Clinical trial NCT03451331
Conditions: Metastatic Urothelial Cancer
Keywords: cisplatin-ineligible gemcitabine carboplatin nivolumab oxaliplatin
Sponsor: Matthew Galsky
Start date: 2018-05-10; Completion date: 2023-07-28
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized phase 2 trial of gemcitabine + carboplatin + nivolumab or gemcitabine + oxaliplatin + nivolumab for the treatment of cisplatin-ineligible patients with metastatic urothelial cancer. Randomization will be stratified on the lymph node only (and/or unresectable primary) metastatic status.

Detailed description:
Patients will be randomized to Arm A: gemcitabine plus carboplatin plus nivolumab versus Arm B: gemcitabine plus oxaliplatin plus nivolumab. Randomization will be stratified on the metastasis status (lymph node only vs. the rest). Patients on both treatment arms will receive up to 6 cycles of combination therapy in the absence of prohibitive adverse effects or disease progression. Patients with at least stable disease at the completion of 6 cycles of treatment may continue "maintenance" single agent nivolumab for up to 12 cycles. Patients who require discontinuation of chemotherapy (i.e., gemcitabine plus carboplatin or gemcitabine plus oxaliplatin) prior to Cycle 6, but who have at least stable disease, may be considered for ongoing treatment with single-agent nivolumab on the "maintenance" phase after discussion with the sponsor-investigator.

Arms: arm 1: Gemcitabine plus carboplatin plus nivolumab arm 2: Gemcitabine plus oxaliplatin plus nivolumab
Interventions: intervention 1: Nivolumab intervention 2: Gemcitabine intervention 3: Carboplatin intervention 4: Oxaliplatin
Intervention descriptions: intervention 1: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \~ 2-4 weeks after completing combination chemotherapy plus nivolumab) intervention 2: 1000 mg/m\^2 intervention 3: AUC 4.5 (based on the Calvert formula) intervention 4: 130 mg/m\^2

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN GU16-287 
 
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Randomized phase 2 trial of gemcitabine + carboplatin + nivolumab versus gemcitabine + 
oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer  
 
 
Sponsor Investigator 
Matthew D. Galsky, MD 
Icahn School of Medicine at Mount Sinai 
Tisch Cancer Institute 
 
 
Co-Principal Investigator 
Noah M. Hahn, MD 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
 
 
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 
BMS # CA209-9GC 
 
Investigational New Drug (IND) # 135842 
 
 
 
Initial Protocol Version Date: 12JUL2017 revised  
Protocol Amendment Version Date:  
13FEB2018 (LEAD SITE ONLY) 
28MAR2018 (PARTICIPATING SITES ONLY) 
05FEB2019 
30DEC2019 
29DEC2020 
12AUG2021 
 
 


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Version Date: 12AUG2021 
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PROTOCOL SIGNATURE PAGE 
 
Randomized phase 2 trial of gemcitabine + carboplatin + nivolumab versus gemcitabine + 
oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer 
 
 
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 
 
 
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Site Investigator Name (printed) 
 
 
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Location of Facility (City and State) 
____________________________________
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SYNOPSIS 
TITLE 
Randomized phase 2 trial of gemcitabine + carboplatin + 
nivolumab versus gemcitabine + oxaliplatin + nivolumab in 
cisplatin-ineligible patients with metastatic urothelial cancer 
PHASE  
II 
OBJECTIVES 
Primary Objective 
Estimate the objective response rate (RECIST 1.1) to treatment 
with gemcitabine + carboplatin + nivolumab and gemcitabine + 
oxaliplatin + nivolumab in cisplatin-ineligible patients with 
metastatic urothelial cancer. 
 
Secondary Objectives 
 Determine the safety of gemcitabine + carboplatin + 
nivolumab and gemcitabine + oxaliplatin + nivolumab in 
cisplatin-ineligible patients with metastatic urothelial 
cancer (CTCAE v4) 
 Estimate the duration of response to treatment with 
gemcitabine + carboplatin + nivolumab and gemcitabine + 
oxaliplatin + nivolumab in cisplatin-ineligible patients 
with metastatic urothelial cancer 
 Estimate the progression-free survival 
 Estimate the overall survival. 
 
Exploratory Objectives 
 Explore the effects of treatment on peripheral blood 
biomarkers of immune modulation and immunogenic cell 
death.  
 Explore the impact of genomic/genetic alterations, 
including DNA damage response gene alterations, on 
clinical outcomes.  
 Explore the tumor immune microenvironment including 
the composition and frequency of immune cells and 
expression of immune checkpoints in archival tumor 
tissue and the relationship with clinical outcomes. 
STUDY DESIGN 
This is a randomized phase 2 trial of gemcitabine + carboplatin + 
nivolumab or gemcitabine + oxaliplatin + nivolumab for the 
treatment of cisplatin-ineligible patients with metastatic 
urothelial cancer.  Randomization will be stratified on the lymph 
node only (and/or unresectable primary) metastatic status.


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ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility) 
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. Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤ 2. 
 
4. Able to comply with the study protocol, in the investigator’s 
judgment. 
  
5. Histologically documented, locally advanced (T4b, any N; or 
any T, N 2−3) or metastatic urothelial carcinoma (mUC) 
(M1, Stage IV) (also termed TCC or UCC of the urinary 
tract; including renal pelvis, ureters, urinary bladder, and 
urethra)  Patients with mixed histologies are required to have 
a dominant transitional cell pattern.  Locally advanced 
bladder cancer must be inoperable on the basis of 
involvement of pelvic sidewall or adjacent viscera (clinical 
Stage T4b) or bulky nodal metastasis (N2−N3).  
 
6. Measurable disease, as defined by RECIST v1.1. 
  
7. Representative formalin-fixed paraffin-embedded (FFPE) 
tumor specimens in paraffin blocks (blocks preferred) or at 
least 15 unstained slides. If archival tissue is not available, 
enrollment will be considered on a case by case basis after 
discussion with the sponsor investigator.  
 
8. No prior chemotherapy for inoperable locally advanced or 
mUC. For patients who received prior adjuvant/neoadjuvant 
chemotherapy or chemo-radiation for urothelial carcinoma, a 
treatment-free interval > 12 months between the last 
treatment administration and the date of recurrence is 
required in order to be considered treatment naive in the 
metastatic setting. 
 
9. Cisplatin-ineligible as defined by at least one of the 
following2: 
 Calculated creatinine clearance ≥30 but ≤ 60 mL/min 
(Cockroft-Gault) 
 ECOG performance status = 2 
 
 CTCAE v4 Grade ≥ 2 audiometric hearing loss


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10. 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
≥30 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 
(See SPM) 
 
11.Women of childbearing potential (WOCBP) and male 
subjects must use appropriate method(s) of contraception as 
outlined in Section 5.6. 
 
12. Women of childbearing potential must have a negative serum 
or urine pregnancy. 
 
Exclusion Criteria 
1. Active infection requiring systemic therapy. 
 
2. Pregnant or breastfeeding (NOTE: breast milk cannot be 
stored for future use while the mother is being treated on 
study). 
 
3. Any serious or uncontrolled medical disorder that, in the 
opinion of the site 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.   
 
4. Prior malignancy active within the previous 3 years except for 
locally curable cancers that have been apparently cured. 
 
5. Subjects with active, known or suspected autoimmune 
disease. Subjects with vitiligo, type I diabetes mellitus, 


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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.   
 
6. 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.  
 
7. 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. 
 
8. Grade ≥ 2 neuropathy (NCI CTCAE version 4).  
 
9. 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.  
 
10. Known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS).   
 
11. Evidence of interstitial lung disease or active, non-infectious 
pneumonitis. 
 
12. Significant cardiovascular disease, such as New York Heart 
Association cardiac disease (Class III or greater), myocardial 
infarction within 3 months prior to randomization, unstable 
arrhythmias, or unstable angina. 
 
13. Known left ventricular ejection fraction (LVEF) < 40%  
Patients with known coronary artery disease, congestive heart 
failure not meeting the above criteria, or LVEF 40%−50% 
must be on a stable medical regimen that is optimized in the 
opinion of the treating physician, in consultation with a 
cardiologist if appropriate. 
 
14. Solid organ or tissue transplant including stem cell transplant


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STATISTICAL 
CONSIDERATIONS 
 
A randomized, open-labeled phase 2 ‘pick a winner design’ 
will be employed.1 Two regimens are to be studied and the 
expected baseline response rate is ~40%. With 21 patients 
per arm, we have probability 0.9 of selecting the regimen that 
has a true response rate of 40%+20%=60% [or, allows 
selection of the regimen that is 18% better (in terms of 
response rate) than the other regimen with 0.88 probability 
and 15% better with 0.83probability]. We will inflate the 
sample size on each study arm to account for early drop-
outs/unevaluable patients to 24 patients per arm.
TOTAL  
NUMBER OF 
SUBJECTS 
N= 48 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 30 months 
ESTIMATED 
STUDY DURATION  
Estimated 48 months 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 9 
1. 
Background and Rationale ................................................................................... 10 
2. 
Study Objectives and Endpoints........................................................................... 14 
3. 
Eligibility Criteria .................................................................................................. 15 
4. 
Subject Registration............................................................................................... 17 
5. 
Treatment Plan....................................................................................................... 18 
7. 
Study Calendar & Evaluations ............................................................................. 30 
8. 
Biospecimen Studies and Procedures ................................................................... 36 
9. 
Criteria for Disease Evaluation ............................................................................ 37 
10. Drug Information ................................................................................................... 41 
11 
Adverse Events ....................................................................................................... 50 
12 
Statistical Methods ................................................................................................. 53 
13 
Trial Management ................................................................................................. 58 
14. Data Handling and Record Keeping .................................................................... 59 
15 
Ethics ....................................................................................................................... 60 
16 
References ............................................................................................................... 61 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Standard treatment for cisplatin-ineligible patients with metastatic urothelial cancer 
Cisplatin-based combination chemotherapy is standard first-line treatment for patients with 
metastatic urothelial cancer. However, a large proportion of patients with metastatic urothelial 
cancer are suboptimal candidates for such treatment due renal impairment and/or other smoking- 
and age-related comorbidities.2–4 Carboplatin-based regimens, such as the doublet of gemcitabine 
plus carboplatin, have been substituted in cisplatin-ineligible patients but are associated with 
inferior efficacy.5 Recently, single agent-PD-1 or PD-L1 inhibition as first-line treatment for 
cisplatin-ineligible patients with metastatic urothelial cancer has shown promise with 
encouraging safety and durable anticancer activity.6 However, only ~20-25% of patients respond 
to treatment highlighting the need for combination regimens which extend these therapeutic 
benefits to a larger proportion of patients.6 
 
1.2 
Standard cytotoxic chemotherapy may induce immunogenic cell death 
There is growing interest in regimens combining cytotoxic chemotherapy and immune 
checkpoint blockade.7 The potentially favorable effects of chemotherapy on the antitumor 
immune response can be broadly grouped into two categories: (1) inducing immunogenic cell 
death and (2) disrupting strategies that tumors exploit to evade the immune response (e.g., 
modulating the quantity or function of immune cell subsets). Importantly, inducing immunogenic 
cell death may occur as part of the intended therapeutic effects of chemotherapy and therefore 
likely occurs at standard doses and schedules of chemotherapy (though based on data in model 
systems, is very much drug dependent). Alternatively, in model systems, various 
chemotherapeutic drugs can also deplete negative regulators of the immune response such as 
myeloid derived suppressor cells or regulatory T cells. Compared with the induction of 
immunogenic cell death, however, these effects of chemotherapy on the immune system are 
likely much more dose and schedule dependent (and may occur predominantly at unconventional 
doses and schedules). Despite a considerable literature on the impact of cytotoxic chemotherapy 
on the antitumor immune response, the vast majority of combination strategies being explored in 
the clinic to date simply combine cytotoxic drugs utilized for a particular disease indication with 
immune checkpoint blockade which may overlook the critical importance of the specific 
cytotoxic agents utilized. Optimizing combination strategies requires an understanding of the 
immunomodulatory effect of chemotherapy one is seeking to exploit and ideally demonstrating 
both clinical and pharmacodynamic evidence to support further study.  
 
Immunogenic cell death refers to the process of cell death accompanied by release of tumor 
antigens along with the emission of danger-associated molecular patterns (DAMPs).8,9 While 
normal apoptosis is non-immunogenic, and may even be tolerogenic, immunogenic cell death 
can induce an immune response through activation of dendritic cells and subsequently T cells. 
Immunogenic cell death occurs primarily as a result of endoplasmic reticulum stress and 
production of reactive oxygen species leading to translocation of DAMPs to the cell surface of 
the dying cell where it functions as an “eat me” signal. DAMPs involved in immunogenic cell 
death, including calreticulin and high-mobility group protein box-1 (HMGB1), bind to several 
pattern recognition receptors, such as Toll-like receptors (TLRs), which are expressed on antigen 
presenting cells. Importantly, genetic polymorphisms of the HMGB1-TLR4 axis have been 
shown to be associated with worse outcomes in patients with breast cancer and colon cancer 


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treated with chemotherapy underscoring the potential clinical relevance of immunogenic cell 
death.10,11 Importantly, immunogenic cell death requires all four events to take place: (1) cell 
death, (2) calreticulin exposure, (3) ATP secretion and (4) HMGB1 release. 
 
1.3 
Oxaliplatin, but not cisplatin or carboplatin, induces immunogenic cell death in 
model systems 
The platinum-based drugs cisplatin, carboplatin, and oxaliplatin are among the most widely used 
cytotoxics in oncology. Their main mechanism of action is believed to be the induction of cancer 
cell apoptosis as a response to covalent binding to DNA. However, the mechanistic basis for the 
anticancer effects of platinum drugs is likely much more complex based on studies indicating 
that cellular molecules other than DNA may potentially act as targets, and that the antitumor 
effects of platinum drugs may occur in part through immune modulation. Importantly, cisplatin 
and carboplatin do not induce immunogenic cell death, despite their presumed identical 
mechanism of action to that of oxaliplatin.12,13 This is attributed to the lack of calreticulin 
exposure after cisplatin/carboplatin treatment as these compounds do induce ATP and HGMB-1 
release. Indeed, the ability of drugs to trigger immunogenic cell death as a standalone 
intervention thereby converting dying cancer cells into a “vaccine” that is efficient in the absence 
of adjuvants is shared by a relatively restricted set of lethal triggers. Among studies of triggers 
of immunogenic cell death in model systems to date, oxaliplatin has been consistently 
identified.12–14  
 
1.4 
The doublet of gemcitabine plus oxaliplatin has shown safety and activity in 
cisplatin-ineligible patients with metastatic urothelial cancer 
Though the doublet of gemcitabine plus carboplatin is generally considered standard therapy for 
cisplatin-ineligible patients with metastatic urothelial cancer, several phase 2 studies have 
explored the combination of gemcitabine plus oxaliplatin (Table 1) demonstrating both efficacy 
and safety in this patient population.  
 
Table 1. Select Phase 2 Trials of Gemcitabine plus Oxaliplatin in Metastatic Urothelial 
Cancer 
Authors 
N 
Cisplatin-ineligible? 
Response Rate 
Eroglu15 
18 
Majority 
36% 
Carles16 
46 
Yes 
48% 
Theodore17 
30 
Yes 
47% 
 
1.5 
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-
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 


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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.  
 
1.6 
Nivolumab in urothelial cancer 
The safety and activity of single-agent nivolumab in 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.18 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  who 
had progressed despite prior platinum-based chemotherapy.19 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 other prior indications (Table 2 and 3). 
 
Table 2. 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 3. 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 
 
1.7 
Combining nivolumab with platinum-based chemotherapy 
An expansion of the 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).20 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.21 This trial demonstrated similar findings with no new safety signals observed with the 
combination regimens.  
 
1.8 
Rationale for current trial 
This trial will test a straightforward, but as yet unexplored, hypothesis – that the choice of 
cytotoxic agents matters with regards to potential synergy when combining chemotherapy and 
immune checkpoint blockade. Specifically, we will test whether integration of a cytotoxic agent 
capable of inducing immunogenic cell death will improve outcomes in combination with PD-1 
blockade.  
 
In summary, the proposed trial is supported by the following lines of evidence: 
 
1. The development of therapies for cisplatin-ineligible patients with metastatic urothelial 
cancer is an unmet need. 
2. Single agent PD-1/PD-L1 blockade has shown durable responses in cisplatin-ineligible 
patients with metastatic urothelial cancer but only 20-25% of patients respond to treatment. 
3. Chemotherapy has demonstrated immunomodulatory effects in model systems. In particular, 
induction of immunogenic cell death may lead to synergy in combination with immune 
checkpoint blockade. However, combination regimens have generally advanced to the clinic 
without consideration of the potential importance of the choice of cytotoxic agent.  


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4. Establishing proof-of-concept for the immunomodulatory effects of chemotherapy is likely 
best pursued in the chemotherapy-naïve setting (i.e., because achieving cell death is a 
prerequisite for achieving immunogenic cell death, chemotherapy naïve cancers will likely be 
most amenable).  
5. Oxaliplatin has consistently been demonstrated to induce immunogenic cell death in model 
systems.  
6. Gemcitabine plus oxaliplatin has already demonstrated safety and activity in multiple phase 2 
trials in cisplatin-ineligible patients with metastatic urothelial cancer. 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
 Estimate the objective response rate (RECIST 1.1) to treatment with gemcitabine + 
carboplatin + nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-
ineligible patients with metastatic urothelial cancer. 
 
2.1.2 Secondary Objectives 
 Determine the safety of gemcitabine + carboplatin + nivolumab and gemcitabine + 
oxaliplatin + nivolumab in cisplatin-ineligible patients with metastatic urothelial cancer 
(CTCAE v4). 
 Estimate the duration of response to treatment with gemcitabine + carboplatin + 
nivolumab and gemcitabine + oxaliplatin + nivolumab in cisplatin-ineligible patients with 
metastatic urothelial cancer. 
 Estimate the progression-free survival 
 Estimate the overall survival. 
 
2.1.3 Correlative/Exploratory Objectives 
 Explore the effects of treatment on peripheral blood biomarkers of immune modulation 
and immunogenic cell death  
 Explore the impact of genomic/genetic alterations, including DNA damage response gene 
alterations, on clinical outcomes.  
 Explore the tumor immune microenvironment including the composition and frequency 
of immune cells and expression of immune checkpoints in archival tumor tissue and the 
relationship with clinical outcomes.  
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
 Response rate as determined by RECIST v1.1 
 
2.2.2 Secondary Endpoints 
 Safety will be determined according to the NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4 


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 Duration of response will be the time from the first documentation of RECIST 1.1 
response to the time of progression as per RECIST 1.1. 
 Progression-free survival which is defined as the time from randomization to death or 
progression, depending on which occurs first 
 Overall survival is defined as the time from randomization to death  
 
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. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
 
4. Able to comply with the study protocol, in the investigator’s judgment.  
 
5. Histologically documented, locally advanced (T4b, any N; or any T, N 2−3) or metastatic 
urothelial carcinoma (mUC) (M1, Stage IV) (also termed TCC or UCC of the urinary 
tract; including renal pelvis, ureters, urinary bladder, and urethra)  Patients with mixed 
histologies are required to have a dominant transitional cell pattern.  Locally advanced 
bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or 
adjacent viscera (clinical Stage T4b) or bulky nodal metastasis (N2−N3).  
 
6. Measurable disease, as defined by RECIST v1.1.  
 
7. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (metastatic 
specimens preferable but if not available primary tumor specimens that are at least 
muscle-invasive are acceptable) in paraffin blocks (blocks preferred) or at least 15 
unstained slides. If archival tissue is not available, subjects may be considered for 
enrollment on a case by case basis after discussion with the sponsor-investigator.  
 
8. No prior chemotherapy for inoperable locally advanced or mUC.  For patients who 
received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial 
carcinoma, a treatment-free interval > 12 months between the last treatment 
administration and the date of recurrence is required in order to be considered treatment 
naive in the metastatic setting. 
 
9. Cisplatin-ineligible as defined by at least one of the following2: 
 
Calculated creatinine clearance ≥ 30 but ≤ 60 mL/min (Cockroft-Gault) 
 
ECOG performance status = 2 
 
 
CTCAE v4 Grade ≥ 2 audiometric hearing loss 


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10. 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 clearance2
≥ 30 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 
2 
Cockcroft-Gault formula will be used to calculate creatinine clearance (See SPM) 
 
11. Women of childbearing potential must have a negative serum or urine pregnancy. 
 
12. Women of childbearing potential (WOCBP) and male subjects must use appropriate 
method(s) of contraception as outlined in Section 5.6 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Active infection requiring systemic therapy. 
 
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
 
3. Any serious or uncontrolled medical disorder that, in the opinion of the site 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.   
 
4. Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured. 
 
5. 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.   
 
6. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 


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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.  
 
7. 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. 
   
8. Grade ≥ 2 neuropathy (NCI CTCAE version 4).  
  
9. Known positive result 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 at screening is not required. 
 
10. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).   
 
11. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 
 
12. Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class III or greater), myocardial infarction within 3 months prior to randomization, unstable 
arrhythmias, or unstable angina. 
  
13. Known left ventricular ejection fraction (LVEF) < 40%  Patients with known coronary artery 
disease, congestive heart failure not meeting the above criteria, or LVEF 40%−50% must be 
on a stable medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate.   
 
14. Solid organ or tissue transplant including 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 and randomized prior to starting protocol therapy. Subjects must 
begin therapy within 7 business days of registration.  
 
4.1 
Randomization and Stratification 
Randomization will be stratified on the metastasis status (unresectable primary and/or lymph 
node only vs. the rest). 
 
 
 


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5. 
TREATMENT PLAN 
Patients will be randomized to Arm A: gemcitabine plus carboplatin plus nivolumab versus Arm 
B: gemcitabine plus oxaliplatin plus nivolumab. Randomization will be stratified on the 
metastasis status (lymph node only vs. the rest). Patients on both treatment arms will receive up 
to 6 cycles of combination therapy in the absence of prohibitive adverse effects or disease 
progression. Patients with at least stable disease at the completion of 6 cycles of treatment may 
continue “maintenance” single agent nivolumab for up to 12 cycles. Patients who require 
discontinuation of chemotherapy (i.e., gemcitabine plus carboplatin or gemcitabine plus 
oxaliplatin) prior to Cycle 6, but who have at least stable disease, may be considered for ongoing 
treatment with single-agent nivolumab on the “maintenance” phase after discussion with the 
sponsor-investigator. 
 
5.1 
Pre-Medication Guidelines  
 
5.1.1 Gemcitabine, Carboplatin or Oxaliplatin 
Institutional standards may be used for infusion of chemotherapy including premedication 
administration.  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. Body surface area and chemotherapy drug dose recalculations may occur 
per institutional standards.  
 
5.1.2 Nivolumab 
There are no required premedications for the administration of nivolumab. 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. An 
infusion window of ± 10 minutes may be applied. 
 
5.2 
Medication Administration 
For both Arms A and B, the sequence of administration should be nivolumab  gemcitabine  
platinum agent. Nivolumab will be administered prior to any other chemotherapy with at least a 
30-minute period between nivolumab administration and the initial chemotherapy. 
 
Arm A: Nivolumab, Gemcitabine, and Carboplatin  
 
Agent 
Route 
Dose 
Administration 
Time 
 
 
Frequency  
(± 3 days) 
Cycle 
Length 
Total # 
Cycles 
Nivolumab 
IV 
360 mg 
30 minutes 
(± 10 minutes) 
 
Day 1 
21 days
6 
Gemcitabine 
IV 
1000 
mg/m2 
Per institutional 
guidelines 
 
Day 1, 8 
Carboplatin 
IV 
AUC 4.51 
Per institutional 
guidelines 
 
Day 1 
1Carboplatin dosing will be based on the Calvert formula [dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 
(ml/min)] Creatinine clearance calculated according to the Cockroft Gault equation to estimate the GFR.  
 
 


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Arm B: Nivolumab, Gemcitabine, and Oxaliplatin 
 
Agent 
Route 
Dose 
Administration 
Time 
Frequency  
(± 3 days) 
Cycle 
Length
Total # 
Cycles 
Nivolumab 
IV 
360 mg 
30 minutes  
(± 10 minutes) 
Day 1 
21 
days 
6 
Gemcitabine
IV 
1000 mg/m2 
Per institutional 
guidelines 
Day 1, 8 
Oxaliplatin 
IV 
130 mg/m2 
Per institutional 
guidelines 
Day 1 
 
Maintenance Single Agent Nivolumab (starting ~ 2-4 weeks after completing combination 
chemotherapy plus nivolumab) 
 
Agent 
Route 
Dose 
Administration 
Time 
Frequency 
(± 3 days) 
Cycle 
Length 
Total # 
Cycles 
Nivolumab 
IV 
480 mg 
30 minutes 
(± 10 minutes) 
Day 1 
28 days 
12 
 
5.3 
Concomitant Medications 
 
5.3.1 Allowed Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
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 or vaccination rests with the site 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the site 
investigator, 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. 
 
 
 


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5.3.2 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  
 
5.4 
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. Growth factors should be not used during Cycle #1 or in lieu of 
recommended dose reductions. 
 
Radiation therapy to a solitary symptomatic site may be considered on a case by case basis after 
discussion with the sponsor-investigator.  
 
5.6 
Reproductive Information 
 
5.6.1 Women Subjects of Childbearing Potential 
Women subjects of childbearing potential who are sexually active and their partners must agree 
to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception 
beginning with time of consent, during the study treatment and for 5 months days after last dose 
of nivolumab (or timeframe outlined per package insert for chemotherapy). This timeframe also 
applies to breast feeding. Two contraception methods can be comprised of two barrier methods, 
or a barrier method plus a hormonal method.  
 
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. 
 
5.6.2 Male Subjects Capable of Fathering a Child 
Male subjects capable of fathering a child that are sexually active with partners of childbearing 
potential must agree to abstain from heterosexual intercourse or to use 2 forms of effective 
methods of contraception beginning with time of consent, during the study treatment and for the 
timeframe outlined per package insert for chemotherapy. This timeframe also applies 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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5.6.3 Methods of Contraception 
 
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* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal sponge 
 Male condom without spermicide  
 Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
 Female condom (A male and female condom must not be used together) 
 
6. 
DOSE DELAYS/MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 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 (provided criteria in Section 6.7 also met):  
 ANC ≥ 1.5 K/mm3 
 Platelets ≥ 100 K/mm3 
 Resolution of non-hematologic toxicities to ≤ Grade 1 or baseline 
 AST, ALT and  3.0 x ULN  
 


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Subjects requiring treatment to be held for toxicity > 4 weeks will be removed from study 
treatment and should proceed with definitive management of their tumor as per their treatment 
physician.  
 
6.2 
Treatment Limiting Adverse Event 
A treatment-limiting adverse event is any adverse event related to study treatment (includes 
carboplatin or oxaliplatin, gemcitabine and nivolumab) experienced during the study resulting in 
treatment termination.   
 
6.3 
Dose Adjustments for Gemcitabine, Carboplatin, and Oxaliplatin 
The following dose reductions should be utilized as directed by the guidance detailed in Sections 
6.4-6.6.  
 
Dose level 
Gemcitabine 
Carboplatin 
Oxaliplatin 
Dose level -1 
800 mg/m2 
AUC 4 
100 mg/m2 
Dose level -2 
600 mg/m2 
AUC 3.5 
80 mg/m2 
 
6.4 
Dose Delays/Modifications for Treatment Related Hematological Toxicity 
Treatment with nivolumab will also be HELD until patients meet criteria to resume dosing with 
gemcitabine and carboplatin or gemcitabine and oxaliplatin respectively.   
 
Gemcitabine and Carboplatin/Oxaliplatin Dose Reductions for Hematologic Toxicity 
Neutrophils  
(x109 cells/L)
 
Platelets  
(x 109 cells/L)
Gemcitabine Dose 
Carboplatin 
Dose
Oxaliplatin 
Dose
Day 1 
 
 
 
 
 
≥1.5
AND
≥100
100%
AUC 4.5
-
≥1.5 
AND 
≥100 
100% 
- 
130 mg/m2 
<1.5
OR
<100
Delay*
Delay*
-
<1.5
OR
<100
Delay*
-
Delay*
Day 8
≥1.5
AND
≥100
100%
-
-
1.0-<1.5
AND
≥100
Reduce 1 dose level
-
-
<1.0
OR
<100
Delay**
-
-
 
*Once ANC ≥ 1500 and platelets ≥ 100,000, resume therapy with gemcitabine reduced by 1 dose 
level. If gemcitabine has already been reduced to dose level -1, reduce carboplatin/oxaliplatin by 
1 dose level. If gemcitabine and carboplatin/oxaliplatin have already been reduced to dose level -
1, reduce gemcitabine to dose level -2. If gemcitabine has already been reduced to dose level -2, 
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. 
 
 
 


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**If ANC ≥ 1500 and platelets ≥ 100,000 within 14 days, proceed with “Day 8” gemcitabine 
reduced by 1 dose level. If gemcitabine has already been reduced to dose level -2, discuss further 
dose reductions with sponsor-investigator. If dose delay >14 days required for recovery of ANC 
≥ 1500 and platelets ≥ 100,000, omit “Day 8” dose of cycle and resume treatment with the 
subsequent cycle of treatment with gemcitabine and carboplatin/oxaliplatin reduced by 1 dose 
level. If gemcitabine has already been reduced to dose level -2, discuss dose reduction with 
sponsor-investigator. 
 
If gemcitabine plus carboplatin/oxaliplatin is held on Day 1 of a treatment cycle for hematologic 
toxicity as outlined above, nivolumab will also be held until criteria are met to initiate the cycle of 
treatment. 
 
There should be no dose re-escalation after a dose reduction.  
 
6.5 
Febrile Neutropenia 
If febrile neutropenia develops in a given cycle, hold gemcitabine, carboplatin/oxaliplatin, and 
nivolumab during febrile neutropenia.  
 
Resume gemcitabine and carboplatin/oxaliplatin 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. 
 
6.6 
Dose Delays/Modifications for Other Treatment Related Non-Hematological 
Toxicity Secondary to Gemcitabine or Carboplatin/Oxaliplatin 
Dose delays/reductions for non-hematologic toxicities attributable to gemcitabine or 
carboplatin/oxaliplatin (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. 
 
Dose Reductions of Gemcitabine/Carboplatin/Oxaliplatin for Non-Hematologic Toxicities* 
 
Non-Hematologic toxicity 
Gemcitabine/Carboplatin/Oxaliplatin 
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 
*See specific guidance for oxaliplatin-related neuropathy below  
 
 
 


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Dose Reductions for Oxaliplatin-related Neuropathy 
 
Neuropathy grade 
Oxaliplatin dose 
Grade 1 
No change 
Grade 2 (persisting until next cycle) 
100 mg/m2 
Grade 3 (>7 days but resolved before next cycle) 
100 mg/m2 
Grade 3 (persisting until next cycle) or 4 
Discontinue 
 
Dose re-escalation after a dose reduction for non-hematologic toxicity should not occur without 
discussion with the sponsor-investigator. 
 
If toxicity is specifically attributable to gemcitabine or carboplatin/oxaliplatin and warrants 
discontinuation of that particular agent, patients may be considered for continuation on treatment 
with carboplatin/oxaliplatin (or gemcitabine) and nivolumab but this must be discussed with the 
sponsor-investigator. 
 
6.7 
Dose Modifications for Nivolumab 
Dose reductions or dose escalations are not permitted. 
 
6.7.1 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 carboplatin/oxaliplatin 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: 
 Grade 3 lymphopenia or leukopenia does not require dose delay. 
 If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥ 2 toxicity. 
 If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥ 3 toxicity. 
 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. 


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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. 
 
6.7.2 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).   
 
6.7.3 Management Algorithms for Immune-Related Events 
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. 
These algorithms are found in the Nivolumab IB [and in Appendix A] of this protocol. The 


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guidance provided in these algorithms should not replace the site investigator’s medical 
judgment but should complement it. 
 
6.7.4 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 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. 
 
 
 


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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 
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 for Nivolumab 
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 carboplatin/oxaliplatin 
despite discontinuing nivolumab. Continuing treatment with gemcitabine plus 
carboplatin/oxaliplatin 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 
 
 


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 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 
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 [as allowed by protocol] 
 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. NOTE: If 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   


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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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7. 
STUDY CALENDAR & EVALUATIONS 
 
Study Evaluation  
Cycle = 21 days  
 
Screening 
Treatment 
Cycles 1-6 
Disease 
Progression12 
Safety follow 
up visit13 
Long-term 
Follow up14 
-28 days 
Day 1 
± 2 days
Day 8 
± 2 days
30/100 days  
post last dose
± 14 days 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical History including Smoking History1 
X
Physical Exam
X
X
D30
Vital signs and ECOG Performance Status2
X
X
D30
AEs & concomitant medications
X
X
X
X
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)
X 
X4 
X
D30
Comprehensive Metabolic Profile (CMP)3
X
X4 
X
D30
Amylase and Lipase
X
PT/INR and aPTT
X
Thyroid Function (TSH, T4, free T3)5 
X
X5 
Pregnancy test (serum or urine) (WOCBP)6
X
DISEASE ASSESSMENT 
CT of chest7 
X
After Cycle 3 and 
Cycle 6 
X
X14 
CT or MRI of abdomen and pelvis7 
X
X
X14 
TREATMENT  
Arm A: Gemcitabine + Carboplatin
X
Arm B: Gemcitabine + Oxaliplatin
X
Gemcitabine
X
Nivolumab
X
SPECIMEN COLLECTION  
Archival Tumor Tissue8
X
Tumor tissue (obtained for standard clinical purposes)9 
X
Blood for germline10 
C1D1
Whole Blood11 
X11 
 
 
PBMCs11 
X11 
X11 
D3011 
Plasma11 
X11 
X11 
D3011 
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X
 
 
 


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Key to Footnotes  
1. Medical History to include smoking questionnaire and a question about how the subject became aware of this clinical trial. Should also include 
diagnosis and staging information: Tumor Node Metastasis (TNM). Prior genomic or molecular results, performed in laboratories for standard 
clinical purposes (e.g., targeted DNA sequencing panels for “actionable” mutations) are required if available.  
 
2 Vital signs to include blood pressure, weight, and ECOG performance status. Height should be obtained at screening only. 
 
3 CMP to include sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, 
alkaline phosphatase  
 
4 If screening (baseline) CBC and CMP were performed within 7 days of Day 1 of treatment, these do not need to be repeated.  
  
5 Thyroid function testing will be done every other cycle during treatment. TSH, T3 and T4 should be performed; free versus total for T3 and T4 is 
at the site investigator’s discretion. 
 
6 For women of childbearing potential (WOCBP): urine or serum βhCG, within 7 days prior to Day 1. 
 
7 Tumor response assessment will be performed by the site investigator and will consist of evaluation by CT scans of chest and MRI or CT of 
abdomen and pelvis. Imaging selected for each subject should remain the same throughout the study if at all possible. An MRI is strongly 
suggested if the subject cannot have contrast for the CT scans. Tumor imaging to be done at treatment discontinuation at discretion of site 
investigator. If tumor assessments are available for subjects who have not yet experienced progressive disease (PD) at the time treatment is 
discontinued, the follow-up tumor evaluations will be documented in the eCRF until PD or death is confirmed, or until another treatment is 
initiated.  A bone scan will be obtained at baseline if any clinical or laboratory suspicion of metastatic bone involvement. If a bone scan is positive 
at baseline for metastases, it will be included with tumor response assessments as noted above.  
 
8 Archival tissue: Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (metastatic specimens preferable but if not available 
primary tumor specimens that are at least muscle-invasive are acceptable) in paraffin blocks (blocks preferred) or at least 15 unstained slides. If 
archival tissue is not available, subjects may be considered for enrollment on a case by case basis after discussion with the sponsor-investigator. 
Stored samples will be reserved for future unspecified cancer-related research. See Correlative Laboratory Manual (CLM) for additional details. 
 
9 Surplus tissue remaining after routine standard of care procedures (e.g., biopsy of a metastatic lesion) will be collected during this study and 
stored for future unspecified cancer-related research.  
 
10 Peripheral blood will be collected for somatic baseline prior to treatment on C1D1. 
 


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11 Serial blood samples will be collected to support biomarker research. These samples will be separated into whole blood, plasma and PBMCs. 
Timepoints for collection of whole blood: C1D1, C2D1, C3D1; timepoints for PBMCs C1D1, C3D1, progression/safety visit; timepoints for 
plasma C1D1, C2D1, C3D1, progression/safety visit.  See CLM and Table 4 for additional details. 
 
12 Subjects with suspected clinical progression should undergo imaging (CT chest and CT or MRI abdomen and pelvis) to document disease 
progression. An MRI is strongly suggested if the subject cannot have contrast for the CT scans. Bone scans should also be performed in the setting 
of suspicion of bone metastases. Blood samples for research purposes should be collected at the time of disease progression (Table 4). 
 
13The 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. Subjects discontinuing study treatment for disease progression 
who have not already had blood samples drawn for research purposes (Table 4) at “progression” should have specimens drawn at this visit. The 
D100 (± 7 days) safety visit will consist of a phone call, email or other avenues as appropriate to assess AEs.  
 
14 Subjects who discontinue treatment for any reason without documented disease progression will be followed for disease progression every 3 
months x 1.5 years, every 6 months x 1.5 years, and then yearly x 2 years (from treatment discontinuation). 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. Subjects who complete 6 cycles of combination therapy and have no 
evidence of disease progression or prohibitive adverse events should proceed with “maintenance” single agent nivolumab as detailed in the 
calendar of events below. Subjects who require discontinuation of chemotherapy (i.e., gemcitabine plus carboplatin or gemcitabine plus 
oxaliplatin) prior to cycle 6, but who have at least stable disease, may be considered for ongoing treatment with single-agent nivolumab on the 
“maintenance” phase after discussion with the sponsor-investigator.  Long term follow up visits have a window ± 14 days.  
 
 
 
 


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Maintenance Phase (only patients who have at least stable disease after completion of 6 cycles of chemotherapy plus 
nivolumab and for select patients who have at least stable disease but require discontinuation of chemotherapy prior to cycle 6 
due to adverse events). 
 
Maintenance treatment should be initiated ~ 2-4 weeks after completing combination chemotherapy plus nivolumab). 
 
Study Evaluation 
Cycle = 28 days 
Maintenance Phase = Cycles 7-18  
Maintenance 
Cycles 7-18 
Disease 
progression 
Safety follow up 
visit8 
Long-term 
Follow up9 
Day 1 
± 2 days 
30/100 days 
post last dose 
± 7 days
± 14 days 
REQUIRED ASSESSMENTS 
Physical Exam
X
D30
Vital signs and ECOG Performance Status1
X
D30
AEs & concomitant medications
X
X
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
Amylase and Lipase3
X
DISEASE ASSESSMENT 
CT of chest4 
X4
X7
X
CT or MRI of abdomen and pelvis4 
X4
X7
X
TREATMENT  
Nivolumab
X
SPECIMEN COLLECTION 
Tumor tissue (obtained for standard clinical purposes)5
X5
X
PBMCs6
X6 
X6
D306
Plasma6 
X6 
X6 
D306 
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X
 
 
 


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Key to Footnotes  
1: Vital signs to include blood pressure, weight, and ECOG performance status.  
 
2: CMP to include sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, 
alkaline phosphatase  
 
3: Thyroid function, amylase, and lipase testing will be done every other cycle during treatment. TSH, T3 and T4 should be performed; free versus 
total for T3 and T4 is at the site investigator’s discretion. 
 
4: Tumor response assessment will be performed by the site investigator and will consist of evaluation by CT scan of the chest and MRI or CT 
scan of abdomen and pelvis (imaging selected for each subject should remain the same throughout the study if at all possible). An MRI is strongly 
suggested if the subject cannot have contrast for the CT scans. If tumor assessments are available for subjects who have not yet experienced 
progressive disease (PD) at the time treatment is discontinued, the follow-up tumor evaluations will be documented in the eCRF until PD or death 
is confirmed, or until another treatment is initiated. A bone scan will be obtained if any clinical or laboratory suspicion of metastatic bone 
involvement. If a bone scan is positive at baseline for metastases, it will be included with tumor response assessments as noted above. Tumor 
response assessment should occur every 3 months.  
 
5: Surplus fixed paraffin-embedded blocks/slides tissue remaining after routine standard of care procedures (e.g., biopsy of a metastatic lesion) 
will be collected during this study and stored for future cancer-related research. See CLM for additional details. 
 
6: Blood samples will be collected to support biomarker research. Time points for collection of whole blood, PBMCs and plasma include C8D1 
and PBMCs and plasma at time of progression or Safety follow up visit. See Table 4 and CLM for additional details. 
 
7: Subjects with suspected clinical evidence of disease progression should undergo cross sectional imaging (i.e., CT chest and CT or MRI 
abdomen and pelvis). An MRI is strongly suggested if the subject cannot have contrast for the CT scans. Bone scans should also be performed in 
the setting of suspicion of bone metastases. Blood samples for research purposes should be collected at the time of disease progression (Table 4). 
 
8: Safety follow-up visit should 30 days (±7 days) after the last dose of treatment when subjects permanently stop study treatment for whatever 
reasons (toxicity, progression, or at discretion of site investigator). 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. Blood samples to support biomarker research will be collected at the time of safety follow-up visit unless already 
drawn within the prior 30 days. The D100 (± 7 days) safety visit will consist of a phone call, email or other avenues as appropriate to assess AEs. 
 
9: Subjects who discontinue treatment for any reason without documented disease progression will be followed for disease progression every 3 
months x 1.5 years, every 6 months x 1.5 years, and then yearly x 2 years from initiation of study treatment. 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. Long term follow up visits have a window ± 14 days..


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Table 4.  Schedule for correlative blood sample collections 
 
Visit 
Sample 
Purpose 
Collection 
Screening 
Archival 
Tissue 
Outlined 
correlative 
studies and 
banking
Block and H&E or 
15 unstained slides 
and H&E 
Follow Up 
Standard of 
Care Biopsies 
Outlined 
correlative 
studies and of 
post treatment 
tumor tissue
Block and H&E or 
15 unstained slides 
and H&E 
C1D1 
PBMCs 
T-cells 
3 x 8.5 ml ACD 
tubes 
C1D1 
Plasma 
ctDNA 
1 x 10 ml EDTA 
tubes 
C1D1 
Whole blood  
DNA 
1 x 6 ml EDTA 
tube 
C1D1 
Whole blood 
CTCs 
2 x 10 ml Streck 
tubes 
C2D1 
Plasma 
ctDNA 
1 x 10 ml EDTA 
tubes 
C2D1 
Whole blood 
CTCs 
2 x 10 ml Streck 
tubes 
C3D1 
PBMCs 
T-cells 
3 x 8.5 ml ACD 
tubes 
C3D1 
Plasma 
ctDNA 
1 x 10 ml EDTA 
tubes 
C3D1 
Whole blood 
CTCs 
2 x 10 ml Streck 
tubes
C8D1 
PBMCs 
T-cells 
3 x 8.5 ml ACD 
tubes
C8D1 
Plasma 
ctDNA 
1 x 10 ml EDTA 
tubes
C8D1 
Whole blood 
CTCs 
2 x 10 ml Streck 
tubes
Progression/safety 
PBMCs 
T-Cells 
3 x 8.5 ACD tubes 
Progression/safety 
Plasma 
ctDNA 
1 x 10 ml EDTA 
tubes
 
 
 


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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. The schedule of biospecimen collection(s), and ensure this schedule 
is reconciled with the Study Calendar. 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, antigen-specific T cell assays, HLA typing, and 
gene expression.  
 
8.1 
Tissue Samples 
 
8.1.1 Archival Tissue 
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (metastatic 
specimens preferable but if not available primary tumor specimens that are at least muscle-
invasive are acceptable) in paraffin blocks (blocks preferred) or at least 15 unstained slides. If 
archival tissue is not available, subjects may be considered for enrollment on a case by case basis 
after discussion with the sponsor-investigator. Samples will be utilized for studies including 
DNA sequencing, RNA sequencing, and characterization of the tumor and tumor 
microenvironment using existing and emerging technologies. Samples may also be stored for 
future cancer-related research. See Correlative Laboratory Manual (CLM) for additional details. 
 
8.1.2 Tissue collected during routine clinical procedures 
Surplus tissue remaining after routine standard of care procedures (e.g., metastatic biopsies) will 
be collected during this study. Subjects may have tumor tissue obtained during the course of the 
study or at the time of disease progression for clinical purposes (e.g., confirmation of disease 
progression, management of complication of disease progression, etc.). 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.  Subjects will have the option of whether samples obtained 
during standard of care procedures may be used for research purposes. 
 
8.1.3 Tissue Analysis 
Analysis of tumor tissue may include assessment for changes in the composition of immune 
cells, tumor cells, and tumor microenvironment. Immune cell composition and changes in the 
tumor microenvironment will be analyzed by platforms including but not limited to 
immunohistochemistry, flow cytometry, and mass cytometry. An effort will be made to identify 
tumor antigens for each subject using strategies including, but not limited to, collating the 
“antigenome” using immunohistochemistry data as well as identifying mutation-derived tumor 
antigens through genome sequencing and computational biology approaches to predict epitope: 
MHC binding affinity. T-cell responses will be detected using standard ELISPOT and 
intracellular cytokine assays or other emerging technologies.  DNA and RNA will be isolated for 
sequencing.  
 


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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 Table 4.  Collection of blood samples is mandatory for participation in this study. 
 
8.2.1 PBMCs for Immune Cell Analysis 
The quantity and composition of immune cells in the peripheral blood mononuclear cells will be 
analyzed and clonality of T cells may also be assessed. Antigen specific T cell responses may 
also be detected as described above.   
 
8.2.2 Plasma for ctDNA and other analyses 
Plasma DNA will be isolated and analyzed for quantitative expression using sequence specific 
primers and/or for exome sequencing, cytokines/chemokines, and other analytes.  
 
8.2.3 Circulating Tumor Cells Analysis 
Whole blood samples will be collected to isolate circulating tumor cells which will then be used 
to evaluate changes in the quantity of circulating tumor cells as well as the expression of a 
variety of circulating tumor cell-based biomarkers.   
 
8.2.4 Baseline Testing 
Whole blood samples for germline DNA sequencing as a reference for somatic tissue DNA 
sequencing will be collected prior to treatment C1D1. HLA typing may also be performed for 
neoantigen predictions and other correlative analyses. See CLM for additional details. 
 
8.3 
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. 
 
8.4 
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 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 


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9.1.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.2 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
9.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
 
 


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9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1 (Eur J Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm.
Partial Response 
(PR)
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note:  the 
appearance of one or more new lesions is also considered 
progressions).
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
 
9.6 
Evaluation of Non-Target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response.
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of 
overall disease status change, not a single lesion 
increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
 
 
 


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9.7 
Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR 
Non-PD/ or not all 
evaluated
No 
PR 
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
Non-evaluable
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status.  
 
9.8 
Definitions for Response Evaluation – RECIST 1.1 
 
9.8.1 First Documentation of Response 
The time between randomization and first documentation of PR or CR. 
 
9.8.2 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
 
9.8.3 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 
9.8.4 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST 1.1, from the time of randomization until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since treatment initiation. 


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9.8.5 
Disease Control Rate 
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 weeks, or 
partial response (PR), or complete response (CR) according to RECIST 1.1, from the time of 
randomization until disease progression/recurrence (taking as reference for progressive disease 
the smallest measurements recorded since the start of treatment). 
 
9.8.6 Time to Progression 
A measurement from the date of randomization until the criteria for disease progression is met as 
defined by RECIST 1.1. Subjects who have not progressed or have died due to any cause will be 
right-censored at the date of the last disease evaluation or date of death. 
 
9.8.7 Progression Free Survival 
A measurement from the date of randomization until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-censored 
at the date of the last disease evaluation. 
 
9.8.8 Overall Survival 
Overall survival is defined by the date of randomization to date of death from any cause. 
 
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)  
 
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-micro 
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 
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Injection, USP to protein concentrations as low as 0.35 mg/mL. When the dose is fixed (eg, 240 
mg flat dose), 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. Instructions for dilution and infusion of nivolumab injection may be 
provided in the clinical protocol, pharmacy binder, or pharmacy reference sheet. 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. 
 
Nivolumab will be administered as an IV 30-minute infusion and should be administered prior to 
any other chemotherapy for the trial with at least a 30-minute period between nivolumab 
administration and the next chemotherapy. 
 
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.  
 
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 must be maintained to provide to BMS as documentation 
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.   
 
 
 


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10.1.6 Adverse Events 
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. 
 Diarrhea 
 Nausea 
 Abdominal pain 
 Decreased appetite 
 Low red blood cells 
 Fever 
 Joint pain or stiffness 
 
Less common side effects of nivolumab include:  
 Bowel inflammation 
 Liver function blood test abnormalities 
 Loss of color (pigment) from areas of skin 
 Dry mouth 
 Vomiting 
 Weight loss 
 Thyroid gland abnormalities 
 Blood chemistry abnormalities, including low blood phosphate, magnesium, and 
potassium levels. 
 High blood uric acid level 
 Lung inflammation (pneumonitis - see details below) 
 Cough 
 Dizziness 
 Headache 
 Low white blood cells 
 Chills 
 Muscle soreness, weakness, stiffness spasms or paralysis 
 Pain in arms or legs 
 Tingling, burning, or numbness in hands and feet 
 Shortness of breath 
 Abnormal taste  
 Flushing 
 High or low blood pressure 
 Allergic reaction during or between study drug infusions 
 Increased sensitivity of skin to sunlight 
 Constipation 
 Difficulty swallowing 
 Heartburn 
 Low blood platelets (may increase risk of bleeding) 


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Rare but potentially serious side effects of nivolumab include: 
 Low blood oxygen level 
 Acute lung injury or failure 
 Collection of fluid around the lungs 
 Inflammation of the appendix 
 Increase in inflammatory blood proteins (e.g., lipase) 
 Adrenal gland abnormalities 
 Pituitary gland inflammation 
 Changes in vision (including decreased or blurry vision), inflammation of the eye, or 
bleeding into the eye 
 Liver inflammation 
 Acute kidney injury or failure  
 Abnormal blood cell production 
 Inflammation of the mouth and lining of the digestive tract  
 Swelling of the face, arms, or legs 
 Inflammation of the pancreas 
 Back pain 
 Autoimmune disorders, including Guillain-Barre syndrome (associated with progressive 
muscle weakness or paralysis)  
 Chest discomfort 
 Heart palpitations 
 Inflammation of the heart or its lining 
 Collection of fluid around the heart 
 Increased blood sugar 
 Dehydration 
 Infections: including sepsis, lung infections, and skin infections.  
 Decreased movement of the intestines 
 Disorientation 
 Swelling of the optic disc 
 Inflammation of the optic nerve 
 Inflammation or loss of the lining of the brain and spinal cord 
 Drug reaction with rash, blood cell abnormalities, enlarged lymph nodes, and internal 
organ involvement (including liver, kidney, and lung); known as Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS) 
 Myasthenia gravis, a nerve disease that may cause weakness of eye, face, breathing, and 
swallowing muscles. One death in a patient who received nivolumab combined with 
ipilimumab was considered due to myasthenia gravis and severe infection (sepsis). 
 Abnormal brain function due to brain inflammation. 
 Rhabdomyolysis (muscle fiber released into the blood stream which could damage your 
kidney) and polymyositis (chronic muscle inflammation with muscle weakness) has been 
reported in one subject. 
 Lung inflammation or pneumonitis 
 
 
 


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10.2 
Gemcitabine 
Please see product package insert for complete details regarding gemcitabine. 
 
10.2.1. Chemical Name 
1” – Deoxy – 2, 2” – difluorocytidine monohydrochloride, Gemzar, NSC #613327 
 
10.2.2 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). 
 
10.2.3 Availability  
Gemcitabine is commercially available.  
 
 
10.2.4 Storage, Reconstitution, and Administration 
Storage, Reconstitution, and Administration as per institutional guidelines 
 
10.2.5 Side Effects 
Hematologic: In studies in pancreatic cancer, myelosuppression is the dose-limiting toxicity with 
gemcitabine, but <1% of patients discontinued therapy for either anemia, leukopenia, or 
thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence 
of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was 
reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients 
should be monitored for myelosuppression during Gemcitabine therapy and dosage modified or 
suspended according to the degree of hematologic toxicity. 
 
Gastrointestinal: Nausea and vomiting were commonly reported (69%) but were usually of mild 
to moderate severity. Severe nausea and vomiting (WHO Grade 3-4) occurred in <15% of 
patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.  
 
Hepatic: Gemcitabine was associated with transient elevations of 1 or both serum transaminases 
in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with 
either longer duration of exposure to gemcitabine or with greater total cumulative dose. Serious 
hepatotoxicity, including liver failure and death, has been reported very rarely in patients 
receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs.  


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Renal: In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical 
findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 
patients (0.25%) receiving gemcitabine in clinical trials. Four patients developed HUS on 
Gemcitabine therapy, 2 immediately posttherapy. The diagnosis of HUS should be considered if 
the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin 
or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of 
serum creatinine or BUN). Gemcitabine therapy should be discontinued immediately. Renal 
failure may not be reversible even with discontinuation of therapy and dialysis may be required. 
 
Fever: The overall incidence of fever was 41%. This is in contrast to the incidence of infection 
(16%) and indicates that gemcitabine may cause fever in the absence of clinical infection. Fever 
was frequently associated with other flu-like symptoms and was usually mild and clinically 
manageable.  
 
Rash: Rash was reported in 30% of patients. The rash was typically a macular or finely granular 
maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. 
Pruritus was reported for 13% of patients.  
 
Pulmonary: In clinical trials, dyspnea, unrelated to underlying disease, has been reported in 
association with gemcitabine therapy. Dyspnea was occasionally accompanied by bronchospasm. 
Pulmonary toxicity has been reported with the use of gemcitabine (see Pulmonary under Post-
marketing experience, below). The etiology of these effects is unknown. If such effects develop, 
Gemcitabine should be discontinued. Early use of supportive care measures may help ameliorate 
these conditions.  
 
Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. 
Less than 1% of patients discontinued due to edema.  
 
Flu-like Symptoms: “Flu syndrome” was reported for 19% of patients. Individual symptoms of 
fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever 
and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, 
and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like 
symptoms.  
 
Infection: Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).  
 
Alopecia: Hair loss, usually minimal, was reported by 15% of patients.  
 
Neurotoxicity: There was a 10% incidence of mild paresthesias and a <1% rate of severe 
paresthesias. 
 
Extravasation: Injection-site related events were reported for 4% of patients. There were no 
reports of injection site necrosis. Gemcitabine is not a vesicant.  
 


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Allergic: Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has 
been reported rarely. Gemcitabine should not be administered to patients with a known 
hypersensitivity to this drug.  
 
Cardiovascular: During clinical trials, 2% of patients discontinued therapy with gemcitabine due 
to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and 
hypertension. Many of these patients had a prior history of cardiovascular disease (see 
Cardiovascular under Post-marketing experience, below). 
 
Post-marketing experience: The following adverse events have been identified during post-
approval use of gemcitabine. These events have occurred after gemcitabine single-agent use and 
gemcitabine in combination with other cytotoxic agents. Decisions to include these events are 
based on the seriousness of the event, frequency of reporting, or potential causal connection to 
gemcitabine. 
 
Cardiovascular  Congestive heart failure and myocardial infarction have been reported very 
rarely with the use of gemcitabine. Arrhythmias, predominantly supraventricular in nature, have 
been reported very rarely.  
 
Vascular Disorders  Clinical signs of peripheral vasculitis and gangrene have been reported 
very rarely. 
 
Skin  Cellulitis and non-serious injection site reactions in the absence of extravasation have 
been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, 
have been reported very rarely.  
 
Hepatic  Increased liver function tests including elevations in aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and 
bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and 
death has been reported very rarely in patients receiving gemcitabine alone or in combination 
with other potentially hepatotoxic drugs.  
 
Pulmonary  Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, 
pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely 
following 1 or more doses of gemcitabine administered to patients with various malignancies. 
Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last 
gemcitabine dose. Respiratory failure and death occurred very rarely in some patients despite 
discontinuation of therapy.  
 
Renal  Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been reported following 1 
or more doses of gemcitabine. Renal failure leading to death or requiring dialysis, despite 
discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure 
leading to death were due to HUS.  
 
Injury, Poisoning, and Procedural Complications  Radiation recall reactions have been reported  
Pregnancy 


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Pregnancy Category D. Gemcitabine can cause fetal harm when administered to a pregnant 
woman. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete 
ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a 
mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, 
absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended 
human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, 
reduced live litter sizes, and developmental delays. There are no studies of gemcitabine in 
pregnant women. If gemcitabine is used during pregnancy, or if the patient becomes pregnant 
while taking gemcitabine, the patient should be apprised of the potential hazard to the fetus. 
 
Nursing mothers. It is not known whether Gemcitabine or its metabolites are excreted in human 
milk. Because many drugs are excreted in human milk and because of the potential for serious 
adverse reactions from gemcitabine in nursing infants, the mother should be warned and a 
decision should be made whether to discontinue nursing or to discontinue the drug, taking into 
account the importance of the drug to the mother and the potential risk to the infant. 
 
10.3 
Carboplatin 
Please see product package insert for complete details regarding carboplatin. 
 
10.3.1 Availability  
Carboplatin is commercially available  
 
10.3.2 Chemical Name  
Platinum diamine [1,1-cyclobutane- decarbozxylate (2—0,0’)-,(SP-4-2)]) is a platinum 
compound used as a chemotherapeutic agent.  
 
10.3.3 Formulation  
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 
150 mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and 
mannitol. Commercial supplies of carboplatin will be used in this study.  
 
10.3.4 Availability 
Carboplatin is commercially available. 
 
10.3.5 Storage, Preparation, and Administration 
Per Institutional guidelines.  
 
10.3.6 Adverse Events Associated with Carboplatin 
Incidence rates of adverse events associated with carboplatin are provided in the product package 
insert. Some of the adverse events expected with Carboplatin treatment are listed below. 
 
Hematologic: Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia, 
neutropenia, leukopenia, and anemia are common, but typically resolve by Day 28 when 
carboplatin is given as a single agent. 
 


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Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of subjects receiving 
the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm and 
hypotension. The reactions can be successfully managed with standard epinephrine, 
corticosteroid, and antihistamine therapy. 
 
Neurologic: Peripheral neuropathies have been observed in 4% of subjects receiving carboplatin 
with mild paresthesia being the most common. 
 
Gastrointestinal: Nausea and vomiting are the most common GI events; both usually resolve 
within 24 hours and respond to antiemetics. Other GI events include diarrhea, weight loss, 
constipation, and gastrointestinal pain. 
Hepatic Toxicity: Elevated alkaline phosphatase, total bilirubin, and SGOT have been observed. 
 
Other:  Pain and asthenia are the most common miscellaneous adverse events. Alopecia has been 
reported in 3% of the subjects taking carboplatin. 
 
10.4 
Oxaliplatin 
Please see product package insert for complete details regarding oxaliplatin 
 
10.4.1 Availability 
Oxaliplatin will be paid for by the study. 
 
10.4.2 Chemical name 
cis-[(1 R,2 R)-1,2-cyclohexanediamine-N,N'] [oxalato(2)-O,O'] platinum 
 
10.4.3 Storage, Preparation, and Administration 
Per institutional guidelines 
 
10.4.4 Adverse Events 
For a comprehensive list of adverse events please refer to the package insert for oxaliplatin 
 
 Central nervous system: Peripheral neuropathy, fatigue, pain, headache, insomnia, rigors, 
dizziness. 
 Cardiovascular: Edema, chest pain, peripheral edema, flushing, thromboembolism. 
 Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, constipation, anorexia, 
stomatitis, dyspepsia, dysgeusia, flatulence, hiccups, mucositis, gastroesophageal reflux 
disease, dysphagia. 
 Hematologic & oncologic: Anemia, thrombocytopenia, leukopenia, neutropenia. 
 Hepatic: Increased serum AST, increased serum ALT, increased serum bilirubin.  
 Endocrine & metabolic: Dehydration, hypokalemia. 
 Neuromuscular & skeletal: Back pain, arthralgia. 
 Respiratory: Dyspnea, cough, upper respiratory tract infection, rhinitis, epistaxis, 
pharyngitis, pharyngolaryngeal dysesthesia. 
 Renal: Increased serum creatinine  
 Dermatologic: Skin rash, alopecia, palmar-plantar erythrodysesthesia 


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 Hypersensitivity: Hypersensitivity reaction (includes urticaria, pruritus, facial flushing, 
shortness of breath, bronchospasm, diaphoresis, hypotension, syncope) 
 Local: Injection site reaction  
 Ocular: Abnormal lacrimation 
 Miscellaneous: Fever 
 
11 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4 will be utilized for AE 
assessment. A copy of the CTCAE v4 can be downloaded from the CTEP website at 
http://ctep.cancer.gov.  
 
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. 
 
11.1.2 Serious Adverse Event (SAE) 
An 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., 


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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, prescribing information or when it is not included in 
the informed consent document 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)  
 
11.2 
Reporting 
 
11.2.1 Adverse Events  
 AEs will be recorded from time of signed informed consent until 30 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. 
 
 
 


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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.   
 
HCRN will ensure that all SAEs are reported to BMS and any applicable health authority during 
the conduct of the study including periodic reconciliation.  SAEs need to be reconciled every 3 
months by HCRN initiating the reconciliation activity with BMS by emailing 
AEBUSINESSPROCESS@BMS.com and including this information on the regular study status 
update reports. 
 
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 @ 
worldwide.safety@bms.com or fax @ 609-818-3804. 
 
11.2.2.3 
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.   
 
 
 


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11.2.2.4 
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. 
 
11.2.2.5  IND Safety Reports Unrelated to this Trial 
Bristol-Myers Squibb’s will provide to HCRN IND safety reports 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. 
 
12 
STATISTICAL METHODS 
 
12.1 
Study Design 
This is a randomized, open-labeled phase 2 trial of gemcitabine + carboplatin + nivolumab or 
gemcitabine + oxaliplatin + nivolumab for the treatment of cisplatin-ineligible patients with 
metastatic urothelial cancer.  Randomization will be stratified on the lymph node only (and/or 
unresectable primary) metastatic status.  
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
 Response rate as determined by RECIST v1.1 
 
12.2.2 Definition of Secondary Endpoints 
 Safety will be determined according to the NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4 
 Duration of response will be the time from the first documentation of RECIST 1.1 
response to the time of progression as per RECIST 1.1. 
 Progression-free survival which is defined as the time from randomization to death or 
progression, depending on which occurs first 
 Overall survival is defined as the time from randomization to death  
 


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12.3 
Sample Size and Accrual 
A randomized phase 2 ‘pick a winner design’ will be employed.1 Two regimens are to be studied 
and the expected baseline response rate is ~40%. With 21 patients per arm, we have probability 
0.9 of selecting the regimen that has a true response rate of 40%+20%=60% [or, allows selection 
of the regimen that is 18% better (in terms of response rate) than the other regimen with 0.88 
probability and 15% better with 0.83 probability]. We will inflate the sample size on each study 
arm to account for early drop-outs/unevaluable patients to ~24 patients per arm. Because our 
randomization is stratified on the lymph node (LN) only (and/or unresectable primary) metastasis 
status, we further calculate the probability of correctly selecting the better treatment, similar to 
the Table 3 in Simon et al. (1985) 1. In particular, we assume that approximately 30% of patients 
will have LN only metastasis. Response rate can be as high as 60% for this particular group. The 
probabilities of correctly selecting the better treatment are listed in the table below assuming the 
response rate for the LN only metastasis range from 50% to 60%. The overall response rate is 
fixed at 40%. We can see that these probabilities are satisfactory and do not seem to be 
substantially impacted by the stratification.  
 
Probabilities of Correctly Selecting the Better Treatment based on n=22 per Arm 
 
 
Improvement in response rate for the other metastasis 
group 
20% 
18% 
15% 
Using 50% as the response rate of the LN only group
Improvement 
in response 
rate for the 
lymph node 
only 
metastasis 
group 
20% 
0.911
0.895
0.868
18% 
0.903
0.887
0.858
15% 
0.891
0.873
0.843
 
Using 55% as the response rate of the LN only group
20% 
0.913
0.898
0.871
18% 
0.906
0.889
0.861
15% 
0.893
0.876
0.845
 
Using 60% as the response rate of the LN only group
20% 
0.917
0.902
0.876
18% 
0.909
0.893
0.865
15% 
0.897
0.879
0.849
 
12.4 
Data Analysis Plans 
 
12.4.1 Analysis Plans for Primary Objective 
All subjects who have received at least one cycle of treatment and have their disease re-evaluated 
will be evaluable for assessment of the response rate. The objective response rate (PR + CR) and 
its associated 95% confidence interval will be constructed. Comparison between the two 
treatments will be conducted using the Fisher’s exact test. Difference will be estimated using the 
exact method. 
 
 
 


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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. Comparison between the treatments 
will be conducted using the Fisher’s exact test. Time to event outcomes (i.e. Duration of 
response, progression-free survival, and overall survival) will be analyzed using the Kaplan-
Meier method. Comparison between the treatments will be conducted using the log-rank test.  
 
12.4.3 Analysis Plans for Exploratory Objectives 
The effects of treatment on peripheral blood biomarkers of immune modulation and 
immunogenic cell death will be estimated using difference of pre- and post-treatment 
measurements. Association of these markers (i.e. their changes) with the response will be 
explored using t-tests. Their association 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. Similar analyses will be conducted for the tumor tissue 
biomarkers based on a subset of patients (5 patients per arm). However, the small sample size 
may prohibit formal statistical analysis. Impact of somatic mutations, including DNA damage 
response gene alterations on response rate will be conducted using Fisher’s exact test. Their 
impact on the time-to-event outcomes will be explored using the log-rank test. Antigen-specific 
T cell responses in peripheral blood (pre-treatment vs. post-treatment) will be analyzed using t-
tests.  
 
12.5 
Interim Analysis/Criteria for Stopping Study 
The stopping rule will be employed separately for the two arms after 7, 14, and 21 subjects finish 
at least one cycle of treatment. Therefore, it is possible to stop one arm and continue the other 
arm. Two-sided 95% exact binomial confidence intervals (CIs) of these grade ≥ 3 immune-
related adverse event rates will be constructed.  
 
When the trial was initially designed, there were no large datasets in urothelial cancer of 
platinum-based chemotherapy plus PD-1/PD-L1 blockade and limited published studies with 
PD-1/PD-L1 blockade in urothelial cancer in the first-line setting. Based on the datasets available 
at the time, the study was designed such that if the lower bounds of the 95% CI for grade ≥ 3 
immune-related adverse event rate exceeded 3% for either arm, that regimen would be 
considered to be associated with excessive toxicity and enrollment to that arm would be halted. 
However, during the conduct of the current study, two large randomized trials exploring 
platinum-based chemotherapy versus platinum-based chemotherapy plus PD-1/PD-L1 blockade 
versus PD-1/PD-L1 blockade have been published provided much more robust data on which to 
base the grade ≥ 3 immune-related adverse event rate with PD-1/PD-L1 blockade alone in this 
patient population as well as with platinum-based chemotherapy plus PD-1/PD-L1 blockade in 
this patient population. There data are summarized in the tables below. 
 
 
 


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From KEYNOTE 361 (Powles et al, Lancet Oncology, 2021)22 
 
 
 
 


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IMvigor 130 (Galsky et al, Lancet, 202023; see AEs of special interest)  
 
 
 Arm A = platinum-based chemotherapy plus atezolizumab, Arm B = atezolizumab, Arm C = platinum-
based chemotherapy 
 
Based on these large randomized trials in patients with metastatic urothelial cancer, the grade ≥ 3 
immune-related adverse event rate with PD-1/PD-L1 blockade alone or with platinum-based 
chemotherapy plus PD-1/PD-L1 blockade is ~9%. Based on these findings, in the current study, 
if the lower bound of the 95% CI for the grade ≥ 3 immune-related adverse events exceeds 9% 
for either arm, the study regimen being explored in that arm will be considered to have excessive 
toxicity and enrollment to that arm will be halted. This corresponds to ≥ 3+ (3 or more) out of 7, 
≥ 5+ (5 or more) out of 14, and ≥ 6+ out of 21 subjects. 
 
 
 


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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 processing of 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 DSMC for review.  
 
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 the 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. Additional for cause visits may occur as necessary. 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 as well as inspection by appropriate 
regulatory agencies. 
 


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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.   
 
13. 
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.  


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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. 
 
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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