 4.3 (Dose 
Escalation Scheme); 5.0 
(Study Procedures #10); 
7.2.5 (Protocol Dose)
discrepancy; BCG was 
available as 81mg 
Connaught formulation 
when the protocol was 
originally written. 
Currently the only 
formulation available is 
50mg TICE® BCG
Study Schema; 
5.0 (Study Procedures #13); 
8.1 (PK Studies)
Urine PK and Research samples 
were to be collected within 30 
minutes prior to dosing
Removes 30-minute pre-dose 
window for urine PK and 
research samples
A 30-minute window for 
urination is too 
restrictive for patients. 
As long as the PK and 
research samples are 
collected prior to 
dosing, the exact timing 
does not matter.
Study Summary
Included short protocol title
Removes short protocol title
To align with current 
protocol template; short 
title not required
3.1.12 (Inclusion Criteria)
n/a
Adds: “Patients must be willing 
and able to comply with 
scheduled visits, treatment and 
assessments.”
Added to ensure 
patients enrolled are 
evaluable for data.
3.2.2, 3.2.3, 3.2.4, 3.2.5, 
3.2.10, 3.2.11, 3.2.15, 
3.2.16, 3.2.18 (Exclusion 
Criteria)
Language was not cohesive 
throughout eligibility (e.g. 
incomplete sentences, 
“subjects”, “within 4 weeks” v. “≤ 
28 days”)
Updates language to be 
consistent throughout eligibility 
(e.g. independent phrases, 
“patients”, “≤28 days”)
Updated for cohesion 
and clarity per internal 
QA preferences
4.0 (Treatment Plan); 5.0 
(Study Procedures)
n/a
Adds table numbers and titles to 
all tables
Administrative update
4.2.1 (BCG)
“A window of +/-2 days from the 
same day” is permitted for BCG 
treatment
BCG will be injected during 1 or 
2 minutes
Removes “from the same day” – 
“window of +/-2 days” is 
sufficient
BCG will be injected over 1 to 2 
minutes”
Grammatical updates
4.2.1 (BCG); 4.3 (Dose 
Escalation Scheme); 4.4 
(Dose Delays/ Modifications)
Dose modifications were not 
allowed for BCG
Dose reductions will now be 
permitted for BCG following 
standard of care procedures 
listed in section 4.4 – any 
toxicity that requires a delay 
(Grade 2 local toxicity) may also 
merit a dose reduction to half 
the dose within two weeks of 
the last administration.
BCG dose reductions 
are part of standard of 
care, so it is clinically 
appropriate to allow for 
such dose reductions 
during induction 
treatment
4.4 (Dose Delays/ 
Modifications)
“If toxicity does not resolve to 
Grade 0-1 within 2 weeks (14 
days) after last administration, 
trial treatment should be 
discontinued after consultation 
with the PI and DMC”
“If toxicity does not resolve to 
Grade 0-1 within 2 weeks (14 
days) after scheduled dose, 
trial treatment should be 
discontinued after consultation 
with the PI and DMC”
Since language is 
referring to BCG and 
pembrolizumab, 
5.0 (Study Procedures)
Footnote numbers were not 
listed in ascending order in the 
table.
#1: Included respiratory rate as 
a vital sign
#6,7: CBC and Chem were to 
be completed pre-dose on the 
day of dosing
Footnotes were re-numbered 
to align with the order of study 
procedures listed in the table.
#1: Removes respiratory rate 
from required vital signs
#6,7: CBC and Chem labs will 
be permitted within 48 hours 
of dosing
Simplification
#1: Respiratory rate is 
not clinically relevant 
and not part of 
standard clinic 
procedures
#6,7: Pharmacy 
requested window to 
allow more time for 
preparation of BCG 
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when feasible
6.0 (Adverse Events)
Contained web address for NU 
DSMP
Removes web address and 
links the DSMP location as a 
hyperlink
To avoid the need for a 
full amendment if the 
web address is changed
7.1.4 (Storage and Stability); 
7.1.6 (Preparation)
Contained inaccurate language 
about the formulation of 
pembrolizumab –“powder for 
solution for infusion (100mg/4mL 
vial)”
Updates language to account 
for both powder and solution 
formulations - “Pembrolizumab 
is provided as a white to off-
white lyophilized powder (50 
mg/vial) or as a liquid solution 
(100 mg/vial) in Type I glass 
vials intended for single use 
only.”
Inaccurate language 
corrected per pharmacy 
request 
7.2.5 (Protocol Dose)
n/a
Adds “Refer to package insert 
for detailed reconstitution and 
preparation procedures”
Added per pharmacy 
request since the BCG 
formulation is standard 
of care
8.5 (Specimen Banking)
Listed Meeks lab being located in 
Lurie 5th floor
Removes Lurie 5th floor location 
and replaces with “see separate 
lab manual for location details”
The location of the 
Meeks lab has changed 
– to avoid unnecessary 
protocol amendments, it 
is easier to refer to the 
lab manual
Appendix C (Protocol 
History of Changes)
Contained two separate “History 
of Changes” tables
Removes incomplete “History of 
Changes” table and compiles 
into Appendix C
Duplicate table included 
by mistake
Amendment 3 – April 24, 2017
Section(s) Affected
Prior Version
Amendment 3 Changes
Rationale
Cover Page
Timothy Kuzel, MD listed as Sub-
I
Removed Dr. Kuzel.
No longer at institution
Section 3.1.1 (Inclusion 
Criteria)
N/a
Added: Note: Gross disease is 
not allowed, however positive 
urine cytology and carcinoma in 
situ is permitted.
Further clarification of 
patient eligibility 
Section 3.1.3 (Inclusion 
Criteria); Section 5.0 (Study 
Procedures); Section 8.2.1 
(Tissue Procurement); Study 
Schema
Mandatory tumor tissue sample 
required for enrollment 
Removed criteria
Tissue no longer a 
requirement.  Time to 
acquire tissue delayed 
treatment.
Section 3.1.5 (Inclusion 
Criteria)
n/a
Clarified population needing 
imaging as part of inclusion 
criteria.  Added “positive for 
invasion”
Per PI, only patients 
who are positive for 
invasion must have 
imaging prior to 
registering for study.
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Section 3.1.6 (Inclusion 
Criteria)
Eligible patients have an ECOG 
performance status of 0-2
Eligible patients have an ECOG 
performance status of 0-1
Per Sponsor request, 
eligible patients must 
have an ECOG 
performance status of 
0-1.
Section 3.1.7 (Inclusion 
Criteria)
Hemoglobin requirement ≥9 g/dL 
or ≥5.6 mmol/L
Hemoglobin requirement ≥7 
g/dL or ≥5.6 mmol/L
Per PI, updated 
hemoglobin requirement 
to expand patient pool.
Section 3.2.11 (Exclusion 
Criteria)
“Patients who received a live, 
attenuated vaccine ≥ 28 days 
before study registration…”
“Patients who received a live, 
attenuated vaccine ≤ 28 days 
before study registration…”
Prior version mistakenly 
read “≥ 28 days” when it 
should be “≤ 28 days”
Section 3.2.16 (Exclusion 
Criteria)
“Patients with active autoimmune 
disease requiring systemic 
treatment within the past 2 
years…”
“Patients with active 
autoimmune disease requiring 
ongoing systemic treatment.
Washout period of 14 days 
required for eligibility.”
Per PI, reduced 
limitations of 
autoimmune systemic 
treatment to expand 
patient pool.
Section 3.2.17 (Exclusion 
Criteria)
Criteria restricting eligibility of 
patients with a documented 
history of severe autoimmune 
disease or a syndrome that 
requires systemic steroids or 
immunosuppressive agents.
Removed criteria
Per PI, only patients 
who require current 
system treatment are 
ineligible.
Section 3.2.20 (Exclusion 
Criteria)
Restricting patients who have 
had a prior malignancy within 5 
years
Restricting patients who have 
had a prior malignancy within 
12 months
This change was made 
to expand the eligible 
patient population.
Section 4.5.4 (Supportive 
Care Guidelines – 
Pembrolizumab)
n/a
Adds pembrolizumab dose 
delay guidelines for cardiac 
dysfunction (related to 
myocarditis), Stevens-Johnson 
Syndrome, and Toxic Epidermal 
Necrolysis
Additional guidelines 
provided by Merck as a 
result of new safety 
events
Amendment 4 – July 10, 2017
Section(s) Affected
Prior Version
Amendment 4 Changes
Rationale
Section 3.1.2 (Inclusion 
Criteria)
n/a
Included additional criteria: 
“Recurrence after treatment 
with at least 3 doses of a BCG 
refractory agent (for example, 
though not limited to, 
gemcitabine, docetaxel, 
valrubicin and an interferon 
adenovirus).”
Additional criteria was 
included to expand the 
eligible patient 
population.
Section 5 (Study 
Procedures)
n/a
Footnote #5:” Only required for 
patients who are positive for 
invasion…”
Added clarification to 
footnote #5.  Specifying 
imaging for patients 
who are positive for 
invasion was included in 
the previous 
amendment and should 
have also amended this 
footnote.
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Amendment 5 – October 4, 2017
Section(s) Affected
Prior Version
Amendment 5 Changes
Rationale
Title Page
Included Benedito Carneiro as 
sub-investigator.
Removes Benedito Carneiro as 
sub-investigator
Administrative; Dr. 
Carneiro is no longer at 
the institution
Schema Calendar
Included cystoscopy at Week 9 
of the study
Removes cystoscopy at Week 9
Revised for 
consistency; all other 
sections of the protocol 
reference cystoscopy 
starting at Week 17
3.1.2 (Inclusion Criteria)
Patients must have persistent 
high grade disease OR be BCG 
refractory, defined as:

recurrence within 6 months of 
receiving at least 2 courses of 
intravesical BCG (at least 5 or 
6 inductions and at least 2 or 
3 maintenance doses)

T1 high grade disease at the 
first evaluation following 
induction BCG alone (at least 
5 of 6 induction doses); or

Recurrence after treatment 
with at least 3 doses of a 
BCG refractory agent (for 
example, though not limited 
to, gemcitabine, docetaxel, 
valrubicin or an interferon 
adenovirus).
Patients must be BCG-
unresponsive. A patient is BCG-
unresponsive if they meet one 
or more of the following criteria:

Patient has persistent or 
recurrent high-grade Ta/CIS/ 
urothelial carcinoma after 
completing therapy with at 
least induction BCG (≥5 
doses) and first round 
maintenance or second 
induction BCG (≥2 doses). 
Patient has high grade T1 
urothelial carcinoma after 
induction BCG (≥5 doses) 
only or after induction BCG 
(≥5 doses) and first round 
maintenance or second 
induction BCG (≥2 doses).

Patient is disease-free at 
completion of BCG (i.e., 
complete response) but then 
experiences a high-grade 
recurrence before or at the 6 
month follow-up cystoscopy.

Recurrence after treatment 
with at least 3 doses of a 
BCG refractory agent (for 
example, though not limited 
to, gemcitabine, docetaxel, 
valrubicin or an interferon 
adenovirus).
Clarification in the study 
population that was 
intended for the trial. 
3.2.20 (Exclusion Criteria)
n/a
Adds note: “If another 
malignancy is incidentally found 
during study eligibility work up 
and does not require treatment 
the patient will be eligible. This 
should be clearly documented 
in the medical record at the time 
of study registration.”
Clarification 
4.4 (Dose Delays / 
Modifications)
Treatment delays were to take 
place for toxicities occurring 
during induction or maintenance 
phases.
Treatment may be delayed at the 
Adds that treatment can be 
delayed for toxicities occurring 
during pre-induction.
Treatment may be delayed at 
the discretion of the treating 
Clarification 
Clarification; treating 
physician should have 
authority, under 
direction of the protocol, 
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discretion of the PI.
n/a
physician.
Moves language about 
continuing treatment for 
asymptomatic Grade 2 lab AE’s 
to a more relevant paragraph 
that addresses lab 
abnormalities.
to make treatment 
decisions.
Clarification
4.4 (Dose Delays / 
Modification); 6.7 (Reporting 
Requirements for Adverse 
Events);
Data Monitoring Committee 
(DMC)
Data and Safety Monitoring 
Committee (DSMC)
Administrative
5.0 (Study Procedures)
n/a
Adds CBC and Chemistry labs 
to the Pre-Induction visit
Correction of 
discrepancy. Labs 
should be obtained at 
every visit where 
pembrolizumab is given
8.2.1 (Tissue Procurement); 
8.3 (Urinary cytokines and 
lymphocyte phenotypes)
Includes specific details on tissue 
sample size, processing and 
shipping.
Deletes specific details on 
processing and shipping 
correlative samples.
Specific details should 
be reserved for the 
study lab manual. 
Excluding such details 
from the protocol allows 
for easier changes to 
processes, avoiding 
protocol deviations.
Amendment 6 – November 1, 2017
Section(s) Affected
Prior Version
Amendment 6 Changes
Rationale
7.2.5 (Preparation)
Specified that a catheter-tip 
syringe was to be used to 
dispense BCG. 
Removes specification of 
syringe type and instead 
references, “per institutional 
guidelines’
Revised for safety 
concerns; previously 
specified catheter-tip 
syringe has the 
potential to leak, leading 
to possible under-
dosing and accidental 
exposure to the patient 
and site staff. 
Section 4.5.1 (Immune-
related Adverse Events); 
Section 4.5.2 (Management 
of Specific Adverse Events)
Dose modifications for 
pembrolizumab immune-related 
adverse events
Included updated table for 
pembrolizumab immune-related 
adverse events.
New pembrolizumab 
dose modification table 
provided by Merck.
Amendment 7 – January 22, 2019
Section(s) Affected
Prior Version
Amendment 7 Changes
Rationale
Cover Page
Incorrect contact information for 
coordinating center
Updated contact information for 
coordinating center
Administrative update
Study Schema; Study 
Summary; Section 1.3.2 
(Rationale for Dose 
Selection); Section 4.1 
(Overview); Section 4.2 
Maintenance only included 
treatment with pembrolizumab.
Treatment with intravesical 
BCG will continue into 
maintenance
There is growing 
acceptance of 
maintenance BCG since 
initiating this study and 
this would be in the best 
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NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
64
(Treatment Administration); 
Section 4.2.1 (BCG); 
Section 5 (Study 
Procedures)
interest of the patients.
Section 5 (Study 
Procedures)
n/a
Added footnote 5: “Treatment of 
patients who undergo biopsy for 
pathogenic response at weeks 
17, 25, 33, 41, and 49 may be 
held for the outcome at 
discretion of the treating 
surgeon.”
Clarification on whether 
treatment will be held 
for result of biopsy.
Section 5 (Study 
Procedures); Section 8.2.1 
(Tissue Procurement)
“If additional biopsies are 
performed during scheduled 
cystoscopies throughout the 
study, an additional 10 unstained 
slides from each will also be 
obtained for IHC studies”
“ If additional biopsies are 
performed during scheduled 
cystoscopies throughout the 
study, an additional 10 
unstained slides from each will 
also be obtained for IHC studies 
only if the sample contains 
tumor tissue”
To clarify that only 
biopsies containing 
tumor tissue will be 
obtained for imaging. 
Section 8 
(Correlatives/Special 
Studies)
n/a
Updated contact information for 
NU Pathology Core Facility
Administrative update
Amendment 8 – July 12, 2019
Section(s) Affected
Prior Version
Amendment 8 Changes
Rationale
Cover page
Alfred Rademaker listed as 
statistician for study
Denise Scholtens listed as 
statistician for study
Administrative update.  
Dr. Rademaker has 
retired from NU.
Study Schema; Section 5 
(Study Procedures); Section 
8.3 (Urinary cytokines and 
lymphocyte phenotypes)
Mandatory urine collection 
during the 3rd void (4-6 hours 
post treatment)
Optional urine collection during 
the 3rd void (4-6 hours post 
treatment)
Having patients remain 
in clinic for the 3rd void 
has been burdensome 
and will be easier on the 
patients if it is not 
mandatory.
Study Summary; Section 
2.3.6 (Exploratory 
Objectives); Section 5 
(Study Procedures); Section 
8.5 (NGS)
n/a
Include targeted whole exome 
sequencing of DNA and RNA-
seq from the tumors pre and 
post-treatment.
Include additional 
correlatives to explore 
the changes in genetic 
data
Section 5 (Study 
Procedure); Section 8.2.1 
(Tissue Procurement) 
10 FFPE slides collected for 
tissue IHC studies.
5 FFPE slides collected for 
tissue IHC studies.
IHC analysis is being 
done by QualTek and 
they require only 5 
slides.
Amendment 9 – November 22, 2019
Section(s) Affected
Prior Version
Amendment 9 Changes
Rationale
Cover Page and Throughout
Version date: July 12, 2019 
(Version 8)
Updates version date to: 
November 14, 2019 (Version 9)
Administrative update
IRB #: STU00202754-CR0006 Approved by NU IRB for use on or after 1/26/2022 through 1/23/2023.

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
65
Cover Page
Listed Denise Scholtens as the 
Biostatistician
Updates Biostatistician to 
Masha Kocherginsky
Administrative update to 
account for staffing 
change
Section 4.6.2 (Prohibited 
Concomitant Medications)
Prohibited medications include:
Immunotherapy not specified in 
this protocol
Prohibited medications include:
Anti-cancer immunotherapy 
not specified in this protocol
Modification made per 
the request of DSMC to 
clarify that 
immunotherapies are 
permitted for non-
cancerous conditions. 
For example: Antibody- 
based therapy of 
supplemental IgG would 
be permitted for the 
routine maintenance of 
a controlled IgG 
subclass deficiency.
Section 4.6 (UPIRSOs)
Previously stated:
A UPIRSO is a type of SAE that 
includes events that meet ALL of 
the following criteria:
• Is unanticipated in terms of 
nature, severity, or frequency
• Places the research subject or 
others at a different or greater 
risk of harm
• Is deemed to be at least 
possibly related to participation in 
the study.    
Now states:
A UPIRSO is a type of SAE that 
includes events that meet ALL 
of the following criteria:
•is unexpected (in terms of 
nature, severity, or frequency) 
given the procedures described 
in the research protocol 
documents (e.g., the IRB-
approved research protocol and 
informed consent document) 
and the characteristics of the 
human subject population being 
studied
•is related or possibly related to 
participation in the research 
("possibly related" means there 
is a reasonable possibility that 
the incident, experience, or 
outcome may have been 
caused by the procedures 
involved in the research); and 
•suggests that the research 
places human subjects or 
others at a greater risk of harm 
(including physical, 
psychological, economic, or 
social harm) than was 
previously known or recognized, 
even if no harm has actually 
occurred.
Updates the definition of 
UPIRSO.  This is an 
administrative change 
to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 6.7.2 (Expedited 
Reporting to the NU 
QA/DSMC)
N/A
Now requires completed SAE 
forms to include country of 
incidence
Updates the 
requirements for SAE 
forms. This is an 
administrative change 
to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 6.7.2 (Expedited 
Reporting to the NU 
QA/DSMC)
All SAEs will be reported to, and 
reviewed by, the DSMC at their 
next meeting.
All SAEs will be reported to, and 
reviewed by, the DSMC per the 
DSMP.
Updates standard 
language regarding 
reviewing SAEs by the 
DSMC. This is an 
administrative change 
IRB #: STU00202754-CR0006 Approved by NU IRB for use on or after 1/26/2022 through 1/23/2023.

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
66
to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 6.7.3 (Expedited 
Reporting to the 
Northwestern IRB)
•Any death of an NU subject that 
is unanticipated in nature and at 
least possibly related to study 
participation will be promptly 
reported to the NU IRB within 24 
hours of notification. 
•Any death of an NU subject that 
is actively on study treatment 
(regardless of whether or not the 
event is possibly related to study 
treatment)
•Any death of a non-NU subject 
that is unanticipated and at least 
possibly related and any other 
UPIRSOs will be reported to the 
NU IRB within 5 working days of 
notification.
•All other deaths of NU subjects 
not previously reported, other 
non-NU subject deaths that were 
unanticipated and unrelated, and 
any other SAEs that were not 
previously reported as UPIRSOs 
will be reported to the NU IRB at 
the time of annual continuing 
review.
•Any death of an NU subject 
that is unanticipated in nature 
and at least possibly related to 
study participation will be 
promptly reported to the NU IRB 
within 24 hours of notification. 
•Any death of a non-NU subject 
that is unanticipated and at 
least possibly related and any 
other UPIRSOs will be reported 
to Northwestern University and 
to the NU IRB within 5 working 
days of notification.
•Information pertaining to an NU 
subject that fits into any of the 
categories listed on the 
Reportable New Information 
page will be reported to the NU 
IRB within 5 business days of 
knowledge or notification
Updates standard 
language regarding the 
reporting of SAEs to the 
NU IRB. This is an 
administrative change 
to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 10.2 (Amendments)
The Principal Investigator will 
formally initiate all amendments 
to the protocol and/or informed 
consent.
Amendments to the protocol will 
be initiated and maintained by 
the assigned Medical Writer. 
Requests for revisions may 
come from multiple sources, 
including but not limited to the 
Principal Investigator, study 
team, drug company, or FDA.
Updates standard 
language regarding 
protocol amendments. 
This is an administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 10.5.2 (Other 
Protocol Deviations)
A protocol deviation is any 
unplanned variance from an IRB 
approved protocol that: 
•Is generally noted or recognized 
after it occurs.
•Has no substantive effect on the 
risks to research participants.
•Has no substantive effect on the 
scientific integrity of the research 
plan or the value of the data 
collected.
•Did not result from willful or 
knowing misconduct on the part 
of the investigator(s).
A protocol deviation is any 
change, divergence, or 
departure from the study design 
or procedures of a research 
protocol that is under the 
investigator's control and that 
has not been approved by the 
Institutional Review Board 
(IRB). Protocol deviations must 
be reported according to the 
policies and procedures of the 
IRB of record.
Updates standard 
language regarding 
protocol deviations. This 
is an administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
Section 10.5.2 (Other 
Protocol Deviations)
N/A
Adds the following language to 
the definition of promptly 
reportable non-compliance: 
Has compromised the rights 
and welfare of the research 
subject
Updates the definition of 
promptly reportable 
non-compliance. This is 
an administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
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NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
67
language.
Section 10.7 (Publication 
Policy)
All potential publications and/or 
data for potential publications 
(e.g. manuscripts, abstracts, 
posters, clinicaltrials.gov 
releases) must be approved in 
accordance with the policies and 
processes set forth in the Lurie 
Cancer Center DSMP. For trials 
that require high intensity 
monitoring, the assigned QAM 
will prepare a preliminary data 
summary (to be approved by the 
DSMC) no later than 3 months 
after the study reaches its 
primary completion date (the 
date that the final subject is 
examined or receives an 
intervention for the purposes of 
final data collection for the 
primary endpoint). If the 
investigator’s wish to obtain 
DSMC-approved data prior to 
this point (or prior to the point 
dictated by study design), the PI 
must send a written request for 
data to the QAM which includes 
justification. If the request is 
approved, data will be provided 
no later than 4 weeks after this 
request approval. The data will 
be presented to the DSMC at 
their next available meeting, and 
a final, DSMC-approved dataset 
will be released along with any 
DSMC decisions regarding 
publication. The investigators are 
expected to use only DSMC-
approved data in future 
publications. The investigators 
should submit a copy of the 
manuscript to the biostatistician 
to confirm that the DSMC-
approved data are used 
appropriately.  Once the 
biostatistician gives final 
approval, the manuscript may be 
submitted to external publishers.
All potential publications and/or 
data for potential publications 
(e.g. manuscripts, abstracts, 
posters, clinicaltrials.gov 
releases) must be approved in 
accordance with the DSMC 
Data Release Policies and 
Processes. The assigned QAM 
will prepare a preliminary data 
set for DSMC approval no later 
than 3 months after the study 
reaches its primary completion 
date, as defined by 
ClinicalTrials.gov. This is the 
date that the final patient was 
examined or received an 
intervention for the purposes of 
final collection of data for the 
primary outcome, whether the 
clinical trial concluded 
according to the pre-specified 
protocol or was terminated. If 
the investigator would like data 
release to be approved by the 
DSMC prior to when study 
design specifies, and/or prior to 
three months after a study’s 
primary completion date, the PI 
must send a written request for 
data approval to the QAM which 
includes justification. Requests 
must be made a minimum of six 
to eight weeks in advance of the 
expected deadline. The request 
will be presented to the DSMC 
at their next available meeting. 
Any DSMC decisions regarding 
data release will be provided to 
the PI. If the request is 
approved, the QAM will present 
the data set to the DSMC for 
approval. A final, DSMC-
approved dataset, as 
applicable, will then be released 
6-8 weeks after the request was 
made. The investigators are 
expected to use only DSMC-
approved data and statistical 
analyses any time they are 
disseminating trial data. The 
investigators must send a copy 
of the draft 
abstract/poster/manuscript to 
the study’s biostatistician and 
assigned QAM to confirm that 
the DSMC-approved data and 
statistical analyses are used 
appropriately. Once the 
Updates standard 
language regarding the 
publication policy. This 
is an administrative 
change to align with 
Northwestern 
University’s new 
protocol template 
language.
IRB #: STU00202754-CR0006 Approved by NU IRB for use on or after 1/26/2022 through 1/23/2023.

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
68
biostatistician and QAM gives 
final approval, the publication 
may be submitted to external 
publisher.
Throughout
N/A
Minor corrections to 
typographical errors, style, and 
formatting
Administrative update
Amendment 10 – June 16, 2020
Section(s) Affected
Prior Version
Amendment 10 Changes
Rationale
Cover Page and Throughout
Protocol date/version: 
November 14, 2019 (Version 9)
Updates date/version to: 
June 16, 2020 (Version 10)
Administrative update
Table of Contents
N/A
Updates page numbers.
Administrative update
Study Summary
Exploratory Objective:
• To document the duration of 
remission associated with the 
combination of intravesical 
pembrolizumab and BCG in 
subjects with high risk or BCG-
refractory non-muscle-invasive 
bladder cancer.
Deletes strikethrough text and 
adds bolded text:
Exploratory Objective:
• To document the duration of 
remission progression rate 
associated with the combination 
of intravesical pembrolizumab 
and BCG in subjects with high 
risk or BCG-refractory non-
muscle-invasive bladder cancer.
Corrects typographical 
error to align with what 
is stated in Exploratory 
Objective 2.3.4.
Exploratory Objectives and 
Endpoints (Section 2.3)
The exploratory objective of 
specimen banking was listed in 
the Study Summary but  was not 
listed in the Exploratory 
Objectives and Endpoints 
Section 
Adds specimen banking to the 
Exploratory Objectives and 
Endpoints Section to align with 
the Study Summary.
Administrative update. 
Corrects error. 
Schema;
Study Summary;
Exploratory Objectives and 
Endpoints (Section 2.3);
Follow-Up Visits (Section 
4.9.2);
N/A
Adds new exploratory objective 
of overall survival:
To document the overall 
survival rate associated with 
the combination of 
intravesical pembrolizumab 
and BCG in patients with high 
Adds exploratory 
endpoint of overall 
survival. 
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NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
69
Study Procedures Table 
(Section 5.0);
Statistical Considerations 
(Section 9.0)
risk or BCG-refractory non-
muscle-invasive bladder 
cancer. Overall survival will 
capture all-cause death.
The following sections have 
been updated:
Study Summary and Objectives 
(Section 2.3):
Amended to list the new 
exploratory objective.
Schema, Follow-Up Visits 
(Section 4.9.2), and Study 
Procedures Table (Section 5.0):
Amended to allow for post-
progression follow-up to 
collect survival data.
Statistical Considerations 
(Section 9.0):
Amended to include a 
statistical analysis plan for 
overall survival, which will be 
estimated using the Kaplan-
Meier method and will report 
confidence intervals.
Study Summary;
Exploratory Objectives and 
Endpoints (Section 2.3);
Statistical Considerations 
(Section 9.0)
N/A
Adds new exploratory objective 
of progression free survival:
To document the progression 
free survival rate associated 
with the combination of 
intravesical pembrolizumab 
and BCG in patients with high 
risk or BCG-refractory non-
muscle-invasive bladder 
cancer. Progression free 
survival will capture disease 
progression and all-cause 
death.
The following sections have 
been updated:
Study Summary and Objectives 
(Section 2.3):
Amended to list the new 
exploratory objective.
Statistical Considerations 
(Section 9.0):
Amended to include a 
statistical analysis plan for 
progression free survival, 
which will be estimated 
using the Kaplan-Meier 
method and will report 
confidence intervals.
Adds exploratory 
endpoint of overall 
survival. 
IRB #: STU00202754-CR0006 Approved by NU IRB for use on or after 1/26/2022 through 1/23/2023.

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
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Study Summary;
Exploratory Objectives and 
Endpoints (Section 2.3);
Statistical Considerations 
(Section 9.0)
N/A
Adds new exploratory objective 
to investigate immune markers:
To investigate immune 
markers associated with the 
combination of intravesical 
pembrolizumab and BCG in 
patients with high risk or 
BCG-refractory non-muscle-
invasive bladder cancer. 
Immune marker data that are 
assessed as standard of care 
at any time during trial 
participation will be analyzed 
and correlated with trial 
therapy and response.
The following sections have 
been updated:
Study Summary and Objectives 
(Section 2.3):
Amended to list the new 
exploratory objective.
Statistical Considerations 
(Section 9.0):
Amended to include a 
statistical analysis plan for 
the new exploratory 
objective, which will include 
descriptive statistics.
Adds exploratory 
endpoint to investigate 
immune markers 
collected as standard of 
care. 
Follow-Up Visits (Section 
4.9.2);
Study Procedures Table 
(Section 5.0)
N/A
Adds windows for clinical follow-
up time points.
Administrative update. 
Adds windows for 
clinical follow-up time 
points for flexibility and 
ease of scheduling.
Appendix C (Protocol 
History of Changes)
N/A
Updates protocol history of 
changes to include revisions 
incorporated in protocol 
amendment 10.
Administrative update.
Amendment 11 – November 6, 2020
Section(s) Affected
Prior Version
Amendment 11 Changes
Rationale
Cover Page and Throughout
Protocol date/version: 
June 16, 2020 (Version 10)
Updates date/version to: 
November 6, 2020 (Version 11)
Administrative update
Table of Contents
N/A
Updates page numbers.
Administrative update
IRB #: STU00202754-CR0006 Approved by NU IRB for use on or after 1/26/2022 through 1/23/2023.

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
71
Section 2.3 (Exploratory 
Objectives & Endpoints)
To characterize the 
pharmacokinetics (PK) of 
pembrolizumab in both blood and 
urine when administered 
intravesically in combination with 
BCG. This will be done on the 
first 3 patients only to provide 
exploratory data. PK will be 
evaluated by serial blood and 
urine sampling at specified time 
points before and after treatment 
(described in Section 5) during 
weeks -2 and 4 for determination 
of plasma and urine 
concentration-time profiles and 
PK parameters of 
pembrolizumab. Blood PKs will 
be performed by an outside 
vendor contracted with Merck; 
urine will be collected and stored 
in the Meeks Lab for later 
analysis.
Addition of bolded text; deletion 
of strikethrough text.
To characterize the 
pharmacokinetics (PK) of 
pembrolizumab in both blood 
and urine when administered 
intravesically in combination 
with BCG. This will be done on 
the first 3 patients only to 
provide exploratory data. (A 
limited amount of plasma PK 
testing may be performed on 
additional patients as 
described below.*) PK will be 
evaluated by serial blood and 
urine sampling at specified time 
points before and after 
treatment (described in Section 
5) during weeks -2 and 4 for 
determination of plasma and 
urine concentration-time profiles 
and PK parameters of 
pembrolizumab. Blood PKs will 
be performed by an outside 
vendor contracted with Merck; 
urine will be collected and 
stored in the Meeks Lab for 
later analysis.
*A portion of the blood 
specimens that have been 
collected for cytokine 
analysis (time-points week -2, 
week 0, and week 17) may be 
used in plasma PK assays, 
per Principal Investigator 
discretion.
Second page of Study 
Schema;
Study Summary
Section 5.0 (Study 
Procedures)
Section 8.0 
(Correlative/Special Studies)
N/A
Revised to align with the above-
described revision in Section 
2.3
Expands the PK 
analysis to additional 
patients.
Only samples that were 
previously collected will 
be used for the 
expanded PK analysis. 
No new samples will be 
collected. 
Removes reference to 
contracting process, as 
Merck will not manage 
the expanded PK 
analysis.  
Throughout
N/A
Stylistic and formatting revisions 
to accommodate the inclusion 
of other revisions.
Administrative update
Appendix C (Protocol 
History of Changes)
N/A
Updates protocol history of 
changes to include revisions 
incorporated in protocol 
amendment 11.
Administrative update.
IRB #: STU00202754-CR0006 Approved by NU IRB for use on or after 1/26/2022 through 1/23/2023.

NU Study Number: NU 15U06
Merck Study Number: 3475-265
Protocol Amendment 11 Version Date: November 6, 2020
72
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Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder 
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Powles T, Vogelzang NJ, Fine DG, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity 
in pts with metastatic urothelial bladder cancer (UBC). Journal of Clinical Oncology 2014;32:abstr 5011.
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Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the 
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Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, 
lung and kidney cancer. Nature reviews Clinical oncology 2014;11:24-37.
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Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients 
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Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. 
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