Clinical trial NCT02365766
Conditions: Urothelial Carcinoma Bladder Cancer
Keywords: MK-3475 Gemcitabine Cisplatin Pembrolizumab Neoadjuvant Bladder Cancer
Sponsor: Jason R. Brown
Start date: 2015-05-27; Completion date: 2024-02-23
Enrollment: 83 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a pre-surgical study involving subjects with muscle invasive bladder cancer, or urothelial cancer, who are candidates for neoadjuvant therapy. It is is a two-part trial with a one-arm phase Ib portion followed by a two-arm phase II portion. The study treatment is stratified into two cohorts based on cisplatin eligibility.

Detailed description:
OUTLINE: This is a multi-center study.

INVESTIGATIONAL TREATMENT:

Phase Ib Dose-Finding Cohort I Cisplatin-Eligible:

Phase Ib is a 3+3 design for the cisplatin-eligible group only. Cisplatin-eligible subjects receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days repeated for 4 cycles; cisplatin 70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days). Pembrolizumab will be given every 3 weeks for 5 doses, with a starting dose of 200 mg. NOTE: the last dose of pembrolizumab falls on what would be D8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN.

Phase II Arm A: Cohort I Cisplatin-Eligible:

Cisplatin-eligible subjects receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days repeated for 4 cycles; cisplatin 70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days). Pembrolizumab at recommended phase II dose (RP2D) is given every 3 weeks for 5 doses starting with C1D8. NOTE: the last dose of pembrolizumab falls on what would be day 8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN. Cohort I treatment with gemcitabine and cisplatin will continue for a maximum of 4 cycles (cycle = 21days).

Phase II Arm B: Cohort II:

Cisplatin-ineligible subjects receive gemcitabine 1000mg/m2 IV D1, D8 and D15 every 28 days, repeated for 3 cycles. Pembrolizumab at RP2D is given every 3 weeks for 5 doses starting with C1D8. NOTE: due to the timing of gemcitabine cycles every 4 weeks, and every three week dosing of pembrolizumab, there are two doses of pembrolizumab given during cycle 2: D1 and D22. Additionally, the last dose of pembrolizumab falls on what would be D8 of a 4th 'chemo' cycle; however gemcitabine is NOT GIVEN. Cohort II treatment with gemcitabine will continue for a maximum of 3 cycles (cycle = 28 days)

Subjects will then have surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy.

Eastern Cooperative Oncology Group (ECOC) performance status: 0-1 for cisplatin-eligible subjects; 0-2 for cisplatin-ineligible subjects.

Demonstrate adequate organ function as defined by the following laboratory values at study entry. All screening labs should be performed within 28 days of C1D1.

Hematopoetic:

* Absolute neutrophil count (ANC) ≥1,500 /mcL
* Absolute lymphocyte count ≥350 mcL
* Platelets ≥100,000 / mcL
* Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

Renal:

* Measured or calculated creatinine clearance ≥30 mL/min

Hepatic:

* Serum total bilirubin ≤ 1.25 X ULN OR ≤ 2.5 x ULN for subjects with Gilbert's disease
* Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 2 X ULN

Coagulation:

* International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy and as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Arms: arm 1: Cisplatin-eligible subjects will receive pembrolizumab at starting dose of 200mg (dose level 0), and/or 120mg (dose level -1) in combination with gemcitabine and cisplatin. The MTD will be the highest pembrolizumab dose level in combination with gemcitabine/cisplatin every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days). Once the MTD is established, this portion of the study will close and the phase II will open to cohorts I and II at the recommended phase II dose (RP2D). arm 2: Cisplatin-eligible subjects receive gemcitabine/cisplatin every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days) . Pembrolizumab at RP2D is given every 21 days for 5 doses starting C1D8. Note: the last dose of pembrolizumab falls on what would be day 8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN. Subjects will then have consolidative surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy. arm 3: Cisplatin-ineligible subjects receive gemcitabine every week every 28 days for 3 cycles. Pembrolizumab at RP2D is given every 21 days for 5 doses starting C1D8. NOTE: due to the timing of gemcitabine cycles every 4 weeks, and every 3-week dosing of pembrolizumab, there are two doses of pembrolizumab given during cycle 2: D1 and D22. Additionally, the last dose of pembrolizumab falls on what would be D8 of a 4th 'chemo' cycle; however gemcitabine is NOT GIVEN. Subjects will then have consolidative surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy.
Interventions: intervention 1: Pembrolizumab intervention 2: Gemcitabine intervention 3: Cisplatin intervention 4: Consolidative Surgery
Intervention descriptions: intervention 1: In this dose-finding cohort, pembrolizumab (MK-3475) will be administered (cisplatin-eligible patients only) at starting dose 200mg IV every 21 days for 4 cycles to determine RP2D. Once MTD is established in phase Ib, pembrolizumab will be administered on phase II cohorts I and II at RP2D every 21 days for 5 cycles. intervention 2: For cisplatin-eligible patients on phase Ib and phase II cohort 1, gemcitabine 1000mg/m2 IV, D1 and D8 every 21 days for 4 cycles. For cisplatin-ineligible patients on phase II cohort II, gemcitabine 1000mg/m2 will be administered D1, D8 and D15 every 28 days for 3 cycles. intervention 3: For cisplatin-eligible patients, cisplatin 70mg/m2 IV will be administered D1 every 21 days for 4 cycles. intervention 4: Following completion of treatment, subjects will then have surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy.

Protocol documents:
Prot_SAP_000.pdf: 
GU14-188 
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Phase Ib/II Study of Neoadjuvant Pembrolizumab (MK-3475) with Gemcitabine-Cisplatin 
(cisplatin eligible) or Gemcitabine (cisplatin-ineligible) in Subjects with T2-4aN0M0 
Urothelial Cancer: HCRN GU14-188 
 
 
Sponsor Investigator 
Jason Brown, MD, PhD 
Assistant Professor of Medicine 
Case Comprehensive Cancer Center at 
University Hospitals-Seidman Cancer Center 
11100 Euclid Ave 
Cleveland, OH 44106 
(216) 844-3951 
jason.brown3@uhhospitals.org 
 
Statistician 
Pingfu Fu, PhD 
Associate Professor of Biostatistics 
Case Western Reserve University 
Cleveland OH, 44106 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
 
 
Funding Support and Pembrolizumab (MK-3475) Provided By 
Merck Sharp & Dohme LLC. 
 
Investigational New Drug (IND) Application ID# 
Exempt per FDA 1.15.15 
 
 
Initial Protocol Version Date: 28APR2015 
Amended Protocol Version Date: 
21DEC2015  
17OCT2017 
14AUG2019 
19JUL2022 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol title: Phase Ib/II Study of Neoadjuvant pembrolizumab with Gemcitabine-
Cisplatin (cisplatin eligible) or Gemcitabine (cisplatin-ineligible) in Subjects with  
T2-4aN0M0 Urothelial Cancer: 
HCRN GU14-188 
 
VERSION DATE:13JUL2022 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the 
individual.  I will accept the monitor’s overseeing of the study.  I will promptly submit the 
protocol to applicable ethical review board(s). 
 
 
 
PLASE COMPLETE AND EMAIL COPY TO HCRN 
 
 


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SYNOPSIS 
TITLE 
Phase Ib/II Study of Neoadjuvant Pembrolizumab with 
Gemcitabine-Cisplatin (cisplatin-eligible) or Gemcitabine 
(cisplatin-ineligible) in subjects with T2-4aN0M0 Urothelial 
Cancer: HCRN GU14-188 
SHORT TITLE 
Study of neoadjuvant pembrolizumab in combination with 
gemcitabine based therapy in cis-eligible or -ineligible subjects 
with urothelial cancer 
PHASE  
Phase Ib/II 
OBJECTIVES 
Primary Objective: 
 Phase Ib: safety of pembrolizumab in combination with 
gemcitabine-cisplatin  
 Phase II: rate of pathologic muscle invasive response (PaIR), 
i.e. ypT0, Tis, Ta, T1 ypN0 at radical cystectomy. 
   
Secondary Objectives: 
 Determine the 18month-relapse free survival (RFS) and 
overall survival (OS) 
 To evaluate the safety and tolerability of pembrolizumab in 
combination with gemcitabine or gemcitabine-cisplatin.  
 Determine the radical cystectomy (RC) rate in subjects who 
are cisplatin–eligible and –ineligible 
 
Exploratory Objectives: 
 Assess antitumor activity by PD-L1 immunohistochemistry 
(IHC) grade and correlate with 18mo-RFS for possible 
predictive or prognostic biomarker development. 
 To assess prognostic and predictive associations between pre 
and post-treatment changes in peripheral blood mononuclear 
cells (PBMCs), lymphocyte subsets, with 18 month-RFS. 
 To correlate responses to bladder cancer subtype of basal or 
luminal (and possibly p-53 like, though methodology for 
determining this phenotype in FFPE tissue is in progress)1  
 To correlate pathologic response to prior bacillus Calmette-
Guerin (BCG) exposure.
STUDY DESIGN 
Each subject will participate in the trial for up to 2 years from the 
time the subject signs the Informed Consent Form (ICF) through 
the final contact.  After a screening of up to 28 days, cohort I 
cisplatin eligible subjects will begin phase Ib of the protocol to 
assess safety of the combination.  Treatment is Days 1 and 8 of 
each 3-week dosing cycle. Treatment will continue for 4 cycles of 
gemcitabine-cisplatin (GC).  The experimental intervention, 
pembrolizumab, will be given every 3 weeks, starting C1D8, for 5 


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doses.  Once the maximum tolerated dose (MTD) is determined in 
Phase Ib, cohort I will be treated in the same manner in Phase II 
with a primary endpoint of efficacy.   
 
Once Phase II opens, it will also start accruing cisplatin ineligible 
(though cystectomy eligible), subjects on “cohort II” with 
treatment of weekly gemcitabine (G) x3, on and every 28 day 
cycle for 3 cycles.  Pembrolizumab is the same as in cohort I: 
starts on C1D8 and continues every 3 weeks for 5 doses.   
 
Subjects will then have surgery to remove their primary tumor 
within 2-7 weeks after their last dose of neoadjuvant therapy.  The 
primary Phase II endpoint of PaIR (ypT0, Tis, Ta, T1 ypN0) will 
be determined.  Subjects will then be followed for an additional 18 
months with restaging scans every 12 weeks.
ESTIMATED 
NUMBER OF 
SUBJECTS 
Approximately 81 subjects will be enrolled 
PARTICIPATING 
CENTERS 
Up to 8 centers in the HCRN 
KEY 
ELIGIBILITY 
CRITERIA  
Subject Inclusion Criteria 
1. Have histologically confirmed muscle invasive disease of the 
urinary bladder, renal pelvis, or ureters.  For subjects who 
have tumors limited to the upper tract including renal pelvis or 
ureters, muscle invasive disease does not need to be 
pathologically proven, and a CT urogram must be performed 
(MRI is not acceptable to meet this criterion).  To be eligible, 
subjects with upper tract tumors of the renal pelvis and 
ureter(s) must meet a high risk assessment defined as: tumor 
≥1cm and/or hydronephrosis and/or high grade pathology 
and/or multifocal disease, where a radical NU approach to 
treat localized disease is warranted.2   
2. Histology must be urothelial carcinoma or urothelial 
carcinoma with mixed histology.   
3. Clinical stage cT2-4aN0M0.  See exclusion criteria for 
acceptable N0 determination / lymph node size. 
4. Have surgical intent for radical cystectomy (RC) or 
nephroureterectomy (NU) must be documented by treating 
urologist.   
5. Have an archived tumor block available to submit unstained 
slides for PD-L1 expression, basal and luminal subtype 
analysis- MANDATORY. For subjects without this, a biopsy 
prior to starting therapy is strongly encouraged. (See Study 


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Procedures Manual for collection, labeling and shipping 
instructions.) 
6. Demonstrate adequate organ function as defined in  
7. Table 2, all screening labs should be performed within 28 days 
of study registration. 
  
Cohort I – Cisplatin eligible 
In addition to the inclusion criteria listed above, Cohort I subjects 
must satisfy all of the following criteria: 
 Glomerular filtration rate (GFR) or creatinine clearance 
(Ccr) ≥ 50 mL/min.  (24 hour urine preferred). The cisplatin 
dose will be split over two days for values between 50-59 
mL/min 
 ECOG PS 0, 1 (and not 2) 
 Hearing impaired ≤ grade 1 (may or may not be enrolled in 
a monitoring program)   
 Peripheral neuropathy ≤ grade 1  
 
Cohort II – Cisplatin Ineligible 
In addition to the inclusion criteria listed above, Cohort II subjects 
must also meet any one of the following criteria: 
 GFR or Ccr: 30-49 (24 hour urine preferred). OR 
 ECOG PS 2 OR 
 Hearing impaired ≥ grade 2 as assessed by treating 
physician (may or may not be enrolled in a monitoring 
program).  OR 
 Peripheral neuropathy of Grade 2-4 
See full exclusion criteria for further details  
 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the 
subject: 
1. Is not a surgical candidate. 
2. Has abdomino-pelvic short axis lymph node of ≥15mm 
without biopsy.  See full exclusion criteria for further details.  
3. Has a diagnosis of immunodeficiency or received systemic 
steroid therapy of a prednisone equivalent of greater than 
10mg within 7 days prior to study registration.  Subjects on 
steroids for physiologic replacement due to a non-cancer 
related cause would not be excluded.  
4. Has had a prior monoclonal antibody within 28 days prior to 
study registration or who has not recovered (i.e., ≤ Grade 1 or 
at baseline) from adverse events due to agents administered 
more than 28 days earlier.  
5. Has a known additional malignancy that is progressing or 
requires active treatment ≤ 48 months of study registration.  


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Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy.  See full exclusion 
criteria for further details. 
6. Has active New York Heart Association (NYHA) Stage III/IV 
heart failure.  See full exclusion criteria for further details.   
7. Has known active central nervous system (CNS) metastases 
and/or carcinomatous meningitis.   
8. Has an active autoimmune disease requiring systemic 
treatment within the past 3 months or a documented history of 
clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents.  See 
full exclusion criteria for further details. 
9. Has evidence of interstitial lung disease 
10. Has a history of (non-infectious) pneumonitis that required 
steroids, or currently has pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, 
anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-
associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways). 
13. Has a known history of Human Immunodeficiency Virus 
(HIV) (HIV 1/2 antibodies). 
14. Has known active Hepatitis B (e.g., HBsAg reactive) or 
Hepatitis C (e.g., HCV RNA [qualitative] is detected). 
15. Has received a live vaccine within 30 days prior to study 
registration.  See full exclusion criteria for further details.   
STATISTICAL 
CONSIDERATIONS 
 
Phase Ib:  This is a 3+3 design in the cisplatin-eligible group 
only.  Two pembrolizumab dose levels of 200mg, and 120mg will 
be investigated with gemcitabine/cisplatin.  The MTD will be the 
highest Pembrolizumab dose level in combination with 
gemcitabine/cisplatin at which no more than 1 of 6 subjects 
experience a dose limiting toxicity (DLT) related to 
pembrolizumab (and not of gemcitabine or cisplatin).  Once the 
MTD is established, this portion of the study will close and the 
Phase II will open to cohort I and II at the recommended phase II 
dose (RP2D).  Including a ~4% subject drop out, the maximal 
sample size is 14.   
 
Phase II:  Cohort I and II subjects will be treated at RP2D from 
the phase 1b portion in independent Simon two-stage designs.  For 
cohort I, the null hypothesis that the true pathologic muscle 
invasive response rate (PaIR) is 23% will be tested against a one-
sided alternative.  In the first stage, 15 subjects will be accrued.  If 


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there are 4 or fewer responses in these 15 subjects, cohort I will be 
stopped. Otherwise, 17 additional subjects will be accrued for a 
total of 32. The null hypothesis will be rejected if 12 or more 
responses are observed in 32 subjects.  This yields a type I error 
rate of 4% and power of 86% when the true response rate is 48%.    
For cohort II, the null hypothesis that the true PaIR rate is 18% 
will be tested against a one-sided alternative.  In the first stage, 19 
subjects will be accrued.  If there are 4 or less responses in these 
19 subjects, the cohort will be stopped. Otherwise, 16 additional 
subjects will be accrued for a total of 35. The null hypothesis will 
be rejected if 11 or more responses are observed in 35 subjects.  
This yields a type I error rate of 4% and power of 86% when the 
true response rate is 40%.  
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 16 months  
ESTIMATED 
STUDY 
DURATION  
Estimated 36 months 
 
 
 


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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................................ 9 
1. 
BACKGROUND AND RATIONALE ........................................................................................................ 10 
2. 
STUDY OBJECTIVES & HYPOTHESES ................................................................................................... 17 
3 
ELIGIBLITY CRITERIA ........................................................................................................................... 18 
4. 
SUBJECT REGISTRATION ..................................................................................................................... 23 
5. 
TREATMENT PLAN .............................................................................................................................. 23 
6. 
DOSE MODIFICATIONS AND TOXICITY MANAGEMENT .................................................................... 23 
7. 
TREATMENT DISCONTINUATION ....................................................................................................... 51 
8. 
STUDY SCHEDULE OF EVENTS: ........................................................................................................... 53 
9 
CRITERIA FOR DISEASE EVALUATION................................................................................................. 66 
10. BIOLOGICAL SPECIMEN PARAMETERS FOR CORRELATIVES.............................................................. 74 
11. DRUG INFORMATION ......................................................................................................................... 75 
12. ADVERSE EVENTS ................................................................................................................................ 79 
13. STATISTICAL METHODS ...................................................................................................................... 86 
14. TRIAL MANAGEMENT ......................................................................................................................... 89 
15. DATA HANDLING AND RECORD KEEPING .......................................................................................... 90 
16. ETHICS ................................................................................................................................................. 92 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
Figure 1.  Schema of HCRN GU14-188 trial: neoadjuvant pembrolizumab in combination with gemcitabine based therapy in 
cisplatin-eligible or -ineligible subjects with urothelial cancer.  RP2D, recommended phase II dose; GC, gemcitabine-cisplatin; G, 
gemcitabine; PaIR, pathologic muscle invasive response or p≤T1; RFS, relapse free survival; OS, overall survival 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Background 
 
1.1.1. Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades3.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies4-8.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene PDCD1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2) 9,10.  The structure of murine PD-1 has 
been resolved11.  PD-1 and family members are type I transmembrane glycoproteins containing 
an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which 
is responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade9,12-14.  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 proteins15,16.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs 
and Natural Killer cells17,18.  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells19.  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 tumors15,20-22.  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 tissues15.  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-
cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects 
with melanoma (MEL)23.  This 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. 


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Pembrolizumab (previously known as MK-3475, or SCH 900475) is a potent and highly 
selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly 
block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  It received accelerated 
FDA approval for second line treatment of metastatic melanoma in September 2014.  
 
1.1.2.Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
1.2. 
Rationale 
 
1.2.1. Rationale for the Trial and Subject Population 
Bladder cancer is the second most common genitourinary (GU) malignancy in the US and the 
most common histology is urothelial carcinoma (UC). Distant recurrences occur in 20-50% of 
patients compared to 5-15% locoregional recurrences, and once metastases occur, the 5-year OS 
is 5.4%.  Neoadjuvant chemotherapy followed by radical cystectomy (RC) with pelvic lymph 
node dissection is the current optimal treatment approach for Stage II or III disease based on 
level 1 evidence.  Patients that achieve a pathologic muscle invasive response (PaIR) – defined 
as p≤T1 (and N0M0) disease at RC – have the best chance for cure.24   
 
Neoadjuvant therapy for stage II or III muscle invasive urothelial cancer includes methotrexate, 
vinblastine, doxorubicin, cisplatin (MVAC)22,23 or Gemcitabine-Cisplatin (GC) as extrapolated 
from data in the metastatic setting24-26 and one prospective trial27,24,25 or Gemcitabine-Cisplatin 
(GC) as extrapolated from data in the metastatic setting26-28 and one prospective trial29.  Though 
these regimens remain the standard 1st line option, the survival benefit is limited for non-PaIR 
patients30.  Despite many attempts at improving this outcome with single agents, and some 
pathway targeting agents; no agents have been proven to improve the modest outcomes of the 
GC and MVAC regimens.  Bladder cancer has a high mutation burden31 that can confer 
preserved signaling of driver pathways despite cytotoxic chemotherapy or targeted agents.  A 
strategy that incorporates immune checkpoint blockade can potentially improve both recognition 
and targeted destruction of these neo-antigen expressing cells.   
 
Bladder cancer is an immunogenic cancer that has been shown to be infiltrated by T regulatory 
cells (Tregs), express high levels of inhibitory cytokines, high prevalence of B7-H1 (PD-L1) 
expression32, has survival outcomes that correlate with PD-L1 expression33, and notably, respond 
to a broad lymphocytic inflammatory response to bacillus calmette-guerin (BCG) and BCG-
interferon.  Pembrolizumab blocks the ligation of PD-1 with PD-L1 or PD-L2, a key co-regulator 
interaction that can shift the balance of the immune system towards an anti-tumor response.   
 
The motivating rationale for this combination trial is therefore based on 1) improved release of 
tumor antigen, specifically, urothelial cancer’s high neo-antigen burden, using cytotoxic 
chemotherapy and 2) breaking immune tolerance and allowing renewed host patient immune 
surveillance for antigenic processing and immune mediated tumor cell death.  Gemcitabine is 
cytotoxic to bladder cancer and can thereby cause tumor antigen release, reduces MDSCs to 
enhance immune surveillance47, and also prevents PD-1 dependent CD4+ T cell tolerization50, 
which make it an attractive choice to study in combination with pembrolizumab.  The hypothesis 
being tested in this trial is that the anti-PD-1 antibody, pembrolizumab, plus a gemcitabine 


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backbone (alone or with cisplatin) is a well tolerated neoadjuvant combination that can lead to a 
high rate of deep and durable responses in UC.   
 
1.2.2. Rationale for inclusion of cisplatin-ineligible subjects 
Pembrolizumab is well tolerated with a different side effect profile than MVAC or 
gemcitabine/cisplatin (GC)34 and is therefore an attractive compound to also evaluate in the 
cisplatin-unfit population35.  UC is unfortunately a disease of the elderly and due to age-
associated and disease-associated comorbidities, over 50% of patients are unfit for cisplatin or 
doxorubicin35-38 _ENREF_32.  Common reasons to avoid doxorubicin and/or cisplatin include 
renal dysfunction, performance status of 2, grade 2 or greater hearing loss, neuropathy, or heart 
failure.  Though nearly half of patients older than 70 years old have a Ccr of <50 mL/min 
_ENREF_27and may not be represented well in clinical trials25,39, retrospective data in bladder 
cancer patients does show that cisplatin is tolerated similarly despite age, so long as they are 
otherwise cisplatin eligible40.  Substituting carboplatin for cisplatin in the neoadjuvant setting has 
been evaluated in 3 prospective phase II trials: M-CAVI (methotrexate, carboplatin, vinblastine), 
and 2 trials of combination carboplatin-paclitaxel-gemcitabine (GCT).  The M-CAVI regimen 
treated 47 T2-4N0 bladder cancer patients and found pT0 rates were 26.5% and disease specific 
survival of 42% at 2years41. In a phase II trial of 68 patients with adequate renal function and 
cT2-4N0-1 disease, those who received GCT had a pT0 rate of 22% of the intent to treat 
population.  Unfortunately 79% had grade 3-4 hematologic toxicity42.  SWOG conducted a phase 
II trial of neoadjuvant GCT followed by cystoscopic surveillance or immediate RC for cT0 status 
after therapy43.  Of 74 patients, cT0 was achieved in 34 (46%), - and of these 34, only 10 went on 
to have RC.  Of these 10, 6 (60%) actually had persistent cancer in their RC specimen despite 
cT0 status.  In summary, while these 3 trials did replace cisplatin with carboplatin, they did not 
actually target or include the cisplatin-ineligible patients and failed to show sufficient safety or 
efficacy with these combinations.  
 
Neoadjuvant carboplatin/gemcitabine (CaG) was evaluated in a single institution retrospective 
cohort of cisplatin-ineligible bladder cancer patients with cT2-T4 and/or node positive disease 
and were compared to a contemporary group who received a cisplatin combination regimen.  Of 
the 41 patients included in the CaG cohort, 26.8% had crossed over from up to 3 cycles of a prior 
cisplatin-containing regimen to then finish neoadjuvant with the CaG regimen.  No survival 
advantage was noted.  
 
RC alone has been reviewed in a retrospective cohort of ~1000 patients and found a pathologic 
complete response (pCR) rate of 6.3%.  A prospective evaluation of single modality RC pCR 
rate was determined to be 15% in the comparator arm of the Phase III SWOG 8710 trial24,44.  
These patients had prior diagnostic (and occasionally maximal) transurethral resection of bladder 
tumor (TURBT) to yield a pCR rate of ~15% at RC.  It’s important, however, to understand this 
rate should only be viewed within the context of being a comparator group against which a 
difference with neoadjuvant therapy was assessed within the pre-specified controls of the clinical 
trial.  A pathologic CR rate for RC-only would require a clinical trial that controls for extent of 
TURBT prior to RC, and reproducible pathologic specimen sectioning (compulsive, detailed 
sectioning of whole-mounts may reveal Tis).  Thus, given the available data, a large 
retrospective cohort may actually be a more relevant pCR rate for RC only groups.   
 


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Single agent gemcitabine has activity in invasive urothelial cancer.  It has been studied in one 
phase I trial, 2 Phase II trials of previously treated patients, and 2 trials in previously untreated 
patients in the advanced or metastatic setting.   The phase I trial of 15 patients had one CR, and 3 
PR45.  The two phase II trials of previously treated patients demonstrated a response rate of 28 
and 50%, respectively46,47.  Two Phase II trials of previously untreated patients found an ORR of 
28%- with three CRs in patients with liver metastases, and an ORR of 24.3%, respectively47,48.  
All trials used a weekly gemcitabine times three on a 4-week cycle.  The single agent 
gemcitabine administration regimen for this trial of cohort II- cisplatin-ineligible patients was 
based on this experience. 
 
In summary, there is a need for better outcomes in bladder cancer patients.  The most critical 
need includes those patients that are ineligible to receive cisplatin where current guideline 
recommendations are for RC or clinical trial37.   
 
1.2.3. Rationale for combining pembrolizumab with gemcitabine and/or cisplatin: 
Currently, non-metastatic UC is optimally treated with neoadjuvant cisplatin based therapy: 
gemcitabine-cisplatin (GC); or methotrexate-vinblastine-doxorubicin-cisplatin (MVAC), which 
have well known ‘macro’ effects on the immune system such as neutropenia and lymphopenia; 
however, their effects on tumor-specific immune responses are becoming better appreciated.  
Their ability to augment immune effector and suppressor cells and cytokine milieu can be taken 
advantage of to beneficially modulate pembrolizumab immune checkpoint therapy (Table 1).   
 
Active Bladder Agent  
Immune effects  
Cisplatin  
Class I HLA expression 
Inhibits STAT6 expression of PD-L2 (B7-DC) 
Enhance Fas/ICAM-1 expression for Ag specific CTL killing 
Gemcitabine  
Increased Ag presentation 
Inhibit and reduce myeloid derived suppressor cells 
Enhance Fas expression 
CD40 based T cell stimulation  
Prevent PD-1 dependent CD4+ T-cell tolerization 
 
Table 1:  Immune modulating effects of cytotoxic chemotherapy for bladder cancer. 49-
52_ENREF_43 DC, dendritic cell; HLA, human leukocyte antigen; Ag, antigen; CTL, cytotoxic T 
lymphocyte; MHC, major histocompatibility complex 
 
There is preclinical biology as well as clinical support for the immunomodulating effects of 
bladder-specific neoadjuvant therapies including cisplatin, gemcitabine, vinblastine, doxorubicin, 
and methotrexate.   
 
Cisplatin can stimulate antigen presentation, increase HLA expression, and improve factors for 
cytotoxic T lymphocyte kill.  It also inhibits STAT6 expression of PD-L2 which has unknown 
effects on PD-1 inhibition and tumor surveillance, though likely does not impede it50,51. 
 


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Gemcitabine has been shown in vivo and in clinical trials to favorably augment tumor specific 
CD4+ and CD8+ ratios and to induce responses through effects it also has on the B-
lymphocytes.53,54_ENREF_8 Gemcitabine, reduces myeloid-derived suppressor cells (MDSCs) to 
enhance immune surveillance49 and also prevents PD-1 dependent CD4+ T cell tolerization52.  
Preclinical data with Gemcitabine in combination with pembrolizumab shows synergistic tumor 
inhibition compared to monotherapy in a variety of syngeneic mouse tumor models (MK-3475) 
IB ed.6 rev10Jan2014).  
 
Several ongoing early phase trials combining immune checkpoint inhibitors with platinum 
doublet regimens in non-small cell lung cancer (NSCLC) and SCLC have had manageable 
toxicities (clinicaltrails.gov ID: NCT02039674, NCT01285609, NCT01454102)55,56_ENREF_43.  
In an interim report of the Phase I multi-arm trial of an anti-PD-1 inhibitor in combination with 3 
different platinum doublet regimens for NSCLC, the GC combination arm showed good 
tolerability without any treatment discontinuations and grade 3-4 toxicity limited to 6% 
anemia55. 
 
Based on the SWOG neoadjuvant MVAC trial and recent neoadjuvant phase II trials of dose 
dense/accelerated MVAC24,57,58 a rationale for potential beneficial immunomodulation by 
MVAC was explored.  There are preclinical data that suggest vinblastine and cisplatin could 
support a pembrolizumab directed anti-tumor response.  Methotrexate and doxorubicin, however, 
are more likely to have counterproductive effects when used in combination with 
pembrolizumab.  Doxorubicin has been shown to induce expansion of monocytic myeloid 
suppressor cells which may interfere with anti-PD-1 therapy52.  While methotrexate (MTX) 
exhibits some beneficial immune anti-tumor properties (such as DC-mediated antigen 
presentation), methotrexate also notably has anti-inflammatory effects that are mediated thru its 
primary mechanism of action of dihydrofolate reductase (DHFR) inhibition.  As an anti-cancer 
agent, MTX’s competitive inhibition of DHFR leads to depletion of reduced folates which are 
critical for nucleotide synthesis and cell survival.  This same mechanism also benefits 
autoimmune and rheumatologic conditions by suppressing the inflammatory cascade.  DHFR 
inhibition by MTX leads to adenosine accumulation, an important signaling molecule for 
inhibiting the inflammatory cascade via receptor A2a on T cells59.  (The anti-inflammatory 
mechanisms of MTX may be mediated by additional non-adenosine pathways and are beyond 
the scope of this protocol.)  Of specific relevance, is that adenosine is essential for Treg mediated 
immune suppression60 and acts via stimulating adenosine receptors on T effector cells which 
increases expression of negative co-stimulatory molecules such as PD-1 and CTLA-461,62 
_ENREF_60.  Pembrolizumab combination with MTX could require dose escalation or alternative 
scheduling regimens of pembrolizumab to overcome MTX’s affects on PD-1 and, therefore, a 
MVAC/ddMVAC combination arm is not pursued as an intervention in this protocol.    
 
Timing of cytotoxic chemotherapy in combination with immune checkpoint inhibitors is an 
important consideration for overall efficacy as well as toxicities.  Often, steroids are given as 
supportive care with cisplatin-based regimens as an anti-emetic for up to 4 days after the 
cisplatin dose.  Here we choose to time the delivery of the PD-1 inhibitor at day 8, to avoid 
overlap with dexamethasone and just before immune reconstitution from maximal 
myelosuppression, and, as important, the cisplatin dosing option for subjects with GFR 50-59 is 
to be split over day 1 and 263-66.  This is also a critical time as T-cell subsets emerge from 


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myelosuppression and can have a favorable anti-tumor milieu.  Additionally, while this is a 
‘sensitive’ period for hematopoiesis, and hematopoietic precursors do express PD-L1, there are 
no reports or preclinical data to suggest PD-1 signaling is essential to normal hematopoiesis and 
therefore would not predict dose-limiting cytopenia from this timing and combination. 
 
1.2.4. Rationale for Timing of Consolidative Surgery 
Timing of RC after neoadjuvant therapy is an important consideration for this multimodality 
intervention.  Delivery of cystectomy within 10 weeks from the last dose of a combination 
neoadjuvant chemotherapy regimen of 9-12 weeks in duration was found to not compromise 
survival in a retrospective cohort of 153 patients67.  This HCRN GU14-188 trial delivers 
experimental pembrolizumab therapy 3 weeks after the last dose of gemcitabine (G) or 
gemcitabine-cisplatin (GC), and therefore requires delivery of RC (or nephroureterectomy, NU) 
within 2 to 7 weeks after this dose.   
 
1.2.5. Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is currently being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated and no 
dose-limiting toxicities were observed.  This first in human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date with 10 mg/kg 
Q2W as the highest dose tested in PN001.  Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
Pharmacokinetic (PK) data analysis of pembrolizumab administered Q2W and Q3W showed 
slow systemic clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic (PD) data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  These early PK and PD data provide scientific rationale for tests that 
compared Q2W and Q3W dosing schedules.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of pembrolizumab were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a fixed dose across 
all body weights.  Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 


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1.2.6. Combination Risk Assessment  
Treatment with GC is a standard of care option for eligible subjects with T2-T4aN0M0 urothelial 
cancer.  Myelosuppression/cytopenias is a dose limiting toxicity of gemcitabine; and 
nephrotoxicity and nausea are the most common and/or serious adverse events for cisplatin.   The 
most common adverse event (AE) identified (~10%) to date for pembrolizumab are fatigue, 
nausea, and less commonly, flu-like symptoms and are often grade 1-2.  Phase I trials did not 
reach a MTD as there were very few (<3%) reports of grade 3-4 AE.  Most of these events 
occurred at the 10 m/kg dosing, prior to the PK and clinical efficacy data suggested a flat dose of 
200 mg (this flat dose is ~5-fold lower than the 10 mg/kg dose for an average size adult, see 
section 1.2.5) to be the ideal monotherapy recommended phase II dose (RP2D).  Hematologic 
toxicity has not been noted. As pembrolizumab toxicities are infrequent and mild (and were 
determined at a dose nearly 4-5-fold higher than the current RP2D monotherapy dose), there is 
very little expectation for overlapping toxicities.  
 
1.2.7. Rationale for Endpoints 
 
1.2.7.1. 
Efficacy Endpoints 
The primary efficacy endpoint is pathologic muscle invasive response (PaIR), or ≤ypT1N0, rate 
at RC/NU with lymph node dissection.  It has been shown to correlate with survival in subjects 
treated with neoadjuvant therapy and is the ideal immediate datapoint collected in this 
neoadjuvant trial.  The pathologic staging will be assessed by the study site pathologist and 
compared to the initial clinical TNM (cTNM, Tumor Node Metastasis) at diagnosis (recorded at 
study entry) for primary efficacy endpoint analysis.  CT scan (or MRI per treating physician) 
restaging will be obtained within 21 days prior to planned RC/NU and an additional cTNM  
stage will be determined by the site investigator.  Recognizing that the primary efficacy endpoint 
is dependent on consistent cTNM staging, site investigators shall refer to section 9 (Table 9a) for 
determining cTNM stage at diagnosis (recorded at study entry) and again pre-surgery.  
Investigators may also refer to AJCC staging manual, 7th edition (2009) or the NCCN guidelines 
page ST-2 as an additional reference when considering how to distinguish cT2 (muscle invasion) 
from cT3 (bladder wall thickening) from cT4 (fixed mass on exam under anesthesia or extra-
vesicle extension to perivesicle fat).68,69   
 
Radiographic (CT or MRI) RECIST 1.1 (Section 9.7) will be used for evaluation of disease 
response over time.  
 
1.2.7.2. 
Safety Endpoints 
The safety primary endpoint in this study is the incidence of non-gemcitabine/cisplatin related 
DLTs observed in the DLT evaluation period. Adverse events and laboratory test values 
observed in this study are also safety endpoints. In addition to general laboratory tests, immune 
laboratory tests will be evaluated considering the mode of action of pembrolizumab. 
 
1.2.7.3. 
Biomarker Research 
PD-L1 is a ligand for PD-1 and pembrolizumab attempts to disrupt the interaction of two 
proteins.  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 UC, RCC, 
pancreatic carcinoma, hepatocellular carcinoma, ovarian carcinoma, and NSCLC. The 


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correlation between baseline PD-L1 expression levels and tumor response will be evaluated as an 
exploratory objective. PD-L1 expression levels will be measured in archival tumors or biopsy 
samples determined to be evaluable by central lab.  Pre-treatment tissue samples for this analysis 
are mandatory, and when not available a biopsy should be considered if sufficient neoplastic 
tissue is thought to still be available.  
 
a) PD-L1: correlate with response to PD-1 inhibition   
Source: FFPE- Mandatory submission of unstained slides from an archival biopsy at 
diagnosis or pretreatment biopsy.  When not available, a biopsy should be considered if 
sufficient neoplastic tissue is thought to still be available. 
Metric:  PD-L1 IHC staining 0-3/3 
b) Basal or Luminal subtypes1 – correlate with response to chemotherapy.  
Source:  FFPE- Mandatory submission of unstained slides from an archival biopsy at 
diagnosis or pretreatment biopsy. 
Metrics: IHC: CD 44, CD20, CD 5/6 
 
Selected Sites where possible will participate in additional tissue acquisition for analysis: 
c) FACS of PBMCs  
Source: PBMCs- optional submission of cryopreserved PBMCs for analysis collected at 
pre-treatment: cycle 1 day 1, cycle 1 day 8, cycle 1 day 11-15 (preferably closer to day 11). 
Metrics:  CD3, CD4, CD8, CD25, Foxp3, NK cell, and MDSC markers 
d) Tissue associated lymphocytes for ‘in silica’ Immunoscore  
Source: optional submission of 2 to 3 fresh punch (≥2mm diameter) biopsies of luminal 
surface of the cystectomy specimen obtained within 60 minutes of cystectomy.  Fresh 
frozen samples to be sent overnight. 
Metrics:  Lymphocyte subset analysis using Affymetrix gene array.     
 
2. 
STUDY OBJECTIVES & HYPOTHESES 
 
2.1. 
Primary Objective & Hypothesis 
Determine the safety and efficacy of neoadjuvant pembrolizumab (MK-3475) combination with 
gemcitabine-cisplatin or gemcitabine in subjects with cT2-T4aN0M0 urothelial cancer (UC).  As 
pembrolizumab has been well tolerated and without overlapping toxicity, a short Phase Ib study 
will be done to ensure tolerability in the Gemcitabine/Cisplatin cohort (“cohort I”), which will 
then move to a phase II where the primary endpoint of pathologic muscle invasion response 
(PaIR, ≤ypT1N0) will be measured.  PaIR is defined as the absence of residual muscle invasive 
cancer in the surgical specimen.   
 The PaIR will be determined from standard-of-care RC or NU lymph node dissection and 
assessed by the site investigator and his/her pathologist at their respective study site.   
 
This phase II study will follow a two-stage Simon design to test the null hypothesis in each cohort 
of cisplatin-eligible and cisplatin-ineligible subjects. 
 
Phase Ib: Safety of pembrolizumab in combination with gemcitabine-cisplatin 
 


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Phase II: Rate of pathologic muscle invasive response (PaIR), i.e. ypT0, Tis, Ta, T1 ypN0 at RC 
with pelvic lymph node dissection.or NU with lymph node dissection. 
 
Hypothesis:  Pembrolizumab activity can be modulated by a gemcitabine containing regimen 
and will have efficacy in bladder cancer subjects in the neoadjuvant setting when compared to 
historical controls.   
 
2.2. 
Secondary Objectives & Hypotheses 
 Determine the pT0 rate, 18mo-relapse free survival (RFS) and overall survival (OS) 
 Evaluate the safety and tolerability of pembrolizumab in combination with gemcitabine 
or gemcitabine-cisplatin.  
 Determine the radical cystectomy (RC) rate in subjects who are cisplatin–eligible and –
ineligible 
 
Hypothesis/Rationale:  Multimodality therapy is necessary to attain the best chances at long 
term overall survival for this population of subjects with urothelial cancer.  Reasons for not 
proceeding to RC or NU may include both cancer and non-cancer related issues.   
 
2.3. 
Exploratory Objectives 
 Assess antitumor activity by PD-L1 immunohistochemistry (IHC) grade and correlate 
with 18mo-RFS for possible predictive or prognostic biomarker development. 
 Assess prognostic and predictive associations between pre and post-treatment changes in 
peripheral blood mononuclear cells (PBMCs), and tissue -associated lymphocyte subsets, 
with 18 month-RFS.  
 Correlate responses to bladder cancer subtype of basal or luminal (and possibly p-53 like, 
though methodology for determining this phenotype in FFPE tissue is in progress)13.0 
 
Correlate pathologic response to prior bacillus Calmette-Guerin (BCG) exposure. 
 
3 
ELIGIBLITY CRITERIA 
 
3.1  
Diagnosis/Condition for Entry into the Trial 
Subjects with cT2-4aN0M0 urothelial cancer over the age of 18 whom a urologist has assessed 
and documented to be an appropriate surgical candidate (within 40 days of trial registration) with 
intent for consolidative surgical management.  Histology may be urothelial carcinoma 
(transitional cell carcinoma) or urothelial carcinoma with additional histologic features (such as 
squamous, adenocarcinoma, sarcomatoid, small cell, etc).  Upper tract disease with plan for 
nephroureterectomy (NU) and lymph node dissection is also acceptable.   
 
3.2. 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 
1. Be willing and able to provide written informed consent for the trial. 
 
2. ≥ 18 years of age on day of signing informed consent. 
 
3. ECOG PS ≤ 2; please see section 3.4 for specific details regarding ECOG PS for each cohort 


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4. Have histologically confirmed muscle invasive disease of the urinary bladder.  For subjects 
who have tumors limited to the upper tract including renal pelvis or ureters, muscle invasive 
disease does not need to be pathologically proven, and a CT urogram must be performed 
(MRI is not acceptable to meet this criterion).  To be eligible, subjects with upper tract 
tumors of the renal pelvis and ureter(s) must meet a high risk assessment defined as: tumor ≥ 
1cm and/or hydronephrosis and/or high grade pathology and/or multifocal disease, where a 
radical NU approach to treat localized disease is warranted.2   
 
5. Histology must be urothelial carcinoma (transitional cell carcinoma) or urothelial carcinoma 
with mixed histology/features.   
 
6. Clinical stage cT2-4aN0M0.  Please see exclusion criteria for acceptable N0 
determination/lymph node size.   
 
8. Have a surgical evaluation that documents the plan for multimodality therapy with a 
consolidative radical cystectomy or nephroureterectomy.   
NOTE on surgical intent: Criteria for acceptable surgical risk are not defined and per 
treating urologist.  Minimum guidance on surgical intent includes subjects who do not have 
significant cardiovascular disease such as NHYA class III or IV heart failure, unstable 
arrhythmias or angina, active CAD, and/or EF<25%.  Specific diagnostic testing to determine 
surgical intent is not required and per treating urologist or oncologist discretion.   
 
9. Having an archived tumor block available to submit 11 unstained slides for PD-L1 
expression, basal and luminal subtype analysis is MANDATORY for subjects with bladder 
cancer (and optional for those with tumors limited to the upper tract if sufficient tissue is not 
available). If slides are not available, a biopsy is strongly encouraged to obtain tissue for 
submission (See Study Procedures Manual for collection, labeling and shipping instructions.) 
 
10. Subjects on full dose anticoagulants must be on a stable regimen of warfarin or low 
molecular weight heparin (LMWH) for at least two weeks.  
 
11. Demonstrate adequate organ function as defined in Table 2: All screening labs should be 
performed within 28 days of study registration.   
 
Table 2: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Absolute lymphocyte count
≥350 mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
Renal 
Measured or calculateda creatinine clearance ≥30 mL/min 
Hepatic 
Serum total bilirubin 
≤ 1.25 X ULN OR ≤ 2.5 xULN for subjects 
with Gilbert’s disease
AST (SGOT) and ALT (SGPT)
≤ 2 X ULN 


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System 
Laboratory Value 
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 and as long as PT or PTT 
is within therapeutic range of intended use of 
anticoagulants
aCreatinine clearance is calculated per institutional standard formula. 
 
12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test 
within 72 hours prior to study registration.  If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test is required.   
 
13. Female subjects of childbearing potential must be willing to adequate contraception, be 
surgically sterile, or abstain from heterosexual intercourse for the course of the study and 
through 120 days after the last dose of study medication.  NOTE: Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from menses 
for > 1 year.  
 
14. Male subjects must agree to use a barrier method of male contraception starting with the first 
dose of study therapy and through 120 days after the last dose of study therapy. 
 
3.3. 
Subject Exclusion Criteria 
Subjects may not have any of the following: 
1. A non-surgical approach recommended by the treating urologist due to any reason.   
a) Criteria for surgical intent are not defined and, rather, suitability is determined and 
documented by the subject’s treating urologist.  Minimum guidance on surgical intent 
includes subjects who do not have significant cardiovascular disease such as NHYA class 
III or IV heart failure, unstable arrhythmias or angina, active CAD, and/or EF<25%.  
Specific cardiopulmonary diagnostic testing to determine surgical intent is not required 
and per treating urologist or oncologist discretion.  
 
2. Has abdomino-pelvic short axis lymph node of ≥ 15mm without biopsy.  NOTE: A subject 
with a staging biopsy proving a non-neoplastic process/N0 will meet inclusion. 
 
3. Subjects with disease that is limited to the upper tract urothelial cancer and is considered low 
risk defined as:  unifocal disease and tumor size <1cm, and low grade cytology, and without 
an invasive aspect on CT-urography.2 
 
4. Is currently participating in or has participated in a study of an investigational agent or using 
an investigational device within 28 days prior to study registration.   
 


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5. Has a diagnosis of immunodeficiency or received systemic steroid therapy of a prednisone 
equivalent of greater than 10mg within 7 days prior to study registration.  Subjects on 
steroids for physiologic replacement due to a non-cancer related cause would not be 
excluded.  
 
6. Has had a prior monoclonal antibody ≤ 28 days prior to study registration or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 28 days earlier.  
 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy for 
urothelial carcinoma.    
 
8. Has a known additional malignancy that is progressing or required treatment ≤ 48 months of 
study registration.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, in situ cervical cancer that has undergone potentially curative therapy, 
stable (as defined by PSA change, checked within 30 days) and untreated very low-risk or 
low-risk prostate cancer defined by current NCCN guidelines.   
 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Brain imaging is not required and per discretion of treating physician.   
 
10. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents.  NOTE: Subjects with vitiligo or resolved 
childhood asthma/atopy would be an exception.  Subjects that require intermittent use of 
bronchodilators or local steroid injections would not be excluded from the study.  Subjects 
with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be 
excluded from the study.   
 
11. Has evidence of interstitial lung disease 
 
12. Has a history of (non-infectious) pneumonitis that required steroids, or currently has 
pneumonitis. 
 
13. Has an active infection requiring systemic therapy.  
 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the site investigator.   
 
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 


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16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after 
the last dose of trial treatment. 
17. Has received therapy with hematopoietic growth factor such as G-CSF or GM-CSF in the 14 
days prior to registration.   
 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). 
 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
21. Has received a live vaccine within 30 days prior to the first dose of trial treatment.  NOTE:  
Examples of live vaccines include, but are not limited to, the following:  measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccines.  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. 
 
3.4 
Cohort Assignment 
 
3.4.1 Cohort I – Cisplatin eligible 
In addition to the inclusion criteria listed above in Sections 3.1 and 3.2, Cohort I subjects must 
satisfy all of the following criteria: 
 GFR or Ccr ≥ 50 mL/min (24 hour urine preferred). The cisplatin dose will be split over 
two days for values between 50-59 mL/min. See section 5.5.1 and 5.5.4. 
 ECOG PS 0, 1 (and not 2) 
 Hearing impaired ≤ Grade 1 (may or may not be enrolled in a monitoring program)   
 
Peripheral neuropathy ≤ Grade 1. 
 
3.4.2 Cohort II – Cisplatin Ineligible 
In addition to the inclusion criteria listed above in Sections 3.1 and 3.2, Cohort II subjects must 
also be documented to have surgical intent for radical cystectomy (RC) or nephroureterectomy 
(NU) and also meet any one or more of the following criteria: 
 GFR or Ccr: 30-49 (24 hour urine preferred). OR 
 ECOG PS 2 OR 
 Hearing impaired ≥ Grade 2 as assessed by treating physician (may or may not be 
enrolled in a monitoring program) OR 
 Peripheral neuropathy Grade 2-4  
 


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4. 
SUBJECT REGISTRATION 
All subjects must be registered through the Hoosier Cancer Research Network (HCRN) 
electronic data capture (EDC) system.  A subject will be considered registered when they are 
given an “on study” date in the EDC system.  Subjects must be registered prior to starting 
protocol therapy and begin therapy within five business days of registration. 
 
5. 
TREATMENT PLAN 
 
5.1. 
Overview 
This is a two-part trial with a one-arm Phase Ib portion followed by a two-arm Phase II portion.  
The study treatment is stratified into two cohorts based on cisplatin eligibility: 
 
Phase Ib Cycle = 21 days: 
 Cohort I only (receive treatment in Phase Ib and II): cisplatin eligible subjects receive 
gemcitabine/cisplatin every 3 weeks, repeated for 4 cycles. Subjects with Ccr of 50-59 
mL/min must follow split dosing of cisplatin over two days (see section 5.5.1 and 5.5.4).  
Pembrolizumab will be given every 3 weeks for 5 doses.  The starting dose will be 200 mg 
(Dose level 0). NOTE: the last dose of pembrolizumab falls on what would be day 8 of a 5th 
‘chemo’ cycle, however gemcitabine/cisplatin is NOT GIVEN.   
 
Phase II: 
 Arm A; Cohort I; Cycle = 21 days: (receive treatment in Phase Ib and II): cisplatin eligible 
subjects receive gemcitabine/cisplatin every 3 weeks, repeated for 4 cycles. Subjects with Ccr 
of 50-59 mL/min must follow split dosing of cisplatin over two days (see Table 3).  
Pembrolizumab is given every 3 weeks for 5 doses starting with Cycle 1 Day 8 (C1D8).  
NOTE: the last dose of pembrolizumab falls on what would be day 8 of a 5th ‘chemo’ cycle, 
however gemcitabine/cisplatin is NOT GIVEN (figure 2).   
 Arm B; Cohort II; Cycle = 28 days: (receive treatment in Phase II only): cisplatin ineligible 
subjects receive gemcitabine every week (weekly) for three consecutive weeks, repeated 
every 28 days for 3 cycles.  Pembrolizumab is given every 3 weeks for 5 doses starting with 
Cycle 1 Day 8 (C1D8). NOTE: due to the timing of gemcitabine cycles every 4 weeks, and 
every three week dosing of pembrolizumab, there are two doses of pembrolizumab given 
during cycle 2: days 1 and 22.  Additionally, the last dose of pembrolizumab falls on what 
would be day 8 of a 4th ‘chemo’ cycle; however gemcitabine is NOT GIVEN (figure 2).    
 
 
 


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Figure 2.  Phase II Cisplatin Eligible Treatment Schema 
 
 
5.2 
Phase Ib: Dose Finding for pembrolizumab in cisplatin-eligible subjects 
Cycle = 21 days 
 
1: The last dose of pembrolizumab falls on what would be Cycle 5 Day 8, however gemcitabine-cisplatin is NOT 
GIVEN. 
2: See section 5.5.4 regarding use of split-dose cisplatin.  A Day 1 and 2 regimen is preferred over Day 1 and 8 
though per treating physician discretion.  Subjects with Ccr of ≥ 60 mL/min will receive cisplatin on Day 1 only. 
 
5.2.1 Dose Finding Guidelines 
A given dose cohort may be expanded up to a total of 12 subjects if further evaluation of the 
frequency of a given toxicity is warranted, based upon the observed safety profile in the 6 
subjects already recruited in the cohort, and where the incidence of the confirmed DLT does not 
exceed 33%.   
 
 
 
 
Number of subjects with DLT in 
dose-level cohort 
Action 
0 of 3 subjects
proceed to cohort expansion of an additional 3 subjects
1 of 3 subjects 
accrue 3 additional subjects at current dose level for a 
total of 6 subjects
≤1 of 6 subjects
Proceed to Phase II
2 or more subjects in a dosing cohort 
(up to 6)
MTD has been exceeded.  Reduce dose level and re-
evaluate.


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5.2.2 DLT Definition  
The pembrolizumab DLT is defined as a drug-related AE occurring in the first 4 weeks of 
treatment of pembrolizumab (C1D8 – C2D14) and meeting one of the criteria listed below. 
Ascribing a DLT to a respective drug in this combination with gemcitabine-cisplatin requires 
attention to known DLTs and AEs. As myelosuppression is the recognized DLT of gemcitabine 
and an AE of cisplatin, hematologic toxicity during the Phase Ib should primarily follow the dose 
modification tables for gemcitabine and cisplatin in Section 6.0.   
 
If any of these known AEs do occur, the recommended phase II dose (RP2D) will be discussed 
amongst HCRN, Merck, and the sponsor-investigator prior to finalizing the dose and treatment 
schedule: 
 Grade 4 febrile neutropenia with vasopressor requirements >12 hours.   
 Grade 4 non-hematologic toxicity (see exceptions below) 
 Grade 3 clinically significant non-hematological drug-related AEs that cannot be 
managed with adequate supportive therapy within 14 days of the onset of the event (see 
Table 5) 
 Grade 4 acute pancreatitis: non-alcoholic and non-cholelithiasis related in a subject 
without prior history suggesting a drug induced etiology.   
 Any grade ≥ 3 toxicity occurring beyond the 6 week window of treatment which is 
considered dose-limiting in the judgment of the site investigator and sponsor-investigator.   
 
The following will not be considered DLTs: 
 Grade 4 neutropenia or thrombocytopenia that causes a treatment delay of ≤ 14 days. 
 Acute kidney injury of Grade 3 or 4 that improves to ≤Grade 2 within 14 days following 
appropriate management.   
 ALT or AST ≥ 8x ULN (but <grade 4) without bilirubin elevation (defined as total 
bilirubin ≤ 2.0xULN, or ≤ 3.0 x ULN in a subject with Gilbert’s syndrome, or direct 
bilirubin ≤ 35%) that improves to ≤ Grade 2 within 14 days following appropriate 
management  
 Grade 4 nausea, vomiting, or diarrhea 
 Grade 3 febrile neutropenia and grade 4 that has stabilized (off vasopressor support) 
within 12 hours 
 Grade 3 electrolyte abnormalities that are corrected within 72 hours and without clinical 
sequelae.  
 Grade 3 endocrinopathy that is adequately controlled by hormonal replacement.  
 Grade 3 AE of tumor flare (defined as local pain/spasms, irritation, hematuria) 
 Grade 3 AE of urinary tract obstruction (such as due to tumor flare causing 
hydronephrosis) that resolves to ≤ Grade 2 within 96 hours (with or without intervention).   
 Grade 3 infusion reaction which resolves within 6 hours to ≤ Grade 1. 
 
 
 


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5.3 
Phase II: Cisplatin-Eligible and Cisplatin-Ineligible Subjects 
 
Table 3: Cohort I; Arm A treatment: Gemcitabine/Cisplatin; Cycle = 21 days 
            
1:Subjects with Ccr of 50-59 mL/min (determined each cycle) must follow split dosing of cisplatin over Days 1 and 
2 (preferred) or Days 1 and 8.  Subjects with Ccr of ≥ 60 mL/min will receive cisplatin on Day 1 only. 
2: The last dose of pembrolizumab falls on what would be Cycle 5 Day 8, however, gemcitabine-cisplatin is NOT 
GIVEN.   
 
Table 4:  Cohort II, Arm B (and Cohort I-p) Treatment; Cycle = 28 days 
 
1The last dose of pembrolizumab falls on what would be Cycle 4 Day 8, however, gemcitabine is NOT GIVEN.   
 
5.3.1 Pre-medications 
Dexamethasone should be kept to a minimum and used only during cisplatin use and not when 
gemcitabine is given without cisplatin.  Pre-medications should follow the guidelines below, 
however, the site investigator may select alternative regimens (such as olanzipine containing, or 
other) for specific subjects that require more tailored antiemetic therapy.  Pembrolizumab does 
not need to be given with pre-medications, though non-corticosteroid premeds can be introduced 
depending on overall subject tolerance on an as needed basis. 
 
The following table is adapted from the Antiemesis Guidelines of the National Comprehensive 
Cancer Network (NCCN) v2.2014.  Additional details can be found on page AE-4 for 
Gemcitabine administration, and on page AE-2 for cisplatin. 
 


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5.4 
Study Drug Administration 
Trial treatment will be administered after all procedures/assessments have been completed as 
detailed in the Study Schedule of Events (Section 8).  A treatment window of within ± 3 days of 
each cycle is allowed due to administrative reasons provided the subject meets all treatment 
parameters.  All trial treatments will be administered on an outpatient basis.   
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 2 weeks of the scheduled 
interruption, unless otherwise discussed with the sponsor-investigator. The reason for 
interruption should be documented in the subject's study record. 
  
When applicable, gemcitabine-cisplatin or gemcitabine should be administered prior to the 
pembrolizumab experimental therapy.    
 
Arm A: Cohort I treatment with gemcitabine and cisplatin will continue for a maximum of 4 
cycles (cycle = 21days).   
 
Arm B: Cohort II treatment with gemcitabine weekly will continue for a maximum of 3 cycles 
(cycle = 28 days).   
 
5.4.1. Pembrolizumab Administration 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals may 
be increased due to toxicity as described in Section 6.0).  Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
 


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The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
 
5.4.2. Gemcitabine Administration 
Gemcitabine administration is per institutional guidelines. Where possible, on-time cycles and 
full doses (gemcitabine dose intensity) are important for optimal pathologic outcome in this 
curative-intent setting. Site investigators are STRONGLY ENCOURAGED to use filgrastim to 
minimize gemcitabine dose reductions in the setting of neutropenia (with or without febrile 
neutropenia).  An example would be to dose filgrastim on days 4-6 of a treatment cycle to 
minimize a chance for a D8 dose hold or reduction.  PEG-filgrastim may be considered on D9 of 
a cohort I subject, or filgrastim during the neutropenic phase.  Subjects who experience febrile 
neutropenia should receive filgrastim or PEG-filgrastim (see section 6.3.4).  
 
5.4.3. Cisplatin Administration 
Cisplatin administration is per institutional guidelines.   
 
5.5. 
Dose Calculations 
 
5.5.1. Renal Function Determination 
Estimation of glomerular filtration rate (GFR) may be made using a 24 hour urine or the treating 
institution’s standard for calculation of creatinine clearance (Ccr).  A modified Cockcroft-Gault 
equation is suggested for calculation: 
 
Male: 
 
 
Ccr (mL/min) =  
(ଵସ଴ି௔
 ௜௡ ௬௘௔௥௦)∙(௔௖௧௨௔௟ ௪௘௜௚௛௧ ௜௡ ௞௚)
଻ଶ ∙ (௦௘௥௨௠ ௖௥௘௔௧௜௡௜௡௘)
 
 
Female: 
 
 
 
Ccr (mL/min) = 0.85 ∙
(ଵସ଴ି௔௚௘ ௜௡ ௬௘௔௥௦)∙ (௔௖௧௨௔௟ ௪௘௜௚௛ ௜௡ ௞௚)
଻ଶ ∙ (௦௘௥௨௠ ௖௥௘௔௧௜௡௜௡௘)
  
 
A Ccr from properly collected timed (18-24 hours) urine usually supersedes a calculated value 
for determination of cisplatin eligibility and dosing.  Accuracy of timed urine collection, 
however, is dependent on patient compliance and proper collection instructions should be 
confirmed with the patient.  Improper collection methods disqualify use of the timed collection 
results and a calculated Ccr value should be used.  Results from a measured nuclear GFR study 
may also be used at the discretion of the site investigator.   
 
5.5.2. Pembrolizumab   
The starting dose amount required to prepare the pembrolizumab infusion solution is a fixed dose 
of 200 mg (or 120mg, or RP2D) and does not require calculation.  It is given IV every 21 days 
for 5 cycles.   
 
5.5.3. Gemcitabine  
Cohort I: Cisplatin-eligible subjects: Gemcitabine 1000 mg/m2 IV on Days 1 and 8, every 21 
days for 4 cycles. 
 


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Cohort II: Cisplatin-ineligible subjects: Gemcitabine 1000 mg/m2 IV on Days 1, 8, 15, every 28 
days for 3 cycles. 
 
Site investigators are strongly encouraged to use Filgrastim to minimize gemcitabine dose holds 
or reductions (see section 6.3.4). 
 
5.5.4. Cisplatin and Split Dose Cisplatin  
Subjects with creatinine clearance ≥ 60 mL/min will receive cisplatin at a dose of 70 mg/m2 
IV per institutional guidelines on Day 1 every 21 days for 4 cycles.  At least 1L of normal saline 
will be given IV for hydration prior to cisplatin.  Subjects may receive additional IV hydration, 
mannitol, electrolytes, or furosemide according to institutional practice.   
 
Split-dose cisplatin regimens and schedules for bladder cancer have not yet been evaluated in a 
randomized controlled trial (and currently being evaluated in a Phase II, NCT02030574), 
however is considered for many physicians to be a conventional practice in the appropriate 
setting.  In this trial, at the beginning of any cycle, subjects whose creatinine clearance is ≥50 
and <60 mL/min will be treated with cisplatin 35 mg/m2 IV on Day 1 and Day 2 of the 
cycle. This Day 1 and 2 splitting is considered acceptable conventional care and is strongly 
preferred over the alternative Day 1 and 8 approach in this setting.  Though day 1 and 8 dosing 
may be a more convenient schedule, the day 1 and 2 splitting limits dexamethasone exposure to 
the first 4 days of a cycle and will allow for washout prior to dosing pembrolizumab.  
Additionally, Day 1 and 2 dosing likely preserves the theoretic gemcitabine-platinum anti-
neoplastic synergy.  For extenuating scheduling difficulties (such as subject commutes from over 
90 minutes and unwilling), treating physician should document this and use discretion to allow 
for a Day 1 and 8 split.  In cases of Day 1 and 8 cisplatin splitting, the subject should remain on a 
Day 1 and 8 schedule and not revert to Day 1 and 2 at any point.  Subjects may receive 
additional IV hydration, mannitol, electrolytes, or furosemide according to institutional practice.  
At least 1 L of normal saline will be given IV for hydration prior to cisplatin.   
 
Day 2 or Day 8 renal labs are not required prior to redosing on the split-dose regimen, and per 
treating physician discretion.   
 
If at the beginning of a subsequent cycle, creatinine clearance recovers to ≥ 60 mL/min, subjects 
may resume full cisplatin on Day 1 of the cycle (with any applicable dose modifications). 
 
For prophylaxis of cisplatin-induced emesis, a 5-HT3 antagonist and a corticosteroid course of 
≤4 days are recommended per NCCN guidelines.  NK1 receptor antagonists such as aprepitant 
are also encouraged.    
 
5.5.5. Missed Dose 
Missed doses of gemcitabine-cisplatin or gemcitabine are not made up.  If Day 1 treatment 
cannot be administered, initiation of all protocol treatment for that cycle should be delayed.  
If the dose of gemcitabine-cisplatin or gemcitabine is held/omitted in the middle of a cycle, the 
pembrolizumab should be given per the toxicity criteria outlined in Section 6.0.  If gemcitabine-
cisplatin or gemcitabine is delayed from the beginning of a cycle, pembrolizumab should also be 
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Any delays will be recorded in the appropriate electronic case report form(s).  If needed, a site 
investigator may consult with the sponsor-investigator by contacting the HCRN Project 
Manager.   
 
If a subject discontinues gemcitabine-cisplatin or gemcitabine treatment due to toxicity, the 
subject may elect to receive single-agent pembrolizumab every 3 weeks per the protocol 
schedule for a total of 5 doses, or may discontinue all study treatment and choose second-line 
treatment or consolidative surgery.   
 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The site investigator should discuss any questions regarding this 
with the sponsor-investigator by contacting the HCRN project manager.  The final decision on 
any supportive therapy or vaccination rests with the site 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 site investigator and the subject.  Please contact the HCRN 
project manager in such cases.   
 
5.6.1 Acceptable Concomitant Medications 
All treatments that the site investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the site 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.  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.   
 
5.6.2 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  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab  
 Radiation therapy  
 Live vaccines within 30 days 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.  
 Glucocorticoids for delayed emesis prophylaxis of cisplatin (no longer than 4 day course) 
or to modulate symptoms from an event of clinical interest of suspected immunologic 
etiology are allowed.  Otherwise, a total of prednisone or prednisone equivalent of 10mg 
per day or less is allowed.  Above a prednisone equivalent of 10mg a day of systemic 


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glucocorticoids are not allowed.  The use of physiologic doses of corticosteroids (for 
specific non-cancer related conditions) may be approved after consultation with the 
sponsor-investigator.  Please contact the HCRN project manager.   
 OTC herbals, botanicals, and high dose anti-oxidant vitamins/supplements should be kept 
to an absolute minimum and are discouraged.  While there is no known interacting harm 
nor benefit, the potential for harm while receiving an immunologic agent such as 
pembrolizumab is possible and therefore discouraged.   
 Continuous steroids (premeds of ≤ 5 days as a cisplatin delayed antiemetic regimen is 
acceptable) meet exclusionary criteria, and NSAIDS- other than aspirin for 
cardiovascular risk - should be minimized.   
 Any additional medication prohibited in the Exclusion Criteria.   
 
Subjects who, in the assessment by the site 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 site investigator deems to be medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.7 
Supportive Care 
 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE  
 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use adequate birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. If there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 


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and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to HCRN without delay and within 24 hours if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  The site investigator will 
make every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to HCRN.  If a male subject impregnates his female partner the 
study personnel at the site must be informed immediately and the pregnancy reported to HCRN 
and followed as described above and in the Adverse Event section.   
 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
 
5.8 
Adverse Event Grading and Dose Levels 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used 
to grade adverse events. Subjects will be evaluated for adverse events (all grades), serious 
adverse events, and adverse events requiring study drug interruption or discontinuation at each 
study visit during the treatment portion of the study. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in the Schedule 
of Events. 
 
5.8.1 Dose Levels for Gemcitabine 
Subjects who require more than two permanent dose reductions will be removed from 
gemcitabine treatment.   
 
 
 
 


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5.8.2 Dose Levels for Cisplatin  
 
1Day 1 and 2 splitting is considered acceptable conventional care and is encouraged over the 
alternative Day 1 and 8 approach. See section 5.5.4. 
 
5.9 
Post Neoadjuvant Restaging and Consolidative Surgery 
 
5.9.1 Post chemotherapy Restaging Evaluation 
Subjects should undergo a post neoadjuvant restaging evaluation per conventional care.  This 
may be an extensive evaluation that includes cystoscopy68,69, however, must at the very least be a 
CT of the abdomen-pelvis within 21 days of the planned surgery.  MRI is also acceptable per 
institution practice or treating physician discretion.  A clinical TNM staging prior to surgery 
should be assigned and documented.  Imaging that suggests progression or new lesions, however, 
should be further evaluated with a biopsy prior to making a decision on definitive surgical 
consolidation.  If progression is a concern, pseudo-progression due to tumor lymphocyte 
infiltration should be ruled out with a biopsy, especially if the area of concern involves 
abdomino-pelvic draining lymph nodes.  See irRC criteria (Table 9b) as well.  Progression or 
pseudo-progression at post neoadjuvant chemotherapy that impacts decision making for 
definitive surgery is considered an event of clinical interest and should be discussed with the 
HCRN project manager/sponsor-investigator.   
 
5.9.2 Timing of Consolidative Surgery 
To be evaluable for the primary endpoint analysis, subjects should undergo consolidative surgery 
with radical cystectomy and bilateral lymph node dissection or nephroureterectomy and lymph 
node dissection once subject is appropriately stabilized after neoadjuvant chemotherapy.  Timing 
should fall no sooner than: 2 weeks after the last dose of pembrolizumab, or 3 weeks after the 
last dose of cytoxic chemotherapy, whichever is later.  Completing definitive cancer 
management in a timely manner is important. While both neoadjuvant therapy and surgery with 
lymph node dissection can provide optimal control of the cancer, there may be situations that 
arise where delays due to toxicity of neoadjuvant therapy could lead to poor overall outcome if 
surgery is excessively delayed.  Please see section 6.0 for criteria where treatment should stop 
and focus should turn to toxicity management and optimizing the patient for surgical 
consideration.   
 


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Consolidative surgery should be performed no later than 7 weeks after the last dose of 
pembrolizumab, or whenever safely possible after recovery from toxicity.  It’s encouraged for 
the treating physician to have frequent communication with the subject’s urologist about course 
of neoadjuvant therapy, relevant toxicity, and timing of consolidative surgery.   
 
Surgical approach and diversion is per discretion of the treating urologist and subject and may be 
open, laproscopic, or robotic.   
 
6. 
DOSE MODIFICATIONS AND TOXICITY MANAGEMENT 
Treatment labs, including timed urine, should be obtained no more than 3 days prior to initiating 
a new cycle.  It’s encouraged to obtain the most current labs possible prior to making a dosing 
modification. If multiple values are available, the determining value will be the most current 
available or per site investigator discretion.  Dose timing and dose intensity are important 
paradigms of curative intent therapy and filgrastim administration should be considered to avoid 
dose delays or reductions when possible (see section 6.3.4). 
 
6.1 
Pembrolizumab Dose Modifications and Toxicity Management 
The pembrolizumab dose remains the same during the Phase II portion, and only may change 
during phase Ib.  In general, dose modifications for hematologic toxicity will follow 
chemotherapy-driven management guidelines.  While there may be hematologic parameter 
related delays for pembrolizumab, the future dose level and interval does not change.   It is 
possible, however, to have a pembrolizumab attributable hematologic toxicity, including 
immune related events where a work up is warranted.  If suspected, the treating physician is 
encouraged to work up a suspected immune related hematologic toxicity and discuss a 
treatment plan with the sponsor-investigator.  A total of five pembrolizumab doses should be 
given, and may require additional dosing beyond chemotherapy in the case of delays.  
Permanent discontinuation should be considered for any severe or life-threatening event. 
 
When toxicities are assessed to be most likely associated with pembrolizumab, Table 5 should be 
followed.   
 
In general, if toxicity attributed to pembrolizumab does not resolve to Grade 0-1 within 12 weeks 
after last infusion, pembrolizumab treatment should be discontinued and may discuss with the 
sponsor-investigator for continuation on trial.  With site investigator and sponsor-investigator 
agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue 
treatment in the trial only if asymptomatic and controlled.  There are specific criteria to follow 
for renal, hepatic, and hematologic toxicity discussed in the following sections.   
 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from 
pembrolizumab treatment. 
  
 


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Table 5: Pembrolizumab dose modification guidelines for drug-related adverse events. 
 
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  
Pneumonitis  
Grade 2 
Withhold  
 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 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
Grade 4 
Permanently 
discontinue 


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 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids (initial 
dose of 0.5- 1 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 
Grade 3 or 4  
Permanently 
discontinue 
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
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. 
Hypophysitis 
Grade 2 
Withhold 
 Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1
Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
 
Monitor for signs and symptoms of thyroid 
disorders.  
Grade 2 
Withhold  


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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 
 
Myocarditis 
Grade 1 or 2 
Withhold 
 Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
 Based on type and severity of AE 
administer corticosteroids  
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
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).  
 
 
 
 
 


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6.2 
Hematologic Toxicity; Cohort I; Gemcitabine, Cisplatin and Pembrolizumab  
Gemcitabine and cisplatin doses may be modified separately based on individual toxicity 
according to the rules outlined below. There is no dose reduction below level -2 for gemcitabine 
or cisplatin. If dose reduction below level -2 is required, gemcitabine and/or cisplatin should be 
discontinued. 
 
6.2.1 Cohort I; Initiation of a new cycle with Gemcitabine and Cisplatin 
For Day 1 of each cycle, subjects must have an ANC ≥ 1,500 AND platelets ≥ 100,000 before 
receiving treatment with gemcitabine-cisplatin or pembrolizumab.  Subjects that do not meet 
these values on Day 1 will have their cycle start delayed and any pembrolizumab doses during 
that cycle will be similarly delayed.  Resume the gemcitabine-cisplatin new cycle and 
pembrolizumab dosing once the ANC improves to ≥1,500 AND platelets ≥100,000. 
 
If treatment is/was delayed: 
 For up to 1 week, resume treatment at the previous doses of gemcitabine-cisplatin.  After 
the delay, pembrolizumab dosing and interval should resume to stay “in-sequence” with 
gemcitabine-cisplatin cycle.    
 For more than 1 week and less than 4 weeks, reduce gemcitabine and cisplatin by one 
dose level for this and all subsequent cycles. Once the cycle is resumed, pembrolizumab 
dosing and its’ interval should resume to stay “in-sequence” with gemcitabine-cisplatin 
cycle.  Do not adjust pembrolizumab dose or cycle length.   
 If a second treatment delay of more than one week and less than 4 weeks occurs, reduce 
gemcitabine and cisplatin an additional dose level. Pembrolizumab dosing should restart 
on the planned cycle day (for Cohort I, this is generally Day8). Do not adjust 
pembrolizumab dose or cycle length.   
 Greater than 4 weeks due to hematologic toxicity, discontinue all therapy and initiate 
workup to optimize the subject for surgical consideration.   
 
Workup of cytopenia etiology beyond bone marrow suppression is encouraged at any time, and 
per treating physician judgment.   
 
6.2.2 Cohort I; Arm A; Criteria for Gemcitabine and Cisplatin Day 8 treatment 
A complete blood count with differential must be drawn the day of treatment.  Dose timing and 
dose intensity are important paradigms of curative intent therapy and filgrastim administration 
should be considered to avoid dose delays or reductions when possible (see section 6.3.4). 
 
For ANC 500-999 or platelets 50,000-74,999, decrease gemcitabine by one dose level for this 
and all subsequent doses. For subjects receiving split dose cisplatin during this cycle, decrease 
cisplatin by one dose level for this and all subsequent doses (effective with current dose if on a 
Day 1 and Day 8 regimen, or with the next cycle of a Day 1 and Day 2 regimen, see section 
5.5.4).  Do not adjust pembrolizumab dose or cycle length.   
 
 
 


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For ANC < 500 or platelets < 50,000, skip gemcitabine and decrease gemcitabine by one dose 
level for all subsequent doses. For subjects on split dose cisplatin during this cycle, also skip 
cisplatin and decrease cisplatin by one dose level for this all subsequent doses (effective with 
current dose if on a Day 1 and Day 8 regimen, or with the next cycle of a Day 1 and Day 2 
regimen, (see section 5.5.4).   
 
For second occurrences of Day 8 ANC <500 and platelets <50,000: 
  Modifications should follow the gemcitabine and cisplatin dose reductions as outlined 
above.   
 
Day 8: Cohort I; Arm A; Treatment Toxicity Guidelines for Dose/Interval Changes: 
ANC 
Day 8 
Platelets 
Day 8  
Gemcitabine1 
Day 8 
Split Dose Cisplatin 
Day 82 
Current Cycle 
Pembrolizumab 
Treatment 
Guidelines based on 
Day 83 
≥ 1000 AND 
≥ 100,000 
No dose modification 
No dose modification 
Treat on schedule.   
No modification.
≥ 1000 AND 
75,000 – 
99,999
No dose modification 
No dose modification 
Treat on schedule.   
No modification.
500-999 or 
50,000 – 
74,999 
Decrease by 1 dose level 
for this dose and all 
subsequent doses.
Decrease by 1 dose 
level for this dose and 
all subsequent doses.
Treat on schedule.  
No modification.  
< 500  
or 
< 50,000 
Omit gemcitabine and 
reduce by 1 dose level 
for subsequent doses.  
This dose reduction is 
permanent
Omit cisplatin and 
reduce by 1 dose level 
for subsequent doses.  
This dose reduction is 
permanent
Treat on schedule.   
No modification. 
< 500 AND 
< 50,000 
Omit gemcitabine and 
reduce by 1 dose level 
for subsequent doses.  
This dose reduction is 
permanent
Omit cisplatin and 
reduce by 1 dose level 
for subsequent doses.  
This dose reduction is 
permanent
Treat on schedule.   
No modification. 
1: Gemcitabine dose-levels reductions of-1 or -2 (see section 5.8.1) take effect with the next cycle.  This 
is relevant when considering pembrolizumab interval modification and dosing during the severe cytopenia 
scenarios that distinguish subjects having had gemcitabine dose reduced to -1, or -2.  
2: Only applies when split regimen cisplatin is given on Day 1 and 8; Days 1&2 is the preferred schedule 
and there are no labs or dose modifications necessary on Day 2. 
3: For the purposes of dose modifications, hematologic toxicity will not be attributed to pembrolizumab. 
If suspected due to pembrolizumab, consider a workup and discuss with the sponsor investigator.    
 


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6.3 
Cohort II (and Cohort I-p); Arm B; Gemcitabine and Pembrolizumab 
Gemcitabine doses may be modified separately based on individual toxicity according to the 
rules outlined below. There is no dose reduction below level -2 for gemcitabine. If dose 
reduction below level -2 is required, gemcitabine should be discontinued.  
 
 
Figure 3. Cohort II (and Cohort I-p); Arm B: Arm B treatment includes subjects on Cohort II 
and certain cases of Cohort I-p.  Pembrolizumab treatment interval is every 3 weekswith a total 
of 5 doses.Consolidative surgery and follow up not shown. See also Figure 2 and Table 4.   
 
6.3.1 Cohort II (and Cohort I-p); Arm B; New Cycle Initiation Criteria for Gemcitabine 
and Pembrolizumab  
 
For Day 1 of each Arm B cycle, subjects must have an ANC ≥ 1,500 AND platelets ≥ 100,000 
before receiving treatment with gemcitabine or pembrolizumab.  Resume the gemcitabine new 
cycle and pembrolizumab dosing once the ANC improves to ≥ 1,500 AND platelets ≥ 100,000.  
Dose timing and dose intensity are important paradigms of curative intent therapy and filgrastim 
administration should be considered to avoid dose delays or reductions when possible (see 
section 6.3.4).   
 
If treatment is/was delayed: 
 For up to 1 week, resume treatment at the previous doses of gemcitabine. Pembrolizumab 
should be similarly delayed and restarted on the planned day “within” the gemcitabine 
cycle as shown in Figure 3 or Table 4.  For pembrolizumab dosing within the cycle, see 
guidelines below.  Do not adjust pembrolizumab dose or cycle length. 
 
For more than 1 week and less than 4 weeks, reduce gemcitabine by one dose 
level for this and all subsequent cycles. Once the cycle is resumed, 
pembrolizumab dosing and its interval should be similarly delayed and restarted 
on the planned day “within” the gemcitabine cycle (see Figure 3 or Table 4 for 
pembrolizumab dosing within the cycle).  Do not adjust pembrolizumab dose or 
cycle length. 
 If a second treatment delay of more than 1 week and less than 4 weeks occurs, reduce 
gemcitabine an additional dose level. Pembrolizumab dosing should restart on the 
planned cycle day (see Figure 3 or Table 4 for pembrolizumab dosing within the cycle). 
Do not adjust pembrolizumab dose or cycle length.. 
 Greater than 4 weeks due to hematologic toxicity, discontinue all therapy and initiate 
workup to optimize the subject for surgical consideration.   
 
Workup of cytopenia etiology beyond bone marrow suppression is encouraged at any time, and 


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per treating physician judgment.   
 
6.3.2 Cohort II (and Cohort I-p); Arm B; Criteria for Gemcitabine and Pembrolizumab 
Day 8 & 15 & 22  
 
A complete blood count with differential must be drawn on the days of treatment.   
On Days 8, 15, and [where/when applicable] 22 of each cycle the dose of gemcitabine and 
pembrolizumab may be modified per the tables below.  The modifications for pembrolizumab 
doses that fall on Day 22 of a cycle are the same as the Day 15 guidelines; gemcitabine is never 
dosed on Day 22.  If subjects had a non-permanent gemcitabine dose reduction on day 15 and 
their ANC > 1500 and platelets are > 100,000 by day 1 of the next cycle, they will return to the 
dose prior to the non-permanent reduction.  Dose timing and dose intensity are important 
paradigms of curative intent therapy and filgrastim administration should be considered to avoid 
dose delays or reductions when possible (see section 6.3.4).  See Tables below. 
 
For second occurrences of Day 8, 15, or 22 ANC <500 and platelets <50,000: 
  Modifications should follow the gemcitabine dose reductions as outlined in the toxicity 
tables below.   
 
Do not adjust pembrolizumab dose or cycle length. 
 
Cohort II (and Cohort I-p); Arm B; Day 8 Toxicity Guidelines for Dose/Interval Changes  
ANC 
Day 8 
Platelets 
Day 8  
Gemcitabine 
Day 8 
Is Pembrolizumab Treatment Due? 
Day 8 
≥ 1000 AND 
≥ 
100,000
No dose modification 
Treat on schedule.  No modification. 
500-999 or 
50,000 – 
99,999 
Decrease by 1 dose level.  
This dose reduction is not 
permanent
Treat on schedule.  No modification. 
 
<500 or 
<50,000 
Omit gemcitabine and reduce 
by 1 dose level on day 15.  
This dose reduction is 
permanent 
 If this is Dose 1 or 2, OR no prior 
permanent gemcitabine dose level 
reductions: Treat as scheduled.  No 
modification.    
 If at least one prior cycle gemcitabine 
dose level reduction or 
pembrolizumab-interval increase:  
Delay pembrolizumab and give on Day 
1 of next cycle.  Treat to 5 total doses. 
<500 AND 
<50,000 
Omit gemcitabine and reduce 
by 1 dose level on day 15.  
This dose reduction is 
permanent
Delay pembrolizumab and give on Day 1 
of next cycle.  Treat to 5 total doses. 
Treat to 5 total doses.  
 
 
 


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Cohort II (and Cohort I-p); Arm B; Toxicity Guidelines for Day 15 or Day 22 Dose/Interval 
Changes  
ANC 
Day 15 or 
22 
Platelets 
Day 15 or 
22 
Gemcitabine Dose Modification 
Day 15 only 
Is Pembrolizumab 
Treatment Due? 
Days 15 or 22 
≥ 750 AND 
≥75,000 
If day 8 ANC was ≥1,000 and platelet count was 
≥75,000 then the day #15 gemcitabine dose is the 
same as day 8. 
 
If day 8 ANC was 750-999 and the platelet count 
was ≥75,000 then the day #15 gemcitabine dose 
is the same as day 8. 
 
If day 8 ANC was 500-749 or Platelet 50,000-
74,999 then the day #15 gemcitabine dose is 
reduced one dose level from the day 1 dose. This 
reduction is not permanent. 
 
If day 8 ANC < 500 or platelet < 50,000 then the 
day #15 gemcitabine dose is permanently reduced 
one dose level from the day 1 dose. 
Treat on schedule.  No 
modification. 
500-749 
AND 
50,000-
74,999 
If day 8 ANC was ≥1,000 and platelet count 
was75,000-99,999 then the day #15 gemcitabine 
dose is reduced one dose level from the day 8 
dose. This dose reduction is not permanent. 
 
If day 8 ANC was 750-999 and the platelet count 
was ≥75,000 then the day #15 gemcitabine dose 
is the same as the day 8 dose. 
 
If day 8 ANC was 500-749 or Platelet 50,000-
74,999 then the day #15 gemcitabine dose is 
reduced one dose level from the day 1 dose. This 
reduction is not permanent. 
 
If day 8 ANC was < 500 or platelet < 50,000 then 
the day #15 gemcitabine dose is permanently 
reduced one dose level from the day 1 dose. .
Treat on schedule.  No 
modification. 
<500 or 
< 50,000 
Omit gemcitabine. If the dose of gemcitabine was 
also omitted on Day 8, then reduce the dose of 
gemcitabine on Day 1 of the following cycle by 
one dose level. This dose reduction is permanent. 
Dose 1 or 2, OR no 
permanent 
gemcitabine dose level 
change: Treat as 
scheduled.    
 
Prior cycle permanent 
gemcitabine or 
pembrolizumab 
modification:  Delay 
pembrolizumab and 
give on Day 1 of next 
cycle.  Treat to 5 total 
doses. 
 
 


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<500 AND 
<50,000 
Omit gemcitabine and reduce by 1 dose level on 
day 15.  This dose reduction is permanent 
Delay pembrolizumab 
and give on Day 1 of 
next cycle.  Treat to 5 
total doses. 
 
 
6.3.3 Cohort II (and Cohort I-p); Arm B; Pembrolizumab Dose Modifications for 
Hematologic Toxicity  
In general, dose modifications for hematologic toxicity will follow chemotherapy-driven 
management guidelines.  While there may be hematologic parameter related delays for 
pembrolizumab, the future dose level and interval does not change.   
It is possible, however, to have a pembrolizumab attributable hematologic toxicity, including 
immune related events where a work up is warranted.  If suspected, the treating physician is 
encouraged to work up a suspected immune related hematologic toxicity and discuss a 
treatment plan with the sponsor-investigator.  A total of five pembrolizumab doses should be 
given, and may require additional dosing beyond chemotherapy in the case of delays.  
Permanent discontinuation should be considered for any severe or life-threatening event. 
 
Delays at start of cycle 
If initiation of a new gemcitabine cycle was: 
 Delayed for up to one week: the pembrolizumab dose (as well as gemcitabine) should 
be delayed until ANC ≥ 1,500 AND platelets ≥ 100,000 and the subject should restart 
pembrolizumab as originally described within that specific gemcitabine cycle (see 
Figure 3 or Table 4).  Subsequent intervals should revert to the prior dosing interval of 
every 3 weeks.    
o For example, if was scheduled to be dosed on Day 15 of a cycle where Day 1 was 
delayed for 6 days due to neutropenia; pembrolizumab should be dosed as 
originally sequenced on Day 15 once the new cycle begins (even though this 
means that the interval was 3 weeks and 6 days from the last dose, the subsequent 
interval should be 3 weeks).   
 
Delayed more than 1 week and less than 4 weeks: the pembrolizumab dose should be delayed 
until ANC ≥ 1,500 AND platelets ≥ 100,000.  Pembrolizumab should resume to the “sequence” 
within the current gemcitabine cycle (see Figure 3), subsequent intervals should remain the same 
as prior to the delay.  
 Delayed >4 weeks due to hematologic toxicity, discontinue all therapy and continue 
workup to optimize the subject for surgical consideration.   
 
6.3.4 Febrile Neutropenia 
For febrile neutropenia (defined here as temperature ≥ 38.5° C [101° F] sustained for more than 
one hour concomitant with ANC ≤ 500/mm3) reduce gemcitabine and cisplatin by one dose level 
for this and subsequent cycles.  Consider filgrastim or peg-filgrastim in subsequent cycles.    
 
6.3.5 Hepatic Dysfunction (See Table 6 below) 
Hepatic dysfunction should prompt consideration of workup for etiology such as medication and 
supplement review, infection, imaging, pancreatico-biliary evaluation, and amylase, lipase.  


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Consideration should be given to evaluation of concomitant pancreatitis in the appropriate 
setting.  This evaluation and workup is at the treating physician discretion.   
 
For bilirubin > 1.5 x ULN (or > 3 x ULN for subjects with Gilbert’s syndrome), delay 
pembrolizumab treatment until bilirubin ≤ 1.5 x ULN (< 3 x ULN for subjects with Gilbert’s 
syndrome), then resume with one dose level reduction of gemcitabine and at the previous dose of 
cisplatin. 
 
If bilirubin is > 1.5 x ULN despite two gemcitabine dose reductions, gemcitabine should be 
discontinued but cisplatin and pembrolizumab may be redosed when total bilirubin ≤ 1.5. For 
subjects with Gilbert's syndrome, if bilirubin is > 3 x ULN despite two gemcitabine dose 
reductions, gemcitabine and cisplatin should be permanently discontinued; treatment with 
pembrolizumab may continue once ≤ 3. 
 
Table 6:  Guidelines for Dose Modifications due to LFT abnormalities.   
LFT 
Gemcitabine2 
Cisplatin2 
Pembrolizumab  
AST/ALT >ULN to 2 
x ULN 
 
AND 
 
Total bilirubin >1.5 x 
ULN OR 
 
3 x ULN for subjects 
with Gilbert’s 
syndrome1 
Delay treatment until 
AST/ALT ≤ 2 x ULN and 
total bilirubin ≤ 1.5 x ULN (≤ 
3 x ULN for subjects with 
Gilbert’s syndrome1), then 
resume with one dose level 
reduction of gemcitabine. 
 
After 2 dose level reductions, 
gemcitabine should be 
discontinued.   
Delay treatment until 
AST/ALT ≤ 2 x ULN 
and total bilirubin ≤ 1.5 x 
ULN (≤ 3 x ULN for 
subjects with Gilbert’s 
syndrome1), then resume 
at previous dose of 
cisplatin.   
 
For subjects with 
Gilbert’s, discontinue 
both gemcitabine and 
cisplatin after 2 
occurrences of total 
bilirubin >1.5.  
Delay treatment until 
AST/ALT ≤ 3 x ULN and 
total bilirubin ≤ 1.5 x 
ULN (≤ 3 x ULN for 
subjects with Gilbert’s 
syndrome1), then resume 
at full dose for total of 5 
doses.     
AST/ALT > 2 x ULN 
to ≤ 8 x ULN 
 
AND 
 
Total bilirubin ≤ 1.5 x 
ULN OR  
 
≤ 3 for subjects with 
Gilbert’s syndrome1 
Delay treatment until 
AST/ALT ≤ 2 x ULN and 
total bilirubin ≤ 1.5 x ULN (≤ 
3 x ULN for subjects with 
Gilbert’s syndrome1), then 
resume with one dose level 
reduction of gemcitabine.   
 
Consider hepatologist consult. 
Delay treatment until 
AST/ALT ≤ 2 x ULN 
and total bilirubin ≤ 1.5 x 
ULN (≤ 3 x ULN for 
subjects with Gilbert’s 
syndrome1), then resume 
at previous dose of 
cisplatin.   
 
Consider hepatologist 
consult.   
Hold or discontinue 
pembrolizumab per below 
criteria.  
Monitor LFTs every 48 
hours until decreasing and 
then follow weekly.  If not 
improving consider biopsy 
and additional 
immunosuppressive 
agents. 
    
For grade 3, permanently 
discontinue and administer 
corticosteroids (initial 
dose of 1-2mg/kg/day 
prednisone or equivalent) 
followed by taper over at 
least 2-4 weeks. 
 
For grade 2, administer 
corticosteroids (initial 
dose of 0.5-1mg/kg/day 
prednisone or equivalent) 
followed by taper over 2-4 
weeks. 


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Criteria to restart after 
discussion with sponsor-
investigator include 
resolution to Grade 0 or 1 
and prednisone 
≤10mg/day.  
AST/ALT > 2 x ULN 
to ≤ 8 x ULN 
 
AND 
 
Total bilirubin > 1.5 x 
ULN OR 
 
3 for subjects with 
Gilbert’s syndrome1 
Delay treatment until 
AST/ALT ≤ 2 x ULN and 
total bilirubin ≤ 1.5 x ULN (≤ 
3 x ULN for subjects with 
Gilbert’s syndrome1), then 
resume with one dose level 
reduction of gemcitabine.   
 
After 2 dose level reductions, 
gemcitabine should be 
discontinued. 
 
Consider hepatologist consult. 
Delay treatment until 
AST/ALT ≤2 x ULN and 
total bilirubin ≤ 1.5 x 
ULN (≤3 x ULN for 
subjects with Gilbert’s 
syndrome1), then resume 
at previous dose of 
cisplatin.   
 
For subjects with 
Gilbert’s, discontinue 
both gemcitabine and 
cisplatin after 2 
occurrences of total 
bilirubin >1.5.   
 
Consider hepatologist 
consult.   
Hold or discontinue 
pembrolizumab per below 
criteria.  
Monitor LFTs every 48 
hours until decreasing and 
then follow weekly.  If not 
improving consider biopsy 
and additional 
immunosuppressive 
agents. 
    
For grade 3, permanently 
discontinue and administer 
corticosteroids (initial 
dose of 1-2mg/kg/day 
prednisone or equivalent) 
followed by taper over at 
least 2-4 weeks. 
 
For grade 2, administer 
corticosteroids (initial 
dose of 0.5-1mg/kg/day 
prednisone or equivalent) 
followed by taper over 2-4 
weeks. 
 
Criteria to restart after 
discussion with sponsor-
investigator include 
resolution to Grade 0 or 1 
and prednisone 
≤10mg/day.  
 
 


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AST/ALT > 8 x ULN 
 
AND 
 
Total Bilirubin any 
level 
Delay treatment until 
AST/ALT ≤ 2 x ULN and 
total bilirubin ≤ 1.5 x ULN (≤ 
3 x ULN for subjects with 
Gilbert’s syndrome1), then 
resume with one dose level 
reduction of gemcitabine. 
 
Consider hepatologist consult. 
Delay treatment until 
AST/ALT ≤ 2 x ULN 
and total bilirubin ≤ 1.5 x 
ULN (≤3 x ULN for 
subjects with Gilbert’s 
syndrome1), then resume 
at previous dose of 
cisplatin.   
 
For subjects with 
Gilbert’s, discontinue 
both gemcitabine and 
cisplatin after 2 
occurrences of total 
bilirubin > 1.5. 
 
Consider hepatologist 
consult.   
Discontinue 
pembrolizumab.  
Consider inpatient 
admission.  If not 
improving consider biopsy 
and additional 
immunosuppressive 
agents. 
    
For grade 3 or 4, 
permanently discontinue 
and administer 
corticosteroids (initial 
dose of 1-2mg/kg/day 
prednisone or equivalent) 
followed by taper over at 
least 2-4 weeks. 
Any missed dose(s) will 
not be made up.  
1Subject must have a previous diagnosis of Gilbert’s syndrome documented in their medical record prior to study initiation.   
 
For grade 3 sensory or motor neuropathy, skip cisplatin until the toxicity resolves to ≤grade 2 
and then resume therapy with one dose level reduction of cisplatin on Day 1 of the next 
scheduled cycle. If cisplatin is skipped for two consecutive cycles, permanently discontinue 
cisplatin. Treatment with gemcitabine and pembrolizumab may continue. 
 
For grade 4 sensory or motor neuropathy, skip gemcitabine and cisplatin therapy until resolution 
to ≤ grade 2.  Finish the current cycle planned doses of pembrolizumab.  If sensory neuropathy 
improves to grade 3, but not grade 2 or better, within 4 weeks, resume gemcitabine at the 
previous dose and pembrolizumab without cisplatin.  If the sensory neuropathy remains at grade 
4 within 4 weeks, dose remaining pembrolizumab treatments and discontinue gemcitabine and 
cisplatin, then prepare the subject for surgery within 2-7 weeks after the final dose of 
pembrolizumab.   
 
6.3.6 Gastrointestinal Toxicity 
For grade 3 or 4 nausea or vomiting despite maximal antiemetic therapy (including 5HT-3 
antagonist, corticosteroids up to 5 days, and aprepitant), discontinue cisplatin. Continue 
gemcitabine and pembrolizumab at the previous dose when symptoms resolve to ≤ grade 1. 
 
6.4 Cohort I; Cisplatin-Eligible; Subjects becoming Cisplatin-Ineligible Kidney 
Dysfunction   
A Ccr from properly collected timed (24 hours; 18-24 hours acceptable) urine supersedes a 
calculated value for determination of cisplatin eligibility and dosing.  Accuracy of timed urine 
collection, however, is dependent on patient compliance; proper collection adherence should be 
confirmed with the patient.  Improper collection methods disqualify use of the timed collection 
results and a calculated serum value should be used.    
 
For creatinine clearance < 50 mL/min (measured or calculated) on Day 1 of a cycle, delay all 
treatment until creatinine clearance improves to ≥ 50 mL/min as follows: 
 


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 If creatinine clearance improves to ≥ 60 mL/min within 1 week, resume with one dose 
level reduction for cisplatin and gemcitabine for all subsequent doses, and continue 
pembrolizumab at the same dose and schedule.   
 If creatinine clearance improves to ≥ 50 and < 60 mL/min within 1 week, resume with 
one dose level reduction of cisplatin for this and all subsequent cycles. Administer 
cisplatin as a split dose on Days 1 and 2 (preferred) or Days 1 and 8 of this cycle. Resume 
gemcitabine at the same dose level and continue pembrolizumab at the same dose and 
schedule.   
 If creatinine clearance does not improve to ≥ 50 mL/min within 1 week, skip cisplatin for 
this cycle only. Treat with cisplatin at one lower dose level for this and all subsequent 
cycles with split dosing over Days 1&2 (or Days 1 and 8, per treating physician 
discretion as previously described) and pembrolizumab at the same dose and schedule.  
For a subsequent cycle, if creatinine clearance is again < 50 mL/min, discontinue 
cisplatin [Cohort “I-no platinum” (or, cohort I-p) will be used to refer to those Cohort 
I subjects that have permanently discontinued cisplatin] and treat as follows:  
o If the subject becomes cisplatin ineligible (for renal, neurologic, auditory, or other 
reason per site investigator) after 1 or 2 cycles on Arm A, he or she may continue 
on study in this manner:  switched to cohort I-p and follow Arm B treatment and 
guidelines for the remaining treatments: maximum 3 cycles with gemcitabine 
weekly for three weeks and repeated every 4 weeks.  For instance, if a subject 
completes 1 cycle on Arm A and then continues their treatment according to Arm 
B guidelines, they are referred to as “Cohort I-p” and should complete an 
additional 2 cycles per the Arm B regimen.  Five doses of pembrolizumab should 
still be given.  A discussion with the HCRN project manager to determine the 
proper transition is encouraged.   
o If the subject becomes cisplatin ineligible (for renal, neurologic, auditory, or other 
reason per site investigator) after completion of 3 cycles of therapy on Arm A, he 
or she may continue on study in this manner: switched to cohort I-p and follow 
Arm A and withhold cisplatin for the final fourth cycle.  Treatment should 
continue with gemcitabine on Day 1 and 8 at the prior dose, and pembrolizumab 
should continue for all 5 doses.  
 
For Cohort I cisplatin eligible subjects: Grade 3 or 4 acute kidney injury will be attributed to 
cisplatin.  Subject may continue treatment per guidelines as a Cohort I-p subject as described 
above.  The pembrolizumab dose/schedule will not be modified unless an immune related 
nephritis is determined with serology, urine studies, and/or supporting biopsy and discussed with 
the sponsor-investigator.  Patients with renal dysfunction will be attributed to cisplatin and not 
pembrolizumab for the purposes of drug modifications (and in this case, re-assignment from 
cohort I to I-p).  Table 5 pembrolizumab dose modifications and discontinuation for renal 
toxicity should only be followed if the etiology is determined to be immune-mediated with 
serology, urine studies, and/or supporting biopsy.   
 
On Day 2 or 8 renal labs are not required though may be obtained per treating physician 
discretion during split-dose cisplatin.  If creatinine clearance < 50 mL/min (measured or 
calculated), skip cisplatin for this day (applies only if split-dose cisplatin is indicated for this 


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cycle).  Reduce cisplatin by one lower dose level for all subsequent doses. Refer to section 5.8.2 
above for dose modifications for Day 1 dosing for the next cycle. 
 
6.4.1 Gemcitabine Non-Hematologic Toxicity 
Grade 
Dose Modification 
0-2
Full dose
3-4 
Hold until resolution to ≤ Grade 2, then decrease by 1 dose level from 
current dose.  This dose reduction is not permanent.  If toxicity does not 
resolve within 4 weeks, discontinue gemcitabine treatment.  
 
Grade 3/4 nausea or vomiting only requires dose modifications if it persists > 24 hours despite 
adequate antiemetic medication. Grade 3/4 adverse events not related to treatment such as a 
thrombosis, pulmonary embolus or non-neutropenic infection do not require dose reductions 
when treatment is resumed. 
 
For suspected > Grade 2 pneumonitis, suspect pembrolizumab per Table 5 (despite gemcitabine a 
known confounder) and initiate treatment per Table 8 below.   
 
6.5 
Supportive Care for Other Toxicities 
Subjects should receive appropriate supportive care measures as deemed necessary by the site 
investigator including but not limited to the items outlined below: 
 
6.5.1 Diarrhea  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).  In symptomatic subjects, infectious etiologies should be ruled out, 
and if symptoms are persistent and/or severe, endoscopic evaluation should be considered. 
 In subjects with severe enterocolitis (Grade 3), pembrolizumab will be permanently 
discontinued and treatment with systemic corticosteroids should be initiated at a dose of 1 
to 2 mg/kg/day of prednisone or equivalent.  When symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and continued over at least 1 month. 
 In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be withheld and 
anti-diarrheal treatment should be started.  If symptoms are persistent for more than one 
week, systemic corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or 
equivalent).  When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month.  Regarding guidelines for continuing 
treatment with pembrolizumab.  
 All subjects who experience diarrhea should be advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. 
 
6.5.2 Nausea and Vomiting  
Nausea and vomiting should be treated aggressively, and consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy according to standard 
institutional practice.  Subjects should be strongly encouraged to maintain liberal oral fluid 
intake. 


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6.5.3 Anti-Infectives  
Subjects with a documented infectious complication should receive oral or IV antibiotics or other 
anti-infective agents as considered appropriate by the site investigator for a given infectious 
condition, according to standard institutional practice. 
 
6.5.4 Management of Infusion Reactions  
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 of acute infusion reactions 
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; Pruritus/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor 
pain due to treatment); Urticaria (hives, welts, wheals); Vomiting.  See Table 7 below: 
 
 
 


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Table 7:  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs 
Stop Infusion. 
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 participant is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 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 participant should 
be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study drug treatment 
Participant may be premedicated 
1.5h (± 30 minutes) prior to infusion 
of _____ with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine 
should be used immediately. 
Participant is permanently discontinued 
from further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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6.5.5 
Pneumonitis 
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 pembrolizumab 
associated pneumonitis, the suggested treatment plan is detailed in Table 8. 
 
Table 8 Recommended Approach to Pneumonitis 
Pembrolizumab 
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 12 weeks
Systemic corticosteroids are indicated 
with an initial dose of 1-2mg/kg/day 
prednisone or equivalent followed by 
taper.   
Grade 3 and 
Grade 4 
Discontinue 
pembrolizumab 
Systemic corticosteroids are indicated 
with an initial dose of 1-2mg/kg/day 
prednisone or equivalent followed by 
taper. Consider additional non-
corticosteroid immunosuppression if 
warranted.  Add prophylactic antibiotics 
for opportunistic infections.     Refer to 
the Event of Clinical Interest and 
Immune-related Adverse Event 
Guidance Document for additional 
recommendations.
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules should 
apply: 
 
 First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
 Second episode of pneumonitis 
o Permanently discontinue pembrolizumab if, upon rechallenge, the subject develops 
pneumonitis  Grade 2 
 
7. 
TREATMENT DISCONTINUATION 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the site investigator should any untoward effect occur.  In addition, a subject may 
be withdrawn by the site investigator or the sponsor-investigator/HCRN if enrollment into the 
trial is inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.   
 
If subjects discontinue gemcitabine/cisplatin or gemcitabine chemotherapy treatment due to 
toxicity commonly associated with cytotoxic chemotherapy (such as neuropathy, hearing loss), 


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the patient may elect to receive gemcitabine with pembrolizumab (as in Cohort I-p) or alone per 
the protocol schedule every 3 weeks for a total of 5 doses, or may go off study and choose 
second-line treatment, after consultation with the treating physician and HCRN/sponsor-
investigator.  This does not apply due to gemcitabine related grade 3 or 4 myelopsuppression or 
those with persistent/refractory myelosuppression. 
 
7.1. 
Reasons for Discontinuing Study Treatment 
A subject will be discontinued from the treatment under the following circumstances: 
 Biopsy confirmed radiographic disease progression 
 If the treating physician thinks a change of therapy would be in the best interest of the 
subject. 
 Intercurrent illness that prevents further administration of treatment 
 If the drug(s) exhibit(s) an unacceptable adverse event. 
 If a subject becomes pregnant or is unwilling to use appropriate birth control techniques as 
outlined in the inclusion criteria 
 If there is a treatment interruption for greater than 4 weeks due to treatment related adverse 
event. 
 Subjects can stop participating at any time. However, if they decide to stop participating 
in the study, subjects will continue to be followed for disease progression and survival. 
 
7.2. 
Reasons for Withdrawal from Study 
 Subject withdraws consent for participation 
 Termination of the study 
 Lost to follow-up 
 Death 


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8. 
STUDY SCHEDULE OF EVENTS:  
 
8.1. 
Phase Ib/Cohort I and Phase II/Cohort I/Arm A:  Cisplatin-eligible (cycle = 21 days) 
 
Trial Period:
Screen 
Treatment Cycles 
End of 
Treatment8 
Surgery 
Post-Treatment 
Safety 
Follow-up8 
Survival 
Follow-Up9
Treatment Cycle/Title:
Screen 
Cycle 1 
Cycles 2-4 
Cycle 5 
 
2-7wks 
post 
pembro
30 days post 
EOT 
Every 12 
weeks 
1 
2 
8 
15 
1 
2 
8 
15 
1 
8 
15 
 
 
 
 
Scheduling Window (Days):
-28 to -1
±3 
±1 
±1 
±1 
±3 
±1 
±1 
±1 
±1 
±1 
±1 
 
 
-7/+14 
±14 
REQUIRED ASSESSMENTS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
Vital Signs and Weight 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
Prior and Concomitant Medication 
Review
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
Review Adverse Events 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
Post-study outcome: RFS, OS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY ASSESSMENTS 
Pregnancy Test – Urine or Serum 
β-HCG1
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Comprehensive Metabolic Panel 
and LDH
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
TSH2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
DISEASE ASSESSMENT 
Tumor Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
< 21 days 
pre surgery
 
X 
 
 


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Trial Period:
Screen 
Treatment Cycles 
End of 
Treatment8 
Surgery 
Post-Treatment 
Safety 
Follow-up8 
Survival 
Follow-Up9
Treatment Cycle/Title:
Screen 
Cycle 1  
Cycles 2-4 
Cycle 5 
 
2-7wks 
post 
pembro
30 days post 
EOT 
Every 12 
weeks 
1 
2 
8 
15 
1 
2 
8 
15 
1 
8 
15 
 
 
 
 
Scheduling Window (Days):
-28 to -1
±3 
±1 
±1 
±1 
±3 
±1 
±1 
±1 
±1 
±1 
±1 
 
 
-7/+14 
±14 
TREATMENT EXPOSURE 
Gemcitabine 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Cisplatin (Ccr of ≥ 60 mL/min) 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Cisplatin (Ccr of 50-59 mL/min) 
 
X 
X 
opt 
 
X 
X 
opt 
 
 
 
 
 
 
 
 
Pembrolizumab7 
 
 
 
X 
 
 
 
X 
 
 
X7 
 
 
 
 
 
CORRELATIVE STUDIES 
Unstained Slides-Mandatory3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood collection for PBMC 
analysis OPTIONAL4
 
X 
 
pre&~
D113 
 
 
 
 
 
 
 
 
 
 
 
 
Serum collection for autoimmune 
analysis MANDATORY5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue collection from radical 
cystectomy- OPTIONAL6
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Calendar footnotes: 
opt:  See section 5.5.4- Split-dose cisplatin is on a Day 1 and 2 regimen to avoid overlap of dexamethasone with pembrolizumab treatment.  With documentation of 
extenuating circumstances, an alternative Day 1 and 8 regimen (and not Day 1 and 2) is acceptable.   
1: For females of child bearing potential 
2: TSH will be collected at screening and safety follow up visit.  Monitoring of additional thyroid tests (ex. T3 and FT4) as well as monitoring of thyroid function at 
additional time points are at the site investigator’s discretion. 
3: MANDATORY: Identify for submission unstained slides from archival tissue collection for PD-L1 expression, basal and luminal subtype analysis. Subjects should be 
encouraged to undergo a biopsy prior to starting therapy if archived tumor tissue is not available and sufficient neoplastic tissue is thought to exist. See SPM for 
collection, labeling and shipping instructions. 
4: OPTIONAL whole blood collection for future PBMC extraction and analysis to be collected at: at pre-treatment Cycle 1 Day 1, pretreatment Cycle 1 Day 8 and Cycle 
1 Day 11 to Day 15 (although closer to Day 11 is preferred).  See SPM for collection, processing and shipping instructions. 
5: Serum collection for subsequent autoimmune analysis.  These samples will be banked, and analyzed if a subject develops autoimmune phenomenon on study. If the 
subject does not develop an autoimmune phenomenon the sample will be stored for future cancer related research 
6: OPTIONAL tissue from radical cystectomy or NU to be collected at the time of surgery. Subjects participating at UH Seidman Cancer Center/Case Comprehensive 
Cancer Center will submit fresh frozen cores for analysis.  Other participating centers may submit FFPE block or unstained slides if unable to submit fresh frozen cores.  
See SPM for additional details. 
7: The last dose of Pembrolizumab falls on what would be day 8 of a 5th cycle, however gemcitabine-cisplatin is NOT GIVEN. 
 
 


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8: Post Treatment Safety Follow-Up Visit: This visit should be conducted approximately 30 days (-7/+14) after the last dose of trial treatment or before the initiation of a 
new anti-cancer treatment, whichever comes first.  All subjects should have a safety follow up visit after discontinuation of study treatment whether for progression, 
toxicity or other reasons.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with a treatment related 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.  The pre-cystectomy surgery visit and post treatment safety follow up 
may be combined on the same day but the treating medical oncologist must do the toxicity assessment. 
9: Post-Treatment Survival Follow-up: Subjects will be followed for 18 months post-surgery. If the subject experiences POD, biopsy should be considered to confirm.  
Tumor imaging to be performed within 21 days prior to surgery and every 12 weeks thereafter for 18 months from end of treatment while on study.  Follow up may be 
done ± 14 days.  After 18 months, subjects will be followed for survival every 6 months for 5 years from the end of treatment or until the study is terminated, whichever 
occurs first.  
 
 
 
 


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8.2 
Phase II/Cohort II/Arm B: Cisplatin-Ineligible: (cycle = 28 days) 
 
Trial Period:
Screen 
Treatment Cycles 
End of 
Treatment8 
Surgery 
Post-Treatment 
Safety 
Follow-up8
Survival 
Follow-
Up9 
Treatment Cycle/Title:
Screen 
Cycle 1  
Cycle 2-3 
Cycle 4 
 
2-7wks 
post 
pembro 
30 days 
post EOT 
Every 12 
weeks 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15
22 
Scheduling Window (Days):
-28 to -1 
±3 
±1 
±1 
±1 
±3 
±1 
±1 
±1 
±1
±1
±1
±1 
 
 
-7/+14 
±14 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
Vital Signs and Weight 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
Prior and Concomitant Medication 
Review
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Review Adverse Events 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
Post-study outcome: RFS, OS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY ASSESSMENTS 
Pregnancy Test: 
Urine or Serum β-HCG1
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
Comprehensive Metabolic Panel and 
LDH
X 
X 
 
 
 
X 
 
3D15
2D22
 
X 
 
 
X 
X 
X 
X 
TSH2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
DISEASE ASSESSMENT 
Tumor Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
<21d pre 
cystect 
omy
 
X 
TREATMENT EXPOSURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gemcitabine 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
 
 
X 
 
 
2D1  
3D15 
2D22  
X7  
 
 
 
 
 


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Trial Period:
Screen 
Treatment Cycles 
End of 
Treatment8 
Surgery 
Post-Treatment 
Safety 
Follow-
up8 
Survival 
Follow-
Up9 
Treatment Cycle/Title:
Screen 
Cycle 1  
Cycle 2-3 
Cycle 4 
 
2-7wks post 
pembrolizuma
b  
30 days 
post 
D/C 
Every 12 
weeks 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15
22 
Scheduling Window (Days):
-28 to -1 
 
±1 
±1 
±1 
±3 
±1 
±1 
±1 
±1
±1
±1
±1 
 
 
-7/+14 
±14 
CORRELATIVE STUDIES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unstained Slides-Mandatory3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood Collection for PBMC 
analysis- OPTIONAL4 
 
X 
pre&~
D113 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum collection for autoimmune 
analysis MANDATORY5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue collection from radical 
cystectomy- OPTIONAL6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Calendar footnotes: 
1: For females of child bearing potential 
2: TSH will be collected at screening and safety follow up visit.  Monitoring of additional thyroid tests (ex. T3 and FT4) as well as monitoring of thyroid function at 
additional time points are at the site investigator’s discretion. 
3: MANDATORY: Identify for submission unstained slides from archival or newly obtained tissue collection for PD-L1 expression, basal and luminal subtype analysis. 
Subjects should be encouraged to undergo a biopsy prior to starting therapy if archived tumor tissue is not available and sufficient neoplastic tissue is thought to exist.  
See SPM for collection, labeling and shipping instructions. 
4: OPTIONAL whole blood collection for future PBMC extraction and analysis to be collected at: at pre-treatment Cycle 1 Day 1, pretreatment Cycle 1 Day 8 and Cycle 
1 Day 11 to Day 15 (closer to Day 11 preferred).  See SPM for collection, processing and shipping instructions. 
5: Serum collection for subsequent autoimmune analysis.  These samples will be banked, and analyzed if a subject develops autoimmune phenomenon on study. If the 
subject does not develop an autoimmune phenomenon the sample will be stored for future cancer related research. 
6: OPTIONAL tissue from radical cystectomy or NU to be collected at the time of surgery. Subjects participating at UH Seidman Cancer Center/Case Comprehensive 
Cancer Center will submit fresh frozen cores for analysis.  Other participating centers may submit FFPE block or unstained slides if unable to submit fresh frozen cores.  
See SPM for additional details. 
7: The last dose of pembrolizumab falls on what would be day 8 of a 4th cycle, however gemcitabine is NOT GIVEN. 
8: Post Treatment Safety Follow-Up Visit: This visit should be conducted approximately 30 days (-7/+14) after the last dose of trial treatment or before the initiation of a 
new anti-cancer treatment, whichever comes first.  All subjects should have a safety follow up visit after discontinuation of study treatment whether for progression, 
toxicity or other reasons.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with a treatment related 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.  The pre-cystectomy surgery visit and post treatment safety follow up 
may be combined on the same day but the treating medical oncologist must do the toxicity assessment.  
9: Post-Treatment Survival Follow-up: Subjects will be followed for 18 months post-surgery. If the subject experiences POD, biopsy should be considered to confirm.  
Tumor imaging to be performed within 21 days prior to surgery and every 12 weeks thereafter for 18 months from end of treatment while on study.  Follow up may be 
done ± 14 days.  After 18 months, subjects will be followed for survival every 6 months for 5 years from the end of treatment or until the study is terminated, whichever 
occurs first.  


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8.3 
Phase Ib/Cohort I and Phase II/Cohort I/Arm A: Cisplatin eligible 
8.3.1 Screening (within 28 days prior to registration for study unless otherwise specified) 
 Informed consent 
 Physical exam 
 Concomitant medication review  
 Review adverse events and events of clinical interest 
 Vital signs, weight and height (height during Screening ONLY) 
 ECOG performance status 
 Laboratory Assessments 
o Pregnancy test- urine or serum BHCG for FOCBP 
o PT/INR and aPTT 
o CBC with differential and platelet 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total 
protein,  
o Lactate Dehydrogenase (LDH),  
o Urinalysis (to include blood, glucose, protein, specific gravity, microscopic (if 
abnormal results are noted 
o T3, FT4 and TSH 
 Imaging studies: CT abdomen/pelvis at minimum.  A pelvic MRI may be done in lieu of CT 
abdomen/pelvis per treating physician discretion and local conventional practice. CT of the 
chest should be done only if clinically indicated at the discretion of the site investigator. 
 
8.3.2 Cycle 1 Day 1 
 Physical Exam 
 Concomitant medication review  
 Review adverse events and events of clinical interest 
 Vital Signs including weight  
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total 
protein,  
o Lactate Dehydrogenase (LDH),  
o MANDATORY: Serum collection for subsequent autoimmune analysis.  These 
samples will be banked for future cancer related research if not analyzed for an 
autoimmune phenomenon. Permission will be obtained per informed consent. 
o OPTIONAL: PRE dose whole blood collection for future PBMC extraction and 
analysis  
 Gemcitabine administration 
 Cisplatin administration: For Ccr ≥ 50 and < 60 mL/min Cisplatin given in split dose  


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 MANDATORY: Identify for submission unstained slides from archival tissue collection 
when available and strongly encourage re-biopsy if the subject agrees and has sufficient 
retained neoplastic tissue available 
 
8.3.3 Cycle 1 Day 2 (± 3 day) 
 Cisplatin administration: For Ccr ≥ 50 and < 60 mL/min Cisplatin given in split dose  
 
8.3.4 Cycle 1 Day 8 (±1 day) 
 Laboratory Assessment 
o CBC with differential and platelet count 
o OPTIONAL: PRE dose whole blood collection for future PBMC extraction and analysis  
 Gemcitabine administration 
 OPTIONAL: If Cisplatin NOT GIVEN on C1D2; may be given C1D8 with appropriate 
documentation why C1D2 is not feasible  
 Pembrolizumab administration 
 
8.3.5 Cycle 1 Day 11-15 
 Laboratory Assessment 
o OPTIONAL: PRE dose whole blood collection for future PBMC extraction and analysis.  
Time point closer to Day 11 is preferred when able.   
 
8.3.6 Cycle 1 Day 15 (± 1 day) 
 No scheduled procedures or treatments 
 
8.3.7 Cycle 2-4 Day 1 (± 3 days) 
 Physical Exam  
 Concomitant medication review 
 Review adverse events and events of clinical interest 
 Vital Signs including weight 
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein,  
o Lactate Dehydrogenase (LDH) 
 Gemcitabine administration 
 Cisplatin administration: For Ccr ≥ 50 and < 60 mL/min Cisplatin given in split dose  
 
8.3.8 Cycles 2-4 Day 2 (± 1 day) 
 Cisplatin administration: For Ccr ≥ 50 and < 60 mL/min Cisplatin given in split dose 
 
 
 
 


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8.3.9 Cycles 2-4 Day 8 (± 1 day) 
 Laboratory Assessment 
o CBC with differential and platelet count 
 OPTIONAL: If Cisplatin NOT GIVEN on C1D2; may be given C1D8 with appropriate 
documentation why C1D2 is not feasible  
 Pembrolizumab administration 
 
8.3.10 Cycles 2-4 Day 15 (± 1 day) 
 No scheduled procedures or treatments 
 
8.3.11 Cycle 5 Day 1 (± 1 day) 
 No scheduled procedures or treatments 
 
8.3.12 Cycle 5 Day 8 (± 1 day) 
 Physical Exam  
 Concomitant medication review 
 Review adverse events and events of clinical interest 
 Vital Signs including weight  
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein  
o Lactate Dehydrogenase (LDH) 
 Pembrolizumab administration 
 
8.3.13 End of Treatment (EOT) 
 Physical Exam  
 Review adverse events and events of clinical interest 
 Vital Signs including weight  
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein  
o Lactate Dehydrogenase (LDH) 
 
8.3.14 Surgery (2-7 weeks post last dose Pembrolizumab) 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein,  


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o Lactate Dehydrogenase (LDH),  
o Urinalysis (to include blood, glucose, protein, specific gravity, microscopic (if abnormal 
results are noted 
 Optional tissue from radical cystectomy or NU to be collected at the time of surgery. 
Subjects participating at UH Seidman Cancer Center/Case Comprehensive Cancer Center 
will submit fresh frozen cores for analysis, and is an option for other institutions where 
resources exist. Other participating centers will submit FFPE block, or unstained slides 
 Tumor Imaging-CT Abdomen/ Pelvis is obtained post chemotherapy and within 21 days 
prior to consolidative surgery.  A pelvic MRI may be obtained instead per treating physician 
standard practice 
 
8.3.15 Safety follow up visit; 30 days (-7/+14) after last dose of pembrolizumab  
 Review adverse events and events of clinical interest: all AEs that occur prior to the Safety 
Follow-Up Visit should be recorded. Subjects with a treatment related 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. 
 Physical Exam  
 Vital Signs including weight 
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein,  
o Lactate Dehydrogenase (LDH),  
o TSH, FT4, T3 
 
8.3.16 Relapse and Survival follow up (± 14 days) every 12 weeks up to 18 months post-
surgery 
 Physical Exam  
 Review adverse events and events of clinical interest 
 Vital Signs including weight and height 
 ECOG performance status 
 Laboratory Assessments 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein,  
o Lactate Dehydrogenase (LDH),  
 Restaging with a CT chest/abdomen/pelvis to be performed.  If the subject experiences POD, 
a biopsy should be considered to confirm. 
 After 18 months, subjects will be followed for survival every 6 months for 5 years from the 
end of treatment or until the study is terminated, whichever occurs first.  
 


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8.4 
Phase II/Cohort II/Arm B: Cisplatin Ineligible: 
 
8.4.1 Screening (within 28 days prior to registration for study unless otherwise specified) 
 Informed consent 
 Physical exam 
 Concomitant Medication Review 
 Review adverse events and events of clinical interest 
 Vital signs, weight and height (height during Screening ONLY) 
 ECOG performance status 
 Laboratory Assessments 
o Pregnancy test- urine or serum BHCG for FOCBP 
o PT/INR and aPTT 
o CBC with differential and platelet 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein,  
o Lactate Dehydrogenase (LDH),  
o Urinalysis (to include blood, glucose, protein, specific gravity, microscopic (if abnormal 
results are noted 
o T3, FT4 and TSH 
 Imaging studies: CT abdomen/pelvis at minimum.  A pelvic MRI may be done in lieu of CT 
abdomen/pelvis per treating physician discretion and local conventional practice. CT of the 
chest should be done only if clinically indicated at the discretion of the site investigator. 
 
8.4.2 Cycle 1 Day 1 
 Physical Exam 
 Concomitant medication review 
 Review adverse events and events of clinical interest 
 Vital Signs including weight  
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein 
o Lactate Dehydrogenase (LDH) 
o MANDATORY: Serum collection for subsequent autoimmune analysis.  These samples 
will be banked for future cancer related research if not analyzed for autoimmune 
phenomenon. Permission will be obtained per informed consent. 
o OPTIONAL: PRE dose whole blood collection for future PBMC extraction and analysis  
 Submission of unstained slides from archival tissue collection; MANDATORY 
 Gemcitabine administration 
 
 
 


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8.4.3 Cycle 1 Day 8 (±1 day) 
 Laboratory Assessments 
o CBC with differential and platelet count 
o OPTIONAL: PRE dose whole blood collection for future PBMC extraction and analysis  
 Gemcitabine administration 
 Pembrolizumab administration 
 
8.4.4 Cycle 1 Day 11-15 
 Laboratory Assessment 
o OPTIONAL: PRE dose whole blood collection for future PBMC extraction and analysis.  
Time point closer to Day 11 is preferred when able.   
 
8.4.5 Cycle 1 Day 15 (± 1 day) 
 Laboratory Assessment 
o CBC with differential and platelet count 
 Gemcitabine administration 
 
8.4.6 Cycle 1 Day 22 (± 1 day) 
 No scheduled procedures or treatments 
 
8.4.7 Cycle 2-3 Day 1 (± 3 days) 
 Physical Exam  
 Concomitant medication review 
 Review adverse events and events of clinical interest 
 Vital Signs including weight 
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein  
o Lactate Dehydrogenase (LDH)  
 Gemcitabine administration 
 CYCLE 2 DAY 1 ONLY: Pembrolizumab administration 
 
8.4.8 Cycles 2-3 Day 8 (± 1 day) 
 Laboratory Assessment 
o CBC with differential and platelet count 
 Gemcitabine administration 
 
 
 


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8.4.9 Cycles 2-3 Day 15 (± 1 day) 
 Laboratory Assessments 
o CBC with differential and platelet count 
o CYCLE 3 DAY 15 ONLY: Comprehensive metabolic profile to include: albumin, alk 
phos, ALT, AST, BUN and creatinine, CO2 or bicarbonate (if SOC at site), calcium, 
chloride, glucose, potassium, sodium, magnesium, total bilirubin, direct bilirubin (if total 
bili is > ULN), total protein 
o CYCLE 3 DAY 15 ONLY: Lactate Dehydrogenase (LDH),  
 Gemcitabine administration 
 CYCLE 3 DAY 15 ONLY: Pembrolizumab administration 
 
8.4.10 Cycle 2-3 Day 22 (± 1 day) 
 Laboratory Assessments 
o CYCLE 2 DAY 22 ONLY: Comprehensive metabolic profile to include: albumin, alk 
phos, ALT, AST, BUN and creatinine, CO2 or bicarbonate (if SOC at site), calcium, 
chloride, glucose, potassium, sodium, magnesium, total bilirubin, direct bilirubin (if total 
bili is > ULN), total protein  
o CYCLE 2 DAY 22 ONLY: Lactate Dehydrogenase (LDH)  
 CYCLE 2 DAY 22 ONLY: Pembrolizumab administration 
 
8.4.11 Cycle 4 Day 1 (± 1 day) 
 No scheduled procedures or treatments 
 
8.4.12 Cycle 4 Day 8 (± 1 day) 
 Physical Exam  
 Concomitant medication review 
 Review adverse events and events of clinical interest 
 Vital Signs including weight  
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein  
o Lactate Dehydrogenase (LDH) 
 Pembrolizumab administration 
 
8.4.13 End of Treatment (EOT) 
 Physical Exam  
 Review adverse events and events of clinical interest 
 Vital Signs including weight  
 ECOG performance status 
 
 


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 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein  
o Lactate Dehydrogenase (LDH)  
 
8.4.14 Surgery (2-7 weeks post last dose pembrolizumab) 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein,  
o Lactate Dehydrogenase (LDH),  
o Urinalysis (to include blood, glucose, protein, specific gravity, microscopic (if abnormal 
results are noted 
 Tumor Imaging-CT Abdomen/ Pelvis is obtained post chemotherapy and within 21 days 
prior to consolidative surgery.  A pelvic MRI may be obtained instead per treating physician 
standard practice 
 OPTIONAL tissue from radical cystectomy or NU to be collected at the time of surgery. 
Subjects participating at UH Seidman Cancer Center/Case Comprehensive Cancer Center 
will submit fresh frozen cores for analysis, and is an option for other institutions where 
resources exist.  Other participating centers will submit FFPE block or unstained slides 
 
8.4.15 Safety follow up visit; 30 days (-7/+14) after last dose of pembrolizumab  
 Review adverse events and events of clinical interest: all AEs that occur prior to the Safety 
Follow-Up Visit should be recorded. Subjects with a treatment related 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. 
 Vital Signs including weight 
 ECOG performance status 
 Laboratory Assessments 
o CBC with differential and platelet count 
o Comprehensive metabolic profile (albumin, alk phos, ALT, AST, LDH, C02 or 
bicarbonate (if standard of care at site), uric acid, calcium, chloride, glucose, phosphorus, 
potassium, sodium, magnesium, total bilirubin, direct bilirubin (if total bilirubin is 
>ULN), total protein, BUN, creatinine 
o TSH, FT4, T3 
 
8.4.16 Relapse and Survival follow up (± 14 days) every 12 weeks up to 18 months post-
surgery 
 Physical Exam  
 Review adverse events and events of clinical interest 
 Vital Signs including weight and height 


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 ECOG performance status 
 Laboratory Assessments 
o Comprehensive metabolic profile to include: albumin, alk phos, ALT, AST, , BUN and 
creatinine, CO2 or bicarbonate (if SOC at site), calcium, chloride, glucose, potassium, 
sodium, magnesium, total bilirubin, direct bilirubin (if total bili is > ULN), total protein  
o Lactate Dehydrogenase (LDH)  
 Restaging with a CT chest/abdomen/pelvis to be performed.  If the subject experiences POD, 
a biopsy should be considered to confirm. 
 After 18 months, subjects will be followed for survival every 6 months for 5 years from the 
end of treatment or until the study is terminated, whichever occurs first.  
 
8.5 
Pre-operative and Post-Operative Restaging Evaluation 
CT Abdomen, Pelvis is obtained post neoadjuvant chemotherapy within 21 days prior to 
consolidative surgery.  A pre-operative pelvic MRI may be done instead per site investigator’s 
discretion.  CT Chest, Abdomen, Pelvis 12 weeks post operatively and every 3 months thereafter 
for restaging follow-up.  Subjects with restaging scans that are concerning for relapse should be 
considered for pathologic confirmation.  RECISTv1.1 and irRC evaluation.   
 
8.6 
End of Treatment (EOT) 
Vital signs, history and physical exam, ECOG performance status, CBC and differential, 
comprehensive metabolic profile with LFTs, and review of adverse events should all be 
performed at end of treatment or discontinuation of treatment.  This may occur after dose 5 
pembrolizumab and surgery, or if treatment is discontinued for toxicity.     
 
8.7 
Follow up 
Subject should have a history and physician exam with treating oncologist every 12 weeks (±14 
days) including evaluation of restaging scans, delayed toxicities and performance status.   
 
9 
CRITERIA FOR DISEASE EVALUATION 
Primary efficacy endpoint response is determined at radical cystectomy and lymph node 
dissection (or nephroureterectomy) where the pTNM is compared to the initial clinical TNM 
stage (cTNM) assessed at study entry.  Investigators should work with their team of pathologists 
and urologists to determine the most accurate cTNM and pTNM stage.  It is recognized that 
cTNM staging requires integration of imaging, pathologic, and physical exam findings, and 
reproducibility can be difficult. To limit variation between investigators and institutions, the 
table below outlines cTNM staging.  Investigators may also refer to AJCC staging manual, 7th 
edition (2009) or the NCCN guidelines page ST-2 as an additional reference when considering 
how to distinguish cT2 (muscle invasion) from cT3 (bladder wall thickening) from cT4 (fixed 
mass on exam under anesthesia or extra-vesicle extension to perivesicle fat).68,69  
 
 
 


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Table 9a: Summary of clinical TNM staging of bladder urothelial cancer to guide primary tumor 
stage assessment.  EUA, exam under anesthesia 
Pathology
Cross Sectional Imaging
EUA
cT1 
Tumor does not invade 
muscularis 
May or may not be 
visible, bladder wall not 
thickened 
Bladder and or mass 
may or may not be 
appreciated and not 
fixed
cT2 
Tumor invades muscularis 
propria, depth of 
penetration is sometimes 
described to involve inner 
or outer half (cT2a vs 
cT2b)
Bladder wall not 
thickened; a mass may or 
may not be visible  
Mass is Mobile  
cT3 
Tumor invades 
muscularis, depth of 
penetration is sometimes 
described to include 
perivesical tissue 
Bladder wall is thickened; 
a mass may or may not be 
visible  
Mass is mobile 
cT4a 
Tumor invades 
muscularis, depth of 
penetration is sometimes 
described 
Bladder wall is thickened; 
a mass is often visible 
with attention for 
extravesicular extension 
and may be seen to invade 
prostate, uterus, vagina
Mass is fixed 
cT4b 
Tumor invades 
muscularis, depth of 
penetration is sometimes 
described
Mass visibly extends to 
the pelvic wall or 
abdominal wall 
Mass is fixed 
Response assessments will be made both using the Immune Related Response Criteria (irRC) for 
the pre-surgery restaging scan, and using RECIST v1.1 for all additional post-surgery follow up 
scans.  The same measurable and non-measurable lesions will be followed by both RECIST v1.1 
& irRC.  Post Neoadjuvant chemotherapy/pre-surgery clinical TNM staging should be based on 
RECIST v1.1.  
 
9.1 
Immune related response criteria 
This study will utilize the Immune Related Response Criteria (irRC) during the time the patient 
is treated with pembrolizumab: ie, the post-chemotherapy/pre-surgical restaging evaluation.  
Those subjects that are not surgical candidates and remain on study should also be followed by 
both RECIST v1.1 and irRC.  These response criteria were developed to overcome the variable 
and unusual patterns of response to immunotherapeutic agents, in particular, ipilimumab70. The 
development of the guidelines were prompted by observations, mostly in subjects with metastatic 
melanoma, of initial disease progression followed by later response, late responses, and mixed 
responses with an overall decrease in tumor burden.  
 
9.2 
Antitumor response based on total measurable tumor burden 
For the irRC, only index and measurable new lesions are taken into account (in contrast to 
conventional WHO criteria, which do not require the measurement of new lesions, nor do they 
include new lesion measurements in the characterization of evolving tumor burden). At the 
baseline tumor assessment, the sum of the products of the two largest perpendicular diameters 
(SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions) is calculated. At each 


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subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions (up 
to 5 new lesions per organ; 10 visceral lesions) are added together to provide the total tumor 
burden:  
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions  
 
Table 9b: Comparison of WHO and irRC criteria 
WHO
irRC
New, measurable 
lesions 
Always represent PD 
Incorporated into tumor burden 
New, 
nonmeasurable 
lesions 
Always represent PD 
Do not define progression (but 
preclude irCR) 
Non-index 
lesions
Changes contribute to defining BOR of CR, PR, 
SD, and PD
Contribute to defining irCR (complete 
disappearance required)
CR 
Disappearance of all lesions in two consecutive 
observations not less than 4 wk apart 
Disappearance of all lesions in two 
consecutive observations not less than 
4 wk apart
PR 
≥50% decrease in SPD of all index lesions 
compared with baseline in two observations at 
least 4 wk apart, in absence of new lesions or 
unequivocal progression of non-index lesions 
≥50% decrease in tumor burden 
compared with baseline in two 
observations at least 4 wk apart 
SD 
50% decrease in SPD compared with baseline 
cannot be established nor 25% increase 
compared with nadir, in absence of new lesions 
or unequivocal progression of non-index lesions 
50% decrease in tumor burden 
compared with baseline cannot be 
established nor 25% increase 
compared with nadir
PD 
At least 25% increase in SPD compared with 
nadir and/or unequivocal progression of non-
index lesions and/or appearance of new lesions 
(at any single time point) 
At least 25% increase in tumor burden 
compared with nadir (at any single 
time point) in two consecutive 
observations at least 4 wk apart 
 
9.3 
Time-point response assessment using irRC 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the change in 
tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to 
baseline measurements (i.e., the SPD of all index lesions at screening). The irRC were derived 
from WHO criteria and, therefore, the thresholds of response remain the same. However, the 
irRC response categories have been modified from those of WHO criteria as detailed in Tables 
10 and 11.  
 
9.4 
Overall response using the irRC 
The sum of the products of diameters at tumor assessment using the immune-related response 
criteria (irRC) for progressive disease incorporates the contribution of new measurable lesions. 
Each net Percentage Change in Tumor Burden per assessment using irRC criteria accounts for 
the size and growth kinetics of both old and new lesions as they appear. 
 


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Definition of Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of 
the products of the two largest perpendicular diameters of all index and all new measurable 
lesions (ie., Percentage Change in Tumor Burden). Note: the appearance of new measurable 
lesions is factored into the overall tumor burden, but does not automatically qualify as 
progressive disease until the SPD increases by ≥25% when compared to SPD at nadir. 
 irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
 irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden 
(i.e., taking sum of the products of all index lesions and any new lesions) when compared to 
SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not 
considered in the definition of PR, these terms do not apply. 
 irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden increases 
by 25% (i.e., the SPD at nadir of the index lesions increases by the required amount). 
 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However, their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria (see Table 10): 
 Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions 
(index and nonindex together with no new measurable/unmeasurable lesions) for at least 4 
weeks from the date of documentation of complete response.  
 Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD baseline. 
At each subsequent tumor assessment, the sum of the products of the two largest 
perpendicular diameters of all index lesions and of new measurable lesions are added 
together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, 
relative to baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is 
considered an immune Partial Response (irPR).  
 Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease.  


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 Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute progressive disease: 
 At least 25% increase in the sum of the products of all index lesions over nadir SPD 
calculated for the index lesions. 
 At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between 
the date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study. For the 
assessment of irBOR, all available assessments per subject are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks 
after the criteria for response are first met. 
 
Table 10: Derivation of irRC overall responses 
Measurable response 
Nonmeasurable response 
Overall 
response 
Index and new, measurable lesions (tumor 
burden),*% 
Non-index lesions 
New, nonmeasurable 
lesions 
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal progression 
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
↓≥50 
Unequivocal progression 
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal progression 
Any 
irSD 
≥25 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), including measurable lesions 
only  
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 wk 
apart.  
 
9.5 
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1  
 
9.5.1 Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
9.5.2 Measurable lesions  
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 


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scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
9.5.3 Non-measurable lesions  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 
9.5.4 Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.5.5 Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
9.5.6 Non-target lesions  
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
 
 


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9.6 Response Criteria 
 
9.6.1. Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm.
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of 
one or more new lesions is also considered 
progressions).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study
 
9.6.2. Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm short 
axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response.
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor-investigator. 
 
 
 


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9.6.3 Evaluation of best overall response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
Not evaluated
No
PR
PR 
Non-CR/ Non-PD/ not 
evaluated
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated
No 
SD 
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
9.7 
Definitions for Response Evaluation – RECIST version 1.1 
 
9.7.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.7.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
9.7.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
 
9.7.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 


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9.7.5 Objective response rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST v1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 
9.7.6 Time to Progression: 
A measurement from the date of randomization until the criteria for disease progression is met as 
defined by RECIST 1.1. Subjects who have not progressed or have died due to any cause will be 
right-censored at the date of the last disease evaluation or date of death. 
 
9.7.7 Relapse Free Survival 
A measurement from the date of randomization until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs. Radiographic suggestion of relapse should be followed 
with biopsy to document disease recurrence versus another process.  Subjects who have not 
progressed or relapsed will be right-censored at the date of the last disease evaluation. 
                            
9.7.8 Overall Survival 
Overall survival is defined by the date of randomization to date of death from any cause. 
 
10. 
BIOLOGICAL SPECIMEN PARAMETERS FOR CORRELATIVES 
Please see Study Procedures Manual for additional information regarding collection, labeling and 
shipping instructions. 
 
10.1 
Prior to Treatment Archival Tissue or Biopsy 
 
10.1.1 MANDATORY; PD-L1 Testing  
Submission of 5 unstained slides from an archival tissue collection for PD-L1 expression 
analysis. If archival tissue is not available for slides, subjects are strongly encouraged to undergo 
a biopsy prior to starting.  M1 subjects are not eligible on this trial.  Additionally, tumor tissue 
from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. 
 
Tumor tissue should be of good quality based on total and viable tumor content.  Fine-needle 
aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are 
not acceptable. For core needle biopsy specimens, at least three cores or via TURBT should be 
submitted for evaluation. 
 
10.1.2 MANDATORY; Tumor Subtype Testing  
Submission of 6 unstained slides from archival or, when feasible, newly obtained tissue 
collection for IHC testing of basal and luminal urothelial subtypes. IHC markers that will be 
analyzed are CD44, CD20 and CD5/6. Subjects are strongly encouraged to undergo a biopsy 
prior to starting therapy if archived tumor tissue is not available.  
 
 
 


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10.2 
On Study Surgical Biopsy 
 
10.2.1 OPTIONAL; Fresh Frozen Cores from Surgical Specimen  
Seidman Cancer Center/Case Comprehensive Cancer Center sites as well as other interested sites 
will provide frozen tissue cores (3) collected at the time of radical cystectomy or NU.  Tissue 
will include muscle and obtained from anywhere along the luminal side of the specimen.  
Analysis will include histology, gene and protein analysis for stromal lymphocyte 
characterization.   
 
10.2.2 OPTIONAL; Formalin Fixed Paraffin Embedded (FFPE)  
Encouraged for all sites.  Luminal side tissue that includes muscle measuring at least 0.5cm x 
0.5cm x 0.5cm will be collected from a random site of the radical cystectomy or NU as a FFPE 
block, or 10 unstained slides post sectioning.  Analysis will include histology, and a tissue 
microarray for protein analysis, and stromal lymphocyte characterization.  Data from these 
samples may be limited by ability to characterize lymphocytes in FFPE tissue and assays are 
being optimized.   
 
10.3 
Whole Blood Collection 
 
10.3.1 OPTIONAL; Whole Blood Collection for Future PBMC Analysis  
 Pre-treatment Cycle 1 Day 1  
 Pre-treatment Cycle 1 Day 8 
 One collection during Cycle 1 Day 11-15, with date and time recorded.  Time point closer 
to Day 11 is preferred when able.    
 
10.3.2 MANDATORY; Whole Blood Collection for Banked Serum 
Whole blood for serum collection will be drawn at Pre-dose Cycle 1 Day 1 and will be banked 
for the duration of the study.  The serum sample will be used to determine if a subject who 
develops autoimmune phenomenon had pre-existing antibodies and/or other serum findings that 
are consistent with the subject’s specific autoimmune diagnosis.  If the subject does not develop 
an autoimmune phenomenon the sample will be stored for future cancer related research.  
 
11. 
DRUG INFORMATION 
 
11.1 
Pembrolizumab 
Please refer to the current version of the Investigator’s Brochure for additional information on this 
medication. 
 
11.1.1 Other Names 
Pembrolizumab; MK-3475 [Anti-PD-1 Antibody MK-3475] 
 
11.1.2 Chemical Name and Properties 
Humanized X PD-1_mAb (H409A11) IgG4 


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11.1.3 Availability and Distribution 
Merck will supply pembrolizumab directly to sites at no charge to subjects participating in this 
clinical trial.  
 
Clinical Supplies will be provided by Merck as summarized below. 
 
Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
 
11.1.4 Preparation and Administration 
Please refer to the Pharmacy Manual for a comprehensive description of pembrolizumab 
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 Powder 
for Solution for Infusion, 50 mg/vial, is reconstituted with sterile water for injection prior to use. 
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). The drug product is stored as a stable lyophilized 
powder or liquid solution under refrigerated conditions (2°C - 8°C). 
 
The product after reconstitution with sterile water for injection and the liquid drug product is a 
clear to opalescent solution, which may contain extraneous and proteinaceous particulates. The 
reconstituted product and liquid product is intended for IV administration. The reconstituted drug 
product solution and liquid drug product 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 infusion solution in the IV bag and the infusion solution should 
be immediately administered. If not used immediately, vials and/or IV bags may be stored at 2-8 
°C for up to a cumulative time of 20 hours. If refrigerated, the vials and/or IV bags should be 
allowed to equilibrate to room temperature prior to subsequent use. Pembrolizumab solutions 
may be stored at room temperature for a cumulative time of up to 4 hours. This includes room 
temperature storage of reconstituted drug product solution and liquid drug product in vials, room 
temperature storage of infusion solution in the IV bag and the duration of infusion. 
11.1.5 Adverse Events 
Please see current Investigator’s Brochure for a complete list of adverse events. 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern. Important 
identified risks for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, hypophysitis (including hypothryoidism/hyperthyroidism), hepatitis,  Type I diabetes 
mellitis, uveitis, and nephritis, myositis, Guillain-Barre syndrome, pancreatitis, and severe skin 


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reaction toxic epidermal necrolysis (TEN), some with fatal outcome). A new important risk of 
myocarditis has been identified; cases with fatal outcome have been reported.   
 
The majority of immune-mediated adverse events were mild to moderate in severity, were 
manageable with appropriate care, and rarely required discontinuation of therapy.  
 
In addition to the previously noted identified risks, infusion-related reactions are a risk but are 
not considered immune mediated; these are also further described in the current IB. 
 
11.2 
Gemcitabine 
Please see package insert for detailed information regarding this medication 
 
11.2.1 Other Names  
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar 
 
11.2.2 Classification  
Antimetabolite (nucleoside pyrimidine analogue) 
 
11.2.3 Mode of Action  
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S 
phase) and also blocking the progression of cells through the G1/S phase boundary. Gemcitabine 
is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and 
triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a 
combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to 
inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, 
which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates 
for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction 
in the concentrations of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate 
competes with dCTP for incorporation into DNA. The reduction in the intracellular 
concentration of dCTP (by the action of the diphosphate) enhances the incorporation of 
gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is 
incorporated into DNA, only one additional nucleotide is added to the growing DNA strands. 
After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is 
unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain 
termination).  
 
11.2.4 Storage and Stability 
Unreconstituted drug vials are stored at controlled room temperature (15ºC to 30ºC, 59ºF to 
86ºF). Reconstituted solution should be stored at controlled room temperature and used within 24 
hours. Solutions of gemcitabine should not be refrigerated; as crystallization may occur. The 
unused portion should be discarded. 
 
11.2.5 Preparation  
Gemcitabine may be further diluted with normal saline as per institutional standards. 
 


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11.2.6 Route of Administration  
IV infusion. 
 
11.2.7 Availability  
Gemcitabine is commercially available in 200 mg and 1 gm vials 
 
11.2.8 Side Effects  
Please see package insert for detailed information regarding side effects related to Gemcitabine. 
 
Neutropenia, anemia, thrombocytopenia, and leukopenia are reported.  Rash with pruritis and 
injection-site reactions are can occur.  Nausea and vomiting, diarrhea, constipation and mucositis 
have been reported.  Abnormalities of hepatic transaminase enzymes occur in two-thirds of 
subjects, but they are usually mild, non-progressive, and rarely necessitate stopping treatment. 
Bronchospasm and/or dyspnea within a few hours of infusion of the drug, cough, rhinitis, 
pneumonitis may occur.  Somnolence, insomnia, paresthesia, pain.  Peripheral edema is reported 
in about 30% of subjects. Flu-like symptoms are reported for about 20% of subjects. This 
includes fever, headache, back pain, chills, myalgia, asthenia, and anorexia.  
 
11.3 
Cisplatin 
Please see package insert for detailed information regarding side effects related to this drug. 
 
11.3.1 Other Names  
Cisdiaminedichloroplatinum, Cis-diaminedichloroplatinum (II), diaminedichloroplatinum, cis-
platinum, platinum, Platinol, Platinol-AQ, DDP, CDDP, DACP, NSC 119875. 
 
11.3.2 Classification  
Alkylating agent 
 
11.3.3 Mode of Action  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible mechanisms 
include chelation of DNA and binding to cell membranes thereby stimulating immune 
mechanisms. 
 
11.3.4 Storage and Stability  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible mechanisms 
include chelation of DNA and binding to cell membranes thereby stimulating immune 
mechanisms. 
 
11.3.5 Preparation  
The desired dose of cisplatin is diluted with 250-1000 mL of saline and/or dextrose solution. 
Varying concentrations of 0.225-5% sodium chloride and 5% dextrose may be used. To maintain 
stability of cisplatin, a final sodium chloride concentration of at least 0.2% is recommended. 
 
11.3.6 Administration  
Cisplatin solution must be administered over a 60 to 120 minute period. 
 


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11.3.7 Incompatibilities  
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium bicarbonate, and thiotepa. 
Cisplatin may react with aluminum which is found in some syringe needles or IV sets, forming a 
black precipitate. 
 
11.3.8 Availability  
Commercially available as a mg/mL solution in 50 and 100 mg vials. 
 
11.3.9 Side Effects  
Please see package insert for detailed information regarding side effects related to this drug. 
 
A dose-related ototoxicity, manifested by high-frequency hearing loss and tinnitus, occurs in 
about 30% of subjects.  Mild leukopenia and thrombocytopenia occur in 25-30% of subjects, but 
are rarely dose-limiting. Nausea and vomiting occur in almost 100% of subjects unless adequate 
antiemetic prophylaxis is given.  Allergic reactions are reported in up to 20% of subjects. 
Symptoms include: rash, facial edema, wheezing, hypotension, and tachycardia.  
 
12 
ADVERSE EVENTS 
 
12.1 
Definitions of Adverse Events  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v4 will be utilized for AE assessment.  A copy of the CTCAE v4 can 
be downloaded from the CTEP website at http://ctep.cancer.gov 
 
12.1.1 Adverse Event  
Adverse event (AE) means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An adverse event (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, and does not imply any 
judgment about causality. An adverse event can arise with any use of the drug (e.g., off-label 
use, use in combination with another drug) and with any route of administration, formulation, or 
dose, including 
 
A site investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), v4. Any adverse event which changes 
CTCAE grade over the course of a given episode will have each change of grade recorded on the 
adverse event case report forms/worksheets. 
 
12.1.2 Serious Adverse Event 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
 Results in death NOTE: Death due to progressive disease is not considered a SAE unless 
the event was related to the study drug. 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
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 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above).  Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
12.1.3 Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
12.1.4 Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of 
all suspected adverse reactions where there is reason to conclude that the drug caused the event. 
 
12.1.5 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current AE list, the IB, the package insert or when it is not 
included in the informed consent document as a potential risk. 
 
12.1.6 Attribution 
Attribution is the relationship between an AE or SAE and the study treatment. Attribution will be 
assigned as follows: 
 
Unrelated
The Adverse Event is clearly not related to the study drug
Unlikely 
The Adverse Event is doubtfully related to the study drug
Possible 
The Adverse Event may be related to the study drug
Probable 
The Adverse Event is likely related to the study drug 
Definite 
The Adverse Event is clearly related to the study drug
 
12.2 
Adverse Event Reporting 
 
12.2.1 Site Requirements for Recording Adverse Events 
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days after 
treatment discontinuation, regardless of whether or not the event(s) are considered related to trial 
medications. All AEs considered related to trial medication will be followed until resolution, 
return to baseline, or deemed clinically insignificant, even if this occurs post-trial. 
 


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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. 
 
12.2.2 SAE Reporting from Sites to HCRN 
Sites will report to Hoosier Cancer Research Network (HCRN) any SAE, or follow up to a SAE, 
including death due to any cause that occurs to any subject from the time the consent is signed 
through 90 days following the last dose of study drug, or the initiation of new anti-cancer 
therapy, whichever is earlier, whether or not related to Merck product.  
 
All SAEs will be reported on the SAE/ECI Submission Form and submitted to HCRN per 
guidelines outlined in this section.  In addition, All AEs and SAEs will be recorded on the 
appropriate study specific eCRF within the EDC system.  The original copy of the SAE/ECI 
Submission Form and the e-mail correspondence or the fax confirmation sheet must be kept 
within the Trial Master File at the study site. 
 
Sites must report any SAEs occurring during the course of the study to HCRN within one 
business day of discovery of the event. The completed SAE/ECI Submission Form must be sent 
electronically to safety@hoosiercancer.org.  The site investigator is responsible for informing the 
IRB and/or the Regulatory Authority of the SAE as per local requirements.   
 
Follow-up information will be sent electronically to HCRN to safety@hoosiercancer.org using a 
new SAE/ECI Submission Form. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs.  
 
12.2.3 HCRN Requirements for Reporting SAEs to Merck  
HCRN will report any SAE from the time the consent is signed through 90 days following the 
last dose of study drug, or the initiation of new anti-cancer therapy, whichever is earlier, whether 
or not related to Merck product.  The report will be sent to Merck within one business day of 
receipt of the SAE/ECI Submission Form.  Hoosier Cancer Research Network will fax follow up 
information as reasonably requested to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220. 
 
12.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE/ECI Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 


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12.4 
Reporting to the Food and Drug Administration (FDA) 
The FDA concluded this protocol is exempt from the requirements of an IND on 1.15.15. HCRN 
will continue to facilitate compliance of applicable requirements for the sponsor-investigator in 
relation to this study. This includes but is not limited to 21 CFR 50.20 informed consent, 21 CFR 
Part 56 IRB, and pertinent sections of the Public Health Service Act and FDAAA. 
 
12.5 
Definition of an Overdose for This Protocol and Reporting of Overdose 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥ 5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, 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 from sites to HCRN 
within one business day.  HCRN will report such events to Merck Global Safety within one 
business day of notification of the event. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
12.6 
Reporting of Pregnancy and Lactation  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of the 
site 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.  All subjects and female 
partners of male subjects who become pregnant must be followed to the completion/termination 
of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must 
be reported as serious events (Important Medical Events).  If the pregnancy continues to term, 
the outcome (health of infant) must also be reported. 
Such events must be reported within one business day to HCRN. HCRN will report such events 
to Merck Global Safety within one business day of receiving notification of the event. (Attn: 
Worldwide Product Safety; FAX 215-993-1220). 
 
12.7 
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 SAE/ECI Submission Form.  ECIs are reported 
within one business day by sites to HCRN who will then report to Merck within one business 
day to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). Events of 
clinical interest for this trial include: 


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 An overdose of Merck product, as defined above that is not associated with clinical 
symptoms or abnormal laboratory results.  
 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.* 
 Progression or pseudo-progression at post neoadjuvant chemotherapy that impacts 
decision making for definitive surgery is considered an event of clinical interest and 
should be discussed with the HCRN project manager/sponsor-investigator.   
  
*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. The trial site guidance for assessment and follow up of 
these criteria can be found in the SPM 
 
 


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Table 11 Guidance for evaluating adverse events 
A site investigator who is a qualified physician, will evaluate all adverse events as to: 
 
V4.0 CTCAE 
Grading 
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during treatment with study drug
†Results in death; or
†Is life threatening; or places the subject, in the view of the site investigator, at immediate risk of death from the event as it occurred (Note: This does not include 
an adverse event that, had it occurred in a more severe form, might have caused death.); or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event 
when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the study drug to be discontinued?
Relationship to 
test drug  
Did the study drug cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by a site 
investigator who is a qualified physician. The site investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the 
AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the site investigator in assessing the likelihood of a relationship between the test drug and the adverse 
event based upon the available information.  
The following components are to be used to assess the relationship between the study drug and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
Exposure
Is there evidence that the subject was actually exposed to the study drug such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the study drug? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 


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


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13 
STATISTICAL METHODS 
 
13.1 
Study Design and Stratification 
Subjects who are appropriate for surgical intent must meet eligibility criteria, and are then 
stratified into cohort I: cisplatin eligible and treated on Phase Ib or Phase II, Arm A; or cohort II: 
cisplatin-ineligible and treated on Phase II, Arm B.  See Section 3.3.1 for details of how cisplatin 
-eligible or –ineligible subjects are defined.  Note that though subjects may fit cisplatin-
ineligibility, they still must be fit enough to qualify for surgery per surgeon’s documentation 
stating surgical intent (and therefore NYHA class III and IV are not permitted).   
 
13.2 
Study Phases 
Phase Ib:  This is a 3+3 study design in the cisplatin-eligible, cohort I, group.  Two 
pembrolizumab dose levels of 200mg, and 120mg will be investigated with 
gemcitabine/cisplatin.  The MTD will be the highest pembrolizumab dose level in combination 
with gemcitabine/cisplatin at which no more than 1 of 6 subjects experiences a non-
gemcitabine/cisplatin related DLT.  Once the MTD is established, this portion of the study will 
close and the Phase II will open to cohort I and II.  The recommended Phase II dose (RP2D) will 
be based on the MTD and discussed with and approved by the sponsor-investigator.  Including a 
~4% patient drop out, the maximal sample size is 14.   
 
Phase II:  Cohort I and II subjects will be treated at the RP2D in an independent Simon two-
stage design.  For cohort I, the null hypothesis that the true pathologic muscle invasive response 
rate (PaIR) is 23% will be tested against a one-sided alternative.  In the first stage, 15 subjects 
will be accrued.  If there are 4 or fewer responses in these 15 subjects, cohort I will be stopped. 
Otherwise, 17 additional subjects will be accrued for a total of 32. The null hypothesis will be 
rejected if 12 or more responses are observed in 32 subjects.  This yields a type I error rate of 4% 
and power of 86% when the true response rate is 48%.  For cohort II, the null hypothesis that the 
true PaIR rate is 18% will be tested against a one-sided alternative.  In the first stage, 19 subjects 
will be accrued.  If there are 4 or less responses in these 19 subjects, the cohort will be stopped. 
Otherwise, 16 additional subjects will be accrued for a total of 35. The null hypothesis will be 
rejected if 11 or more responses are observed in 35 subjects.  This yields a type I error rate of 4% 
and power of 86% when the true response rate is 40%.   
 
13.3 
Definition of Primary Endpoint   
Pathologic muscle invasion response (PaIR), or ≤ypT1N0M0, rate is assessed from the 
consolidative surgery (radical cystectomy (RC) / nephroureterectomy (NU) - lymph node 
dissection (LND)) specimen.  
 
13.4 
Definitions of Secondary Endpoints 
Relapse-free survival (RFS) and OS will be measured from the date of randomization to date of 
relapse or death due to any cause, whichever occurs first.  Relapse after curative intent surgery 
usually requires biopsy for confirmation.  Pathologic confirmation is per site investigator, 
however the date of relapse should be recorded as the date of the imaging that prompted the 
biopsy.  Response will be defined per RECIST v1.1, see section 9.7.   
Safety and tolerability of pembrolizumab in combination with gemcitabine – cisplatin will occur 
during Phase Ib and II, and in combination with gemcitabine alone will occur during Phase II.  


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Acute and longer term safety and tolerability data will be collected per adverse event 
documentation performed during, as well as after, neoadjuvant therapy in the follow up 
assessments.    
 
Consolidation surgery after combination neoadjuvant therapy includes completed radical 
cystectomy with pelvic lymph node dissection or nephroureterectomy.  The rate of pT0N0 will 
be determined.  The rate of consolidation surgery amongst the evaluable subjects will be 
determined.   
 
13.5 
Analysis Plan for Primary and Secondary Objectives 
All evaluable subjects will be included in data safety analysis if they complete at least 1 cycle of 
the neoadjuvant portion of treatment as described in the treatment plan, or discontinue treatment 
early for defined toxicity criteria (criteria in section 6 above). Toxicity data will be tabulated. 
Subjects will be evaluable for the primary efficacy endpoint if they complete at least 2 cycles of 
neoadjuvant therapy and 2 doses of pembrolizumab, then have a radical cystectomy with pelvic 
lymph node dissection, or nephroureterectomy with lymph node dissection, where a pathologic T 
and N stage can be assigned (and subjects with a “X” notation for a T or N will not be included 
in the efficacy analysis).  The true response rate (PaIR) of the evaluable subjects will be 
estimated using binomial distribution theory. The rate will be estimated for each cohort. The 
confidence intervals for them will be estimated using Wilson’s method71. The predictive value of 
biomarkers, such as PD-L1 on response rate will be estimated using logistic regression after 
controlling the effects of confounders, such as demographics, baseline histology. 
 
The probabilities of RFS and OS and their median survival times will be estimated by Kaplan-
Meier method for each cohort separately.  Kaplan-Meier estimates for RFS and OS for those 
downstaged or not to PaIR and pT0 will also be compared.  Factors, such as age, gender, 
baseline histology and lab correlates including PD-L1, that predict survivals (RFS, OS) will be 
identified by Cox model or extended Cox model.  2 tests will be used to evaluate the 
relationship between prior BCG use and PaIR.   
 
13.6 
Sample Size/Accrual/Study Duration/Replacement Rules 
Phase Ib:  This is a 3+3 dose design study in the cisplatin-eligible, cohort I, group.  Two 
pembrolizumab dose levels of 200mg, and 120mg will be investigated with 
gemcitabine/cisplatin.  The MTD will be the highest pembrolizumab dose level in combination 
with gemcitabine/cisplatin at which no more than 1 of 6 subjects experience a dose limiting 
toxicity (DLT) related to pembrolizumab (and not of gemcitabine or cisplatin).  Once the MTD is 
established, this portion of the study will close and the Phase II will open to cohort I and II at the 
recommended phase II dose (RP2D).  Including a ~4% subject drop out, the maximal sample 
size is 14.   
 
Phase II:  Cohort I and II subjects will be treated at RP2D from the phase 1b portion in 
independent Simon two-stage designs.  For cohort I, the null hypothesis that the true pathologic 
muscle invasive response rate (PaIR) is 23% will be tested against a one-sided alternative.  In the 
first stage, 15 subjects will be accrued.  If there are 4 or fewer responses in these 15 subjects, 
cohort I will be stopped. Otherwise, 17 additional subjects will be accrued for a total of 32. The 
null hypothesis will be rejected if 12 or more responses are observed in 32 subjects.  This yields 


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a type I error rate of 4% and power of 86% when the true response rate is 48%.    For cohort II, 
the null hypothesis that the true PaIR rate is 18% will be tested against a one-sided alternative.  
In the first stage, 19 subjects will be accrued.  If there are 4 or less responses in these 19 subjects, 
the cohort will be stopped. Otherwise, 16 additional subjects will be accrued for a total of 35. 
The null hypothesis will be rejected if 11 or more responses are observed in 35 subjects.  This 
yields a type I error rate of 4% and power of 86% when the true response rate is 40%.  Subjects 
who are not evaluable for the primary efficacy endpoint (see section 13.5) will be replaced.   
 
Historical Controls 
Current level one evidence for neoadjuvant chemotherapy is based on the SWOG8710 
neoadjuvant MVAC trial24 and the EORTC/MRC neoadjuvant CMV trial72.  Though 
CMV/MVAC was considered, it is not predicted to be a favorable combination with an immune 
checkpoint blockade in this trial design (see section 1.2.3).  Based on data from the metastatic 
setting that show similar survival with MVAC, GC28 has become a standard alternative for use in 
the neoadjuvant setting as well.  Pathologic response correlates with outcome in subjects treated 
with neoadjuvant therapy.  
 
Subject demographics in this trial reflects those used in prior neoadjuvant trials and results will 
be similarly summarized with ability to comment on primary outcome similarities or differences.  
Similar subject characteristics include histology (urothelial carcinoma, transitional cell 
carcinoma, mixed histologies with urothelial carcinoma background) and TNM stage.  
Gemcitabine-cisplatin in the neoadjuvant setting has been evaluated in a prospective phase II 
trial29 as well as in retrospective cohorts30,73 which have reported a PaIR (similarly defined and 
reported as pCR, or p≤T1) rates in the table below 
 
Author 
Neoadjuvant 
Regimen (NAC)
Analysis 
PaIR 
Median Time to 
Cystectomy
comment 
Herchenhorn et 
al29
GC x4 cycles 
prospective Phase 
II
23% 
6.7w  from end 
of NAC
standard 
practice
Galsky et al73
GC x4 cycles
retrospective
27%
N/A
Weight et al30 
GC x4 cycles 
retrospective 
7% 
NAC: 29.7 w 
from diagnosis 
RC only: 6.9w 
from diagnosis
 
Plimack et al74 
dose dense GC 
prospective Phase 
II
45% 
N/A 
closed 
early (tox)
 
Timing of RC after neoadjuvant therapy is an important consideration for this multimodality 
intervention and subjects on this trial will receive RC similar to historical controls.  Delivery of 
cystectomy within 10 weeks from the last dose of a combination neoadjuvant chemotherapy 
regimen of 9-12 weeks in duration was found to not compromise survival in a retrospective 
cohort of 153 subjects67.  This HCRN GU14-188 trial delivers pembrolizumab 3 weeks after the 
last dose of gemcitabine (G) or gemcitabine-cisplatin (GC), and therefore requires delivery of 
surgery (RC or NU) within 2 to 7 weeks after this dose.  In the context of Herchenhorn et al as 
an historical control, this neoadjuvant pembrolizumab trial delivers surgery 5 to 10 weeks after 
standard practice gemcitabine/cisplatin chemotherapy which is within the recommended 10 
weeks and can be compared to this group.  In the context of Weight et al, surgery was delivered 
a median of ~30weeks from diagnosis.  It’s reasonable to assume a 4-8 week ‘setup time’ which 


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may include path resulting time, arrangement of oncology referral, lab and radiographic 
evaluation, and port placement from the time of diagnosis; and an additional 12 weeks of 
gemcitabine/cisplatin chemotherapy.  Therefore, delivery of cystectomy in this cohort is 
estimated to have been ~10-14 weeks after the last chemotherapy and well within the timeframe 
for this neoadjuvant pembrolizumab trial for eventual comparison of results. 
 
Cohort II subjects treated with gemcitabine alone have historical references for response in the 
advanced and metastatic setting where cystectomy was not performed.  It is estimated that the 
primary endpoint for a cohort II patient receiving gemcitabine monotherapy in the neoadjuvant 
setting will have a PaIR ~5% less than their counterparts receiving GC.  We do not yet have 
adequate historical data from randomized trials for RC alone.  RC alone has been reviewed in a 
retrospective cohort of ~1000 subjects and found a pathologic complete response (pCR) rate of 
6.3%.  A prospective evaluation of single modality RC pCR rate was determined to be 15% in 
the comparator arm of the Phase III SWOG 8710 trial24,44.  These subjects had prior diagnostic 
(and occasionally maximal) transurethral resection of bladder tumor (TURBT) to yield a pCR 
rate of ~15% at RC.  It’s important, however, to understand this rate should only be viewed 
within the context of being a comparator group against which a difference with neoadjuvant 
therapy was assessed within the pre-specified controls of the clinical trial.  A pathologic CR rate 
for RC-only would require a clinical trial that controls for extent of TURBT prior to RC, and 
controls for reproducible pathologic specimen sectioning (detailed sectioning of whole-mounts 
may reveal Tis or T1 lesions).   
 
14 
TRIAL MANAGEMENT 
 
14.1 
Data and Safety Monitoring Plan 
The study will be conducted in accord with Case Comprehensive Cancer Center’s Data and 
Safety Monitoring Plan.   
 
HCRN oversight activities include: 
 Review all adverse events requiring expedited reporting as defined in the protocol 
 Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
 Submit data summary reports to the lead institution Data Safety Monitoring Committee 
according to Case Comprehensive Cancer Center’s DSMP. 
 
14.2 
Case Comprehensive Cancer Center’s Data Safety Monitoring Committee 
HCRN will provide the following for the Case Comprehensive Cancer Center’s DSMC to review: 
 Adverse event summary report 
 Audit results if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
 
 


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14.3 
Data Quality Oversight Activities 
 
14.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. During onsite monitoring visits, source documents will be reviewed 
for verification of agreement with data entered into the EDC system.  Additional for cause visits 
may occur as necessary. It is important for the site investigator and their relevant personnel to be 
available for a sufficient amount of time during the monitoring visits or audit, if applicable. The 
site investigator and institution guarantee access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Merck or its designee as well as 
inspection by appropriate regulatory agencies. 
 
14.3.2 Remote Monitoring 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study.  The data entry completion status of each participating site will be 
reviewed on a weekly basis to ensure timeliness of data entry.  Electronic Case Report Form 
(eCRF) constraints will be utilized to prevent data entry errors and ensure complete data entry.  
Automated bi-weekly edit check programs will check for errors in accuracy, validity, and 
consistency in the data.  Listings from the edit check programs will be used to generate queries in 
the EDC system. Corrections will be made in a timely manner by the study site personnel. 
 
14.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
15 
DATA HANDLING AND RECORD KEEPING 
 
15.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, EDC system, a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. All data will be collected and entered 
into EDC system by study site personnel from participating institutions.   
 


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15.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in EDC system and correlative results will 
be captured in the EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in EDC system according to study-
specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should not be 
exported to third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without permission from the sponsor-investigator and HCRN. 
 
15.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
15.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subject will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available.   
 
Information collected will be maintained on secure, password protected electronic systems. 
Paper files that contain personal information will be kept in locked and secure locations only 
accessible to the study team. Samples that are collected will be identified by a subject study 
number assigned at the time of registration to the trial.  Any material issued to collaborating 
researchers will be anonymized and only identified by the subject study number. 
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Merck & Co., IRB, or government agencies, like the 
FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15.5 
Changes to the Protocol 
Study procedures will not be changed without the mutual agreement of the sponsor-investigator, 
HCRN, and Merck & Co.   
 
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (amended protocol) will be generated by the HCRN and must be approved by 
each IRB, Merck & Co., and if applicable, also the local regulatory authority.  Local 
requirements must be followed. 
 


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If a protocol amendment requires a change to the Informed Consent Form, site investigators must 
notify their local IRB.  Approval of the revised Informed Consent Form by the IRB is required 
before the revised form is used.  
 
The site investigator is responsible for the distribution of these documents to his or her IRB, and 
to the staff at his or her center.   
 
Merck & Co’s willingness to supply study drug is predicated upon the review of the protocol.  
HCRN agrees to provide written notice to Merck & Co. of any modifications to the protocol or 
informed consent. 
 
16 
ETHICS 
 
16.1 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved in writing by an IRB.  The site investigator must submit written approval to the HCRN 
office before he or she can enroll any subject into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit subjects for the study.  The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
16.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements. 
 
16.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study.  The site investigator must store the original, signed 
Informed Consent Form.  The site investigator must provide the subject with a copy of the signed 
Informed Consent Form. 
 
 


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17.0 REFERENCES 
 
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5. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: 
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6. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
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7. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature reviews Immunology 
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8. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune 
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9. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. 
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10. Usubutun A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in renal 
cell carcinoma. Journal of experimental & clinical cancer research : CR 1998;17:77-81. 
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