Conditions: Muscle Invasive Bladder Cancer
Keywords: MIBC UC Immunotherapy Bladder Cancer Neoadjuvant Nivolumab Cisplatin Gemcitabine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 43
Healthy volunteers: no

Brief summary:
This is a multi-center Phase II study to determine the safety and efficacy of nivolumab when given in combination with cisplatin and gemcitabine as neoadjuvant treatment in patients with muscle-invasive bladder cancer (MIBC) prior to standard of care radical cystectomy. Patients will receive neoadjuvant treatment with nivolumab in combination with gemcitabine-cisplatin (GC) every 3 weeks for 4 treatment cycles over 12 weeks followed by standard of care radical cystectomy.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Nivolumab intervention 2: Cisplatin intervention 3: Gemcitabine
Intervention descriptions: intervention 1: Nivolumab will be given at a fixed dose of 360 mg IV over 30 minutes on Day 8 every 21 days for 4 cycles. intervention 2: Cisplatin will be given at 70 mg/m2 IV over 30 minutes on Day 1 every 21 days, and based on treating physician's discretion, split-dose cisplatin can be given at 35 mg/m2 IV Day 1 and Day 8 every 21 days for 4 cycles. intervention 3: Gemcitabine will be given at 1000 mg/m2 IV over 30 minutes on days 1, 8, and every 21 days for 4 cycles.

Protocol document:
Prot_SAP_000.pdf: 
Masonic Cancer Center 
University of Minnesota 
 
 
 
Phase II Trial of Neoadjuvant Nivolumab with Cisplatin and Gemcitabine in 
Muscle-Invasive Bladder Cancer (MIBC) Patients  
Undergoing Radical Cystectomy 
BLASST-1  
CPRC #2017LS039 
BMS # CA209-9LK 
IND # 137175 
 
IND Sponsor/Principal Investigator 
Badrinath R Konety, MD, MBA 
Division of Hematology, Oncology and Transplantation 
Masonic Cancer Center, University of Minnesota 
420 Delaware Street, SE  MMC 394 
Minneapolis, MN 55455 
Email: brkonety@umn.edu 
Tel: 612-626-8599 
Fax: 612-624-6468 
 
Co-Principal Investigator  
Shilpa Gupta, MD 
Cleveland Clinic Taussig Cancer Institute 
 
 
 
 
Version Date 
April 25, 2019 
 
 
 
Confidential 
 
 


CPRC #2017LS039: Phase II Trial of Neoadjuvant Nivolumab with GC in MIBC 
 
 
 
 
 
 
April 25, 2019 
Page 2 of 51 
BMS# CA209-9LK 
Revision History 
Revision 
# 
Version 
Date 
Summary of Changes 
Consent 
Revision 
(y/n) 
 
03/31/2017 
Original to CPRC 
n/a 
 
07/27/2017 
In response to CPRC stipulations 
n/a 
 
09/21/2017 
In response to Bristol-Myers Squibb’s review and other 
minor edits – initial version to FDA and IRB 
n/a 
 
10/19/2017 
In response to FDA request for information dated 
10/18/2017: 
• Section 4.2 and Appendix I - Exclusion criteria: clarify 
prior treatment prior systemic therapy directed at MIBC is 
not permitted; however systemic therapy for non-muscle 
invasive BC is permitted as long as prohibited agents are 
not used; add cisplatin, gemcitabine, and/or radiation to 
the bladder as prohibited prior treatments; reorder prior 
therapies in the exclusion criteria to group together and 
move higher up in the list, the 1st occurrence of “prior 
allogeneic stem cell or solid organ transplant was deleted 
(appeared twice in list). Synopsis updated to match. 
• Section 6.1– add criteria for permanent discontinuation of 
study treatment: any Grade 4 drug related AE, any grade 
neurologic event, any grade pneuomonitis 
• Section 6.1 last paragraph – clarify that any person 
receiving at least one dose of study treatment would be 
included in ITT analysis 
• Section 6.3 – add additional off treatment criterion of 
requiring a 2nd treatment delay of more than 2 weeks 
• Section 9 – add ACTH stimulation test at the final 
treatment visit to monitor adrenal function  
• Additional clarifications (not part of the information 
request) 
-Section 6. 1 - for split-dose cisplatin leave to physician 
discretion 
-Section 13.3 – require all affiliate sites to follow UMN 
DSMP for monitoring 
-Section 12 – add definition of clinical deviations and 
reporting requirements to match current MCC template 
yes 
1 
07/19/2018 
Cover page – Add BLASST-1 study number and update fax 
#, delete Paari Murugan as co-I; 
Add Key Abbreviations table 
Edit primary objective for clarity, better define follow-up 
period for progression free survival 
Exclusion criteria: clarify that prior intravesical gemcitabine 
is permitted; however prior IV gemcitabine is not 
Exclusion criteria: expand definition of systemic antibiotic 
use 
yes 


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Revision 
# 
Version 
Date 
Summary of Changes 
Consent 
Revision 
(y/n) 
Exclusion criteria: waive hearing loss exclusion if benefit is 
felt to outweigh potential hearing loss after discussion with 
participant 
Exclusion criteria: expand and clarify additional malignancy 
exclusion language 
Section 5 – revise to match current MCC protocol template 
Sections 6,7, 8, and 9 – expand and edit for clarity 
Section 12 – update deviation reporting to current MCC 
protocol template 
Section 12.2 – clarify grade and expectedness of AEs to be 
collected 
Section 12.3 – add a section for early study stopping rule 
events 
Section 15.6.2 – add an early stopping rule for excessive 
Grade 3 and 4 non-hematologic toxicities 
Add Appendix II – ECOG performance status and NYHA 
classification 
Other minor edits and clarifications – all tracked 
2 
01/14/2019 
Update Schema for clarity and consistency with changes in 
the protocol body. 
Section 4.2 - Exclusion criteria #24 and Appendix I - simplify 
exceptions to “known additional malignancy that is 
progressing or requiring active treatment” 
Section 6.1 – permit screening weight to be used for dose 1 
drug calculations, allow nivolumab to be given per 
institutional practice, add nivolumab should be given 60 min 
(±15 min) after the chemotherapy agent (gemcitabine or 
cisplatin if using a split-dose)  
Section 6.2 – clarify that Nivolumab has an Investigator 
brochure (versus package insert for cisplatin and 
gemcitabine) 
Section 6.2 – Add the statement “Use of ≤ 10 mg 
prednisone or equivalent dose of steroids is allowed for 
short-term use (< 7 days) as supportive care for issues other 
than immune-related adverse events.” 
Section 6.3 – Duration of Treatment section: clarify the End 
of Treatment visit and Final Study Visit.  
Section 6.4 – clarify the CT or PET/CT is of chest, abdomen, 
and pelvis 
Section 6.5 – clarify that the Final Study Visit is also the 
assessment point for SAEs or AE that become SAEs to fulfill 
BMS’s requirement for following patients for 100 days after 
the last dose of nivolumab 
yes  
update 
study 
coordinator 


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Revision 
# 
Version 
Date 
Summary of Changes 
Consent 
Revision 
(y/n) 
Section 9 – clarify the timing and purpose of the End of 
Treatment Visit and Final Study Visit and follow-up, edit x 
chart for clarity 
Section 12.2 – reword AE monitoring and documentation to 
reflect clarification of the End of Treatment Visit and Final 
Study Visit. For clarity add the statement “Adverse events 
related to the surgery are not documented unless they are 
felt to be due to the study treatment.” 
Sections 12.3 and 15.2.6 – clarify that assessment for 
stopping rules ends with the End of Treatment Visit 
Section 13.1 – update Data Management language to 
current template. 
Sections 13.3 and 13.4 – add possibility of MMC monitoring 
services performing affiliate site monitoring 
3 
04/25/2019 
Change Principal Investigator/IND Sponsor from Dr. Gupta 
who is leaving the institution to Dr. Konety a current co-I 
 
Yes – 
update PI 
information 
 
 
 
 


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Table of Contents 
 
Key Abbreviations ......................................................................................................................................... 7 
Protocol Synopsis ......................................................................................................................................... 8 
Study Schema ............................................................................................................................................... 9 
1 
Study Objectives .................................................................................................................................. 10 
1.1 
Primary Objective ........................................................................................................................ 10 
1.2 
Secondary Objectives ................................................................................................................. 10 
1.3 
Exploratory Objectives ................................................................................................................ 10 
2 
Background and Significance .............................................................................................................. 10 
3 
Study Design ........................................................................................................................................ 12 
4 
Patient Selection .................................................................................................................................. 13 
4.1 
Inclusion Criteria ......................................................................................................................... 13 
4.2 
Exclusion Criteria ........................................................................................................................ 13 
5 
Patient Screening and Enrollment ....................................................................................................... 16 
5.1 
Enrollment with the University of Minnesota Clinical Trials Office .............................................. 16 
5.2 
Patient Enrollment in OnCore ..................................................................................................... 16 
5.3 
Patients Who Do Not Begin Study Treatment ............................................................................. 16 
6 
Treatment Plan .................................................................................................................................... 16 
6.1 
Study Drug Administration .......................................................................................................... 16 
6.1.1 
Criteria to Begin a New Treatment Cycle and Required Delays ............................................. 17 
6.1.2 
Discontinuation of Treatment Due to Toxicity ......................................................................... 18 
6.2 
Concomitant Medications and Supportive Care .......................................................................... 18 
6.3 
Duration of Study Treatment and the End of Treatment Visit ..................................................... 19 
6.4 
Pre-Operative Imaging and Radical Cystectomy ........................................................................ 20 
6.5 
Final Study Visit/Assessment 100 Days Post Nivolumab ........................................................... 20 
7 
Dose Modifications and Delay Guidelines ........................................................................................... 20 
7.1 
Hematologic Toxicity (Cisplatin and Gemcitabine) ..................................................................... 21 
7.2 
Renal Impairment (Cisplatin and Gemcitabine) .......................................................................... 21 
7.3 
Hepatic Impairment ..................................................................................................................... 22 
8 
Nivolumab Related Toxicity Management ........................................................................................... 22 
9 
Schedule of Tests and Procedures ...................................................................................................... 27 
10 
Correlative Research Studies ......................................................................................................... 29 
10.1 
Molecular Subtyping of Bladder Cancer Using Decipher® Bladder Cancer Classifier ............... 29 
10.2 
Whole Exome Sequencing (WES) .............................................................................................. 30 
10.3 
PD-L1 Testing of Baseline Pre-Treatment Tumor Tissue ........................................................... 31 
10.4 
Nanostring Pancan Immune Panel Gene Expression ................................................................ 31 
11 
Drug Formulation, Availability, and Preparation .............................................................................. 31 
11.1 
Gemcitabine ................................................................................................................................ 31 
11.2 
Cisplatin ....................................................................................................................................... 32 


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11.3 
Nivolumab ................................................................................................................................... 32 
12 
Adverse Event Monitoring, Documentation, and Reporting ............................................................ 33 
12.1 
Adverse Event and Deviation Terminology ................................................................................. 33 
12.2 
Event Monitoring and Documentation ......................................................................................... 34 
12.3 
Safety Stopping Rule Events Documentation and Reporting Requirements .............................. 35 
12.4 
Additional BMS Requirements for Nivolumab ............................................................................. 35 
12.5 
Institutional Event Reporting ....................................................................................................... 36 
12.6 
MCC Reporting Requirements .................................................................................................... 37 
12.7 
BMS Reporting Requirements .................................................................................................... 37 
13 
Study Data Collection and Monitoring ............................................................................................. 40 
13.1 
Data Management ....................................................................................................................... 40 
13.2 
Case Report Forms ..................................................................................................................... 41 
13.3 
Data and Safety Monitoring Plan (DSMP) .................................................................................. 41 
13.4 
Affiliate Site Monitoring ............................................................................................................... 41 
13.5 
Record Retention ........................................................................................................................ 42 
14 
Study Endpoints .............................................................................................................................. 42 
14.1 
Primary Endpoint ......................................................................................................................... 42 
14.2 
Secondary Endpoints .................................................................................................................. 42 
14.3 
Exploratory Endpoints ................................................................................................................. 43 
15 
Statistical Considerations ................................................................................................................ 43 
15.1 
Study Design and Sample Size Considerations ......................................................................... 43 
15.2 
Statistical Analysis ...................................................................................................................... 43 
15.2.1 
General Considerations ...................................................................................................... 43 
15.2.2 
Analysis of the Primary Endpoint ........................................................................................ 43 
15.2.3 
Analysis of Secondary Endpoints ........................................................................................ 44 
15.2.4 
Analysis of Exploratory Endpoints ....................................................................................... 44 
15.2.5 
Subgroup Analysis .............................................................................................................. 44 
15.2.6 
Safety Stopping Rule .......................................................................................................... 44 
16 
Ethical and Regulatory Considerations ........................................................................................... 46 
16.1 
Good Clinical Practice ................................................................................................................. 46 
16.2 
Ethical Considerations ................................................................................................................ 46 
16.3 
Informed Consent ........................................................................................................................ 46 
17 
References ...................................................................................................................................... 46 
Appendix I – Eligibility Checklist ................................................................................................................. 48 
Appendix II – ECOG Performance Status and NYHA Classification .......................................................... 51 
 
 
 


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Key Abbreviations 
ADL 
activities of daily living 
AE 
adverse event 
BCG 
Calmette-Guerin 
BID 
bis in die (twice a day) 
BLASST 
Bladder Cancer Signal Seeking Trial-1 
BMS 
Bristol-Myers Squibb 
BSA 
body surface area 
CNS 
central nervous system 
CrCl 
creatinine clearance 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trials Office 
DSMC 
Data and Safety Monitoring Council 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
e-CRF 
electronic case report forms 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
GC 
gemcitabine-cisplatin 
G-CSF 
granulocyte colony stimulating factor 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
human immunodeficiency virus 
IND 
investigational new drug 
irAE 
immune related adverse event 
ITT 
intention-to-treat 
IV 
Intravenous  
MCC 
Masonic Cancer Center 
MIBC 
muscle-invasive bladder cancer 
OnCore 
Online Enterprise Research Management Environment 
PaR 
pathologic response rate 
PCRC 
Primary Clinical Research Coordinator 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PET/CT 
positron emission tomography–computed tomography 
PFS 
progression free survival 
PHI 
personal health information 
PO 
per os (by mouth) 
PS 
performance status 
SAE 
serious adverse event 
TURBT 
transurethral resection of bladder tumor 
ULN 
upper limit of normal 
UMN 
University of Minnesota 
WES 
whole exome sequencing 
 
 


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Protocol Synopsis 
 
Phase II Trial of Neoadjuvant Nivolumab with Cisplatin and Gemcitabine in Muscle-
Invasive Bladder Cancer (MIBC) Patients Undergoing Radical Cystectomy 
 
Study Design: 
This is a multi-center Phase II study to determine the safety and efficacy of nivolumab when given 
in combination with cisplatin and gemcitabine as neoadjuvant treatment in patients with muscle-
invasive bladder cancer (MIBC) prior to standard of care radical cystectomy.  
Eligible, consenting patients receive neoadjuvant treatment with nivolumab in combination with 
gemcitabine-cisplatin (GC) every 3 weeks for 4 treatment cycles over 12 weeks followed by 
standard of care radical cystectomy.  
Primary Objective: 
To determine the efficacy of nivolumab and GC neoadjuvant therapy for MIBC as measured by the 
pathologic response rate (PaR) at time of radical cystectomy. PaR is defined as a pathologic 
down-staging to ≤pT1pN0, which includes pT0, pT1,pTa and pTis. 
Secondary 
Objectives: 
 
• 
To determine the safety of nivolumab when given with GC as neoadjuvant therapy in patients 
with MIBC prior to radical cystectomy. 
• 
To determine the progression free survival (PFS) measured from the date of radical cystectomy 
to date of progression or death from disease recurrence for a maximum of 2 years from surgery. 
Exploratory 
Objectives: 
 
• 
Evaluate molecular subtypes associated with resistance to platinum-based neoadjuvant 
chemotherapy in patients with MIBC and evaluate whether addition of nivolumab alters the 
response to platinum-based neoadjuvant therapy. 
• 
Whole Exome Sequencing (WES) of the pre-treatment bladder cancer biopsy tissue and its 
correlation with response. 
• 
Determine correlation between PD-L1 expression and response to nivolumab. 
• 
Nanostring pancan immune panel gene expression at baseline and at cystectomy (archival 
biopsy and any fresh residual tumor at cystectomy). 
Key Inclusion 
Criteria: 
• Patients with MIBC (predominantly urothelial carcinoma in cases of mixed histology) with clinical 
stage T2-T4a and N≤1 disease (solitary lymph node measuring < 2 cm) and M0 deemed eligible 
for radical cystectomy.  
• ECOG PS 0-1. 
Key Exclusion 
Criteria: 
• Presence of N2-3 or M1 disease. 
• Ineligible to receive cisplatin.  
• Prior systemic therapy (intravenous) is not permitted. Prior intravesical therapy is including 
intravesical gemcitabine permitted for non-muscle invasive disease.  
• Prior treatment with cisplatin 
• Prior treatment with anti-PD-1, and CTLA-4, or anti-a PD-L1 therapeutic antibody or pathway-
targeting agents. 
• Prior radiation to the bladder. 
• History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel 
disease, Wegener's granulomatosis, vascular thrombosis associated with antiphospholipid 
syndrome, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, systemic vasculitis, 
or glomerulonephritis. 
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.  
• Active infection requiring systemic antibiotics for > 7 days within 3 days of Cycle 1, Day 1.   
• Prior allogeneic stem cell or solid organ transplant. 
• Concomitant use of systemic corticosteroids at physiologic doses or >10 mg/day of prednisone 
or equivalent.  
Enrollment Plan:  
41 patients will be enrolled. This study will be conducted at 3 sites with an estimated accrual of 13-
14 patients at each site over 2 years. 
 
 
 


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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
END OF TREATMENT VISIT  
Approximately 30 days after the last nivolumab dose 
And PET/CT or CT of chest, abdomen, and pelvis 
Prior to Surgery 
Radical cystectomy within 6-8 weeks of last neoadjuvant 
therapy - tumor tissue from radical cystectomy for 
assessment of PaR and tissue correlatives  
NEOADJUVANT THERAPY: 
Gemcitabine 1000 mg/m2 IV Day 1 and 8  
Cisplatin 70 mg/m2 IV on Day 1 or, if using split-dose 
cisplatin, 35 mg/m2 IV Day 1 and 8  
Nivolumab at a fixed dose of 360 mg IV on Day 8 
 
Repeat every 21 days +/- 3 days for 4 cycles (Total 12 weeks)  
Consent and Screening 
N=41 
Archived baseline TURBT tumor tissue 
available for staging and tissue 
correlatives (or obtain fresh tissue) 
FINAL STUDY VISIT - Final 
assessment for SAE’s 100 days after 
last dose of nivolumab  
(approximately 6 weeks post-surgery 
Follow for Disease Response every 3 months 
from surgery until progression, then survival only 
for 2 years from surgery 


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1 Study Objectives 
1.1 Primary Objective 
To determine the efficacy of nivolumab when administered with GC as neoadjuvant 
therapy for MIBC as measured by the pathologic response rate (PaR) at time of radical 
cystectomy. PaR is defined as pathologic down-staging to ≤pT1pN0, which includes pT0, 
pT1,pTa and pTis. 
1.2 Secondary Objectives 
• 
To determine the safety of nivolumab when given with GC as neoadjuvant therapy in 
patients with MIBC prior to radical cystectomy. 
• 
To determine the progression free survival (PFS) measured from the date of radical 
cystectomy to date of progression or death from disease recurrence for a maximum of 
2 years from surgery. 
1.3 Exploratory Objectives 
• 
Whole Exome Sequencing (WES) of the pre-treatment bladder cancer biopsy tissue 
and its correlation with response. 
• 
Evaluate molecular subtypes associated with resistance to platinum-based 
neoadjuvant chemotherapy in patients with MIBC and evaluate whether addition of 
nivolumab alters the response to platinum-based neoadjuvant therapy. 
• 
PD-L1 expression in tumor tissue at baseline and correlation with response to therapy.  
• 
Nanostring pancan immune panel gene expression at baseline and at cystectomy 
(archival biopsy and any fresh residual tumor at cystectomy) 
2 Background and Significance 
Cisplatin based neoadjuvant chemotherapy is standard of care in muscle-invasive bladder 
cancer (MIBC) based on two phase III studies have shown improvement in overall survival in 
patients who received cisplatin-based chemotherapy prior to cystectomy compared with 
cystectomy alone. 1,2 A meta-analysis of 3005 patients with MIBC showed a significant survival 
benefit with platinum-based neoadjuvant chemotherapy prior to cystectomy.3,4 Methotrexate, 
vinblastine, doxorubicin, and cisplatin (MVAC) is an established standard neoadjuvant 
regimen 1 In metastatic urothelial carcinoma, dose-dense MVAC (DD-MVAC)5 and 
gemcitabine plus cisplatin (GC)6 have demonstrated similar overall survival rates compared 
to MVAC. Given the favorable safety profile of GC over MVAC in metastatic setting,6 GC is 
not only increasingly used in this setting, but also in the neoadjuvant setting. 7 
 
The survival benefit in the neoadjuvant clinical trials correlated with pathologic response 
(complete response (pCR) or to ≤ pT1N0M0). 1,2,8,9 Strategies to improve pathologic response 
at cystectomy are urgently needed to improve outcomes in MIBC patients receiving cisplatin-
based chemotherapy, while limiting toxicity and combination of chemotherapy with 
immunotherapy agents, especially anti-PD-1/PD-L1 agents may be a promising approach.  
 


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Significant activity of various anti-PD-1/PD-L1 therapies in patients with locally advanced and 
metastatic urothelial carcinoma (UC) progressing on a platinum-containing regimen has been 
established.10-15  
 
Atezolizumab, an anti-PD-L1 antibody was approved by the FDA in May 2016 based on the 
results from the IMvigor 210 trial of 315 patients in which atezolizumab showed significant 
objective response rate (ORR) and durability of responses in patients with advanced or 
metastatic UC progressing after a platinum-based therapy.12 Several other checkpoint 
inhibitors, including nivolumab, pembrolizumab, avelumab, and durvalumab have now been 
approved for platinum-refractory advanced UC. In addition, atezolizumab and pembrolizumab 
are approved in the 1st-line metastatic cisplatin-ineligible UC patients.  
 
Nivolumab, a fully human IgG4 monoclonal antibody against PD-1 and currently approved in 
melanoma, Hodgkin lymphoma, non-small cell lung cancer, head and neck cancer, renal cell 
cancer, and advanced urothelial carcinoma (UC) after failure of platinum-based therapy. The 
approval in UC was based on the CheckMate 275 study in 270 patients with advanced locally 
advanced or metastatic UC who had disease progression during or following platinum-
containing chemotherapy, or whose disease progressed within 12 months of neoadjuvant or 
adjuvant treatment with platinum-containing chemotherapy.15 Nivolumab showed an ORR of 
19.6%; the median time to response was 1.9 months, and the median duration of response 
was not reached at the time of analysis.15 Median progression-free survival was 2 months 
(1.87 months in patients with <1% PD-L1 expression (n = 143) and 3.55 months in patients 
with PD-L1 expression of >1% (n = 122)). Median overall survival was 8.74 months (5.95 
months in patients with PD-L1 <1% and 11.3 months in patients with PD-L1 expression of 
>1%) 16. ORR was 28.4% in patients expressing PD-L1 >5% and 15.8% in patients 
expressing PD-L1 <5%. Nivolumab was very well tolerated with Grade 3-4 adverse events 
occurring in 18% of patients with fatigue and diarrhea being most common, each occurring in 
2% of patients. In addition, there was improvement in quality of life from baseline.15 
 
The promising efficacy and safety of nivolumab in advanced and refractory UC13,15, provide a 
rationale to study its efficacy and safety in as neoadjuvant treatment in MIBC prior to 
cystectomy, in combination with GC. 
  
While conventional chemotherapy directly targets tumor cell replication, there is preclinical 
evidence that the antitumor effects of cytotoxic chemotherapy also occur through modulation 
of the immune system.16 Preclinical evidence suggests that platinum agents utilize signaling 
pathways leading to immunogenic cell death, resulting in uptake and processing of tumor 
antigens.17 In addition, gemcitabine inhibits B-cell proliferation and selectively depletes 
immunosuppressive myeloid-derived suppressor cells and regulatory T cells in mouse models 
of malignant mesothelioma and lung cancer, implying it is not detrimental to specific antitumor 
cellular immunity and may be useful in combination with immunotherapy agents. 17 
 
Based on the population pharmacokinetic modeling, established flat exposure-response 
relationships for efficacy and safety, and clinical safety, the benefit-risk profile of flat dose 


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nivolumab 240 mg Q2 week dosing  was comparable to 3 mg/kg Q2 week dosing  and the 240 
mg IV Q week dose is approved across majority of indications. Nivolumab 360 mg Q3 week 
dose has been combined safety with platinum-based chemotherapy doublets in metastatic 
lung cancer and the combination showed encouraging synergy and activity. 18  
 
In addition, several ongoing trials are utilizing nivolumab dosing of 360 mg intravenously every 
21 days alone or with chemotherapy or other agents in a variety of cancers including bladder 
cancer. 
(www.clinicaltrialsgov; 
NCT03101566, 
NCT03117309, 
NCT03081689, 
NCT03081689, NCT01454102).  
 
Given the favorable safety profile of nivolumab and non-overlapping toxicities with GC, this 
combination is expected to be well-tolerated in MIBC patients receiving neoadjuvant therapy. 
For this study, we will utilize the 360 mg every 21 day dosing of nivolumab along with GC 
regimen which is administered every 21 days.   
 
This study would provide crucial information on whether addition of immunotherapy to 
chemotherapy improves outcomes in MIBC, which in turn would translate into long-term 
improved outcomes. Furthermore, the exploratory genomics data from the tissues in this trial 
would provide information on correlation between genomic and immunologic changes in tumor 
tissues with clinical outcomes. 
3 Study Design 
This is a multi-center Phase II study to determine the safety and efficacy of nivolumab when 
given in combination with gemcitabine/cisplatin (GC) as neoadjuvant treatment in patients with 
muscle-invasive bladder cancer (MIBC) prior to standard of care radical cystectomy.  
This study is open to patients diagnosed with MIBC who are medically eligible for neoadjuvant 
GC and for whom a radical cystectomy is planned. Eligible, consenting patients receive 
neoadjuvant treatment with nivolumab in combination with GC every 21 days for 4 treatment 
cycles over 12 weeks followed by standard of care radical cystectomy.  
The outcomes of the surgical procedure will not be evaluated as a part of this study other than 
related to pathology.  
The primary efficacy endpoint of pathologic response rate (PaR) will be evaluated in a one-
arm, single stage design. Forty-one (41) subjects will be enrolled and the treatment will be 
worthy of further study (and the null hypothesis rejected) if pathologic response is seen at the 
time of cystectomy in more than 19 patients.  
 
 


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4 Patient Selection 
Study entry is open to patients 18 years and older regardless of gender, race, or ethnic 
background. Enrollment in this study is expected to be no different than other similar studies 
at the University of Minnesota and other participating institutions. 
4.1 Inclusion Criteria 
1. Diagnosis of MIBC (predominantly urothelial carcinoma, except for small-cell variants) with 
clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring < 2 cm) and M0 
and deemed eligible for radical cystectomy.  
2. Age ≥ 18 years. 
3. ECOG Performance Status of 0 or 1 (Appendix II). 
4. Required initial laboratory values within 14 days of study enrollment: 
• Absolute Neutrophil Count ≥ 1500 cells/mm3 
• Platelets ≥ 100,000 cells/mm3 
• Hemoglobin  ≥ 9.0 g/dL 
• Bilirubin ≤ 1.5 times the upper limit of normal (ULN) for the institution (For patients 
with known Gilbert's disease: bilirubin ≤ 3 x ULN) 
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN for the 
institution 
• Creatinine clearance ≥ 50 ml/min by Cockcroft-Gault formula (CrCl = [140-age 
(years)] x actual weight (kg) / [72 x serum Cr (mg/dL)] - if patient is female multiply 
the above by 0.85) or 24 hour urinary creatinine clearance. 
• Alkaline phosphatase ≤ 2.5 x ULN for the institution 
• INR and aPTT ≤ 1.5 x ULN if not on therapeutic anticoagulation. Patients receiving 
therapeutic anticoagulation will be allowed if maintained on a stable dose. 
5. 
Females of childbearing potential and males who are not surgically sterile and with 
partners of childbearing potential must agree to use effective contraception during study 
treatment for 5 months for females and 7 months for males after the last dose of 
nivolumab. 
6. 
Patient must agree to submission of archived tumor (20-25 formalin-fixed paraffin 
embedded (FFPE) slides of 5-10 microns in thickness) from TURBT and radical 
cystectomy tissues. If archived samples are not available fresh tissue will be used. 
7. 
Ability to provide written consent prior to the initiation of any research related 
procedures. 
4.2 Exclusion Criteria 
1. 
Presence of N2-3 or M1 disease. 
2. 
Ineligible to receive cisplatin by meeting one or more of the following criteria:  
• 
creatinine clearance of < 50 mL/min,  
• 
hearing loss of 25 dB at two contiguous frequencies with testing required if a patient 
has hearing loss – At the investigator’s discretion, and after discussion with the 
patient, this exclusion may be waived if the potential benefit of cisplatin therapy is 
felt to outweigh the risk of further hearing loss. 
• 
CTCAE v4 Grade 2 or higher peripheral neuropathy,  
• 
New York Heart Association Class III or IV heart failure (Appendix II),  


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• 
ECOG performance status 2 or higher (Appendix II).  
3. 
Prior systemic therapy (intravenous) is not permitted. Prior intravesical therapies 
including intravesical gemcitabine is permitted for non-muscle invasive disease (i.e. T1 
or lower).  
4. 
Prior treatment with cisplatin for bladder cancer.  
5. 
Prior treatment with anti-PD-1, CTLA-4, or anti-PD-L1 therapeutic antibody or pathway-
targeting agents. 
6. 
Prior therapeutic radiation to the bladder.  
7. 
Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need 
for a major surgical procedure during the course of the study. 
8. 
Any of the following within the 6 months prior to study drug administration: 
• 
myocardial infarction,  
• 
severe/unstable angina,  
• 
symptomatic congestive heart failure (New York Heart Association Class III or IV),  
• 
stroke, serious cardiac arrhythmia. 
9. 
Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome 
(AIDS)-related illness. 
10. Pregnancy, lactation, or breast-feeding. Women of childbearing potential must have a 
negative urine pregnancy test at screening.  
11. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, Wegener's granulomatosis, vascular thrombosis associated with 
antiphospholipid syndrome, Sjogren's syndrome, Guillain-Barre syndrome, multiple 
sclerosis, systemic vasculitis, or glomerulonephritis. 
12. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) 
scan, history of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
13. Active hepatitis B virus (HBV, chronic or acute, defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C antibody. Patients with past 
HBV infection or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA must be obtained in 
these patients prior to Cycle 1, Day 1 and confirmed to be negative. Patients positive for 
hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative 
for HCV RNA. 
14. Active tuberculosis or BCG infection 
15. Active infection requiring systemic antibiotics for more than 7 days within 3 days prior to 
Cycle 1, Day 1. Prophylactic short-term antibiotics will be allowed. 
16. Administration of intravesical bacillus Calmette-Guerin (BCG) within 4 weeks before 
Cycle 1, Day 1. 
17. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study. 


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18. Persisting toxicity from prior therapy (NCI CTCAE v4.03 Grade >1); however alopecia 
or other Grade ≤2 AEs not constituting a safety risk, based on Investigator’s judgement, 
are acceptable.  
19. History of or active bone marrow disorders expected to interfere with study therapy (e.g. 
acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic 
lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory 
myeloma). 
20. Prior allogeneic stem cell or solid organ transplant. 
21. Known primary central nervous system (CNS) malignancy.  
22. Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted but patients with psoriasis require a baseline ophthalmologic exam to rule out 
ocular manifestations. Rash must cover less than 10% of body surface area (BSA) and 
must be well controlled at baseline and only requiring topical steroids.  
23. Any other chronic medical condition or psychiatric condition, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment complications 
24. Known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin or in situ cervical cancer that has undergone potentially curative therapy. Patients 
on androgen deprivation therapy as part of adjuvant therapy after radiation for prostate 
cancer or patients on adjuvant hormonal therapies for breast cancer will be allowed if 
they are being considered for curative intent for bladder cancer.  
25. Treatment with systemic immunostimulatory agents (including but not limited to 
interferon-a or interleukin-2) within 4 weeks or five half-lives of the drug (whichever is 
shorter) prior to Cycle 1, Day 1 
26. Concomitant use of systemic corticosteroids at physiologic doses or >10 mg/day of 
prednisone or equivalent.  
27. Concomitant use of another investigational agent and/or treatment with an 
investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five half-lives of 
the investigational product, whichever is longer). 
28. Use of bisphosphonate therapy for osteoporosis will be allowed if started prior to study 
enrollment. 
 
 


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5 Patient Screening and Enrollment 
Written consent must be obtained prior to the performance of any research related tests or 
procedures. Consent is obtained before eligibility is confirmed. 
5.1 Enrollment with the University of Minnesota Clinical Trials Office 
Any patient who has been consented is to be entered in OnCore by the site Primary 
Clinical Research Coordinator (PCRC) or designee. If a patient is consented but is not 
enrolled, the patient’s record is updated in OnCore as a screen failure and reason for 
exclusion recorded.  
Complete enrollment information is found in the study’s Procedures Manual for Affiliate 
Sites. 
Affiliate sites only: Affiliates are responsible for fulfilling any local registration 
requirements. 
5.2 Patient Enrollment in OnCore 
To be eligible for study enrollment, the patient must sign the treatment consent and meet 
each inclusion criteria and none of the exclusion criteria on the eligibility checklist 
(Appendix I) based on an eligibility assessment documented in the patient’s medical 
record. 
 
The Primary Clinical Research Coordinator (PCRC) or designee enters the study arm and 
adds the on treatment date in OnCore. 
5.3 Patients Who Do Not Begin Study Treatment 
If a patient is registered to the study and is later found unable to begin study treatment the 
patient will be removed from study and treated at the physician’s discretion. The study 
staff will update OnCore of the patient’s non-treatment status (off study). The reason for 
removal from study prior to starting study treatment will be clearly indicated in OnCore. 
The patient will be replaced to complete enrollment. 
6 Treatment Plan 
6.1 Study Drug Administration 
Treatment will be administered on an outpatient basis. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent 
to treat the patient's cancer. Patients will receive neoadjuvant treatment with cisplatin, 
gemcitabine and nivolumab every 21 days for 4 cycles over 12 weeks prior to radical 
cystectomy.  
The sequence and time between gemcitabine and cisplatin administration is per 
institutional usual practice. On Day 8, nivolumab should be given after the chemotherapy 
with the time from the end of the chemotherapy and the start of the nivolumab infusion per 
institutional usual practice. 


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The patient’s weight will be obtained on Day 1 or within the 3 days prior of each cycle. For 
Cycle 1 Day 1, the screening weight may be used. The patient’s weight used for Day 1 
dose calculation may also be used for Day 8 dosing. The adjustment of doses of 
gemcitabine and cisplatin based on weight change from Cycle 1 Day 1 weight can be done 
per Institutional standards.  
For cycle 2 and beyond, Day 1 treatment may be given using a ± 3 day window. 
Cisplatin is given at 70 mg/m2 IV over 30 minutes on Day 1 every 21 days; however, 
based on treating physician’s discretion, split-dose cisplatin can be given at 35 mg/m2 IV 
Day 1 and Day 8 every 21 days for 4 cycles. Recommended dose of prophylactic 
dexamethasone (Decadron) up to 8 mg IV or PO on day of cisplatin treatment followed by 
up to 4 mg PO BID for 3 days. Other antiemetics may be given per the investigator’s 
discretion and institutional guidelines. 
Gemcitabine is given at 1000 mg/m2 IV over 30 minutes on Day 1 and Day 8 every 21 
days for 4 cycles. There should be a minimum of 7 days between gemcitabine doses with 
a + 3 day window for Day 8 treatment. 
Nivolumab is given at a fixed dose of 360 mg IV over 30 minutes or per institutional 
practice on Day 8 after the chemotherapy (gemcitabine, and, if given, cisplatin) every 21 
days for 4 cycles. Nivolumab should be given 60 min (±15 min) after the chemotherapy 
agent (gemcitabine or cisplatin if using a split-dose). 
Prophylactic granulocyte colony stimulating factor (G-CSF) support will be allowed as 
standard of care based on treating physician’s discretion. 
Study treatment is permanently discontinued for any of the following situations: 
• 
Any Grade 4 drug related adverse event – without exceptions 
• 
Any grade neurologic event 
• 
Any grade pneumonitis 
• 
Recurrent Grade 2 or 3 immune-related adverse event (refer to Section 8 – Nivolumab 
Related Toxicity Management) 
6.1.1 Criteria to Begin a New Treatment Cycle and Required Delays 
The following criteria must be met prior to starting Day 1 of any cycle based on lab work 
performed on the day of treatment or up to 3 days prior to Day 1 treatment:   
• 
ANC ≥ 1500 cells/mm3 for Cycle 1 Day 1 only, ANC ≥ 1000 cells/mm3 for Day 1 of all 
subsequent cycles. 
• 
Hemoglobin ≥ 9 g/dl 
• 
Platelet ≥ 100,000/mm3 
• 
Bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if Gilbert’s disease) 
• 
Creatinine clearance ≥ 50 ml/min (beginning with Cycle 2, if CRCL ≥ 45, but < 50 
ml/min with other criteria for treatment met, treatment may be administered with 
cisplatin/gemcitabine given at 75% dose per Section 7.2). Creatinine clearance is 


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calculated by the Cockcroft-Gault formula (CrCl = [140-age (years)] x actual weight 
(kg) / [72 x serum Cr (mg/dL)] (if patient is female multiply the above by 0.85). 24 hour 
urinary clearance can be obtained as well and the results from this can be used 
instead. 
 
In addition, the patient must not have experienced unacceptable toxicity since Day 1 of 
the previous treatment cycle (defined as Grade 4 nivolumab related adverse event, any 
grade neurologic event, any grade pneumonitis or Recurrent Grade 2 or 3 immune-related 
adverse event) per Section 6.1.2. 
 
For Cycle 2 and beyond, if any of the above criteria is not met, treatment is delayed 1 
week and the patient re-evaluated. Treatment may be delayed for up to 3 weeks for a 
given cycle start. If after a 3 week delay the patient is still unable to restart treatment, the 
patient will be discontinued from study treatment. If a patient who has had a previous 
treatment cycle delay, requires a delay of more than 2 weeks in a subsequent cycle, the 
patient will be discontinued from study treatment. 
6.1.2 Discontinuation of Treatment Due to Toxicity 
Study treatment is permanently discontinued for any of the following: 
• 
Any Grade 4 drug related adverse event – without exceptions 
• 
Any grade neurologic event 
• 
Any grade pneumonitis 
• 
Recurrent Grade 2 or 3 immune-related adverse event (refer to Section 8 – 
Nivolumab Related Toxicity Management) 
 
For Cycle 2 and beyond, if a patient is unable to receive nivolumab due to any of the above, 
the patient may continue to receive future cycles of cisplatin and gemcitabine on the study, 
if meet the criteria for receiving those drugs.  
 
For Cycle 2 and beyond, if a patient cannot receive cisplatin and gemcitabine due to 
toxicities or patient refusal, the patient will be taken off study treatment and treated at the 
discretion of the medical provider.  
 
Any patient receiving at least one dose of study treatment (nivolumab) will be included in 
the study’s intention-to-treat (ITT) analysis. 
6.2 Concomitant Medications and Supportive Care 
Medications to prevent or reduce the severity of expected side effects for cisplatin, 
gemcitabine, and nivolumab, may be given per the package insert (Investigator Brochure 
for nivolumab) or institutional standards. Recommended dose of prophylactic 
dexamethasone (Decadron) up to 8 mg IV or PO on day of cisplatin treatment followed by 
up to 4 mg PO BID for 3 days. Other antiemetics can be given per Investigator’s discretion 
and Institutional guidelines.  


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Hydration prior to cisplatin will be given using institutional guidelines and may include 
mannitol, electrolytes, or furosemide according to institutional practices. 
 
Prophylactic granulocyte colony stimulating factor (G-CSF) support will be allowed as 
standard of care based on treating physician’s discretion. 
 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care. During the study, 
supportive therapy can include antibiotics, analgesics, pain control, transfusions, 
psychotherapy, growth factors, hydration or any other symptomatic therapy as clinically 
indicated.  
Steroids will be allowed to treat any immune-related adverse events from nivolumab as 
outlined in Section 8 for management of immune-relates adverse events. Use of ≤ 10 mg 
prednisone or equivalent dose of steroids is allowed for short-term use (< 7 days) as 
supportive care for issues other than immune-related adverse events. 
6.3 Duration of Study Treatment and the End of Treatment Visit 
Treatment consists of four 21 day treatment cycles of nivolumab in combination with 
gemcitabine and cisplatin given over approximately 12 weeks unless one of the following 
occurs: 
• 
Patient experiences unacceptable toxicity as defined in Section 6.1.2 
o Any Grade 4 drug related adverse event 
o Any grade neurologic event 
o Any grade pneumonitis 
o Recurrent Grade 2 or 3 immune-related adverse event (refer to Section 8 – 
Nivolumab Related Toxicity Management) 
• 
Patient is unable to receive nivolumab after at least 1 treatment cycle. In such 
situations, the patient may continue GC on treatment, provided they meet the 
criteria to continue. 
• 
More than 3 weeks delay occurs between 2 treatment cycles OR requires a 2nd 
treatment delay between 2 cycles of more than 2 weeks 
• 
Continuation of therapy is no longer in the best interest of the patient in the opinion 
of the treating investigator 
• 
Patient withdraws consent or is non-compliant 
An End of Treatment (EOT) visit will occur approximately 30 days after the last dose of 
nivolumab to assess for ongoing treatment related toxicity. However, per Section 12.7 
serious adverse events (SAEs) or adverse event (AEs) that become SAEs must be 
assessed through the Final Study Visit (approximately 100 days after the last dose of 
nivolumab).  
Any patient leaving the study prior to completing 4 treatment cycles will be treated as 
the physician’s discretion. The patient is still considered on study (unless consent is 


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withdrawn) and will follow the study plan of pre-operative imaging and obtaining tissue 
samples at the time of surgery per Section 10. 
6.4 Pre-Operative Imaging and Radical Cystectomy 
After the completion of the treatment, but prior to the surgery, the patient will undergo 
a PET/CT or CT of the chest, abdomen and pelvis.  
 
Radical cystectomy will be scheduled per surgeon’s discretion as standard of care 
procedure, preferably within 6-8 weeks after completion of neoadjuvant chemotherapy. 
Tissue samples will be acquired for research related testing per Section 10. 
6.5 Final Study Visit/Assessment 100 Days Post Nivolumab 
A Final Study Visit occurs after surgery. Most visits will occur approximately 6 weeks 
post-surgery, but a visit outside of this timeframe is permissible. This visit also serves 
as the final assessment for nivolumab related serious adverse events (SAEs) or 
adverse event (AEs) that become SAEs through 100 days after the last dose of 
nivolumab per Section 12.7. After the final study visit, patients will be followed by record 
review until disease progression and then for survival only for 2 years from the time of 
cystectomy. 
7 Dose Modifications and Delay Guidelines 
No dose modifications are permitted for nivolumab but the dose may be skipped based on 
occurrence of significant immune-related AE as described in Section 8. 
Management of toxicities from gemcitabine and cisplatin will be per the package insert and 
standard institutional guidelines. 
The below dose modification guidelines serve as a general guideline only. The treating 
physician’s discretion can be used to further modify the dose of cisplatin and gemcitabine. If 
a treatment cycle is delayed, all drugs should be delayed.  In addition, after Cycle 1, cisplatin 
may be changed to split-dose schedule if, in Investigator’s judgement, it would be better 
tolerated by patient.  
 
 


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7.1 Hematologic Toxicity (Cisplatin and Gemcitabine) 
 
Day 1 Cycle 2 and subsequent cycles 
ANC 
 
Platelet count 
Gemcitabine 
Cisplatin  
>1000/mm3 
and 
≥100,000/mm3 
Give 100% dose 
Give 100% dose 
< 1000/mm3 
and/or 
<100,000/mm3 
Delay new cycle start 
by 1 week per 
Section 6.1.1 
Delay new cycle 
start by 1 week 
per Section 6.1.1 
 
*If a Day 8 gemcitabine/cisplatin is withheld due to hematologic toxicity the dose will not be made up. Only 
nivolumab will be administered on Day 8, unless criteria are met in Section 8 to also skip that dose.  
 
G-CSF should be considered with subsequent cycles if a patient develops neutropenic 
complications in the immediate previous cycle.  
If febrile neutropenia requiring antibiotic therapy or Grade 4 thrombocytopenia occurs, the 
cisplatin and gemcitabine dose will be reduced by 25% for subsequent treatment cycles.  
7.2 Renal Impairment (Cisplatin and Gemcitabine) 
Day 1 and Day 8 (after Cycle 1 Day 1) 
CrCl 
Gemcitabine 
Cisplatin  
≥50 ml/mil 
Give 100% dose 
Give 100% dose 
≥45 but <50 ml/min 
Day 1: give 75% dose if all 
other criteria to start a new 
cycle is met per Section 6.2.1 
Day 8: give 75% dose 
Day 1: give 75% dose if all other criteria to 
start a new cycle is met per Section 6.2.1 
Day 8 (if split dose): give 75% dose 
<45 ml/min 
Day 1: delay cycle start per 
Section 6.2.1  
Day 8: skip treatment* 
Day 1: delay cycle start per Section 6.2.1 
Day 8 (if split dose): skip treatment* 
**If a Day 8 gemcitabine/cisplatin is withheld due to renal impairment the dose will not be made up. Only 
nivolumab will be administered on Day 8, unless criteria are met in Section 8.2 to also skip that dose. 
The weight from Day 1 can be used to calculate creatinine clearance on Day 8.  
Cisplatin may be changed to split-dose schedule if, in Investigator’s judgement, it would 
be better tolerated by patient. 
Day 8 of Cycle 1 and Subsequent Cycles* 
ANC 
 
Platelet count 
Gemcitabine 
Cisplatin 
(if using split-
dose cisplatin) 
≥1,000/mm3 
and 
≥ 75,000/mm3 
Give 100% dose 
Give 100% dose 
≥1,000/mm3 
and 
50,000-74,999 
Give 75% dose 
Give 100% dose 
<1,000/mm3 
or 
< 50,000/mm3 
Skip treatment. 
Reduce dose by 25% 
for next treatment. 
Skip treatment 


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7.3 Hepatic Impairment  
No dose adjustments are required for cisplatin or gemcitabine. 
 
Nivolumab does not need to be held for hepatic dysfunction, unless immune 
related hepatic AEs are suspected from nivolumab, then follow the Nivolumab 
related toxicity management as outlined in Section 8. 
 
Discontinuation of treatment should be considered if drug induced liver injury is 
suspected (cisplatin, gemcitabine or nivolumab)  
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN and total bilirubin >2 × ULN or INR >1.5 (if INR testing 
is applicable/evaluated) 
• ALT or AST >3 × ULN with the appearance of symptoms suggestive of liver 
injury (e.g. right upper quadrant pain or tenderness) and/or eosinophilia 
(>5%) 
 
These treatment discontinuation recommendations are based on the FDA 
Guidance for Industry (Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009). 
8 Nivolumab Related Toxicity Management 
Immune-related adverse events (irAEs) from nivolumab will be managed depending on 
severity (NCI CTCAE V4.0 grading) as outlined below.  
 
Note: if Nivolumab cannot be given on Day 8 of a cycle, dosing will be skipped for that cycle.  
Nivolumab dosing may be resumed no sooner than Day 8 of the next cycle. 
 
Immune-Related (ir) Adverse Events Management – General Guidelines  
 
Grade 1 to 2: Treat symptomatically or with moderate dose steroids, more frequent 
monitoring. 
 
Grade 1 to 2 (persistent):  Manage similar to Grade 3 to 4 irAE 
Grade 3 to 4: Treat with high dose corticosteroids, typically 1-2 mg/kg of prednisone or IV 
steroid equivalent and 
Grade 4 irAEs permanently discontinue treatment with nivolumab  


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Grade 3 irAEs requires withholding nivolumab except for any of the following: Transient 
(≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical management, 
transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to Grade ≤ 1 and single laboratory values out of normal range (excluding Grade ≥ 3 
liver function test increase) that are unlikely related to study treatment according to the 
Investigator, do not have any clinical correlate, and resolve to Grade ≤ 1 within 7 days with 
adequate medical management 
Any Grade 2 irAEs should be managed as follows: 
If a Grade 2 irAE resolves to Grade ≤ 1 by the next planned cycle, treatment may continue. 
If a Grade 2 irAE does not resolve to Grade ≤ 1 by the next planned cycle, treatment should 
be withheld at next cycle. If at the end of the following cycle the event has not resolved to ≤ 
Grade 1, the subject should permanently discontinue treatment with nivolumab (except for 
hormone insufficiencies, that can be managed by replacement therapy).  
Upon the recurrence of the same Grade 2 irAE (except for hormone insufficiencies that can 
be managed by replacement therapy) in the same subject, treatment with nivolumab should 
be permanently discontinued.  
 
Treatment of gastrointestinal, dermatological, pulmonary, hepatic and endocrine irAEs should 
follow guidelines in the following table. 
 
 


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GI irAEs 
Severity of Diarrhea/Colitis 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day 
over baseline 
Colitis: asymptomatic  
Continue nivolumab therapy 
Symptomatic treatment (for example, 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2 or 3 to 4  
Grade 2 
Diarrhea:  4 to 6 stools per 
day over baseline; IV fluids 
indicated < 24 hours; not 
interfering with ADL 
Colitis:  abdominal pain; 
blood in stool  
Withhold nivolumab for the current 
cycle  
Symptomatic treatment 
If improves to Grade ≤1:  
Resume nivolumab on Day 8 of the next 
cycle 
 
If worsens: treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 
stools per day over 
Baseline; incontinence; IV 
fluids ≥ 24 hrs.; interfering 
with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs 
Grade 4:  life-threatening, 
perforation 
Grade 3: Withhold nivolumab for the 
current cycle 
Grade 4 or recurrent Grade 3: 
permanently discontinue nivolumab  
 
Begin methylprednisolone 1.0 to 2.0 
mg/kg/day IV or equivalent 
 
Add prophylactic antibiotics for 
opportunistic infections  
 
Consider colonoscopy if needed  
If improves, continue steroids until Grade < 
1, then taper over at least 1 month,  
Resume nivolumab on Day 8 of the next 
cycle  
 
If worsens, persists > 3 to 5 days, or recurs 
after improvement, add infliximab 5 mg/kg (if 
no contraindication), Note: Infliximab should 
not be used in cases of perforation or sepsis  
Dermatological irAEs 
Grade of Rash 
Management 
Follow-up 
Grade 1 to 2 
Covering  for Grade 3 30% 
body surface area 
Symptomatic therapy (for example, 
antihistamines, topical steroids) 
Continue nivolumab 
If persists > 1 to 2 weeks or recurs: 
Consider skin biopsy 
 
Consider methylprednisolone 0.5 to 1.0 
mg/kg/day IV or oral equivalent. Once 
improving, taper steroids over at least 1 
month, consider prophylactic antibiotics for 
opportunistic infections. If worsens. treat as 
Grade 3 or 4 
Grade 3 to 4 
Covering > 30%  
Grade 4: body surface area; 
life threatening 
consequences  
Grade 3: Skip nivolumab for the current 
cycle 
Grade 4 or recurrent Grade 3: 
Permanently discontinue nivolumab 
Consider skin biopsy  
Dermatology consult  
methylprednisolone 1.0 to 2.0 
mg/kg/day IV or IV equivalent  
 
 
 
If improves to ≤ Grade 1, taper steroids over 
at least 1 month and add prophylactic 
antibiotics for opportunistic infections 
Resume nivolumab therapy Day 8 of next 
cycle for Grade 3 


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Pulmonary irAEs 
Grade of Pneumonitis 
Management 
Follow-up 
Grade 1 
Radiographic changes only  
Permanently discontinue nivolumab 
per Section 6.1.2 
Monitor for symptoms every 2 to 3 days  
Consider pulmonary and Infectious 
disease consults 
If worsens, treat as Grade 2 or 3 to 4  
Grade 2 
Mild to moderate new 
symptoms  
Permanently discontinue nivolumab 
per Section 6.1.2 
Pulmonary and Infectious Disease 
consults 
Monitor symptoms daily, consider 
hospitalization  
methyl-prednisolone 1.0 mg/kg/day IV 
or oral equivalent  
Consider bronchoscopy, lung biopsy  
When symptoms improve to Grade ≤1, taper 
steroids over at least 1 month   
 
If not improving after 2 weeks or worsening, 
treat as Grade 3 to 4  
Grade 3 to 4 
Severe new symptoms; New 
/ worsening hypoxia; life-
threatening  
Permanently discontinue nivolumab per 
Section 6.1.2 
Hospitalize  
Pulmonary and Infectious Disease 
consults 
methyl-prednisolone 2 to 4 mg/kg/day 
IV or IV equivalent  
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung biopsy  
When symptoms improve to Grade ≤ 1, taper 
steroids over at least 1 month  
 
If not improving after 48 hours or worsening:, 
add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test 
Elevation 
Management 
Follow-up 
Grade 1 
Grade 1 AST or ALT > ULN 
to 3.0 x ULN and/or total 
bilirubin > ULN to 1.5 x ULN  
Continue nivolumab 
Continue liver function monitoring  
If worsens, treat as Grade 2 or 3 to 4  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and / or total bilirubin > 
1.5 to ≤ 3 x ULN  
Skip nivolumab for the current cycle 
Increase frequency of monitoring to 
every 3 days  
If returns Grade ≤ 1, resume routine 
monitoring, resume nivolumab on Day 8 of 
the next cycle 
If elevations persist > 7 days or worsens, 
methylprednisolone 0.5 to 1 mg/kg/day or oral 
equivalent and when LFT returns to Grade ≤ 1
taper steroids over at least 1 month, resume 
nivolumab on Day 8 of next cycle 
Grade 3 to 4  
AST or ALT > 5 x ULN and / 
or total bilirubin > 3 x ULN  
Permanently discontinue nivolumab  
Increase frequency of monitoring to 
every 1 to 2 days  
methylprednisolone 1.0 to 2.0 
mg/kg/day IV or IV equivalent 
Consult gastroenterologist 
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted  
If returns to Grade ≤1, taper steroids over at 
least 1 month  
If does not improve in > 5 days, worsens or 
rebounds, add mycophenolate mofetil 1 
gram (g) twice daily  
If no response within an additional 3 to 5 
days, consider other immunosuppressants 
per local guidelines  


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Cardiac irAEs 
Myocarditis 
Management 
Follow-up 
New onset cardiac 
signs/symptoms and/or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, 
CK-MB, BNP) or cardiac 
imaging suggestive of 
myocarditis  
Skip nivolumab for the current cycle 
Hospitalize. 
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis, consider myocardial 
biopsy 
 
If symptoms improve and immune-mediated 
etiology is ruled out, resume nivolumab Day 
8 of next cycle.  
 
If symptoms do not improve or worsen, and 
immune-mediated etiology is suspected or 
confirmed manage as immune-mediated 
myocarditis. 
Immune-mediated 
myocarditis 
Permanently discontinue nivolumab 
Methylprednisolone 1 to 2 mg/kg/day. 
 
Once improving, taper steroids over at least 
1 month  
If no improvement or worsening, consider 
additional immunosuppressants (e.g. 
azathioprine, cyclosporine A) 
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-up 
Asymptomatic TSH 
abnormality  
Continue nivolumab   
If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent 
measurements: include T4 at subsequent cycles as clinically indicated; consider 
endocrinology consult  
Hypophysitis 
Grade 2 or 3 
Evaluate endocrine function  
Consider pituitary scan  
Withhold nivolumab 
1 mg/day prednisone  equivalents  
Initiate appropriate hormone therapy as 
indicated 
Consider Endocrinology consult   
If improves (with or without hormone 
replacement):  
Taper steroids over at least 1 month  
Resume nivolumab on Day 8 of next cycle 
 
Grade 4 
Permanently discontinue nivolumab 
 
Adrenal Insufficiency 
Grade 2 
 
Withhold nivolumab 
Evaluate endocrine function 
Consider Endocrinology consult 
If improves to Grade ≤1, 
Resume nivolumab Day 8 of next cycle 
 
Grade 3 or 4  
Permanently discontinue nivolumab 
Consider Endocrinology consult 
prednisone 1 to 2 mg/kg/day or 
equivalents    
 


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9 Schedule of Tests and Procedures  
For Cycle 2 and beyond, Day 1 treatment may be given using a ±3 day window. Gemcitabine 
should be given on Day 1 and Day 8 of each cycle and there should be a minimum of 7 days 
between gemcitabine doses, with a + 3 day window for Day 8 treatment. The lab work for Day 
1 may be performed the day of treatment or up to 3 days before.  
 
The End of Treatment (EOT) may be performed any time prior to surgery but is targeted for 
approximately 30 days after the last dose of nivolumab. This visit also serves as the end of 
assessment for safety stopping rule events per Section 12.3. 
 
A Final Study Visit occurs after surgery. Most visits will occur approximately 6 weeks post-
surgery, but a visit outside of this timeframe is permissible. This visit also serves as the end 
of 100 day post-nivolumab monitoring for serious adverse events (SAEs) and adverse events 
(AE) that became serious per Section 12.7. 
 
After the Final Study Visit, follow-up visits with disease assessments are per standard of care. 
Patients are followed for response until disease progression, and then survival status only for 
up to 2 years after surgery. This information may be obtained by in person visits, record review 
or other methods of obtaining disease and survival status.   
 
 


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Screening 
within 28 
days of 
Cycle 1 
Day 1 
Every 
Treatment 
Cycle 
End of 
Treatment 
visit  
prior to surgery  
(~ 30 days after 
last nivo dose) 
Final Study Visit 
and Final SAE 
Assessment at time 
of SOC post-surgery 
(~120 day after last 
dose nivo) 
Follow-up every 3 
months13  
from surgery per SOC 
until PD, then survival 
only for 2 years from 
surgery  
Day 
1 
Day 
8 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Eligibility Confirmation 
X 
 
 
 
 
 
Prior treatment  
X 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
 
Weight (Height also during screen) 
X 
X1 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
 
X 
X 
 
ECG –single, at rest 
X 
 
 
 
 
 
Audiology Assessment (refer to Section 4.2 #2) 
X 
 
 
 
 
 
Assessment of AEs  
 
X 
X 
X 
X2 
 
Assessment for safety stopping rule events 
 
X 
X 
X 
 
 
LABORATORY ASSESSMENTS 
Complete Blood Count with diff (CBC) 
X 
X3 
X 
X 
X 
 
Comprehensive Metabolic Profile (CMP)3 
X 
X3 
X 
X 
X 
 
LDH, phosphorus, Mg  
X 
X 
X 
 
X 
 
ACTH stimulation test 
 
 
 
X11 
 
 
TSH 
X 
 
 
 
X 
 
INR, aPTT 
X 
 
 
 
X 
 
Hepatitis B, C, HIV serology 
X 
 
 
 
 
 
Creatinine clearance 
X 
X 
X12 
 
 
 
Pregnancy test (urine) WOCBP 
X5 
X6 
 
 
 
 
RESPONSE ASSESSMENT AND SURVIVAL STATUS 
CT of chest, abdomen and pelvis or PET/CT  
X 
 
 
X 
X (optional – if 
performed for SOC) 
X 
Survival status 
 
 
 
 
 
X 
TREATMENT EXPOSURE 
Gemcitabine 
 
X 
X1 
 
 
 
Cisplatin  
 
X 
X1,7 
 
 
 
Nivolumab 
 
 
X 
 
 
 
CORRELATIVE STUDIES  
Blood and tissue collection (TURBT) 8 
X 
 
 
 
 
GenomeDx from TURBT9 (SOC) 
X 
 
 
 
 
Tissue collection10 
X  
 
 
X 
 
1. 
Weight from Day 1 (or within 3 days prior or screening weight if Cycle 1) may be used to calculate the doses of the Day 8 gemcitabine and if given, 
cisplatin. No adjustment in dose is required if < 10% weight change from Cycle 1 Day 1 weight. 
2. Per Section 12.4 BMS requires monitoring for Serious Adverse Events (SAEs) through 100 days of discontinuation of nivolumab dosing.   
3. 
 If screening (baseline) labs were performed within 7 days of Day 1 of treatment, these do not need to be repeated; For Cycle 2 or later, lab work 
may be performed up to 3 days prior to Day1   
4. 
CMP to include sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline 
phosphatase  
5. 
For women of childbearing potential (WOCBP): urine pregnancy test within 14 days prior to study enrollment. If a urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.  
6. 
Women of childbearing potential must get a pregnancy test at each Cycle.  
7. 
Cisplatin will be given on Day 1, unless using split-dose when it will be given on Day 1 and Day 8 
8. 
Whole blood (5 cc in EDTA tube for germline DNA extraction) and archival tissue from TURBT or fresh tissue will be collected for WES and shipped 
to UMN (Section 10.2) 
9. 
The archival tissue from TURBT will be sent for molecular subtyping using Deciper testing from Genome Dx directly from all sites.  
10. 20-25 formalin-fixed paraffin embedded (FFPE) slides of 5-10 microns in thickness from TURBT and radical cystectomy tissues will be stored for 
future correlative studies 
11. Required of all patients at the final End of Treatment visit (pre-surgery); if abnormal, manage as medically appropriate 
12. Estimated creatinine clearance by Cockcroft-Gault formula (use cycle’s Day 1 actual weight for calculating Day 8) or by 24 hour collection urine 
collection 
13. Follow-up after the final treatment visit is by in person visits, record review or other methods of obtaining disease and survival status 
 
Refer to the Laboratory Manual for complete details of research sample handling and 
shipping. 


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10 Correlative Research Studies 
10.1 Molecular Subtyping of Bladder Cancer Using Decipher® Bladder Cancer 
Classifier 
We will evaluate molecular subtypes associated with resistance to platinum-based 
neoadjuvant chemotherapy in patients with MIBC and evaluate whether addition of 
nivolumab alters the response to neoadjuvant therapy. Decipher® Bladder is a Genomic 
Subtyping Classifier (GSC) that uses whole transcriptome oligonucleotide microarrays 
interrogating the RNA expression of 149 gene-level biomarkers. The test provides a 
molecular genomic classification of Muscle Invasive Bladder Cancer Tumors (MIBC) from 
TURBT samples. The tissue is classified into one of four molecular subtypes namely, (a) 
Basal, (b) Basal Claudin-Low (c) Luminal, and (d) Luminal Infiltrated, based on the 
functional molecular pathways. These molecular subtypes may predict response to 
neoadjuvant cisplatin-based chemotherapy in bladder cancer patients. Decipher® 
Bladder, which is based on the consensus of two previously established classification 
systems UNC (Damrauer et al 2014) and TCGA (Cancer Genome Atlas Research 
Network 2014), was developed as a single sample classifier from TURBT specimens of 
223 muscle invasive bladder cancer patients treated with neoadjuvant chemotherapy and 
radical cystectomy from five different institutions. Independent validation was performed 
in 82 MIBC patients from two institutions.19 Luminal tumors had the best OS independent 
of neoadjuvant chemotherapy, and patients with tumors classified as UNC basal, MDA 
basal and TCGA cluster III experienced the greatest improvement in overall survival after 
neoadjuvant chemotherapy compared to surgery alone. Tumors assigned as UNC 
claudin-low had the worst overall survival irrespective of treatment regimen. This data 
provides an insight into benefit form neoadjuvant cisplatin-based chemotherapy. We will 
be studying for the 1st time whether addition of immunotherapy to cisplatin-based 
chemotherapy alters the impact on outcomes in different molecular subtypes. 19 
The following work plan will be used for performing the molecular subtyping using 
Decipher® Bladder Cancer Classifier 
Specimen selection 
Select the TURBT specimen that was used to make the decision to treat the patient with 
radical cystectomy and contains tumor within the muscularis propria. Re-evaluate the H&E 
slide most representative of the blocks current tissue level and select the appropriate block 
with: 
a) Tumor invading the muscularis propria bladder wall 
b) Largest area of representative muscularis propria invasive tumor 
c) Tumor focus with at least 50% tumor cell content 
 
Pathology sampling 
Tissue sampling will be performed according to the pathology instructions detailed in the 
Study’s Laboratory Manual. Briefly, for each patient specimen 2 X 1.5 mm in diameter 
punch (e.g., as obtained with a tissue microarray coring device or GenomeDx provided 


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punch tools) will be sampled and placed in separate Eppendorf microfuge tubes. 
Alternatively, 9 x 5um sections and 1 x HE representative of the block may be provided 
for macrodissection. Tissue punches/sections must be stored at 4°C until shipment (and 
then shipped with cold gel packs).  
 
Note: Tissue blocks may be submitted to GenomeDx pathology department to perform the 
appropriate sampling.  
Tissue logistics 
All blocks, tissue cores or sections will be sent to the GenomeDx Biosciences CAP/CLIA 
certified laboratory located in San Diego, CA. The punch cores or sections will be used for 
the transcriptome-wide expression analysis. RNA will be extracted from a single 1.5 mm 
punch. For situation where not enough RNA or QC failures, the second 1.5mm punch will 
be extracted.  
Transcriptome-wide analysis of FFPE specimens 
The transcriptome-wide expression analysis will be performed using GenomeDx’s clinical-
grade high-density oligonucleotide microarray expression platform and cloud-based 
informatics pipeline. The extracted RNA will be used as template for whole transcriptome 
amplification and hybridization to 1.4 million feature gene expression microarrays. 
GenomeDx will perform quality control on the raw microarray data. Samples that fail array 
QC will be re-amplified from a second aliquot of RNA. After generation of all the array data 
and QC analysis, the Decipher® Bladder algorithm is applied. Decipher® Bladder detects 
the expression of 149 pre-specified gene-level biomarkers and uses a generalized linear 
model with elastic net regularization (GLMNET) to derive probability scores for each of the 
subtypes. For each patient sample, four scores will be generated. The score, represented 
by a value between 0% and 100%, indicates the likelihood of the sample belonging to 
each of the four subtypes.  While the subtype with the highest probability is designated as 
the ‘true’ subtype, the probabilities for each subtype will also be reported. 
Unused tissue specimens or tissue derivatives (e.g., RNA) will be returned by GenomeDx 
to the submitting institution.  
Sampling Instructions for affiliate sites will be provided in the Laboratory Manual Tissue 
will be shipped directly from affiliate sites to GenoneDx. 
10.2 Whole Exome Sequencing (WES) 
We will sequence tumor (FFPE or fresh) and matched normal samples (obtained from a 
peripheral blood sample) from patients enrolled in the trial. DNA extracted from tumor 
samples will be sequenced to an average depth of 150X and the DNA extracted from the 
matched normal tissue (peripheral blood) to a mean depth of 50X. Bioinformatics analysis 
will be conducted to eliminate germline variants and construct an index of mutational load 
based on the number of somatic single nucleotide substitutions and short indels. The 
mutational load will likely be defined iteratively based on the percentage of tumor cells that 
harbor particular mutations to identify an optimal mutational load index. 
 


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Samples are shipped the day of the collection (Monday-Thursday) for next day delivery to 
Dr. Bharat Thyagarajan’s lab at the University of Minnesota. The archival tissue and whole 
blood is shipped with the pre-treatment blood sample. Refer to the Laboratory Manual for 
Dr. Thyagarajan’s lab address and additional details. 
10.3 PD-L1 Testing of Baseline Pre-Treatment Tumor Tissue 
Tumor tissue slides from TURBT will be sent out to Quest Diagnostics to evaluate PD-L1 
status using IHC 28-8 pharmDx immunohistochemistry test, available through Dako. We 
will determine correlation between PD-L1 expression and response to nivolumab. 
10.4 Nanostring Pancan Immune Panel Gene Expression 
Archival/fresh tissue from TURBT and fresh tissue from the radical cystectomy will be 
stored for future evaluation with Nanostring pancan immune panel gene expression. 
11 Drug Formulation, Availability, and Preparation 
11.1 Gemcitabine 
Refer to the FDA-approved package insert for gemcitabine for product information, 
extensive preparation instructions, and a comprehensive list of adverse events. 
Gemcitabine is a nucleoside analogue in the pyrimidine antimetabolite class which is S-
phase specific. Its phosphorylated product is incorporated into DNA and interferes with 
DNA synthesis. Gemcitabine also exhibits self-potentiation by causing an enzymatically-
mediated reduction in the intracellular nucleotide pool.  
Availability  
Gemcitabine is commercially supplied as a powder for reconstitution in 200 and 1 gram 
vials.  
Storage and Stability  
Intact vials containing sterile powder are stored at room temperature. When prepared as 
directed, reconstituted vials are reportedly stable for 35 days at room temperature and 
protected from light. Further diluted solutions of gemcitabine are stable for up to 7 days at 
room temperature when protected from light. However, the manufacturer recommends 
that solutions be used within 24 hours. The diluted solution should be clear and colorless 
to light straw-colored solution.  
Preparation and Administration 
Gemcitabine will be prepared and administered intravenously according to institutional 
guidelines. 
 
 


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11.2 Cisplatin 
Refer to the FDA-approved package insert for cisplatin for product information, extensive 
preparation instructions, and a comprehensive list of adverse events. 
  
Cisplatin is a platinum-containing heavy metal complex which acts as an alkylating agent. 
Cisplatin inhibits DNA synthesis by the formation of interstrand and intra-strand DNA 
crosslinkages, denaturation of the DNA double helix, and covalent binding to DNA bases.  
 
Availability  
Cisplatin is commercially available as a 1 mg/mL concentration aqueous injection in multi-
dose vials of 50 mL, 100 mL, and 200 mL.  
 
Storage and Stability  
Intact vials should be stored at room temperature and be protected from light. Solutions 
diluted in 0.9% or 0.45% NaCl to a concentration of 0.05-2mg/mL are stable for up to 72 
hours at room temperature and protected from light.  
 
Preparation and Administration  
Cisplatin is to be administered as an intravenous infusion according to institutional 
practice. Patients should receive intravenous hydration with at least 1 L of NaCl prior to 
cisplatin. Needles, syringes, catheters, or IV administration sets containing aluminum 
parts should not be used, as contact with cisplatin yields a black precipitate. 
11.3 Nivolumab 
Nivolumab is a PD-1 blocking antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.   
 
Availability  
Nivolumab will be provided as investigational supply for this study by Bristol-Myers Squibb 
without cost. 
 
Storage and Stability  
Nivolumab must be dispensed only from official study sites and to eligible patients under 
the supervision of the site investigator. Nivolumab should be stored in a secure area 
according to local regulations. It is the responsibility of the site investigator to ensure that 
study drug is only dispensed to patients on this study.   
 
Store nivolumab under refrigeration at 2°C to 8°C (36°F to 46°F). Protect nivolumab from 
light by storing in the original package until time of use. Do not freeze. 
 
The product does not contain a preservative. The administration of nivolumab infusion 
must be completed within 24 hours of preparation. If not used immediately, the infusion 
solution may be stored under refrigeration conditions (2°C to 8°C, 36°F to 46°F) for up to 
24 hours, and a maximum of 8 hours of the total 24 hours can be at room temperature 


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(20°C to 25°C, 68°F to 77°F) and room light. The maximum of 8 hours under room 
temperature and room light conditions includes the product administration period.  
 
Administration  
Refer to the current Investigator Brochure for the most up to date information. 
Nivolumab is to be administered as an intravenous infusion over 30 minutes or per 
institutional practice.  
 
Toxicities 
Refer to the current Investigator Brochure for the most up to date information. 
 
The most common (>10%) adverse events reported in patients treated with Nivolumab 
are: rash, pruritus, cough, upper respiratory tract infection and peripheral edema. 
Laboratory abnormalities reported in >10% of patients include increased AST, increased 
alkaline phosphatase, hyponatremia, increased ALT and hyperkalemia. 
12 Adverse Event Monitoring, Documentation, and Reporting 
Toxicity and adverse events will be classified and graded according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE) and reported on the schedule below. 
A copy of the CTCAE can be downloaded from 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
The following definitions of adverse events (AEs) and serious adverse events (SAEs) will 
determine whether the event requires expedited reporting via the OnCore SAE Report Form in 
addition to routine documentation in the OnCore AE case report form (CRF).  
12.1 Adverse Event and Deviation Terminology 
An AE is any untoward medical occurrence or worsening of a pre-existing medical 
condition in a subject. AE will be graded using the National Cancer Institute CTCAE 
version 4.0. A laboratory test abnormality considered clinically relevant, e.g., causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the investigator, should be reported as an AE.  
 
Serious Adverse Event (SAE) 
AEs are classified as serious or non-serious.  A serious adverse event (SAE) is any AE 
that is:  
1. fatal 
2. life-threatening 
3. requires or prolongs hospital stay 
4. results in persistent or significant disability or incapacity 
5. a congenital anomaly or birth defect 
6. an important medical event. Important medical events are those that may not be 
immediately life threatening, but are clearly of major clinical significance. They may 


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jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above.  For example, drug overdose or abuse, a seizure that did not 
result in in-patient hospitalization or intensive treatment of bronchospasm in an 
emergency department would typically be considered serious. 
 
Unexpected Event: An AE or SAE or suspected AE is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the 
current application, as amended.  
 
The categories for AE attribution are as follows:  
• 
Definite  
• 
Probable  
• 
Possible  
• 
Unlikely  
• 
Unrelated  
 
Major Deviation: A deviation or violation that impacts the risks and benefits of the research; 
may impact subject safety, affect the integrity of research data and/or affect a subject’s 
willingness to participate in the research. Deviations that place a subject at risk, but do not 
result in harm are considered to be major deviations. 
 
Minor Deviation: A deviation or violation that does not impact subject safety, compromise 
the integrity of research data and/or affect a subject’s willingness to participate in the 
research. 
 
12.2 Event Monitoring and Documentation 
Adverse event monitoring and documentation begins with the patient’s written consent to 
participate in the study through 30 days after the last dose of nivolumab or the End of 
Treatment visit, whichever is shorter. Patients will continued to be monitored for Serious 
Adverse Events (SAEs) through 100 days of discontinuation of dosing of nivolumab (per 
Section 12.4) or the Final Study visit, whichever is shorter. 
Adverse events related to the surgery are not documented unless they are felt to be due 
to the study treatment. 
 
 


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For the purposes of this study, AE documentation requirements will be determined based 
on grade, expectedness and relationship to each of the study drug (nivolumab, cisplatin 
and gemcitabine): 
 
CTCAE 
Grade 1 
CTCAE Grade 2 
CTCAE Grade 3 
CTCAE Grade 4 
and 5 
Expected or 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not 
required 
Not required 
Not 
required 
Required 
Required 
Possible 
Probable 
Definite 
Not required 
Not 
required 
Required 
Required 
Required 
Required 
 
In addition any event meeting the definition of a serious adverse event (SAE) regardless 
of attribution that occurs during this period will be documented in the source document 
and recorded in OnCore.  
 
After the End of Treatment visit, monitoring for adverse event will become less frequent 
based on the schedule in Section 9. 
12.3 Safety Stopping Rule Events Documentation and Reporting Requirements 
The following events at or prior to the End of Treatment visit count toward an early study 
stopping rule per Section 15.2.6 and must be reported to the MCC Affiliate Sites Manager 
using the Early Stopping Rule Form found OnCore under the reports tab: 
• Grade 3 or 4 neutropenia 
• Grade 3 or 4 thrombocytopenia 
• Grade 3 or 4 anemia  
• Grade 3 or 4 non-hematologic toxicities 
 
An event that counts toward an early stopping rule does not necessarily constitute a SAE 
and should be reported as such only if they meet the criteria for reporting as defined in 
Section 12.6. 
12.4 Additional BMS Requirements for Nivolumab 
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE (AE that is not an SAE) information should begin at 
initiation of study drug. All non-serious adverse events (not only those deemed to be 
treatment-related) should be collected continuously during the treatment period and for a 
minimum of 30 days following the last dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study 
treatment as appropriate.  
 
 


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Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the subject to have study drug discontinued 
or interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a non-serious 
or serious AE, as appropriate, and reported accordingly. 
Serious Adverse Events (SAEs) 
BMS requires monitoring for Serious Adverse Events (SAEs) that occur following the 
subject’s written consent to participate in the study through 100 days of discontinuation of 
nivolumab dosing. 
12.5 Institutional Event Reporting  
The SAE Report Form found in OnCore (not MedWatch) is used for this study. Individual 
institutional sites are responsible for reporting any event meeting local reporting 
requirements to their institutional IRB and/or other research oversight committees. 
 
 
Event Type 
Reporting 
Timeframe 
Form in OnCore 
to Use 
Report to 
Any event meeting the 
definition of a SAE within 
100 days of discontinuing 
nivolumab 
 
Within 24 hours 
of knowledge 
SAE Report 
Form 
Masonic Cancer Center (MCC) 
Affiliate Sites Manager  
affiliates@umn.edu 
 
Local institutional IRB or other entities 
per institutional policies and 
guidelines. 
 
 
 
Event counting toward the 
safety stopping rule as 
defined in Section 12.3 
Within 24 hours 
of knowledge 
Stopping Rule 
Event Form 
Major Deviations, as 
defined in Section 12.1. 
Within 5 working 
days of 
knowledge 
Deviation 
Report Form 
Minor Deviations, as 
defined in Section 12.1. 
Per Institutional 
Policy  
n/a (record in 
Deviations Tab) 
but it is not 
necessary to 
report the event 
to MCC 
For UMN MCC only: minor deviations 
are reported to the UMN IRB by the 
study’s regulatory specialist per IRB 
reporting requirements. 
 
For Affiliate Sites: minor deviations are 
not reportable to the Masonic Cancer 
Center. Report to local institutional IRB 
or other entities per institutional 
policies and guidelines. 


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12.6 MCC Reporting Requirements 
As the study sponsor, the Masonic Cancer Center has the following expedited reporting 
responsibilities for events reported in Section 12.5.  
 
In each IND safety report, the sponsor must identify all IND safety reports previously 
submitted to the FDA concerning a similar suspected adverse reaction and must analyze 
the significance of the suspected adverse reaction in light of the previous, similar reports 
or other relevant information. 
12.7 BMS Reporting Requirements 
NOTE for Affiliate Sites: All reports are submitted to the University of Minnesota Masonic 
Cancer Center (MCC) Affiliate Sites Manager (affiliates@umn.edu) who will be 
responsible for forwarding reportable events to BMS and other entities as applicable.  
• 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent 
to participate in the study through 100 days of discontinuation of dosing must be 
reported 
to 
BMS 
Worldwide 
Safety 
(worldwide.safety@bms.comaebusinessprocess@bms.com. 
• 
Medwatch or CIOMS should be used to report SAEs. The BMS protocol ID number 
must be included on whatever form is submitted by the Sponsor/Investigator. 
• 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be 
associated with protocol-specified procedures. The investigator should report any SAE 
occurring after these time periods that is believed to be related to study drug or 
protocol-specified procedure.  
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
UMN IRB 
(UMN 
patients only) 
Unanticipated death of a locally enrolled subject(s); 
New or increased risk; Any adverse event that require 
a change to the protocol or consent form – refer to the 
IRB website for complete details  
 
Deviations that occur at MCC meeting the IRB’s 
reporting requirements. 
5 Business 
Days 
 
IRB Report 
Form  
 
irb@umn.edu 
FDA 
 
Unexpected and fatal or unexpected and  life 
threatening suspected adverse reaction 
no later than 
7 Calendar 
Days 
MedWatch 
Form 
3500A 
Submit to FDA as 
an amendment to 
IND with a copy 
to BMS and each 
affiliate institution 
 
1) Serious and unexpected suspected adverse 
reaction or 
2)  increased occurrence of serious suspected adverse 
reactions over that listed in the protocol or investigator 
brochure or 
3) findings from other sources (other studies, animal 
or in vitro testing) 
no later than 
15 Calendar-
Days 
BMS 
Refer to Sections 12.7 
Masonic 
Cancer Center 
SAE 
Coordinator 
Events that count toward the early study stopping rule. 
At time of 
reporting 
Stopping 
Rule Event 
Form 
mcc-
saes@umn.edu 


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• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (ie, not 
previously described in the IB). In the European Union (EU), an event meeting these 
criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of an expedited safety report 
(ESR).  
o Other important findings which may be reported by the as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with 
study procedures that could modify the conduct of the study, lack of efficacy that 
poses significant hazard to study subjects, clinically significant safety finding from a 
nonclinical (eg, animal) study, important safety recommendations from a study data 
monitoring committee, or sponsor decision to end or temporarily halt a clinical study 
for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR 
with the IB. Where required by local regulations or when there is a central IRB/IEC 
for the study, the sponsor-investigator will submit the ESR to the appropriate IRB/IEC. 
The investigator and IRB/IEC will determine if the informed consent requires revision. 
The investigator should also comply with the IRB/IEC procedures for reporting any 
other safety information.  
o In addition, suspected serious adverse reactions (whether expected or unexpected) 
shall be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate 
reports). 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 1 business day of receipt at the University of Minnesota. SAEs and 
pregnancies must be recorded on a MedWatch or CIOMS Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
For studies conducted under an Investigator IND in the US, any event that is both serious 
and unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the investigator’s or institution’s initial receipt of the information. BMS 
will be provided with a simultaneous copy of all adverse events filed with the FDA.  
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 


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MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should be followed to resolution or stabilization. 
• An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
• For studies with long-term follow-up periods in which safety data are being reported, 
include the timing of SAE collection in the protocol. 
• If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
• If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
• If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours 
to BMS using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization. All SAEs should be followed to 
resolution or stabilization. 
Potential Drug Induced Liver Injury (DILI)  
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs. Potential drug induced liver 
injury is defined as: 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
Pregnancy 


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If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety).  
The investigator must immediately notify Worldwide Safety @BMS.com of this event via 
the MedWatch or CIOMS Form in accordance with SAE reporting procedures.  
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form [provided upon request from BMS]. 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
13 Study Data Collection and Monitoring 
13.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota CTSI’s 
instance of OnCore® (Online Enterprise Research Management Environment).  
 
The OnCore database resides on dedicated secure and PHI compliant hardware 
consisting of 3 physical servers: dev, DR, and production. All the data servers are 
managed by the Academic Health Center – Information Systems (AHC-IS) virtual servers 
which utilize clustered infrastructure to provide real-time failover of virtual servers. All 
relevant AHC IS procedures related for PHI compliant servers (as required by the Center 
of Excellence for HIPAA Data) apply to OnCore databases. 
 
The integrated data will be stored in PHI compliant servers managed by AHC IS with 
access given to those authorized users in the Clinical and Translation Science Institute 
Informatics team (CTSI BPIC and MCC CISS). The data will be integrated and extracted 
to researchers through the CTSI Informatics team and will be delivered through secure 
and compliant mechanisms (e.g. AHC IE data shelter, BOX, sftp, etc). If data de-
identification is needed, then compliant AHC IE data de-identification tools will be used. 
The informatics team will grant the IRB approved study team members access to data. 
 
Key study personnel are trained on the use of OnCore and will comply with protocol 
specific instructions embedded within the OnCore. 


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13.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case report forms (e-
CRF) developed within OnCore based on its library of standardized forms. The e-CRF will 
be approved by the study’s Principal Investigator and the Biostatistician prior to release 
for use. The Primary Clinical Research Coordinator or designee will be responsible for 
registering the patient into OnCore at time of study entry, completing e-CRF based on the 
patient specific calendar, and updating the patient record until patient death or end of 
required study participation. 
13.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the University of 
Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan (DSMP), which can 
be accessed at http://z.umn.edu/dmsp. 
 
For the purposes of data and safety monitoring, this study is classified as high risk (under 
a locally held IND). Therefore the following requirements will be fulfilled: 
 
 
At least quarterly review of the study’s progress by the Masonic Cancer Center Data 
and Safety Monitoring Council (DSMC). 
 
The University of Minnesota (lead site) Sponsor/Investigator will comply with at least 
twice yearly monitoring of the study by the Masonic Cancer Center monitoring 
services. 
 
The local site PIs will comply with at least twice yearly monitoring of the project by the 
site’s internal monitoring staff or by the Masonic Cancer Center monitoring services. 
 
The Masonic Cancer Center PI will oversee the submission of all reportable adverse 
events per Section 12.6 to the Masonic Cancer Center’s SAE Coordinator, the 
University of Minnesota IRB, BMS, and the FDA.  
 
The PI with the CTO has oversight responsibility for trial monitoring at affiliate sites 
 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the Sponsor-Investigator (Dr. Gupta) will 
submit a progress report annually. The report is to be submitted within 60 days of the 
anniversary date that the IND went into effect.  
13.4 Affiliate Site Monitoring 
The PI (Dr. Shilpa Gupta) with the Clinical Trials Office (CTO) has oversight responsibility 
for trial monitoring at affiliate sites.  
Affiliate sites that are a NCI designated cancer center may self-monitor using their 
institutional Data and Safety Monitoring Plan or monitoring may be done by the Masonic 
Cancer Center monitoring services. Refer to the University of Minnesota Masonic Cancer 
Center Data and Safety Monitoring Plan (DSMP - http://z.umn.edu/dmsp) and the CTO 
Affiliate and Satellite Site Monitoring SOPs for additional details.  


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The investigator will permit study-related monitoring, audits, and inspections by the study’s 
Principal Investigator and/or IND sponsor and/or any designees, the local IRB, 
government regulatory bodies, and University of Minnesota compliance groups. The 
investigator will make available all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data, etc.). The investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.) will be available for trial related monitoring, audits, or regulatory 
inspections. Routine teleconferences may be arranged to discuss patient updates with 
lead and affiliate sites.  
13.5 Record Retention 
The investigator will retain study records including source data, copies of case report form, 
consent forms, HIPAA authorizations, and all study correspondence in a secured facility 
for at least 6 years after the study file is closed with the IRB and FDA.  
 
Please contact the Masonic Cancer Center CTO before destroying any study related 
records. 
14 Study Endpoints 
14.1 Primary Endpoint 
Pathologic response (PaR) - defined as pathologic downstaging to <pT1pN0, which 
includes pT0, pT1,pTa and pTis. 
14.2 Secondary Endpoints 
• 
To determine the safety of nivolumab when given with gemcitabine/cisplatin as 
neoadjuvant therapy in patients with muscle invasive bladder cancer prior to radical 
cystectomy. 
• 
To determine the progression free survival (PFS) measured from the date of radical 
cystectomy to date of progression or death from disease recurrence based on 
RECIST. 
 
 


CPRC #2017LS039: Phase II Trial of Neoadjuvant Nivolumab with GC in MIBC 
 
 
 
 
 
 
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14.3 Exploratory Endpoints 
• 
Whole Exome Sequencing (WES) of the pre-treatment bladder cancer biopsy tissue 
and its correlation with response. 
• 
Evaluate molecular subtypes associated with resistance to platinum-based 
neoadjuvant chemotherapy in patients with MIBC and evaluate whether addition of 
nivolumab alters the response to platinum-based neoadjuvant therapy. 
• 
PD-L1 expression in tumor tissue at baseline and correlation with response to therapy.  
• 
Nanostring pancan immune panel gene expression at baseline and at cystectomy 
(archival biopsy and any fresh residual tumor at cystectomy). 
15 Statistical Considerations 
15.1 Study Design and Sample Size Considerations 
This trial will use a single-arm, one-stage design. For the purposes of the design, we 
specify a null response rate of 0.35 and an alternative hypothesis of 0.55. Historical 
pathologic response rates of pT1 or less with cisplatin based chemotherapy are around 
35%. 1,2,7 We propose that the addition of nivolumab to gemcitabine and cisplatin as 
neoadjuvant therapy in MIBC patients would lead to an increase in the pathologic 
response rates to 55% at cystectomy. A total of 41 subjects will be enrolled and we will 
test the null hypothesis using Fisher’s exact test, in which case we will reject the null 
hypothesis if at least 20 of 41 subjects have a tumor response. This design will provide 
83% power to reject the null hypothesis of a response rate of 0.35, assuming an alternative 
hypothesis of a response rate of 0.55 and a type-I error rate of 0.05. 
15.2 Statistical Analysis 
15.2.1 General Considerations 
The analysis of the primary, secondary and correlation endpoints will be completed using 
all evaluable patients. Evaluable patients are defined as patients that receive at least one 
dose of nivolumab. All statistical analyses will be completed using SAS 9.1 (Cary, NC, 
USA) or the R statistical programming language.20 P-values less than 0.05 will be 
considered statistically significant unless otherwise noted. 
15.2.2 Analysis of the Primary Endpoint 
Pathologic response will be summarized by the pathologic response rate (PAR) as 
estimated by the sample proportion with exact 95% confidence intervals. Hypothesis 
testing of the PAR will be completed using Fisher’s exact test with a null hypothesis of a 
PAR less than or equal to 0.35. Secondary analyses of the PAR will involve univariate 
tests of the association between demographic and baseline clinical covariates and the 
PAR using Fisher’s exact test or the two-sample t-test, as appropriate. Multivariate 
associations between demographics and baseline clinical covariates will be estimated by 
logistic regression. 


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15.2.3 Analysis of Secondary Endpoints 
The analysis of secondary endpoints will be primarily descriptive. Binary endpoints 
(radiological response, adverse events, etc.) will be tabulated and summarized by the 
sample proportion with exact 95% confidence intervals. Progression free survival (PFS) 
will be summarized by the Kaplan-Meier curve. In addition, we will also complete 
secondary analyses to evaluate the univariate and multivariate associations between 
demographic and baseline clinical covariates and secondary endpoints using logistic 
regression for binary endpoints (radiological response, adverse events, etc.) or cox 
proportional hazards regression for survival endpoints (PFS), as appropriate. 
15.2.4 Analysis of Exploratory Endpoints 
We will evaluate the association between correlative endpoints (whole exome sequencing, 
molecular subtyping and PD-L1 status) and the primary and secondary endpoints. 
Univariate and multivariate associations will be evaluating using logistic or Cox 
proportional hazards regression, as appropriate. This analysis is exploratory and we 
therefore will not apply a multiple comparison adjustment to the p-values for the analysis 
of correlative. 
15.2.5 Subgroup Analysis 
We will complete a pre-planned subgroup analysis of all endpoints by clinical stage (T2 
vs. T3 and T4). The analyses within subgroup will follow the analytical approach described 
in Sections 15.2.2 -15.2.4. Multivariate analysis within subgroups will be dependent on the 
presence of an adequate sample size within subgroups. This trial is not adequately 
powered to detect significant differences within subgroup and, therefore, subgroup 
analyses will be considered exploratory and p-values will not be adjusted for multiple 
comparisons. 
15.2.6 Safety Stopping Rule 
The background AE rate for gemcitabine/cisplatin (GC) is high, whereas the rate of Grade 
3 and 4 AEs for Nivolumab is 10%. Therefore, our safety stopping rules will be based on 
the expected rate of toxicity assuming that the two drugs do not act synergistically. Safety 
stopping will be based on the rate of Grade 3 and 4 neutropenia, thrombocytopenia and 
anemia and non-hematologic toxicities of Grade 3 or 4.  
 
Hematologic Toxicities: 
Pocock-type sequential stopping boundaries will be used to monitor the toxicity rate and 
accrual will be halted if excessive number of adverse events are observed at or prior to 
the End of Treatment visit.21 For neutropenia and thrombocytopenia, we will stop the trial 
if there is strong evidence that the rate of Grade 3 and 4 AEs exceeds 0.64 and for anemia, 
we will stop the trial if there is strong evidence that the rate of Grade 3 and 4 AEs exceeds 
0.4.  
 
The corresponding stopping boundaries can be found in the table provided below. These 
rates were chosen based on the published rate of Grade 3 and 4 AEs for GC and assuming 
a 10% grade 3-4 AE rate for nivolumab. The probability of crossing the stopping 


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boundaries for neutropenia or thrombocytopenia is 0.05 if the true rate is 0.64 and 0.60 if 
the true rate is 0.80 and the probability of crossing the stopping boundaries for anemia is 
0.05 if the true rate is 0.40 and 0.73 if the true rate is 0.60.   
Number of 
Subjects 
# of Grade 3 and 4 
Neutropenia to 
stop 
# of Grade 3 and 4 
Thrombocytopenia to stop 
# of Grade 3 and 
4 Anemia to stop 
1 
- 
- 
- 
2 
- 
- 
- 
3 
- 
- 
- 
4 
- 
- 
- 
5 
- 
- 
5 
6 
- 
- 
6 
7 
- 
- 
7 
8 
- 
- 
7 
9 
- 
- 
8 
10 
10 
10 
8 
11 
11 
11 
9 
12 
12 
12 
10 
13 
13 
13 
10 
14 
13 
13 
11 
15 
14 
14 
11 
16 
15 
15 
12 
17 
16 
16 
12 
18 
17 
17 
13 
19 
17 
17 
13 
20 
18 
18 
14 
21 
19 
19 
14 
22 
20 
20 
15 
23 
20 
20 
15 
24 
21 
21 
16 
25 
22 
22 
16 
26 
23 
23 
17 
27 
23 
23 
18 
28 
24 
24 
18 
29 
25 
25 
19 
30 
26 
26 
19 
31 
26 
26 
20 
32 
27 
27 
20 
33 
28 
28 
21 
34 
28 
28 
21 
35 
29 
29 
22 
36 
30 
30 
22 
37 
31 
31 
22 
38 
31 
31 
23 
39 
32 
32 
23 
40 
33 
33 
24 
41 
34 
34 
24 
*”-“ indicates that the stopping boundary cannot be cross for this sample size 
 
 
 


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Non-Hematologic Toxicities: 
We will stop the trial if there is strong evidence that the rate of Grade 3 and 4 AEs 
observed at or prior to the End of Treatment visit exceeds 0.4. 
16 Ethical and Regulatory Considerations 
16.1 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory requirement(s). 
Essential clinical documents will be maintained to demonstrate the validity of the study 
and the integrity of the data collected. Master files should be established at the beginning 
of the study, maintained for the duration of the study and retained according to the 
appropriate regulations.  
16.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation in order 
to safeguard the rights, safety and well-being of the patients. The study will only be 
conducted at sites where IRB approval has been obtained. The protocol, informed 
consent, written information given to the patients, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB by the investigator.  
16.3 Informed Consent 
All potential study participants will be given a copy of the IRB-approved consent to review. 
The investigator or designee will explain all aspects of the study in lay language and 
answer all questions regarding the study. If the participant decides to participate in the 
study, he/she will be asked to sign and date the Consent document. Patients who refuse 
to participate or who withdraw from the study will be treated without prejudice. 
17 References 
1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared 
with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859-66. 
2. International Collaboration of T, Medical Research Council Advanced Bladder Cancer Working P, 
European Organisation for R, et al. International phase III trial assessing neoadjuvant cisplatin, 
methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results 
of the BA06 30894 trial. J Clin Oncol 2011;29:2171-7. 
3. Advanced Bladder Cancer Meta-analysis C. Neoadjuvant chemotherapy in invasive bladder cancer: 
a systematic review and meta-analysis. Lancet 2003;361:1927-34. 
4. Advanced Bladder Cancer Meta-analysis C. Neoadjuvant chemotherapy in invasive bladder cancer: 
update of a systematic review and meta-analysis of individual patient data advanced bladder cancer 
(ABC) meta-analysis collaboration. Eur Urol 2005;48:202-5; discussion 5-6. 
5. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of 
high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial 
tract tumours. Eur J Cancer 2006;42:50-4. 


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6. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial 
comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in 
patients with bladder cancer. J Clin Oncol 2005;23:4602-8. 
7. Gandhi NM, Baras A, Munari E, et al. Gemcitabine and cisplatin neoadjuvant chemotherapy for 
muscle-invasive urothelial carcinoma: Predicting response and assessing outcomes. Urol Oncol 
2015;33:204 e1-7. 
8. Isbarn H, Karakiewicz PI, Shariat SF, et al. Residual pathological stage at radical cystectomy 
significantly impacts outcomes for initial T2N0 bladder cancer. J Urol 2009;182:459-65; discussion 
65. 
9. Sonpavde G, Goldman BH, Speights VO, et al. Quality of pathologic response and surgery correlate 
with survival for patients with completely resected bladder cancer after neoadjuvant chemotherapy. 
Cancer 2009;115:4104-9. 
10. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced 
Urothelial Carcinoma. N Engl J Med 2017. 
11. Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients with locally 
advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b 
study. Lancet Oncol 2017;18:212-20. 
12. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced 
and metastatic urothelial carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-20. 
13. Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial 
carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet 
Oncol 2016;17:1590-8. 
14. Massard C, Gordon MS, Sharma S, et al. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-
Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial 
Bladder Cancer. J Clin Oncol 2016;34:3119-25. 
15. Galsky MDR, M.; Siefker-Radtke, A.O.; Baron, A.; Necchi, A.; Bedke, J.; Plimack, E.R.; Vaena, D.;, 
Grimm MOB, S.; et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic, 
study. ucmwhrptRftpIC-, In Proceedings of the 2016 ESMO Congress C, Denmark, 7–11 October 
2016. Abstract LBA31. 
16. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune 
system to anticancer chemotherapy and radiotherapy. Nat Med 2007;13:1050-9. 
17. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat 
Rev Immunol 2008;8:59-73. 
18. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in Combination With Platinum-Based Doublet 
Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 
2016;34:2969-79. 
19. Seiler R, Winters, B, Douglas J, Bas Wg et al. Muscle-invasive bladder cancer: Molecular subtypes 
and response to neoadjuvant chemotherapy. J Clin Oncol 35, 2017 (suppl 6S; abstract 281). 
20 R Core Team (2013). R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria. URL http://www.R-project.org/. 
21 Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in phase II trials 
in oncology. Biometrics 61: 540-545. 


Appendix I – Eligibility Checklist 
Phase II Trial of Neoadjuvant Nivolumab with Cisplatin and Gemcitabine in Muscle-Invasive Bladder 
Cancer (MIBC) Patients Undergoing Radical Cystectomy (BLASST-1) 
CPRC #2017LS039   BMS # 2017-NIV-0823 
Patient name or initials: _________________________ 
 
Patient ID17039 
-
 
 
 
 
 
 
 
 
 
 
   3 letter site code – Seq # (i.e. 01, 02, 03, etc.) 
 
Eligibility Checklist – page 1 of 3 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
 
 
 
Yes     No 
1. 
Diagnosis of MIBC (predominantly urothelial carcinoma except for small-cell variants) with 
clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring < 2 cm) and M0 and 
deemed eligible for radical cystectomy  
 
 
2. 
Age ≥ 18 years 
 
 
3. 
ECOG Performance Status of 0 or 1 (Appendix II) 
 
 
4. 
Required initial laboratory values within 14 days of study enrollment: 
Test 
Required value 
Patient’s Value 
Date of Testing 
Absolute 
Neutrophil Count 
≥ 1500 cells/mm3 
 cells/mm3 
/
/
 
Platelets 
≥ 100,000 
cells/mm3 
 
cells/mm3 
/
/
 
Hemoglobin 
≥ 9.0 g/dL 
.
  g/dL 
/
/
 
Bilirubin 
≤ 1.5 x ULN* 
.
  mg/dL 
/
/
 
AST 
≤ 3.0 x ULN 
 
/
/
 
ALT 
≤ 3.0 x ULN 
 
/
/
 
Creatinine 
clearance** 
≥ 50 ml/min 
.
  ml/min 
/
/
 
Alkaline 
phosphatase 
≤ 2.5 x 
institutional ULN 
 
/
/
 
INR 
≤ 1.5 x ULN** 
.
 
/
/
 
aPTT 
≤ 1.5 x ULN** 
.
 sec 
/
/
 
* For patients with known Gilbert's disease: bilirubin ≤ 3 x ULN 
** By Cockcroft-Gault formula or 24 hour urinary clearance 
***if not on therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable 
dose 
 
 
5. 
Females of childbearing potential and males who are not surgically sterile and with partners of 
childbearing potential must agree to use effective contraception during study treatment and for 5 
months for females and 7 months for males after the last dose of nivolumab. 
 
 
6. 
Patient must agree to submission of archived tumor (20-25 formalin-fixed paraffin embedded (FFPE) 
slides of 5-10 microns in thickness) from TURBT and radical cystectomy tissues. If archived samples 
are not available fresh tissue will be used. 
 
 
7. 
Ability to provide written consent prior to the performance of any research related procedures. 
 
 


CPRC #2017LS039: Phase II Trial of Neoadjuvant Nivolumab with GC in MIBC 
 
 
 
 
 
 
April 25, 2019 
Page 49 of 51 
BMS# CA209-9LK 
Phase II Trial of Neoadjuvant Nivolumab with Cisplatin and Gemcitabine in Muscle-Invasive Bladder 
Cancer (MIBC) Patients Undergoing Radical Cystectomy (BLASST-1) 
CPRC #2017LS039   BMS # 2017-NIV-0823  
Patient  ID17039 
-
   
 
 
 
Eligibility Checklist – page 2 of 3 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
 
Yes     No 
1.  
Presence of N2-3 or M1 disease. 
 
 
2.  
Ineligible to receive cisplatin by meeting one or more of the following: 
• 
creatinine clearance of < 50 mL/min,  
• 
hearing loss of 25 dB at two contiguous frequencies with testing required if a patient has 
hearing loss – At the investigator’s discretion, and after discussion with the patient, this 
exclusion may be waived if the potential benefit of cisplatin therapy is felt to outweigh the risk 
of further hearing loss. 
• 
CTCAE v4 Grade 2 or higher peripheral neuropathy,  
• 
New York Heart Association Class III or IV heart failure (Appendix II),  
• 
ECOG performance status 2 or higher (Appendix II).  
 
 
3.  
Prior systemic therapy (intravenous) is not permitted. Prior intravesical therapy including intravesical 
gemcitabine is permitted for non-muscle invasive disease (i.e. superficial bladder cancer (T1) 
 
 
4.  
Prior treatment with cisplatin for bladder cancer. 
 
 
5.  
Prior treatment with anti-PD-1, CTLA-4, or anti-PD-L1 therapeutic antibody or pathway-targeting 
agents. 
 
 
6.  
Prior therapeutic radiation to the bladder 
 
 
7.  
Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major 
surgical procedure during the course of the study 
 
 
8.  
Any of the following within the 6 months prior to study drug administration: myocardial infarction, 
severe/unstable angina, symptomatic congestive heart failure (New York Heart Association Class III 
or IV), stroke, serious cardiac arrhythmia 
 
 
9.  
Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-
related illness 
 
 
10. 
Pregnancy, lactation, or breast-feeding. Women of childbearing potential must have a negative urine 
pregnancy test at screening. 
 
 
11. 
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune 
hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
Wegener's granulomatosis, vascular thrombosis associated with antiphospholipid syndrome, 
Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, systemic vasculitis, or 
glomerulonephritis 
 
 
12. 
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia 
(i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan, history of radiation pneumonitis in 
the radiation field (fibrosis) is permitted. 
 
 
13. 
Active hepatitis B virus (HBV, chronic or acute, defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) or hepatitis C antibody. Patients with past HBV infection or 
resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence 
of HBsAg) are eligible. HBV DNA must be obtained in these patients prior to Cycle 1, Day 1 and 
confirmed to be negative. Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
 
 
14. 
Active tuberculosis or BCG infection 
 
 
15. 
Active infection requiring systemic antibiotics for more than 7 days within 3 days prior to Cycle 1, Day 
1. Prophylactic short-term antibiotics will be allowed. 
 
 


CPRC #2017LS039: Phase II Trial of Neoadjuvant Nivolumab with GC in MIBC 
 
 
 
 
 
 
April 25, 2019 
Page 50 of 51 
BMS# CA209-9LK 
Phase II Trial of Neoadjuvant Nivolumab with Cisplatin and Gemcitabine in Muscle-Invasive Bladder 
Cancer (MIBC) Patients Undergoing Radical Cystectomy (BLASST-1) 
CPRC #2017LS039   BMS # 2017-NIV-0823 
Patient ID   17039 
-
   
 
 
 
Eligibility Checklist – page 3 of 3 
EXCLUSION CRITERIA (continued) 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
Having reviewed each of the inclusion/exclusion criteria, I verify that this patient is eligible  
 
 
 
 
 
 
 
 
 
 
 
 
Signature of enrolling physician 
 
 
 
Date 
 
Yes    No 
16. 
Administration of intravesical bacillus Calmette-Guerin (BCG) within 4 weeks before Cycle 1, Day 1 
 
 
17. 
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation 
that such a live attenuated vaccine will be required during the study. 
 
 
18. 
Persisting toxicity from prior therapy (NCI CTCAE v4.03 Grade >1); however alopecia or other 
Grade <2 AEs not constituting a safety risk, based on Investigator’s judgement, are acceptable. 
 
 
19. 
History of or active bone marrow disorders expected to interfere with study therapy (e.g. acute 
leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic lymphocytic 
leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma). 
 
 
20. Prior allogeneic stem cell or solid organ transplant. 
 
 
21. Known primary central nervous system (CNS) malignancy.  
 
 
22. 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted but 
patients with psoriasis require a baseline ophthalmologic exam to rule out ocular manifestations. 
Rash must cover less than 10% of body surface area (BSA) and must be well controlled at 
baseline and only requiring topical steroids.  
 
 
23. 
Any other chronic medical condition or psychiatric condition, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation of the results 
or render the patient at high risk from treatment complications 
 
 
24. 
Known additional malignancy that is progressing or requires active treatment. Exceptions include 
basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer 
that has undergone potentially curative therapy. Patients on androgen deprivation therapy as part 
of adjuvant therapy after radiation for prostate cancer or patients on adjuvant hormonal therapies 
for breast cancer will be allowed if they are being considered for curative intent for bladder cancer.  
 
 
25. 
Treatment with systemic immunostimulatory agents (including but not limited to interferon-a or 
interleukin-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, 
Day 1 
 
 
26. Concomitant use of systemic corticosteroids at physiologic doses or >10 mg/day of prednisone or 
equivalent.  
 
 
27. 
Concomitant use of another investigational agent and/or treatment with an investigational agent 
within 4 weeks prior to Cycle 1, Day 1 (or within five half-lives of the investigational product, 
whichever is longer). 
 
 
28. Use of bisphosphonate therapy for osteoporosis will be allowed if started prior to study enrollment. 
 
 


CPRC #2017LS039: Phase II Trial of Neoadjuvant Nivolumab with GC in MIBC 
 
 
 
 
 
 
April 25, 2019 
Page 51 of 51 
BMS# CA209-9LK 
Appendix II – ECOG Performance Status and NYHA Classification 
 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 
 
 
 
New York Heart Association Functional Classification 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. 
shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
Ref:   The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.