Clinical trial NCT03558087
Conditions: Bladder Cancer
Keywords: muscle-invasive
Sponsor: Matthew Galsky
Start date: 2018-07-13; Completion date: 2024-03-07
Enrollment: 76 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 2 trial seeking to define the safety and activity of gemcitabine, cisplatin, plus nivolumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer and to define the role of clinical complete response in predicting benefit in patients opting to avoid cystectomy.

Detailed description:

Arms: arm 1: Combination Therapy: Nivolumab 360mg IV, Gemcitabine 100mg/m\^2 IV ,Cisplatin 70mg/m\^2 IV for four 21-day cycles. At restaging, subjects with cT0 or cTa status may undergo cystectomy or continue maintenance Nivolumab 240mg IV for up to 8 14-day cycles. Subjects with \> cTa status will undergo cystectomy.
Interventions: intervention 1: Nivolumab intervention 2: Gemcitabine intervention 3: Cisplatin
Intervention descriptions: intervention 1: Nivolumab 360mg will be administered on Day 1 of each 21 day cycle for four 21-day cycles. Based on response and a balanced patient-physician discussion, subjects may receive nivolumab 240 mg for 8 cycles (cycle = 14 days). intervention 2: Gemcitabine 1000mg/m\^2 will be administered on Days 1 and 8 for four 21-day cycles. intervention 3: Cisplatin 70mg\^m2 will be administered on Day 1 for four 21-day cycles.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN GU16-257 
 
Neoadjuvant gemcitabine, cisplatin, plus nivolumab in patients with muscle-
invasive bladder cancer with selective bladder sparing  
 
Sponsor Investigator 
 
Matthew D. Galsky, MD 
Icahn School of Medicine at Mount Sinai 
Tisch Cancer Institute 
 
Co-Principal Investigators 
 
Sumanta Pal, MD 
City of Hope Comprehensive Cancer Center 
 
Sia Daneshmand, MD 
University of Southern California 
 
Statistician 
 
Menggang Yu, PhD 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 Interactive Way Suite 120 
Indianapolis, IN 46278 
 
 
Trial Supported by  
Bristol-Myers Squibb Company 
CA209-9AU  
 
Investigational New Drug (IND) #: 136858 
 
 
Initial Protocol Version Date: 01MAY2018 
Protocol Amendment Version Date:  
11JUL2019 
15JUL2020 
29DEC2020 
12AUG2021 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Neoadjuvant gemcitabine, cisplatin, plus nivolumab in patients with muscle-
invasive bladder cancer with selective bladder sparing  
 
 
VERSION DATE: 12AUG2021 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 
 
____________________________________ 
________________________ 
Signature of Site Investigator  
 
 
  
Date 
 
 
____________________________________ 
Site Investigator Name (printed) 
 
 
____________________________________ 
Site Investigator Title 
 
 
Name of Facility 
 
 
Location of Facility (City and State) 
____________________________________
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SYNOPSIS 
TITLE 
Neoadjuvant gemcitabine, cisplatin, plus nivolumab in patients with 
muscle-invasive bladder cancer with selective bladder sparing
PHASE  
II 
OBJECTIVES 
Primary Objectives 
 Determine the clinical complete response rate with gemcitabine, 
cisplatin, plus nivolumab 
 Determine the ability of clinical complete response (cT0 or cTa) to 
predict benefit from treatment. Benefit will be defined as a 
pathologic complete response (<pT1) in patients undergoing 
cystectomy and 2 year metastasis-free in patients pursuing 
surveillance 
 
Secondary Objectives 
 Determine the safety of neoadjuvant gemcitabine, cisplatin, plus 
nivolumab 
 Describe the proportion of patients with a clinical complete 
response to pursue cystectomy versus surveillance 
 Determine the association between a prespecified panel of 
genomic biomarkers and benefit from treatment in patients 
achieving a clinical complete response. Benefit will be defined as 
a pathologic complete response (p<T1) in patients undergoing 
cystectomy and 2 years metastasis-free in patients pursuing 
surveillance 
 Determine the pathologic complete response rate (<pT1) in 
patients pursuing cystectomy 
 Determine the 2-year metastasis free survival.  
 Determine overall survival (and bladder-intact overall survival 
rate) 
 Determine the recurrence-free survival 
 
Exploratory Objectives 
 Explore the association of immune biomarkers, genomic 
alterations, circulating tumor DNA, gene expression, and 
radiographic characteristics (including radiomics) with clinical 
complete response rate, <pT1 rate (where applicable), recurrence-
free survival, the bladder-intact overall survival, and overall 
survival 
 Explore potential genomic and immunologic biomarkers in the 
urine and blood that correlate with treatment benefit
 
 


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STUDY 
DESIGN 
This is a phase 2 trial seeking to define the safety and activity of 
gemcitabine, cisplatin, plus nivolumab as neoadjuvant therapy in patients 
with muscle-invasive bladder cancer and to define the role of clinical 
complete response in predicting benefit in patients opting to avoid 
cystectomy
KEY 
ELIGIBILITY 
CRITERIA (See 
Section 3 for 
FULL eligibility 
criteria) 
Inclusion Criteria 
 
1. Written informed consent and HIPAA authorization for release of 
personal health information prior to registration. NOTE:  HIPAA 
authorization may be included in the informed consent or obtained 
separately. 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status of ≤ 1 within 28 days prior to registration. 
4. Histological evidence of clinically localized muscle-invasive 
urothelial cancer of the bladder (i.e., cT2-4N0M0). Candidate for 
cystectomy as per treating physician. 
5. Demonstrate adequate organ function as defined in the table below. 
All screening labs to be obtained within 28 days prior to registration. 
System 
Laboratory Value 
Hematological
Absolute Neutrophil Count (ANC) 
≥ 1.5 x 109/L 
Hemoglobin (Hgb)
≥ 9 g/dL
Platelets
≥ 100 x 109/L
Renal
Calculated creatinine clearance1
Creatinine ≤ 1.5  or creatinine 
clearance ≥ 60 mL/min
Hepatic 
Bilirubin 
≤ 1.5 × upper limit of normal 
(ULN) (except subjects with 
Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL) 
Aspartate aminotransferase (AST) 
≤ 3 × ULN  
Alanine aminotransferase (ALT) 
≤ 3 × ULN  
1 
Cockcroft-Gault formula will be used to calculate creatinine clearance  
 
6. All subjects must have adequate archival tissue identified at screening 
(i.e., at least 15 unstained slides or paraffin block). Subjects without 
archival tissue must be discussed with the sponsor-investigator.  
 
7. Women of childbearing potential must have a negative serum or urine 
pregnancy within 7 days prior to C1D1. NOTE: “Women of 
childbearing potential” is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization 
(hysterectomy or bilateral oophorectomy) or who is not 
postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over 45 in the absence of other biological or 


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physiological causes. In addition, women under the age of 62 must 
have a documented serum follicle stimulating hormone (FSH) level 
less than 40 mIU/mL.  
 
NOTE: Women of childbearing potential (WOCBP) receiving nivolumab 
must be willing to abstain from heterosexual intercourse or to use 2 forms 
of effective methods of contraception from the time of informed consent 
to 5 months after the last dose of nivolumab or for the timeframe outlined 
per package insert for chemotherapy. This timeframe also applies to 
breastfeeding. The two contraception methods can be comprised of two 
barrier methods, or a barrier method plus a hormonal method.  
 
Male subjects capable of fathering a child that are sexually active with 
partners of childbearing potential must be willing to abstain from 
heterosexual intercourse or to use 2 forms of effective methods of 
contraception from the time of informed consent to the timeframe outlined 
per package insert for chemotherapy. Contraception is not required for 
nivolumab. The timeframes described in the previous 2 sentences apply to 
sperm donation. Two contraception methods can be comprised of two 
barrier methods, or a barrier method plus a hormonal method. 
 
Exclusion Criteria 
1. Prior treatment with systemic chemotherapy for muscle-invasive 
urothelial cancer of the bladder 
2. Active infection requiring systemic therapy 
3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for 
future use while the mother is being treated on study). 
4. Any serious or uncontrolled medical disorder that, in the opinion of 
the investigator, may increase the risk associated with study 
participation or study drug administration, impair the ability of the 
subject to receive protocol therapy, or interfere with the interpretation 
of study results.   
5. Prior malignancy active within the previous 3 years except for locally 
curable cancers that have been apparently cured. 
6. Subjects with active, known or suspected autoimmune disease. 
Subjects with vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are 
permitted to enroll.   
7. Subjects with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 


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8. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CTLA-4 antibody, or any other antibody or drug specifically targeting 
T-cell co-stimulation or immune checkpoint pathways. 
9. Grade ≥ 2 neuropathy (NCI CTCAE version 4.03).  
10. Prior radiation therapy for bladder cancer 
11. Positive test for hepatitis B virus surface antigen (HBV sAg) or 
hepatitis C virus ribonucleic acid (RNA) or hepatitis C antibody (HCV 
antibody) indicating acute or chronic infection.   
12. Known history of testing positive for human immunodeficiency virus 
(HIV) or known acquired immunodeficiency syndrome (AIDS).   
13. Evidence of interstitial lung disease or active, non-infectious 
pneumonitis. 
STATISTICAL 
CONSIDER 
ATIONS  
Our sample size is based on the confidence interval width of the positive 
predictive value (PPV) of clinical complete response to treatment. For full 
details, please see the Statistical Methods section.  
TOTAL  
NUMBER OF 
SUBJECTS 
N = 76 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 30 months 
ESTIMATED 
STUDY 
DURATION  
Estimated 48 months 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 8 
1. 
Background and Rationale ..................................................................................... 9 
2. 
Study Objectives and Endpoints........................................................................... 17 
3. 
Eligibility Criteria .................................................................................................. 18 
4. 
Subject Registration............................................................................................... 21 
5. 
Treatment Plan....................................................................................................... 21 
6. 
Dose Delays/Modifications .................................................................................... 25 
7. 
Study Calendar & Evaluations ............................................................................. 34 
8. 
Biospecimen Studies and Procedures ................................................................... 43 
9. 
Criteria for Disease Evaluation ............................................................................ 45 
10. Drug Information ................................................................................................... 46 
11 
Adverse Events ....................................................................................................... 49 
12 
Statistical Methods ................................................................................................. 53 
13 
Trial Management ................................................................................................. 56 
14. Data Handling and Record Keeping .................................................................... 58 
15 
Ethics ....................................................................................................................... 59 
16 
References ............................................................................................................... 60 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
For baseline and  restaging imaging studies after gemcitabine + cisplatin + nivolumab, an MRI abdomen and pelvis 
should be performed (see Table 7) unless contraindicated in which case a CT can be performed 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Standard treatment of muscle-invasive bladder cancer 
There are approximately 77,000 new cases of bladder cancer diagnosed each year in the United 
States. Approximately 30% of patients present with muscle-invasive bladder cancer (MIBC) 
without evidence of distant metastatic disease. Standard treatment for such patients is radical 
cystectomy; however, this approach is associated with a life-changing need for urinary diversion 
and a 90-day mortality rate of ~2-10%.1–4 Furthermore, despite being performed with curative 
intent, approximately 50% of patients still develop lethal metastatic recurrence.5 Accordingly, 
population-based data demonstrate that a large subset of patients with MIBC in the United States 
do not undergo radical cystectomy.6  
 
In an attempt to improve outcomes, randomized trials have explored the integration of 
neoadjuvant cisplatin-based chemotherapy. Two randomized trials and a meta-analysis have 
demonstrated an improvement in survival with the use of neoadjuvant chemotherapy with an 
absolute survival benefit of approximately 5-10%.7–9  
 
 
Radiation therapy, with or without concurrent chemoradiation, also represents a potential 
treatment options for MIBC. However, such treatment is associated with grade 3-4 toxicities in 
20-30% of patients, late grade  3 pelvic toxicity in approximately 7% of patients, and the need 
for salvage cystectomy in 15-30% of patients.10  
 
Together, these findings highlight the need for novel bladder-sparing treatment strategies for 
MIBC.  
 
1.2 
A large subset of patients with MIBC treated with neoadjuvant chemotherapy 
achieve a pathologic complete response 
After patients undergo treatment with neoadjuvant chemotherapy followed by radical 
cystectomy, the bladder specimen is assessed for pathologic evidence of residual cancer. 
Important, in a subset of patients treated with neoadjuvant chemotherapy, there is no pathologic 
evidence of residual disease (i.e., pathologic complete response or pCR) and this finding has 
been associated with improved long term clinical outcomes. For example, in the Southwest 
Oncology Group 8710 trial comparing cystectomy alone versus 3 cycles of MVAC 
(methotrexate, vinblastine, doxorubicin, plus cisplatin) followed by cystectomy, 38% of patients 
treated with neoadjuvant chemotherapy achieved a pCR. The median survival of patients treated 
with neoadjuvant chemotherapy followed by cystectomy achieving a pCR was not reached 
compared with 3.8 years in patients with residual disease in the cystectomy specimen.7 Several 
other analyses have confirmed that achieving a pCR is highly correlated with improved 
recurrence-free survival and overall survival (Table 1).11  
 
 
 


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Table 1. Pooled analysis of Nordic neoadjuvant studies demonstrating impact of pCR on 
outcomes according to clinical T stage (N=449; adapted from Rosenblatt et al11) 
 
Clinical T stage
5-year survival rate 
Neoadjuvant arm
5-year survival rate 
Control arm
p value 
All
88.2
57.1
0.001
T2
86.2
59.1
0.023
T3
90.5
50
0.023
T4
100
–
 
1.3 
Systemic chemotherapy alone as definitive treatment for patients with MIBC 
Because neoadjuvant cisplatin-based chemotherapy achieves a pCR in approximately 30-40% of 
patients with MIBC, a logical question is why this subset of patients requires surgical removal of 
the bladder (in which case the resected bladder specimen ultimately reveals no evidence of 
cancer)? The use of transurethral resection of bladder tumor (TURBT) plus systemic 
chemotherapy alone for the treatment of MIBC is not a new concept. In fact, this approach has 
been explored since the early 1990’s.12–15 In a series from Herr et al (Table 2), patients achieving 
a clinical CR (i.e., no evidence of disease on post-chemotherapy cystoscopy, TURBT, and CT 
scan) with chemotherapy and not undergoing cystectomy demonstrated similar rates of long term 
survival to patients undergoing immediate cystectomy.13  
 
Table 2. Outcome of patients who achieved clinical T0N0M0 status after Neoadjuvant 
MVAC Chemotherapy (n=60) (adapted from Herr at al13) 
 
Patients with 
Invasive Local 
Relapse
10-Year Survival
 
 
Overall 
Bladder Intact 
Post-MVAC 
Treatment
No. of 
Patients
No. 
% 
No. 
% 
No. 
% 
No cystectomy
28
8
29
21
75
17
61
Partial cystectomy 
15 
5 
33 
11 
73 
8 
53 
Radical 
cystectomy
17 
0 
0 
11 
65 
0 
0 
 
The body of literature describing the role of TURBT plus systemic therapy was systematically 
and comprehensively reviewed by Moran and colleagues in 2017.16 This systematic review and 
meta-analysis revealed key findings highlighting the potential benefit of this strategy and the 
need for further study. These key findings are summarized below: 
 
 Much of the literature describing chemotherapy plus TURBT as definitive management 
of MIBC is based on retrospective series and/or single center series. 
 Prior studies of this approach have included a mix of approaches including the use of 
carboplatin-based chemotherapy, lack of post-treatment TURBT, and offering 
surveillance to patients even without a clinical complete response to treatment. 
 Meta-analysis of these studies revealed an estimated 5-year survival rate of 72%. 
 There have only been two contemporary prospective studies exploring chemotherapy plus 


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TURBT as definitive management for MIBC (described in further detail below). Despite 
the use of carboplatin-based chemotherapy in Southwest Oncology Group (SWOG) 0219 
in all patients, and in the Solsona trial in a subset of patients, both studies demonstrated 
similar survival rates in patients opting for surveillance after chemotherapy versus 
cystectomy. 
 
1.3.1 SWOG 0219 
Southwest Oncology Group trial 0219 enrolled 74 patients with MIBC who received 
chemotherapy with a regimen of paclitaxel, gemcitabine, plus carboplatin.14 Patients achieving a 
clinical CR to chemotherapy on this study could elect immediate cystectomy or proceed with 
cystoscopic surveillance alone (those without a clinical CR were to undergo immediate 
cystectomy). A clinical CR was achieved in 34 of 74 patients (46%). Of the 34 patients with a 
clinical CR, 10 underwent immediate cystectomy, 6 of whom had pathologic evidence of 
residual cancer.  With a median follow-up of 22 months the Kaplan-Meier estimate of 2-year 
survival for the entire study population was 59% (95% CI 45, 72). Among the 34 patients with a 
clinical CR after chemotherapy, the 2-year survival estimate was 75% (95% CI 57, 93). Of the 
24 patients with clinical CR who did not undergo cystectomy, the 2-year overall survival 
estimate was 76%. Of the 10 patients with a clinical CR who underwent cystectomy, the 2-year 
overall survival estimate was 70%. While long term outcomes were similar among the small 
subgroups of patients achieving clinical T0 status undergoing immediate cystectomy versus 
cystoscopic surveillance alone, the disconnect between clinical and pathologic CR status led the 
authors to conclude that definitive cystectomy after completion of chemotherapy should still be 
strongly considered. However, this study utilized a carboplatin-based regimen and cisplatin-
based chemotherapy is standard neoadjuvant chemotherapy in MIBC and has been associated 
with higher complete response rates.17 Further, this interpretation minimizes the potential role of 
salvage cystectomy. 
 
Indeed, these considerations are exemplified in a recent retrospective series describing the 
outcomes of patients with MIBC achieving a clinical CR to cisplatin-based chemotherapy.18 A 
series from Meyer et. al. included 109 patients treated at a single institution, 32 of whom 
achieved a clinical CR with neoadjuvant chemotherapy. Of 25/32 patients who declined radical 
cystectomy after achieving a clinical CR, 7 experienced local relapse during follow-up and 
proceeded to radical cystectomy. In the 25/32 patients who elected bladder preservation after 
achieving a clinical CR with neoadjuvant chemotherapy, the 5-year cancer specific survival was 
88%. 
 
1.3.2 Solsona trial 
Solsona and colleagues enrolled 146 patients with MIBC, with persistent microscopic evidence 
of  disease on re-staging TURBT, in a prospective trial.19 Patients enrolled in this study could 
elect to proceed with radical cystectomy versus a bladder-sparing approach involving systemic 
chemotherapy alone. Systemic therapy was comprised of combination chemotherapy which 
evolved during the course of the study and could include carboplatin-based therapy in patients 
with impaired renal function. In this study, 75 patients opted for TURBT + chemotherapy and 71 
patients opted for radical cystectomy and despite the lack of randomization, there was no 
significant difference between important covariates in these groups. Of the patients opting for the 
bladder-sparing approach, the cancer specific survival and progression-free survival with bladder 


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preserved at 5 years were 64.5% and 59.8% respectively, and at 10 years were 52.6% and 34.5%, 
respectively.  Comparing the cancer specific survival of the bladder-sparing and radical 
cystectomy cohorts, there was no significant difference between them. Though this study differs 
in important ways from other TURBT plus chemotherapy approaches as definitive management 
of MIBC (i.e., the decision to pursue bladder-sparing was made prior to initiation of 
chemotherapy and there was no risk stratification based on clinical response to chemotherapy), 
comparable outcomes were still observed relative to the cystectomy cohort. 
 
Together, the collective literature evaluating TURBT plus systemic therapy for the 
management of MIBC demonstrates the feasibility of this approach and relatively similar 
longer term outcomes based on non-randomized comparisons with patients underoing 
immediate cystectomy.  However, aditional prospective studies are required as are improved 
systemic therapy approaches and potential predictive biomarkers to fully realize this potential 
paradigm shift in MIBC care.  
 
1.4 
Somatic mutations in DNA damage response genes, and high somatic mutational 
load, are associated with a high likelihood of achieving a pCR with neoadjuvant 
cisplatin-based chemotherapy 
High throughput comprehensive genomic analyses of solid tumors, including MIBC, have 
uncovered recurrent somatic alterations providing clues to disease pathogenesis and identifying 
potential therapeutic targets. Somatic alterations in genes encoding proteins involved in DNA 
damage response and repair are relatively common in MIBC. Indeed, analysis of data from 389 
urothelial cancer specimens from The Cancer Genome Atlas reveals deleterious (nonsense, 
frameshift, splice site, or hotspot missense) alterations in DNA damage response genes (DDR) in 
approximately ~28% of bladder cancers. Because computational predictions, and functional 
analyses, of many such alterations suggest these alterations result in loss of function, this raises 
the hypothesis that cancer cells with faulty DNA damage response and repair machinery may be 
particularly susceptible to DNA-damaging chemotherapy. Indeed, at least four studies have now 
demonstrated that the presence of somatic mutations in DDR genes correlates with an increased 
likelihood of achieving a pCR to cisplatin-based combination chemotherapy in patients with 
MIBC.20–23 In an analysis of a cohort of 50 patients with MIBC (25 patients achieving a pCR and 
25 patients not achieving a pCR with neoadjuvant chemotherapy), Rosenberg and colleagues 
performed whole exome sequencing on the pre-chemotherapy transurethral resection of bladder 
tumor (TURBT) specimens and demonstrated that the presence of mutations in ERCC2 were 
found exclusively in the patients achieving a pCR.21 ERCC2 encodes a nucleotide excision repair 
protein and is mutated in ~12% of MIBCs. The correlation between ERCC2 mutations and pCR 
was subsequently validated in an independent cohort.22 Plimack et al performed targeted exome 
sequencing on a cohort of patients with MIBC treated with dose-dense MVAC.23 These 
investigators demonstrated that alterations in one or more of three DDR genes (ATM, RB1, and 
FANCC) predicted pCR (p<0.001, 87% sensitivity, 100% specificity) and better overall survival 
(p=0.007). Notably, in both the studies from Rosenberg and Plimack, higher somatic mutational 
load was also associated with an increased likelihood of achieving a pCR. Iyer and colleagues 
performed targeted exome sequencing on a cohort of patients with MIBC treated on a phase 2 
trial of neoadjuvant dose-dense gemcitabine plus cisplatin.20 Mutations in a set of 29 DDR genes 
were correlated with pathologic response revealing that deleterious DDR gene mutations were 
associated with achieving a pCR with 92% specificity and a positive predictive value of 88%.  


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The performance characteristics of ATM, RB1, FANCC, and ERCC2 for predicting pCR with 
cisplatin-based chemotherapy are shown in Table 3. Together, these studies suggest that the 
presence of deleterious somatic DDR alterations, or high somatic mutational load, may aid in the 
identification of patients for bladder-sparing with TURBT plus systemic chemotherapy. 
However, the relatively poor sensitivity of these biomarkers indicates that this approach, if 
validated, would only identify a subset of patients suitable for this approach. Further validation 
and additional biomarker discovery is therefore indicated.   
 
Table 3. Studies correlating DDR mutations with response to neoadjuvant chemotherapy 
 
Gene(s)/Cohort
N 
Sensitivity 
Specificity 
PPV 
NPV 
ATM, RB1, FANCC 
Discovery 
34 
87% 
100% 
100% 
90% 
Validation 
24 
64% 
85% 
78% 
73% 
ERCC2 
Discovery 
50 
36% 
100% 
100% 
61% 
Validation 
48 
80% 
93% 
80% 
93% 
 
Derived from Van Allen et al, Cancer Discovery, 2014; Plimack et al, European Urology, 2015; Liu et al, JAMA Oncology, 2016 
PPV, positive predictive value; NPV, negative predictive value 
 
1.5 
DDR mutations may also increase the likelihood of response to immune checkpoint 
blockade 
Though several putative predictive biomarkers of response to PD-1/PD-L1 blockade have been 
explored in clinical trials to date, mutational load (i.e., the number of non-synonymous mutations 
per tumor specimen) has been consistently demonstrated to correlate with response across 
several solid tumors including urothelial cancer of the bladder.24,25 A higher mutational load is 
postulated to lead to a higher number of potential neoantigens thereby increasing the probability 
of developing an antitumor immune response.26,27 In a prior study of patients with MIBC 
undergoing cystectomy, recurrence-free survival was significantly better in patients with DDR 
mutations, independent of the use of perioperative chemotherapy.28 These findings raised the 
hypothesis that the improvement in outcomes associated with DDR mutations was the result of 
faulty DNA repair leading to an increase in mutational burden, neoantigen expression, and 
ultimately an antitumor immune response. Indeed, DNA mismatch repair gene mutations in 
colorectal and other cancers have been correlated with a particularly high response rate to 
immune checkpoint blockade.29 However, the association between other DDR pathway gene 
mutations (e.g., homologous recombination, nucleotide excision repair, etc) and both mutational 
load and response to immune checkpoint blockade has been underexplored. To explore this 
notion, we utilized three cohorts: (1) TCGA MIBC cohort (n = 389), (2) Mount Sinai (MS) 
cohort (n = 67) of bladder cancer (cystectomy) specimens subjected to targeted exome 
sequencing for 341 genes (MSK-IMPACT), and (3) Phase 2 trial of gemcitabine, cisplatin, plus 
CTLA-4 blockade with ipilimumab (GCI) in metastatic urothelial cancer from which 28/36 
enrolled patients had specimens suitable for whole exome sequencing. Deleterious mutations in 


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DDR genes were defined as nonsense, frameshift, splice site, or hotspot point mutations. 
Notably, the mutational load using all genes in the TCGA cohort, and restricted to the 341 
IMPACT genes, were highly correlated (rs= 0.81, p < 0.001). Associations between deleterious 
DDR mutations and mutational load are shown in Table 4. In the MS cohort, CD8+cells/mm2 by 
IHC were higher in tumors with deleterious DDR mutations versus no DDR mutations (p = 
0.04). In the GCI cohort, the sensitivity, specificity, positive predictive value, and negative 
predictive value of a deleterious DDR mutation for objective response to treatment was 40.9% 
(95% CI 20.7-63.7%), 86.7% (95% CI 42.1-99.4%), 90% (55.5-99.8%), and 31.6% (95% CI 
12.6-56.6%), respectively. Notably, 2 of 9 patients with deleterious DDR mutations, and with the 
highest mutational loads, achieved complete responses after GCI and are alive without evidence 
of disease at 2.1+ and 1.8+ years. These findings demonstrate that DDR mutations are associated 
with higher mutational load in bladder cancer, a high likelihood of response to chemotherapy 
plus immune checkpoint blockade, and may identify a subset of patients with metastatic 
urothelial bladder cancer achieving durable disease control. Further, these findings support 
exploring cisplatin-based chemotherapy with more efficacious immune checkpoint blockade in 
bladder cancer (i.e., PD-1 blockade) in patients with DDR-mutant, or high mutational load 
harboring, bladder cancer.   
 
Table 4. Association between deleterious DDR mutations and mutational load in 
independent datasets 
 
Cohort 
N 
Deleterious DDR mutation 
Mut Load SNV/tumor, median (range) 
p 
Deleterious DDR mutation
Other
TCGA
389
28%
271 (26-3617)
148 (22-1016)
<0.001
MS
67
21%
31 (17-66)
18 (9-42)
<0.001
GCI
28
32%
344 (101-4292)
232 (84-1010)
0.027
 
Finally, the association between DDR mutations and response to PD-1/PD-L1 blockade was 
reported by Teo and colleagues.30 Sixty patients with urothelial cancer enrolled in prospective 
trials of anti-PD-1/PD-L1 antibodies were analyzed. Any DDR and known or likely deleterious 
DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of 
any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A 
higher response rate was observed in patients whose tumors harbored known or likely deleterious 
DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in 
those whose tumors were wild-type for DDR genes (19%; P < .001). DDR alterations also were 
associated with longer progression-free and overall survival. 
 
Together, these findings indicate that the presence of DDR mutations might predict response 
to cisplatin-based chemotherapy and PD-1/PD-L1 blockade independently and might identify 
patients particularly sensitive to combination therapy.  
 
1.6 
Nivolumab 
Nivolumab (BMS-936558 or MDX1106) is a fully human monoclonal immunoglobulin (Ig) G4 
antibody that binds to the programmed cell death receptor-1 (PD-1), a negative regulatory 
molecule expressed by activated T and B lymphocytes. Inhibition of the interaction between PD-


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1 and its ligands promote immune responses and antigen-specific T cell responses to both foreign 
and self antigens.  
 
Nivolumab has demonstrated clinical activity as monotherapy, and as combination therapy in 
several tumor types including renal cell carcinoma, melanoma, non-small cell lung cancer, 
urothelial cancer, and some lymphomas. The majority of responses have been durable and 
exceeded 6 months. The overall safety experience with nivolumab, as a monotherapy or in 
combination with other therapeutics, is based on experience in approximately 4,000 subjects 
treated to date. For nivolumab monotherapy, the safety profile has been similar across tumor 
types.  
 
1.7 
Nivolumab in urothelial cancer 
The safety and activity of single-agent nivolumab advanced urothelial cancer has been explored 
in two prospective clinical trials to date. CheckMate 032 was a phase 1/2 study enrolling 86 
patients to treatment with nivolumab 3 mg/kg every 2 weeks; 78 received at least one dose of 
treatment.31 A confirmed objective response was achieved in 19 (24.4%, 95% CI 15.3-35.4) of 
78 patients and the vast majority of responses were durable. Based on these results, a large phase 
II trial was initiated to confirm the safety and activity of nivolumab in metastatic urothelial 
cancer. CheckMate 275 enrolled 270 patients with metastatic urothelial cancer that had 
progressed despite prior platinum-based chemotherapy.32 With a minimum follow-up of 7 
months, the objective response rate was 19.6% (95% CI 15.0-24.9%). While higher tumor PD-L1 
expression (as measured by immunohistochemistry) on tumor cells was associated with a 
numerically higher objective response rate, responses were seen even in patients with PD-L1 
expression < 1% [objective response rate = 16.1% (95% CI 10.5–23.1]. Responses occurred 
rapidly [median time to response = 1.9 months (1.6–5.9)] and were durable; at a median follow-
up of 7 months, 77% of responses were ongoing. The safety profile of nivolumab was consistent 
with what has been observed across indications (Table 5 and 6). 
 
Table 5. Treatment-related adverse events in ≥5% of patients (n=270) 
 
Event 
% Any Grade 
%Grade 3–4 
All treatment-related adverse events 
64.4 
17.8 
Fatigue 
16.7 
1.9 
Pruritus 
9.3 
0 
Diarrhea 
8.9 
1.9 
Decreased appetite 
8.1 
0 
Hypothyroidism 
7.8 
0 
Nausea 
7.0 
<1 
Asthenia 
5.9 
1.5 
Rash 
5.9 
1.1 
Pyrexia 
5.6 
0 
Treatment-related adverse events leading to discontinuation 
4.8 
3.0 


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Table 6. Immune mediated adverse events (n=270) 
 
Events 
%, Any Grade 
%, Grade 3–4 
Skin 
Rash 
17.4 
5.9 
1.5 
1.1 
Endocrine 
Hypothyroidism 
14.4 
7.8 
<1 
0 
Gastrointestinal 
Diarrhea 
Colitis 
9.3 
8.9 
<1 
2.2 
1.9 
<1 
Pulmonary 
Pneumonitis 
4.1 
3.7 
1.1 
<1 
Hepatic 
Elevated ALT enzymes 
Elevated AST enzymes 
3.7 
3.0 
2.2 
1.9 
<1 
1.1 
Renal 
1.1 
<1 
 
Given the experience with nivolumab in patients with metastatic urothelial cancer, the Food and 
Drug Administration approval of atezolizumab (PD-L1 antibody) for the treatment of patients 
with platinum-resistant metastatic urothelial cancer24, and the demonstration of an improvement 
in survival with pembrolizumab (PD-1 antibody) compared with chemotherapy in patients with 
platinum-resistant metastatic urothelial cancer, exploring PD-1/PD-L1 blockade in earlier 
bladder cancer disease states is warranted.  
 
1.8 
Combining nivolumab with chemotherapy 
An expansion of CheckMate 012 study explored nivolumab in combination with platinum-based 
chemotherapy in patients with advanced non-small cell lung cancer including combination 
regimens with gemcitabine plus cisplatin, paclitaxel plus carboplatin, or pemetrexed plus 
cisplatin (n= 56).33 The safety profile of nivolumab plus platinum-based chemotherapy was 
consistent with that expected for the individual agents. A second trial explored the combination 
of nivolumab 10 mg/kg + gemcitabine plus cisplatin, pemetrexed plus cisplatin, paclitaxel plus 
carboplatin plus bevacizumab or docetaxel (n=24) in patients with advanced non-small cell lung 
cancer.34 This trial demonstrated similar findings with no new safety signals observed with the 
combination regimens.  
 
1.9 
Rationale for current trial 
This is a phase 2 trial seeking to define the safety and activity of gemcitabine, cisplatin, plus 
nivolumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer and to 
determine the potential role of a clinical complete response in identifying patients who can be 
definitively managed without cystectomy.   
 
 
 


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The current study is supported by several lines of evidence 
1. Radical cystectomy is potentially curative for patients with MIBC but is a life-changing 
operation and achieves cure in only 50% of unselected patients. Further, the risk of 
mortality within 90-days of cystectomy in the United States is approximately 8%.4 
2. Neoadjuvant chemotherapy results in an absolute survival improvement of approximately 
5-10%. However, patients treated with neoadjuvant chemotherapy achieving a pCR have 
markedly improved outcomes. 
3. TURBT plus chemotherapy as definitive management for MIBC, in patients achieving a 
clinical CR, has been shown to be feasible, leads to a relatively high rate of bladder-intact 
disease-free and overall survival, and achieves outcomes comparable immediate 
cystectomy in non-randomized studies. However, there have been a paucity of 
prospective studies seeking to refine this approach.  
4. Chemotherapy and PD-1 blockade are non-cross resistant in urothelial cancer and are 
theoretically synergistic based on mechanistic considerations. Such combinations have 
already been shown to improves outcomes in other solid tumors (e.g., non-small cell lung 
cancer). Therfore, TURBT plus chemotherapy plus PD-1 blockade may represent a novel 
paradigm-shifting curative bladder sparing approach to patients with MIBC achieving a 
clinical complete response to treatment. 
5. Genomic biomarkers may allow refinement of this approach and warrant further 
investigation.  
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
 Determine the clinical complete response rate (cT0 or cTa) with gemcitabine, cisplatin, 
plus nivolumab 
 Determine the ability of clinical complete response (cT0 or cTa) to predict benefit from 
treatment. Benefit will be defined as a pathologic complete response (<pT1) in patients 
undergoing cystectomy and 2 year metastasis-free in patients pursuing surveillance 
 
2.1.2 Secondary Objectives 
 Determine the safety of neoadjuvant gemcitabine, cisplatin, plus nivolumab 
 Describe the proportion of patients with a clinical complete response to pursue 
cystectomy versus surveillance 
 Determine the association between a prespecified panel of genomic biomarkers and 
benefit from treatment in patients achieving a clinical complete response. Benefit will be 
defined as a pathologic complete response (p<T1) in patients undergoing cystectomy and 
2 years metastasis-free in patients pursuing surveillance 
 Determine the pathologic complete response rate (<pT1) in patients pursuing cystectomy 
 Determine the 2-year metastasis free survival.  
 Determine overall survival (and bladder-intact overall survival rate) 
 Determine the recurrence-free survival 
 


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2.1.3 Exploratory Objectives 
 Explore the association of immune biomarkers, genomic alterations, circulating tumor 
DNA, gene expression, and radiographic characteristics (including radiomics) with 
clinical complete response rate, <pT1 rate (where applicable), recurrence-free survival, 
the bladder-intact overall survival, and overall survival. 
 Explore potential genomic and immunologic biomarkers in the urine and blood that 
correlate with treatment benefit 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
 Clinical complete response rate will be defined as cT0 or cTa disease after gemcitabine, 
cisplatin, plus nivolumab. Benefit from treatment will be defined as a pathologic 
complete response (<pT1) in patients undergoing cystectomy and 2 years metastasis-free 
in patients proceeding with surveillance.  
 
2.2.2 Secondary Endpoints 
 Safety will be determined according to the NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4.03 
 Bladder-intact overall survival is defined as the time from initiation of treatment until 
death or cystectomy 
 Recurrence-free survival is defined as the time from initiation of treatment to death or 
recurrence, depending on which occurs first 
 Overall survival is defined as the time from initiation of treatment to death  
 Pathologic complete response rate in patients undergoing radical cystectomy is defined as 
the proportion of patients with <pT1  
 Positive predictive value of a panel of genomic alterations in predicting benefit from 
treatment 
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all the following applicable inclusion criteria to participate in this study:  
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of ≤ 1 within 28 days prior to registration. 
 
4. Histological evidence of clinically localized muscle-invasive urothelial cancer of the 
bladder (i.e., ct2-4n0m0). candidate for cystectomy as per treating physician.  
 
 
 


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5. Demonstrate adequate organ function as defined in the table below. All screening labs to 
be obtained within 28 days prior to registration. 
System 
Laboratory Value 
Hematological
Absolute Neutrophil Count (ANC)
≥ 1.5 x 109/L
Hemoglobin (Hgb)
≥ 9 g/dL
Platelets
≥ 100 x 109/L
Renal
Calculated creatinine clearance1
Creatinine ≤1.5 or creatinine clearance ≥ 60 mL/min
Hepatic
Bilirubin 
≤ 1.5 × upper limit of normal (ULN) (except subjects 
with Gilbert Syndrome, who can have total bilirubin < 
3.0 mg/dL)
Aspartate aminotransferase (AST) 
≤3 × ULN 
Alanine aminotransferase (ALT) 
≤ 3 × ULN  
1: Cockcroft-Gault formula will be used to calculate creatinine clearance  
 
6. All subjects must have adequate archival tissue identified during screening (i.e., at least 
15 unstained slides or paraffin block). Subjects without available archival tissue must be 
discussed with the sponsor-investigator.   
 
7. Women of childbearing potential must have a negative serum or urine pregnancy within 7 
days prior to C1D1. NOTE: “Women of childbearing potential” is defined as any female 
who has experienced menarche and who has not undergone surgical sterilization 
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is 
defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of 
other biological or physiological causes. In addition, women under the age of 62 must 
have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.  
 
NOTE: Women of childbearing potential (WOCBP) receiving nivolumab must be 
willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of 
contraception from the time of informed consent to 5 months after the last dose of 
nivolumab or for the timeframe outlined per package insert for chemotherapy. This 
timeframe also applies to breastfeeding. The two contraception methods can be 
comprised of two barrier methods, or a barrier method plus a hormonal method.  
 
Male subjects capable of fathering a child that are sexually active with partners of 
childbearing potential must be willing to abstain from heterosexual intercourse or to use 2 
forms of effective methods of contraception from the time of informed consent to the 
timeframe outlined per package insert for chemotherapy. Contraception is not required 
for nivolumab. The timeframes described in the previous 2 sentences apply to sperm 
donation. Two contraception methods can be comprised of two barrier methods, or a 
barrier method plus a hormonal method. 
 


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HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
 Male condoms with spermicide 
 Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as 
Mirena by WOCBP subject.  
 Nonhormonal IUDs, such as ParaGard 
 Tubal ligation  
 Vasectomy 
 Complete Abstinence which is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs.  
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal sponge 
 Male Condom without spermicide  
 Female Condom. A male and female condom must not be used together 
 Progestin only pills by WOCBP subject  
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. No prior systemic chemotherapy for muscle-invasive urothelial cancer of the bladder 
 
2. Active infection requiring systemic therapy 
 
3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
 
4. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.   
 
5. Prior malignancy active within the previous 3 years except for locally curable cancers 
that have been apparently cured. 
 
6. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll.   
 
7. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 
days of study drug administration. Inhaled or topical steroids and adrenal replacement 


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doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease.  
 
8.  Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or immune 
checkpoint pathways. 
  
9. Grade ≥ 2 neuropathy (NCI CTCAE v4).  
 
10. Prior radiation therapy for bladder cancer 
 
11. Known history of positive test for hepatitis B virus surface antigen (HBV sAg) or 
hepatitis C virus ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) 
indicating acute or chronic infection. Testing not required. 
 
12. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). Testing not required 
 
13. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 
 
14. Solid organ or allogeneic stem cell transplant 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “on study” date is entered into the EDC system.  
 
Subjects must be registered prior to starting protocol therapy. Subjects must begin study 
treatment within 7 business days of registration.  
 
5. 
TREATMENT PLAN 
 
5.1 
Treatment Overview 
Subjects with cT2-T4aN0M0 urothelial cancer of the bladder will be enrolled. After completing 
four cycles of neoadjuvant gemcitabine, cisplatin, plus nivolumab, subjects will undergo a 
restaging MRI of the abdomen and pelvis (and CT chest). A CT of the abdomen and pelvis may 
be performed if there are contraindications for MRI. Patients will also undergo a restaging 
cystoscopy and biopsies/TURBT. If there is evidence of gross residual disease at cystoscopy, 
biopsies/TURBT may be performed at the discretion of the treating physician but such patients 
will be considered as having not achieved a clinical complete response and will proceed with 
cystectomy.  
 
Patients achieving a clinical complete response to treatment (defined in section 9.1) may opt to 
proceed with cystectomy or may opt to proceed with an additional 8 cycles of single agent 
nivolumab followed by surveillance. This decision should be based on a balanced discussed with 
the treating physician and documented in the medical record. Patients opting for surveillance will 


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sign a separate consent form outlining the potential risks, benefits, and knowledge gaps 
regarding this approach.  
 
For restaging imaging studies after gemcitabine + cisplatin + nivolumab, an MRI abdomen and pelvis should be 
performed unless contraindicated – the preferred MRI protocol is outlined in Table 7. 
 
5.2 
Pre-Medication Guidelines  
 
5.2.1 Gemcitabine 
There are no required/recommended premedications for the administration of gemcitabine. 
Antiemetics may be administered per institutional guidelines. 
 
5.2.2 Cisplatin 
The antiemetic regimen is at the discretion of the site investigator and according to institutional 
guidelines. However, non-steroid containing pre-medication regimens are preferred when 
possible given the incompletely defined impact of such medications on response to immune 
checkpoint blockade. 
 
5.2.3 Nivolumab 
There are no required premedications for the administration of nivolumab.  
 
5.3 
Medication Administration 
 
Cycles 1-4: Gemcitabine, Cisplatin, plus Nivolumab 
Agent 
Route 
Dose 
Administration 
Time 
Frequency * 
(± 2 days) 
Cycle 
Length
Total # 
Cycles 
Nivolumab 
IV 
360 mg 
30 minutes 
Day 1 
21 
days 
4 cycles 
Gemcitabine
IV 
1000 mg/m2 
Per institutional 
guidelines 
Day 1, 8 


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Cisplatin 
IV 
70 mg/m2 
Per institutional 
guidelines 
Day 1 
Cycles 5-12: Maintenance Single Agent Nivolumab (starting ~ 2-6 weeks after completing 
Cycle 4 of gemcitabine, cisplatin, plus nivolumab) [only in patients achieving cT0 or cTa 
status on restaging after 4 cycles of gemcitabine, cisplatin, plus nivolumab and opting to 
proceed without cystectomy] 
Agent 
Route 
Dose 
Administration 
Time 
Frequency *
(± 2 days) 
Cycle 
Length 
Total # 
Cycles 
Nivolumab 
IV 
240 mg 
30 minutes 
Day 1 
14 days 
8 cycles 
 
NOTE: * Infusions may be given ± 2 days for reasons such as observed holidays, inclement 
weather, scheduling conflicts, etc. It should be clearly documented in patient’s chart and case 
report forms. During Cycles 1-4, nivolumab should be administered first followed by 
gemcitabine then cisplatin. An infusion window of – 5 minutes and + 10 minutes may be 
applied. 
 
The body surface area and chemotherapy drug dose should be recalculated ONLY if the patient’s 
weight changes by > 10% during the course of the study. 
 
5.4 
Concomitant Medications 
 
5.4.1 Allowed Concomitant Medications 
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial.  If there is a clinical indication for any medication specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required.  The site investigator should 
discuss any questions regarding this with the sponsor-investigator.  The final decision on any 
supportive therapy rests with the site investigator and/or the subject's primary physician.  
However, the decision to continue the subject on trial therapy schedule requires the mutual 
agreement of the site investigator, the sponsor-investigator and the subject. 
 All treatments that the site investigator considers necessary for a subject’s welfare may 
be administered at the discretion of the treating investigator in keeping with the 
community standards of medical care.   
 All concomitant medications received within 30 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
 Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation and 
the treatment discontinuation visit. 
 Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low-molecular-weight heparin or warfarin at 
a stable dose level), or other allowed maintenance therapy should continue their use.  
Females of reproductive potential should use highly effective means of contraception as 
outlined in the eligibility.  
 
 


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5.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Treatment Phase of this 
trial: 
 Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol 
 Immunotherapy not specified in this protocol 
 Radiation therapy 
 
5.5 
Supportive Care 
The use of supportive care will be permitted as clinically indicated and according to institutional 
guidelines. The use of white blood cell and red blood cell growth factors should be consistent 
with ASCO guidelines. However, growth factors should be not used during Cycle #1 or in lieu of 
recommended dose reductions. 
 
6. 
DOSE DELAYS/MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will be used to 
grade adverse events. 
   
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Section 7. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation at each study visit for the duration of 
their participation in the study.   
 
6.1 
Initiation of New Cycle of Treatment 
Dose modifications will be based on blood counts within 3 days prior to Day 1 or Day 8 of each 
cycle.  
 
Each treatment cycle will begin only when the criteria below and those outlined in Section 6.5 
(Dose Delays for Nivolumab) are met:  
 ANC ≥ 1.5 K/mm3 
 Platelets ≥ 100 K/mm3 
 Resolution of non-hematologic treatment-related toxicities to ≤ Grade 1 or baseline 
 
Subjects requiring treatment to be held for toxicity > 4 weeks should proceed with definitive 
management of their tumor (e.g., cystectomy) as appropriate as determined by their treatment 
physician.  
 
6.2 
Treatment Limiting Adverse Event 
A treatment-limiting adverse event is any adverse event related to study treatment (includes 
cisplatin, gemcitabine and nivolumab) experienced during the study resulting in treatment 
termination.   
 
 
 
 


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6.3 
Dose Delays/Modifications for Treatment Related Hematological Toxicity 
 
6.3.1 Dose Delays/Modifications for Day 1 of Treatment (Cycle 1 through Cycle 4) 
The following dose modifications will be based on blood counts done within 3 days prior to Day 
1 of each Cycle of therapy. 
 
Treatment with nivolumab will also be HELD until patients meet criteria to resume dosing with 
gemcitabine and cisplatin.   
ANC 
 
Platelets 
Cisplatin dose 
Lowest 
gemcitabine 
dose in prior 
Cycle 
Day 1  
dose of 
gemcitabine 
≥ 1.5 K/mm3 
And 
≥ 100 K/mm3 
Continue dose of 
cisplatin from prior 
cycle (eg, if no prior 
dose reductions, 
continue at 70 mg/m2) 
1000 mg/m2 
1000 mg/m2 
≥ 1.5 K/mm3 
And 
≥ 100 K/mm3 
800 mg/m2 
800 mg/m2 
≥ 1.5 K/mm3 
And 
≥ 100 K/mm3 
600 mg/m2 
600 mg/m2 
< 1.5 K/mm3 
Or 
< 100 K/mm3 
*Hold and recheck 
CBC with differential 
Any 
*Hold and 
recheck CBC 
with differential 
*Once ANC ≥ 1500 and platelets ≥ 100,000, resume therapy with gemcitabine reduced by 1 dose level. 
If gemcitabine has already been reduced by 1 dose level, discuss dose reduction with sponsor-
investigator. Granulocyte colony stimulating factors may be used at the discretion of the site 
investigator; however, growth factors should be not used during Cycle #1 or in lieu of recommended 
dose reductions.
 
6.3.2 Dose Delays/Modifications for Day 8 Treatment (Cycle 1 through Cycle 4) 
The following dose modifications of gemcitabine will be based on blood counts done within 3 
days prior to Day 8 of each Cycle of therapy. 
 
ANC 
 
Platelets 
if Day 1 dose level of 
gemcitabine was: 
then Day 8 dose level 
of gemcitabine will be:
≥ 1.5 K/mm3 
And 
≥ 100 K/mm3 
1000 mg/m2 
1000 mg/m2 
≥ 1.5 K/mm3 
And 
≥ 100 K/mm3 
800 mg/m2 
800 mg/m2 
≥ 1.5 K/mm3 
And 
≥ 100 K/mm3 
600 mg/m2 
600 mg/m2 
1.0 K/mm3 to 
1.4 K/mm3
And 
≥ 100 K/mm3 
1000 mg/m2 
800 mg/m2 
1.0 K/mm3 to 
1.4 K/mm3
And 
≥ 100 K/mm3 
800 mg/m2 
600 mg/m2 
<1.0 K/mm3 
Or 
< 100 K/mm3 
Any 
Hold and recheck CBC 
with differential* 
*Treatment held on Day 8 should not be made up at a later date; resume next cycle as scheduled 
with gemcitabine reduced by 1 dose level. 


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There should be no dose re-escalation after a dose reduction.  
 
6.3.3 Febrile Neutropenia 
If febrile neutropenia develops in a given cycle, hold gemcitabine, cisplatin, and nivolumab 
during febrile neutropenia.  
 
Resume gemcitabine and cisplatin at one dose lower than the dose administered in the last cycle. 
This dose should be used for all subsequent cycles. The dose of nivolumab will be unchanged. 
Granulocyte colony stimulating factors may be used at the discretion of the site investigator. 
 
6.4 
Dose Delays/Modifications for Other Treatment Related Non-Hematological 
Toxicity Secondary to Gemcitabine or Cisplatin 
Dose delays/reductions for non-hematologic toxicities attributable to gemcitabine or cisplatin 
(with the exception of alopecia or nausea/vomiting not optimally managed with antiemetics) are 
outlined in the table below. Only the drugs felt to be contributing to the toxicity per the site 
investigator should be dose reduced. Patients with treatment-related nausea that is Grade ≥ 2 
despite optimal use of antiemetics will be dose reduced by 1 dose level.  
 
If the Day 8 dose of gemcitabine is held for non-hematologic toxicity, the “Day 8” dose of 
gemcitabine may be administered the following week provided the adverse event was adequately 
improved or resolved. If the adverse event has not adequately improved or resolved within 2 
weeks, the “day 8” dose of gemcitabine should be held for that cycle and treatment should 
resume (once the adverse event improves/resolves) with the next cycle of treatment. 
 
6.4.1 Dose Modifications for Non-Hematologic Toxicities 
Non-Hematologic toxicity 
Gemcitabine/Cisplatin 
Grade 0-2 
No change 
Grade 3 
Hold until Grade ≤ 1 and resume 
treatment reduced by 1 dose level
Grade 4 
Hold until Grade ≤ 1 and resume 
treatment reduced by 1 dose level
 
6.4.2 Dose Modifications for Gemcitabine and Cisplatin 
Dose level 
Gemcitabine 
Cisplatin 
Dose level -1 
800 mg/m2 
60 mg/m2 
Dose level -2 
600 mg/m2 
50 mg/m2 
 
Dose re-escalation after a dose reduction for nonhematologic toxicity should not occur without 
discussion with the sponsor-investigator. 
 


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If toxicity is specifically attributable to cisplatin or gemcitabine and warrants discontinuation of 
that particular agent, patients may be considered for continuation on treatment with cisplatin (or 
gemcitabine) and nivolumab but this must be discussed with the sponsor-investigator. 
 
6.5 
Dose Delays for Nivolumab 
Dose reductions or dose escalations are not permitted. 
 
6.5.1 Dose Delay Criteria 
Because of the potential for clinically significant nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for 
suspected AEs of selected categories. [see current Investigator Brochure and Appendix A] 
 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the 
event is attributed to nivolumab). All study drugs must be delayed until treatment can resume. In 
rare circumstances, treatment with gemcitabine plus cisplatin could potentially be continued in 
the setting of select adverse events related to nivolumab after discussion and approval from the 
sponsor-investigator. 
 
Nivolumab administration should be delayed for the following 
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
 Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay 
 Any Grade 3 skin, drug-related AE 
 Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase: 
o Grade 3 lymphopenia or leukopenia does not require dose delay. 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity. 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity. 
o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis does not require dose 
delay. The sponsor-investigator should be consulted for such Grade ≥ 3 amylase 
or lipase abnormalities. 
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the site 
investigator, warrants delaying the dose of study medication. 
 
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently 
if clinically indicated and resume nivolumab dosing when re-treatment criteria are met. 
 
 
 


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6.5.2 Criteria to Resume Treatment 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, with the following exceptions: 
 Subjects may resume treatment in the presence of Grade 2 fatigue  
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
 Subjects with baseline Grade 1 AST, ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST, ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST, ALT OR total bilirubin 
 Subjects with combined Grade 2 AST, ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 
 Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed.  
 Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment. 
 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the next scheduled 
timepoint per protocol, the next scheduled timepoint will be delayed until dosing resumes. 
 
If treatment is delayed or interrupted for > 4 weeks, the subject must be permanently 
discontinued from study therapy, and should proceed with definitive treatment of their primary 
tumor as per their treating physician, unless otherwise discussed and approved by sponsor-
investigator (e.g., in the setting of completion of a steroid taper).   
 
6.6 
Management Algorithms 
Guidelines for the management of immune related events can be found in the current Investigator 
Brochure AND in the Appendix A. Site investigators should decide the appropriate source of AE 
management for each protocol. 
 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology 
agent in this protocol. Early recognition and management of AEs associated with immuno-
oncology agents may mitigate severe toxicity. Management algorithms have been developed to 
assist investigators in assessing and managing the following groups of AEs: Gastrointestinal, 
Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological. 
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the algorithms. 
The guidance provided in these algorithms should not replace the site investigator’s medical 
judgment but should complement it. 
 
 
 


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6.7 
Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms of allergic-like reactions.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE v4.03 guidelines. Treatment 
recommendations are provided below and may be modified based on local treatment standards 
and guidelines as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
 Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 
minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
 Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms 
recur, then no further nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes 
before additional nivolumab administrations. If necessary, corticosteroids (recommended 
dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory 
support indicated).  
 Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, 
and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 


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solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids). 
 
6.8 
Discontinuation Criteria 
Treatment with nivolumab should be permanently discontinued for the following (while all study 
therapy should be discontinued for the majority of these scenarios, there are rare situations in 
which it could be acceptable to continue treatment with gemcitabine plus cisplatin despite 
discontinuing nivolumab. Continuing treatment with gemcitabine plus cisplatin should be 
discussed and approved by the sponsor-investigator): 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment  
 Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, and infusion reactions, and endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
 Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:  
o AST or ALT > 5 x ULN 
 
o Total bilirubin > 3 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
o Grade 4 lymphopenia or leukopenia 


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o Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval 
from the sponsor-investigator. 
 Any dosing interruption lasting > 6 weeks with the following exceptions (these potential 
exceptions must be reviewed and approved by the sponsor-investigator): 
o Dosing delays or interruptions to allow for prolonged steroid tapers to manage 
drug-related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted or delayed 
o Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-related 
reasons may be allowed if approved by the sponsor-investigator. Prior to re-
initiating treatment in a subject with a dosing interruption lasting > 6 weeks, the 
sponsor-investigator must be consulted. Tumor assessments should continue as 
per protocol even if dosing is interrupted 
 Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the site investigator, presents a substantial clinical risk to the subject with continued 
nivolumab dosing 
 
6.9 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities, a subject will also be 
discontinued from protocol therapy and followed per protocol under the following circumstances 
outlined below.  The reason for discontinuation of protocol therapy will be documented on the 
electronic case report form (eCRF)   
 Documented disease progression  
 
Site investigator determines a change of therapy would be in the best interest of the 
subject 
 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
 
Female subject becomes pregnant  
 
Protocol therapy interruptions as defined above   
 
6.10 
Protocol Discontinuation 
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 


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SCHEMA FOR CALENDARS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gem, Cis, Nivo 
x 4 cycles 
 
CALENDAR 
Initial 
Treatment 
Restaging evaluation 
> cTa 
Cystectomy  
 
CALENDAR 
Cystectomy  
cT0 or cTa 
Cystectomy  
 
CALENDAR 
Cystectomy  
 
Nivolumab 
Maintenance 
 
CALENDAR 
Maintenance 
Nivolumab 


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7. 
STUDY CALENDAR & EVALUATIONS 
Initial Treatment Calendar 
Study Evaluation  
Cycle = 21 days (total of 4 cycles) 
 
Screen 
Treatment 
Cycles 1-4 
Restaging  
(within 4 weeks 
of GC+N)11 
Post Restaging 
Visit12 
Subjects who do not proceed  
with maintenance nivo or  
cystectomy13 
-28 days 
Day 1 
Day 8 
± 2 days 
REQUIRED ASSESSMENTS 
See Footnote 13  
for complete details 
 
A D100 visit will occur to 
assess adverse events.  
(± 7 days) 
 
After the D100 visit, subjects 
enter long term follow up for 
disease progression (local and 
distant) per Table 8  
(± 14 days). 
 
Once disease progression is 
documented, subjects enter 
survival follow up for 2 years  
(± 14 days). 
 
Informed Consent15 
X15 
X15 
Medical History1 
X
Physical Exam
X
X
Vital signs and ECOG Performance Status2
X
X
AEs & concomitant medications
X
X
X14 
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)
X 
X5 
X
Comprehensive Metabolic Profile (CMP)3
X
X5 
X
PT/INR and aPTT
X
Thyroid Function (TSH, T4, free T3)4 
X
C3D1 
Pregnancy test (serum or urine) (WOCBP)5
X5 
X5 
DISEASE ASSESSMENT 
CT of chest6 
X
X6
MRI of abdomen and pelvis (MRI preferred; 
CT may be performed if MRI contraindicated)6 
X6 
 
 
X6 
 
Rigid Cystoscopy + biopsies/TURBT8 
X8
Urine cytology6 
X6 
TREATMENT  
Cisplatin 
X
Gemcitabine
X
X
Nivolumab
X
SPECIMEN COLLECTION  
Archival Tumor Tissue7
X
Tumor and/or Normal tissue8 
X8,14 
Blood Samples9
X9 
X9,14
Urine Sample10 
X10,14
BANKING SAMPLES  
Blood Sample11
X11 
FOLLOW UP  
Survival
 


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Key to Footnotes  
1. Medical history will include (1) diagnosis and staging information, (2) prior anti-cancer treatment, (3) smoking questionnaire (4) trial awareness 
question and (5) genetic sequencing information. 
 
2. Vital signs to include blood pressure, weight, and ECOG performance status. Height should be obtained at screening only. 
 
3 If screening (baseline) CBC and CMP were performed within 7 days of Day 1 of treatment, these do not need to be repeated. CMP to include 
sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline 
phosphatase. CMP at screening to include magnesium, phosphate, uric acid, lactate dehydrogenase 
 
4 Thyroid function testing will be done at screening and Cycle 3. TSH will be performed in addition to T3 and T4 (free versus total per physician’s 
discretion). 
 
5 For women of childbearing potential (WOCBP): urine or serum βhCG, within 7 days prior to Day 1. 
 
6 Imaging studies need not be performed at baseline if completed within 30 days of registration.Within 4 weeks of completion of 4 cycles of 
gemcitabine, cisplatin, plus nivolumab, subjects will undergo urine cytology and a restaging CT chest and MRI of the abdomen and pelvis. The 
standard of care preferred imaging sequences for the post-chemotherapy MRI abdomen and pelvis are outlined in Table 7. For patients with 
contraindications, to MRI, a CT of the abdomen and pelvis may be performed. CT/MRI scans will be submitted for central analysis and images 
will be de-identified prior to sending to a central location. See Correlative Laboratory Manual (CLM) for additional details.  
 
7 Archival tissue must be identified at screening and shipped by C2D1. Subjects without available archival tissue must be discussed with the 
sponsor-investigator. Fixed paraffin-embedded blocks/slides will be obtained in all patients for next generation genomic sequencing as well as for 
additional research. See Correlative Laboratory Manual (CLM) for additional details. 
 
8 Fixed paraffin-embedded blocks/slides will be requested from any restaging or progression cystoscopy/TURBTs/urothelial biopsies. Fresh tissue 
may be obtained at select sites.  Snap frozen sections will be obtained from the cystectomy specimen. These will include specimens from 
specimens without evidence of cancer (“complete response” specimens). Samples should be shipped by post-restaging follow-up visit (for TURBT 
and/or biopsy specimens). A sample of tissue is required if available to be used for correlative analysis. See CLM for additional details. 
 
9 Serial blood samples will be collected to support biomarker research. Blood will be collected pre- dose C1D1, C3D1, after completion of Cycle 4 
(i.e., at time of restaging evaluation or on follow-up to review restaging results) and at progression. See CLM and for additional details. 
 
10 Urine will be collected after completion of 4 cycles of gemcitabine, cisplatin, plus nivolumab at the time of restaging or at post-restaging/D30 
safety visit as detailed in the CLM. 
 


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11 A blood sample will be collected prior to treatment C1D1 and banked for future unspecified cancer related research. See CLM for additional 
information. 
 
12 The post restaging visit will be done within about 2 weeks of the restaging evaluation. Procedures completed during the restaging or post-
restaging assessment will meet the requirements of the D30 safety visit for those subjects not proceeding to nivolumab maintenance. During this 
visit the following will be done (1) review restaging studies, (2) confirm collection and submission of tissue and blood biospecimens and (3) 
determine plans for cystectomy versus maintenance nivolumab versus other treatment. Subjects who have achieved a cT0 or cTa disease with gem 
+ cis + nivolumab may opt to proceed to the single agent nivolumab phase of the study and be followed per the nivolumab maintenance calendar. 
Subjects who have achieved a cT0 or cTa disease with gem + cis + nivolumab who opt to proceed to cystectomy will be followed per the 
cystectomy calendar. Subjects who have > cTa disease with gem + cis + nivolumab will proceed with cystectomy as per standard care and be 
followed per the cystectomy calendar. Patients who do not proceed directly to other treatment will be followed per the calendar above.  
 
13 A D100 visit (± 7 days) to assess adverse events will occur for subjects that do not proceed with maintenance nivolumab or any definitive local 
therapy for any reason. This may be accomplished via clinic visit, phone call, or other avenues as appropriate. After the D100 visit, these subjects 
will be followed for disease progression (local and distant) per Table 8. Follow up information may be obtained via clinic visit, phone call, or other 
avenues as appropriate. Once disease progression is documented, subjects will enter a survival follow up period every 6 months for 2 years from 
the time of documented progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
  
14 Correlative samples and AE/conmeds collection done after completion of Cycle 4 should be done at one visit if possible (i.e., EITHER at time of 
restaging evaluation OR at post-restaging/D30 safety visit). If samples or AE/conmeds were missed at the time of the restaging evaluation, they 
may be collected at the post-restaging/D30 safety visit. This will not be considered a deviation.  
 
15 The main consent should be obtained prior to any study related procedures being performed. An additional consent (Addendum ICF) will be 
obtained at the post staging visit for subjects who have achieved a cT0 or cTa disease with gem + cis + nivolumab and opt to proceed to the single 
agent nivolumab phase of the study. 
 
 
 
 
 
 
 
 


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Cystectomy Calendar 
 
 
Treatment 
Follow Up Visit #1 
D100 visit4 
Follow Up 
Visit #25 
Long Term 
Follow Up6 
Disease 
progression  
± 14 days 
Survival 
Follow Up7 
Cystectomy 
30-60 days  
post-cystectomy 
~3 months 
post  
Visit #1
± 14 days 
± 14 days 
REQUIRED ASSESSMENTS 
 
 
 
See Table 8 
 
 
Physical Exam 
 
X 
 
 
 
AEs & concomitant medications 
 
X 
 
 
 
LABORATORY ASSESSMENTS 
 
 
 
 
 
Complete Blood Cell Count with diff (CBC) 
 
X 
 
 
 
Comprehensive Metabolic Profile (CMP) 
 
X 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
CT of chest1 
 
 
X1 
 
 
CT or MRI of abdomen and pelvis1 
 
 
X1 
 
 
SPECIMEN COLLECTION 
 
 
 
 
 
Tumor and/or Normal tissue2 
X2 
X2 
X2 
X2 
 
Blood Samples3 
 
X3 
X3 
X3 
 
FOLLOW UP 
 
 
 
 
 
Survival 
 
 
 
 
X7 
 
1 The standard of care preferred imaging sequences for the post-chemotherapy MRI of the abdomen and pelvis are outlined in Table 7 and the 
CLM. For patients with contraindications to MRI, a CT of the abdomen and pelvis may be performed. CT/MRI images scans will be submitted for 
central analysis and images will be de-identified prior to sending to a central location. See CLM for additional details.  
 
2 Tissue from the cystectomy specimen is required and will be shipped by the post-cystectomy visit. Fixed paraffin-embedded blocks/slides will be 
requested from any restaging or progression cystoscopy/TURBTs/urothelial biopsies. See CLM for additional details.  
 
3 Blood samples will be collected to support biomarker research at Follow Up Visit #1, Follow Up Visit #2 and at progression. See CLM for 
additional details. 
 
4. Follow Up Visit #1 will occur 30-60 days after cystectomy. This visit will be considered the D100 safety visit.  
 
5 Follow Up Visit #2 will occur about 3 months after Follow Up Visit #1.  


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6 Subjects will be followed for disease progression (local and distant) during Long Term Follow Up per Table 8. Follow up information may be 
obtained via clinic visit, phone call, or other avenues as appropriate.  
 
7 Once disease progression is documented, subjects will enter a survival follow up period every 6 months for 2 years from the time of documented 
progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
  
 
 
 
 


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Maintenance Nivolumab Calendar (only in subjects who have achieved a cT0 or cTa disease with gem + cis + nivolumab (see 
section 9) and opt for surveillance; treatment should be initiated ~2-6 weeks after completing gem + cis + nivolumab) 
 
Study Evaluation 
Cycle = 14 days 
Single agent nivolumab phase = Cycles 5-12  
(total of 8 cycles) 
Cycles 5-12 
Restaging  
Safety follow 
up visits7 
Long-term 
Follow up8 
Progression 
Survival 
Follow Up9 
Day 1 
± 2 days 
After 4 months  
(after Cycle 12)5 
30/100 days 
post last dose 
± 7 days
± 14 days 
± 14 days 
± 14 days 
REQUIRED ASSESSMENTS 
Per Table 8 
Informed Consent
X
Physical Exam
X
D30
Vital signs and ECOG Performance Status1
X
D30
AEs & concomitant medications
X
D30/100
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)
X
D30
Comprehensive Metabolic Profile (CMP)2
X
D30
Thyroid Function (TSH, T4, free T3)3 
X
DISEASE ASSESSMENT 
CT of chest4 
X 
CT or MRI of abdomen and pelvis4 
X 
Cystoscopy +/- biopsies4 
X
Urine cytology4
X
TREATMENT  
Nivolumab
X
SPECIMEN COLLECTION 
Tumor and/or Normal tissue5
X
D305 
X5
Blood Samples6
X6 
D306 
X6
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X9 
 
 
CMP to include sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, 
alkaline phosphatase  
CBC with differential and platelet count to include Hgb, platelet count and neutrophil count. 
 
 
 


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Key to Footnotes  
1 Consent for treatment with nivolumab maintenance will be obtained prior to C1D1. 
 
2 Vital signs to include blood pressure, weight, and ECOG performance status.  
 
3Thyroid function testing will be done prior to C5D1 then every other cycle during treatment (C7, C9, etc.). TSH will be performed in addition to 
T3 and T4 (free versus total per physician’s discretion). 
 
4After 4 months of treatment (approximately after cycle 12) of single agent maintenance nivolumab, subjects will undergo a restaging CT chest, 
MRI or CT of the abdomen and pelvis, and urine cytology. The standard of care preferred imaging sequences for the post-chemotherapy MRI 
abdomen and pelvis are outlined in Table 7. For patients with contraindications, to MRI, a CT of the abdomen and pelvis may be performed. A 
restaging cystoscopy +/- biopsies will be performed. Subjects with cT0 or cTa disease will follow-up as described in Table 8. For definition of cT0 
or Ta disease, see Section 9. Patients with cT0 or cTa disease, but with positive cytology, will undergo evaluation as per their treating physician. 
Subjects with cTis disease may receive intravesical therapy as per their treating urologist. Subjects with  cT1 disease will proceed with definitive 
local treatment as per discussions with their treating physician. . Such patients should subsequently be followed up as per the cystectomy calendar. 
CT/MRI images will be submitted for central analysis and images will be de-identified prior to sending. See CLM for additional details.   
 
5 Fixed paraffin-embedded blocks/slides will be requested from any restaging or progression cystoscopy/TURBTs/urothelial biopsies. These 
samples may also be obtained at progression. These samples may also be obtained at the safety visit after disease progression. See CLM for 
additional details. 
 
6Serial blood samples will be collected to support biomarker research; blood will be collected pre-dose Cycle 8, Cycle 12, and at the time of 
progression. These samples may also be obtained at the safety visit after disease progression. See CLM for additional details. 
 
7 The initial safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, progression, 
or at discretion of site investigator) and should be performed 30 days (±7 days) after the last dose of treatment. Subjects who have an ongoing ≥ 
grade 2 or serious AE (SAE) at this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, deemed clinically 
insignificant, and/or until a new anti-cancer treatment starts, whichever is earlier. The Day 100 safety follow up visit may be done via phone call 
or other avenues as appropriate. 
 
8 For subjects who complete single-agent maintenance nivolumab with no evidence of ≥ cTis, or who discontinue treatment early for any reason 
with no evidence of ≥ cTis, follow-up should proceed as per Table 8. For subjects with > cTis disease proceeding with cystectomy (or subjects 
with ≤ cTis disease who opt to proceed to cystectomy), subsequent follow-up should be according to Table 8. For subjects who develop cTis, 
treatment should proceed as per the treating physician. 
 


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9 Once disease progression is documented, subjects will enter a survival follow up period every 6 months for 2 years from the time of documented 
progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate.  
 
 
 
 


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Table 7. Preferred standard MRI sequences (see CLM for details) 
COR HASTE T2 ABD_PEL 
AX HASTE T2 ABD_PEL 
SAG T2 PEL 
AX T2 PEL 
COR T2 PEL 
AX DWI ABD* 
AX DWI PEL* 
ABD_PEL_T1 in -and-out-of-phase 
PRE_UROGRAM 
AX_ABD_PEL_VIBE_PRE 
Abd_Pel_AX_VIBE 
POST_Urogram 
 
 
Table 8. Long term follow-up  
Procedure
Frequency
Urine cytology (for patients not undergoing 
cystectomy) 
~q3 months; Year 1 and 2
~q6 months; Year 3 and 4 
~Annually; Year 5  
Subsequently as per treating physician
Cystoscopy (for patients not undergoing 
cystectomy) 
~q3 months Year 1 and 2 
~q6 months Year 3 and 4 
~Annually Year 5 
Subsequently as per treating physician
MRI or CT abdomen/pelvis and CT chest 
(for all subjects) 
~q3 months Year 1 and 1.5  
~q6 months Year 2 and 2.5  
~Annually Year 3
*Once disease progression is documented, subjects will enter a survival follow up period every 6 months for 2 years from the time of documented 
progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
 
 
 


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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Tumor tissue, peripheral blood, and possibly normal urothelium will be used for biospecimen-
based research in this study. Full details of specimen collection and processing can be found in 
the CLM. Correlative studies will include genomic sequencing of tumor tissue and/or peripheral 
blood and immune monitoring studies including T cell receptor sequencing and flow cytometry 
and/or mass cytometry on tissue and/or peripheral blood, and antigen-specific T cell assays.  
Plasma will also be collected for ctDNA analyses and gene expression profiling. HLA-typing 
may also be performed to facilitate neoantigen predictions or mechanisns of immunotherapy 
resistance. Urine will also be collective for correlative analyses including but not limited to 
circulating DNA and/or cellular subsets.  
 
8.1 
Tissue Collection 
 
8.1.1 Archival Tissue 
Tumor tissue obtained during the initial TURBT (i.e., prior to study enrollment) will be 
identified at screening and shipped by C2D1. Subjects without available archival tissue must be 
discussed with the sponsor-investigator. Fixed paraffin-embedded blocks/slides will be requested 
from any restaging cystoscopy/TURBTs/urothelial biopsies.  
 
8.1.2 Tumor and normal tissue collection 
Normal and tumor tissue from standard of care procedures (i.e., tumor and normal tissue 
obtained during restaging cystoscopies with TURBT or random bladder biopsies) or from other 
clinical evaluations (e.g., confirmation of disease progression, management of complication of 
disease progression, etc.) will be collected during this study. Specimens obtained in these 
settings may be accessed by the research team to facilitate an understanding of the 
pharmacodynamic effects of treatment at the level of the tumor and microenvironment including 
mechanisms of treatment resistance. Cystectomy specimens will be collected and processed for 
FFPE and snap freezing. Samples will be shipped by post-restaging follow-up visit (for TURBT 
and/or biopsy specimens) and by the post-cystectomy visit for cystectomy specimens. Fresh 
tissue may also be collected from the procedures outlined above. 
 
8.1.3 Tissue Analysis/Genomic Sequencing 
Archival baseline TURBT tissue will be first utilized for mutation analyses by next generation 
sequencing at Caris Life Sciences (http://www.carislifesciences.com) using the Caris Molecular 
Intelligence assay. The assay used in this study is the same assay that is commercially available 
from Caris Life Sciences and performed in the Caris CLIA, CAP, ISO 18159 and NY State 
accredited/certified laboratory. Therefore, results will be returned to treating physicians given the 
potential for the information to inform later lines of treatment should subjects experience disease 
progression on this protocol. However, the results of this testing will be returned after a decision 
has been made in subjects achieving a complete clinical response regarding surveillance versus 
cystectomy and will not be used to assign treatment in this study. Direct sequence analysis will 
be performed on genomic DNA isolated from a formalin-fixed paraffin-embedded tumor sample 
using the Illumina NextSeq platform. An Agilent custom-designed SureSelect XT assay will be 
used to enrich 592 whole-gene targets. Copy number variation will also be determined for a 
subset of the targets. All variants reported by this assay are detected with >99% confidence based 


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on the frequency of the mutation present and the amplicon coverage. This assay requires samples 
to have at least 20% tumor nuclei, following microdissection. 
 
Upon satisfying sample requirements for next generation sequencing, additional nucleic acids 
extracted from tissue will be stored for future genetic analysis. All remaining tissue will be 
stored for future immunohistochemistry analyses.   
 
Additional tissue based analyses from baseline, on-treatment, and post-treatment tissue collected 
as outlined in 8.1.1 and 8.1.2 may include RNA (including the potential for single-cell RNA 
sequencing)-based analyses, DNA-based analyses (targeted or whole exome sequencing), T-cell 
receptor sequencing, flow cytometry or mass cytometry, and protein based analyses such as 
multiplex immunohistochemistry or tissue imaging technologies (e.g., MIBI) 
 
8.2 
Whole Blood Samples 
For blood samples, the volume of blood and type of tube to be used for each collection is 
specified in the CLM. Collection of whole blood samples is mandatory for participation in this 
study. 
 
8.2.1 Whole Blood for T-Cell Analysis 
The quantity and composition of immune cells in the peripheral blood will be analyzed by flow 
cytometry and/or mass cytometry. Antigen specific T cell responses may also be assessed.   
 
8.2.2 Plasma for ctDNA and Gene Expression Profiling 
Plasma will be collected for ctDNA.  ctDNA will be isolated and analyzed for quantitative 
expression using sequence specific primers and/or for exome sequencing. RNA may also be 
isolated from plasma for gene expression profiling.  
 
8.2.3 Whole Blood for Banking 
Whole blood will be collected pre-dose C1D1 for banking for future unspecified cancer related 
research. 
 
8.3 
Urine Samples 
Urine will be collected after completion of 4 cycles of gemcitabine, cisplatin, plus nivolumab at 
the time of restaging as detailed in the CLM. Urine will be used to assess for potential 
biomarkers of benefit from treatment including but not limited to cell free DNA, circulating 
tumor DNA, and immune cell subsets. 
 
8.4 
Storage of Biospecimens 
Excess biospecimens not completely utilized in these experiments will be stored indefinitely at 
HCRN for future use in research focused on GU malignant diseases that are yet to be 
determined. All specimens collected will maintain the assigned unique study number of the 
corresponding patient. Coded samples may be shared with other research institutions. We believe 
that allowing for storage and usage of the remaining samples for future research is ethically 
justified and a preferred option to discarding these materials given the potential impact on 
improving clinical outcomes for subjects with bladder cancer. Subjects will be given the option 
to store excess specimens during the informed consent process. 


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8.5 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s study number assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s study number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
 
9.1 
Clinical Complete Response 
 
A clinical complete response, or cT0/cTa disease, will be defined as follows: 
 
Modality 
Result 
Rigid 
cystoscopy
No evidence of disease or papillary lesions that are resected and confirmed as Ta 
tumors
Bladder biopsies 
(if applicable)
< or = to Ta  
Urine Cytology 
Negative (Subjects with positive urine cytology but otherwise meeting all criteria 
for a clinical complete response may continue on single-agent nivolumab or 
surveillance as per protocol but should undergo appropriate workup as per their 
treating physicians). 
Cross sectional 
imaging 
No definitive evidence of local disease as per the treating physician. Given that 
residual bladder wall thickening, or even the appearance of a mass, can be 
observed in patients with a complete pathologic response, the assessment should 
be made by the treating investigator in consultation with the local radiologist and 
sponsor investigator and in the context of the bladder biopsy results (e.g., patients 
with residual bladder wall thickening and no evidence of malignancy on biopsies 
may be considered to have a complete clinical response). 
 
No evidence of distant metastatic disease. Equivocal lesions should be biopsied 
for confirmation if possible.
 
 
9.9.3 Recurrence-Free Survival 
A measurement from the date of initiation of treatment until the development of local or distant 
recurrence or death occurs. Local recurrence will be defined as invasive recurrences in the intact 
bladder. Distant recurrence will be defined as per RECIST 1.1. Subjects who have not 
progressed will be right-censored at the date of the last disease evaluation. 
 
9.9.4 Metastasis-Free Survival 
Metastasis-free survival is defined as the time from initiation of treatment to the development of 
metastatic disease. Confirmation of metastatic recurrence with a biopsy is recommended in all 
situations.  
 
9.9.5 Overall Survival 
Overall survival is defined as the date of initiation of treatment to date of death from any cause. 
 
 
 


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10. 
DRUG INFORMATION 
 
10.1 
Nivolumab 
Nivolumab is an anti-PD1 antibody. Nivolumab is a soluble protein consisting of 4 polypeptide 
chains, which include 2 identical heavy chains and 2 identical light chains.  
 
Other Names: Nivolumab, BMS-936558, MDX1106, anti-PD-1;Molecular Wt.:146,221 
daltons (143,619.17 daltons, protein portion); Appearance: Clear to opalescent, colorless to pale 
yellow liquid, few particulates may be present; Solution pH: 5.5 to 6.5 
 
10.1.1 Supplier/How Supplied 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) – Investigational Product will be provided.  
 
BMS will supply nivolumab at no charge to subjects participating in this clinical trial.  
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
10.1.2 Preparation  
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding in-line filter at the protocol-specified doses and infusion times. It 
is not to be administered as an IV push or bolus injection. Nivolumab injection can be infused 
undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to protein concentrations as low as 0.35 mg/mL.  When the dose if fixed, 
nivolumab injection can be infused undiluted or diluted so as not to exceed a total infusion 
volume of 120 mL. During drug product preparation and handling, vigorous mixing or shaking is 
to be avoided. Care must be taken to assure sterility of the prepared solution as the product does 
not contain any antimicrobial preservative or bacteriostatic agent. No incompatibilities between 
nivolumab and polyvinyl chloride (PVC) and non-PVC/non-DEHP (di(2-ethylhexyl)phthalate) 
containers/IV components or glass bottles have been observed. 
 
10.1.3 Storage and Stability 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL)  
Vials of nivolumab injection must be stored at 2° to 8°C (36° to 46°F) and protected from light 
and freezing.   
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container.  
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°to 
8°C, 36°to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20° to 25°C, 68° to 77°F) and room light. The maximum 8-hour period under 
room temperature and room light conditions includes the product administration period. 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs.  


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10.1.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
A copy of the drug destruction certificate should be maintained for provision to BMS at the end 
of the study.  
 
10.1.5 Dispensing 
Nivolumab must be dispensed only from official study sites and to eligible subjects 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 subjects.   
 
10.1.6 Adverse Events 
For a detailed list of adverse events please see the current investigator’s brochure. The most 
common side effects of nivolumab are: 
 Fatigue  
 Skin reactions: including rash, itching, hives, redness, and dry skin.  Toxic epidermal 
necrolysis, a potentially life threatening disease characterized by blistering and peeling of 
the top layer of skin resembling that of a severe burn, has occurred in one subject who 
received ipilimumab after nivolumab treatment. 
 Diarrhea 
 Nausea 
 Abdominal pain 
 Decreased appetite 
 Low red blood cells 
 Fever 
 Joint pain or stiffness 
 
10.2 
Cisplatin 
 
10.2.1 Drug Name 
Cisplatin Other: Platinol (NSC-119875); Cis-diamminedichloroplatinum 
 
10.2.2 Classification 
Alkylating agent 
 
10.2.3 Action  
Cisplatin forms covalent bonds with nucleophilic sites on guanine present in all DNA. As 
cisplatin is a bifunctional agent, it is able to bind to 2 sites in a DNA strand. This results in the 
formation of inter- and intra- chain cross-linkings, which interferes with cellular transcription 
and replication. Regulatory mechanisms detect the abnormal DNA and so activate a chain of 
responses to try and correct it. This, ultimately, causes cell death (apoptosis). 
 
10.2.4 Availability  
Cisplatin is commercially available. 


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10.2.5 Storage, Reconstitution, and Administration 
Cisplatin should be stored, reconstituted, and administered as per institutional guidelines.  
 
10.2.6 Side Effects 
For a detailed list of side effects, please see the current prescribing information. Side effects of 
cisplatin may include:  
 Nephrotoxicity 
 Ototoxicity 
 Hematologic toxicity (low leukocyte or platelet count, decreased hemoglobin 
 Nausea, vomiting, diarrhea 
 Hair loss 
 Electrolyte disturbances 
 Peripheral neuropathy 
 Vision problems 
 Liver toxicity 
 Infusion reaction 
 
10.3 
Gemcitabine 
 
10.3.1 Drug Name 
Gemcitabine 
Other:  1” – Deoxy – 2, 2” – difluorocytidine monohydrochloride, Gemcitabine, NSC #613327 
 
10.3.2 Classification 
Nucleoside analogue 
 
10.3.3 Action 
Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate 
(dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is 
attributed to a combination of 2 actions of the diphosphate and the triphosphate nucleosides, 
which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits 
ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the 
deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate 
nucleoside causes a reduction in the concentrations of deoxynucleotides, including dCTP. 
Second, gemcitabine triphosphate competes with dCTP for incorporation into DNA. The 
reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances 
the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the 
gemcitabine nucleotide is incorporated into DNA, only 1 additional nucleotide is added to the 
growing DNA strands. After this addition, there is inhibition of further DNA synthesis. DNA 
polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA 
strands (masked chain termination). 
 
10.3.4 Availability 
Gemcitabine is commercially available  
 
 
 


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10.3.5 Storage, Reconstitution, and Administration 
Gemcitabine should be stored, reconstituted, and administered according to institutional 
guidelines. 
 
10.3.6 Side Effects 
For a detailed list of side effects, please see the current prescribing information. Side effects of 
gemcitabine may include:  
 Nephrotoxicity 
 Hematologic toxicity (low platelet count, decreased hemoglobin 
 Nausea, vomiting, diarrhea 
 Hair loss 
 Peripheral neuropathy 
 Liver toxicity 
 Infusion reaction 
 Fever 
 Infection 
 Rash 
 Pulmonary toxicity 
 Edema 
 Flu-like symptoms 
 
11 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4.03 will be utilized for AE 
assessment. A copy of the CTCAE v4.03 can be downloaded from the CTEP website at 
http://ctep.cancer.gov.  
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests  Hospitalization for elective 
surgery or routine clinical procedures that are not the result of an AE (e.g., surgical insertion of 
central line) should not be recorded as an AE. Disease progression should not be recorded as an 
AE, unless it is attributable to the study regimen by the site investigator. 
 
 
 


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11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB or when it is not included as a potential risk. 
Unexpected also refers to AEs that are mentioned in the IB as occurring with a class of drugs or 
are anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.   
 
11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
 
 


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11.2 
Reporting 
 
11.2.1 Adverse Events  
 AEs will be recorded from time of signed informed consent until 100 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
 AEs considered related to study drug(s) will be followed until resolution to        
 ≤ Grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 Transient asymptomatic laboratory abnormalities that do not require treatment will not be 
collected as adverse events. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
 SAEs will be reported from time of signed informed consent until 100 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed in 11.2.2.1), sites must submit a 
follow-up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
 
 


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11.2.2.2 
HCRN Requirements for Reporting SAEs to Bristol-Myers Squibb Company 
HCRN will report all SAEs to BMS within 1 business day of receipt of the SAE Submission 
Form from a site. Follow-up information will be provided to BMS as it is received from site. 
HCRN will submit all SAEs to BMS Global Pharmacovigilance (GPV&E) via email to 
worldwide.safety@bms.com or fax @ 609-818-3804. 
 
The sponsor-investigator will reconcile the clinical database SAE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of 
reconciliation must be every 3 months and prior to the database lock or final data summary. 
BMS GPV&E will email, upon request from the Investigator, the GPV&E reconciliation report. 
Requests for reconciliation should be sent to aepbusinessprocess@bms.com. The data elements 
listed on the GPV&E reconciliation report will be used for case identification purposes. If the 
Investigator determines a case was not transmitted to BMS GPV&E, the case should be sent 
immediately to BMS. 
 
11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.4 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
Bristol-Myers Squibb’s parent IND at the time of submission. Additionally, HCRN will submit a 
copy of these documents to Bristol-Myers Squibb’s at the time of submission to FDA. 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report. Additionally, HCRN will submit a copy of these reports to 
Bristol-Myers Squibb’s at the time of submission to FDA. 
 
11.5 
IND Safety Reports Unrelated to this Trial 
Bristol-Myers Squibb’s will provide to HCRN IND safety reports (through the FastTrack Portal) 
from external studies that involve the study drug(s) per their guidelines.  HCRN will forward 
safety reports to the sponsor-investigator who will review these reports and determine if 
revisions are needed to the protocol or consent. HCRN will forward these reports to participating 
sites within 1 business day of receiving the sponsor-investigator’s review.  Based on the 
sponsor-investigator’s review, applicable changes will be made to the protocol and informed 
consent document (if required).  All IND safety reports will also be made available to sites via 
the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
 
 


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12 
STATISTICAL METHODS 
 
12.1 
Study Design 
This is a phase 2 trial seeking to define the safety and activity of gemcitabine, cisplatin, plus 
nivolumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer and to define 
the role of clinical complete response in predicting benefit in patients opting to avoid 
cystectomy.   
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
Clinical complete response rate will be defined as cT0 or cTa disease after gemcitabine, 
cisplatin, plus nivolumab. Benefit from treatment will be defined as a pathologic complete 
response (<pT1) in patients undergoing cystectomy and 2 years metastasis-free in patients 
proceeding with surveillance 
 
12.2.2 Definition of Secondary Endpoints 
 Safety will be determined according to the NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4.03 
 Bladder-intact overall survival is defined as the time from initiation of treatment until 
death or cystectomy 
 Recurrence-free survival which is defined as the time from initiation of treatment to death 
or recurrence, depending on which occurs first 
 Overall survival is defined as the time from initiation of treatment to death 
 Pathologic complete response rate in patients undergoing radical cystectomy is defined as 
the proportion of patients with <pT1 
 Positive predictive value of a panel of genomic alterations in predicting benefit from 
treatment  
 
12.3 
Sample Size and Power Analysis 
In our sample size justification and power analysis, we make the following assumptions.   
1. Patients without a clinical complete response (i.e, cT0 or cTa disease post-treatment) 
would not be suitable for surveillance (i.e., patients with cT0 or cTa disease will not have 
a pathologic complete response). Non clinical complete response implies no benefit.  
2. Approximately 40% of patients will have clinical complete response (though few studies 
have prospectively explored the clinical complete response rate with cisplatin-based 
chemotherapy, note that the clinical complete response rate with gemcitabine, 
carboplatin, plus paclitaxel in  was 46% in the SWOG 0219 study from carboplatin-based 
chemotherapy was 46%). 
3. Approximately 35% of patients will have a pathologic complete response (or if not 
undergoing cystectomy will be metastasis-free at 2 years). True benefit rate is around 
35% 
4. The overall prevalence of having at least one of the genomic alterations pre-specified in 
our analysis is 19%~37% per the table below. 
 


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Biomarker 
Functional Prediction* 
Prevalence 
FANCC, ATM, RB1, and/or 
ERCC2 
Pathogenic + Presumed Pathogenic 
19.3% 
Pathogenic + Presumed Pathogenic + 
Variant of Unknown Significance
32.9% 
FANCC, ATM, RB1, ERCC2, 
and/or high Tumor Mutational 
Load 
Pathogenic + Presumed Pathogenic 
26.6% 
Pathogenic + Presumed Pathogenic + 
Variant of Unknown Significance
37.1% 
*Presumed benign and benign mutations excluded 
 
Our primary analysis will focus on the ability of clinical complete response (cT0 + cTa) to 
predict benefit as defined by <pT1 in patients undergoing cystectomy and 2-years metastasis-free 
in patients opting for surveillance. However, a secondary analysis will incorporate the 
association between having at least one of the biomarkers noted above and benefit as based on 
prior data, the use of the biomarker panel may increase specificity compared with clinical 
response assessment but decrease sensitivity. Then the assumption 1 basically implies that the 
negative predictive value (NPV) of clinical complete response alone is 1. Our sample size is then 
based on the confidence interval width of the positive predictive value (PPV) of clinical 
complete response alone. From our assumptions 1, 2, and 3, we have the following table (Table 
9):  
 
Table 9: Distribution of cT0 and benefit status 
  
Clinical complete 
response 
No clinical 
complete response 
Total 
Benefit=”yes” 
35% 
0% 
35%
Benefit=”no” 
5% 
60% 
65%
Total
40%
60%
100%
  
The PPV from the table is 87.5%. The sample size is generated such that the lower bound of the 
95% one-sided confidence interval exceeds 80%. Based on the formula from Steinberg et al35 
available from the “bdpv” package in the r language, a sample size of 68 satisfies this criterion. 
Assuming a 10% missing data rate (e.g. due to unmeasurable biomarker or unobservable 
outcome), we propose to recruit 76 patients.  
 
Next we consider the association between the prespecified panel of genomic biomarkers and 
benefit from treatment in patients achieving a clinical complete response. In particular, we will 
test whether the presence of alternations in the prespecified panel of genomic biomarkers (which 
we name as biomarker+) is associated with benefit among patients achieving a clinical complete 
response. With 68 patients, we assume 28 will achieve a clinical complete response. Now based 
on preliminary results of the biomarker association (Table 3 in Section 1.4), we assume 90% of 
the biomarker+ patients will achieve a clinical complete response. Assuming also that at least 
90% of the biomarker+ and clinical complete response patients will have benefit=”yes”, the 
power levels based on the Fisher’s exact test (with type I error of 0.05) range from 0.39 to 0.92 
when the overall prevalence of being biomarker+ goes from 19% to 37%. The two extreme cases 
are listed in the following two tables (Tables 10 and 11).   


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Table 10: Power = 0.39 for the association between biomarker and pCR among cT0=”yes” 
patients 
 
  
Clinical complete 
response 
No clinical complete response 
Total 
Biomarker+ Biomarker-
Benefit=”yes” 
5 
18 
0 
23
Benefit=”no” 
1 
4 
40 
45
Total
6
22
40
68
 
 
Table 11: Power = 0.92 for the association between biomarker and pCR among cT0=”yes” 
patients 
 
  
Clinical complete response 
No clinical complete 
response 
Total 
 
Biomarker+ 
Biomarker- 
 
Benefit=”yes” 
11 
12 
0 
23
Benefit=”no” 
0 
5 
40 
45
Total
11
17
40
68
 
12.4 
Data Analysis Plans 
 
12.4.1 Analysis Plans for Primary Objective 
All subjects who have received at least one cycle of treatment will be evaluable for the primary 
endpoint. To determine the ability of clinical complete response (cT0 or cTa) to predict benefit 
from treatment, sensitivity, specificity, PPV, and NPV will be calculated, together with 
confidence intervals. Concordance measure such as Cohen's Kappa between clinical complete 
response and benefit will also be calculated. 
 
12.4.2 Analysis Plans for Secondary Objectives 
Any subject who receives at least one dose of treatment on this protocol is evaluable for toxicity. 
Toxicity rates will be summarized using frequency tables. Time to event outcomes (i.e. local 
recurrence free survival, overall survival, and bladder-intact overall survival) will be analyzed 
using the Kaplan-Meier method. Pathologic complete response rate in patients undergoing 
radical cystectomy will be summarized using frequency tables. PPV (and sensitivity and 
specificity) of the panel of genomic alterations in predicting benefit from treatment will also be 
analyzed.   
 
12.4.3 Analysis Plans for Exploratory Objectives 
Association of markers of immune among themselves will be conducted using the Pearson 
correlation. Association of markers of immune with the time-to-event clinical outcomes will be 
explored using the Cox proportional hazards model. Model assumptions will be checked and if 
violated, other models will be attempted. Association of markers of immune modulation with 
clinical complete response, and benefit status where applicable, will be conducted using t-test. 


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Association between genomic alterations and clinical complete response, and benefit status, will 
be conducted using Chi-square test. Association between genomic alterations and time-to-event 
outcomes will be explored using the log-rank test. These analyses will also be performed on 
circulating tumor DNA, gene expression, and radiographic characteristics.  
 
12.5 
Interim Analysis/Criteria for Stopping Study 
We will use three stopping rules for this study.  
1. The first is for excessive immune-related Grade ≥ 3 adverse events,  
2. The second is for high muscle-invasive local recurrence rates, and the  
3. Third is for high metastatic recurrence rates.  
 
The first stopping rule is for all subjects whereas the second and third rules are among those 
subjects achieving clinical complete response and proceeding with surveillance. 
 
The first stopping rule will be employed after 7, 14, and 21 subjects finish at least one cycle of 
treatment. This safety stopping rule will be performed with respect to immune-related Grade ≥ 3 
adverse events. Two-sided 95% exact binomial confidence intervals (CIs) of these Grade ≥ 3 
immune-related adverse event rates will be constructed. If their lower bounds exceed 3%, the 
study drug will be considered unacceptably toxic for this patient population and enrollment will 
be halted. The 3% is chosen based on the toxicity profile of single agent PD-1 or PD-L1 
blockade in patients with urothelial cancer.24,36 This corresponds to ≥ 2+ (2 or more) out of 7, ≥ 
3+ (3 or more) out of 14, and ≥ 3+ out of 21 subjects. 
 
The second and third stopping rule will be employed only among those subjects achieving 
clinical complete response and proceeding with surveillance, and excessive muscle-invasive 
bladder cancer recurrence and/or metastatic recurrence would be of concern. We will stop the 
trial if we are confident that either the muscle-invasive local recurrence rate or the metastatic 
recurrence rate exceed 30%.13 Two-sided 95% exact binomial confidence intervals (CIs) of this 
recurrence rate will be constructed. If their lower bounds exceed 30%, enrollment will be halted. 
This corresponds to 5 out of 5, ≥ 7+ (7 or more) out of 10, ≥ 9+ out of 15 subjects, and ≥ 11+ out 
of 20 subjects. 
 
Enrollment will not be held for data maturations/stopping rule assessments. 
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the Icahn School of Medicine/Tisch Cancer 
Institute’s DSMP  
 
HCRN oversight activities include: 
 Review and process all adverse events requiring expedited reporting as defined in the 
protocol 
 Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
 Submit data summary reports to the DSMB for review according to DSMB Charter 


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13.2 
Tisch Cancer Institute Cancer Center Data Safety Monitoring Committee 
 
HCRN will provide the following for the DSMC to review: 
 Adverse event summary report 
 Audit results, if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The DSMC will review study data at least every 6 months. Documentation of DSMC reviews 
will be provided to sponsor-investigator and HCRN.  Issues of immediate concern by the DSMC 
will brought to the attention of the sponsor-investigator and other regulatory bodies as 
appropriate.  The sponsor-investigator will work with HCRN to address the DSMC’s concerns.   
 
13.3 
Data Quality Oversight Activities 
Remote validation of EDC system data will be completed on a continual basis throughout the life 
cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel. Participating sites may also be subject to quality assurance audits as well as 
inspection by appropriate regulatory agencies. 
 
13.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. Selected source documents will be reviewed for verification of 
agreement with data entered into the EDC system.  It is important for the site investigator and 
their relevant personnel to be available for a sufficient amount of time during the monitoring 
visits or audit, if applicable. The site investigator and institution guarantee access to source 
documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by the sponsor-investigator or its 
designee, as well as inspection by appropriate regulatory agencies. 
 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
 


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14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, a system compliant with Good Clinical Practices 
and Federal Rules and Regulations.  HCRN personnel will coordinate and manage data for 
quality control assurance and integrity. All data will be collected and entered into the EDC 
system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Bristol-Myers Squibb’s, IRB, or government agencies, 
like the FDA, may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
 
 


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15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 
 


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APPENDIX A: AE MANAGEMENT ALGORITHMS 


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