Clinical trial NCT03101566
Conditions: Biliary Tract Neoplasms
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2017-09-08; Completion date: 2021-06-07
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to evaluate the effect of investigational drug nivolumab in combination with either gemcitabine/cisplatin chemotherapy, or in combination with another investigational agent ipilimumab in patients with advanced unresectable biliary tract cancer.

Gemcitabine/cisplatin is the standard of care treatment for biliary tract cancer.

Nivolumab and ipilimumab are types of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack the cancer cells. Nivolumab (Opdivo) is FDA approved for the treatment of several cancers including metastatic melanoma, advanced lung, kidney, head \& neck and bladder cancer. The combination of nivolumab and ipilimumab (Yervoy) is FDA approved for metastatic melanoma.

Detailed description:

Arms: arm 1: Drug: Gemcitabine 1000 mg/m2 IV on days 1,8 every 3 weeks

Drug: Cisplatin 25 mg/m2 IV on days 1,8 every 3 weeks

Drug: Nivolumab 360 mg IV on day 1 every 3 weeks

If there is continued benefit after 6 months, then:

Drug: Nivolumab 240 mg IV on day 1 every 2 weeks arm 2: Drug: Ipilimumab

1 mg/kg IV on day 1 every 6 weeks

Drug: Nivolumab 240 mg IV on day 1 every 2 weeks
Interventions: intervention 1: Gemcitabine intervention 2: Cisplatin intervention 3: Ipilimumab intervention 4: Nivolumab
Intervention descriptions: intervention 1: Gemcitabine 1000 mg/m2 IV intervention 2: Cisplatin 25 mg/m2 IV intervention 3: Ipilimumab 1 mg/kg IV intervention 4: Nivolumab 360 mg or 240 mg IV

Protocol documents:
Prot_SAP_000.pdf: 
UMCC 2017.026 
A Multi-Center Randomized Phase II Study of Nivolumab in Combination with 
Gemcitabine/Cisplatin or Ipilimumab as First Line Therapy for Patients with Advanced 
Unresectable Biliary Tract Cancer [CA209-9FC] 
Principal Investigator: 
Vaibhav Sahai, MBBS, MS 
Division of Hematology/Oncology Department of Internal Medicine 
University of Michigan 
Coordinating Center: 
University of Michigan 
Biostatistician: 
Kent Griffith, MPH, MS 
University of Michigan 
Center for Cancer Biostatistics, School of Public Health 
Study Drug: 
 
Nivolumab (Opdivo®) 
Ipilimumab (Yervoy®) 
Initial version: 
02/24/2017 
Amended:
03/01/2017 
 
05/08/2017
07/06/2017 
02/28/2018 
NCT03101566


Protocol UMCC 2017.026 
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TABLE OF CONTENTS 
STUDY SYNOPSIS ..........................................................................................................6 
1.0 
BACKGROUND AND RATIONALE ............................................................9 
1.1 
Biliary Tract Cancer - Disease Overview ......................................................................... 9 
1.2 
Role of Checkpoint Inhibitors in BTC ............................................................................... 9 
1.3 
Role of Chemotherapy in Conjunction with Checkpoint Inhibitors ................................ 11 
1.4 
Rationale ........................................................................................................................ 11 
1.5 
Correlative Studies ........................................................................................................ 11 
2.0 
STUDY OBJECTIVES .................................................................................12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................... 12 
2.3 
Exploratory Objectives ................................................................................................... 12 
2.4 
Endpoints Assessment .................................................................................................. 12 
3.0 
PATIENT ELIGIBILITY ................................................................................12 
3.1 
Eligibility Criteria ............................................................................................................ 13 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES .......14 
5.0 
TREATMENT PLAN ....................................................................................16 
5.1 
Treatment Dosage and Administration .......................................................................... 16 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 17 
5.3 
Management Algorithms for Immuno-Oncology Agents ................................................ 21 
5.4 
Concomitant Medications/Treatments ........................................................................... 21 
5.5 
Other Modalities or Procedures ..................................................................................... 21 
5.6 
Duration of Therapy ....................................................................................................... 21 
5.7 
Off Treatment Criteria .................................................................................................... 21 


Protocol UMCC 2017.026 
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5.8 
Duration of Follow-Up .................................................................................................... 22 
5.9 
Off Study Criteria ........................................................................................................... 22 
5.10 
Patient Replacement ..................................................................................................... 22 
6.0 
STUDY PROCEDURES ..............................................................................22 
6.1 
Screening/Baseline Procedures .................................................................................... 22 
6.2 
Time and Events Table/Schedule of Events/Study Calendar........................................ 22 
7.0 
MEASUREMENT OF EFFECT...................................................................25 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 25 
7.2 
Safety/Tolerability .......................................................................................................... 30 
8.0 
ADVERSE EVENTS .....................................................................................30 
8.1 
Adverse Event Reporting Requirements ....................................................................... 30 
8.2 
Definitions ...................................................................................................................... 31 
8.3 
Adverse Event Characteristics ...................................................................................... 33 
8.4 
Serious Adverse Event Reporting Guidelines ............................................................... 33 
8.5 
Routine Reporting .......................................................................................................... 34 
8.6 
Reporting of Pregnancy ................................................................................................. 34 
8.7 
Reporting of Unanticipated Problems ............................................................................ 34 
8.8 
Safety Report Reconciliation ......................................................................................... 35 
8.9 
Stopping Rules .............................................................................................................. 35 
9.0 
DRUG INFORMATION ................................................................................35 
9.1 
Gemcitabine ................................................................................................................... 35 
9.2 
Cisplatin ......................................................................................................................... 37 
9.3 
Nivolumab ...................................................................................................................... 39 
9.4 
Ipilimumab ..................................................................................................................... 42 
10.0 
CORRELATIVES/TRANSLATIONAL STUDIES ....................................45 
10.1 
Tissue Collection ........................................................................................................... 45 


Protocol UMCC 2017.026 
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10.2 
Blood Collection ............................................................................................................. 45 
10.3 
Centralized Imaging ....................................................................................................... 45 
10.4 
Specimen Banking ......................................................................................................... 45 
11.0 
STATISTICAL CONSIDERATIONS ..........................................................45 
11.1 
Study Design/Study Endpoints ...................................................................................... 46 
11.2 
Sample Size and Accrual .............................................................................................. 46 
11.3 
Data Analyses Plans ...................................................................................................... 46 
12.0 
ADMINISTRATIVE PROCEDURES ..........................................................46 
12.1 
Ethics and Good Clinical Practice ................................................................................. 46 
12.2 
Data Management ......................................................................................................... 46 
12.3 
Record Retention ........................................................................................................... 47 
13.0 
DATA AND SAFETY MONITORING ........................................................47 
14.0 
QUALITY ASSURANCE AND AUDITS ...................................................47 
15.0 
CLINICAL MONITORING PROCEDURES ..............................................48 
16.0 
REFERENCES ..............................................................................................50 
17.0 
APPENDICES ...............................................................................................52 


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ABBREVIATIONS: 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
BTC 
Biliary Tract Cancer 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
UaP 
Unanticipated Problem 
UMCCC 
University of Michigan Comprehensive Cancer Center 
WBC 
White Blood Cells 
 
 
 


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STUDY SCHEMA 
 
 
STUDY SYNOPSIS 
Title 
A Multi-Center Randomized Phase II Study of Nivolumab in Combination with 
Gemcitabine/Cisplatin or Ipilimumab as First Line Therapy for Patients with 
Advanced Unresectable Biliary Tract Cancer 
Phase 
Phase II 
Methodology 
Randomized, open-label 
Study Duration 
3 years 
Study Center(s) 
Multi-Center: up to 7 sites total including lead site: University of Michigan 
Objectives 
Primary objective: 
1. Determine the PFS rate at 6 months in patients with advanced BTC treated 
with nivolumab, gemcitabine and cisplatin, or nivolumab and ipilimumab. 
 
Secondary objectives: 
1. Evaluate the ORR, median PFS and OS of patients with advanced BTC. 
2. Evaluate the safety of nivolumab in combination with gemcitabine and 
cisplatin, or ipilimumab in this patient population. 
 
Exploratory objectives: 
1. To explore predictors of biomarker response and mechanisms of resistance 
based on the exploratory analysis of tumor tissue obtained through serial 
biopsies and blood. 
a) Levels of PD-L1 (B7-H1), PD-L2, CTLA-4, T cell subset, myeloid-derived 
cell subset infiltration by immunohistochemistry (IHC) at baseline, at 2 months 
and progression (for patients enrolled at University of Michigan). 
b) Whole exome genomic and transcriptomic (RNAseq) analysis for tumor 
biology and immune signature profiling at baseline and progression. 
c) PBMC collection for immune cell subset analysis including serum for future 
biomarker analysis. 
Number of Subjects 
64 
Eligibility Criteria 
1. Patients must have a pathologically confirmed adenocarcinoma of the biliary 
tract (intra-hepatic, extra-hepatic (hilar, distal) or gallbladder) that is not 
 


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eligible for curative resection, transplantation, or ablative therapies. Tumors 
of mixed histology are excluded. 
2. Patients may not have received prior systemic treatment (chemotherapy or 
targeted therapy) for advanced BTC. Prior adjuvant chemotherapy is 
permitted provided it was completed > 6 months from registration.  
3. Prior radiation, chemoembolization, radioembolization or other local ablative 
therapies or hepatic resection is permitted if completed ≥ 4 weeks prior to 
registration AND if patient has recovered to ≤ grade 1 toxicity. Extrahepatic 
palliative radiation is permitted if completed ≥ 2 weeks prior to enrollment AND 
if patient has recovered to ≤ grade 1 toxicity. 
4. Patients must have radiographically measurable disease (as per 
RECISTv1.1) in at least one site not previously treated with radiation or liver 
directed therapy (including bland, chemo- or radio-embolization, or ablation) 
either within the liver or in a metastatic site. 
5. Must be ≥ 18 years of age 
6. Must have a Child-Pugh score of A  
7. Must have an ECOG performance status of 0-1 
8. Ability to understand and willingness to sign IRB-approved informed consent 
9. Willing to provide archived tissue, if available, from a previous diagnostic 
biopsy 
10. Must be able to tolerate CT and/or MRI with contrast 
11. Must have adequate organ function obtained ≤2 weeks prior to registration 
(absolute neutrophil count >1500/mm3, hemoglobin >9 g/dL, platelets 
>100,000/mm3, serum creatinine < 1.5 x upper limit normal (ULN), creatinine 
clearance ≥ 50 mL/min, albumin >3.0 g/dL, AST/ALT <3.0 x ULN (<5 x ULN if 
liver metastasis), total bilirubin < 1.5 x upper limit normal, INR < 1.5 upper 
limit normal) 
12. Must not have a diagnosis of immunodeficiency, or have received systemic 
steroid therapy, or any other form of immunosuppressive therapy within 7 
days prior to trial treatment. Short bursts of steroids of 5-7 days (for COPD 
exacerbation or other similar indication) are allowed. 
13. Must not have known Hepatitis B, Hepatitis C, or HIV seropositivity. Testing 
is not required in absence of clinical suspicion. 
14. Must not have prior history of organ transplantation or brain metastasis. 
15. Must not have undergone a major surgical procedure < 4 weeks prior to 
registration. 
16. Must not have an active second malignancy other than non-melanoma skin 
cancer or cervical carcinoma in situ. Patients with history of malignancy are 
eligible provided primary treatment of that cancer was completed > 1 year 
prior to registration and the patient is free of clinical or radiologic evidence of 
recurrent or progressive malignancy. 
17. Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours 
off antibiotics). 
18. Must not have received a live vaccine within 30 days of planned start of the 
study therapy. 
19. Must not have a psychiatric illness, other significant medical illness, or social 
situation which, in the investigator’s opinion, would limit compliance or ability 
to comply with study requirements. 
20. Women must not be pregnant or breastfeeding since study drugs may harm 
the fetus or child. All females of childbearing potential (not surgically sterilized 
and between menarche and 1 year post menopause) must have a negative 
screening pregnancy test. 
21. Women of child-bearing potential and men must agree to use 2 methods of 
adequate contraception (hormonal plus barrier or 2 barrier forms) OR 
abstinence prior to study entry, for the duration of study participation, and for 
5 months (for women) and 7 months (for men) following completion of study 


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therapy.  
22. Participants with an active, known or suspected autoimmune disease which 
may 
affect 
vital 
organ 
function, 
or 
has/may 
require 
systemic 
immunosuppressive therapy for management are excluded. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, 
skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 
23. Participants must not have a condition requiring systemic treatment with either 
corticosteroids 
(>10 
mg 
daily 
prednisone 
equivalent) 
or 
other 
immunosuppressive medications within 7 days of start of treatment. Inhaled 
or topical steroids, and adrenal replacement steroid doses >10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
 
Study Product(s), 
Dose, Route, 
Regimen 
Arm A:  
Gemcitabine 1000 mg/m2 IV  
Cisplatin 25 mg/m2 IV  
Nivolumab 360 mg IV  
 
Arm B:  
Nivolumab 240 mg IV  
Ipilimumab 1 mg/kg  
Duration of 
Administration 
Patients may be treated on study for no longer than 2 years. 
 
Arm A: If patient has stable disease after 8 cycles, then gemcitabine/cisplatin 
will be discontinued and patient will continue single agent nivolumab at 240 mg 
IV every 2 weeks, in absence of disease progression or unacceptable toxicity.  
 
Arm B: The patient can continue nivolumab and ipilimumab every 2 weeks in 
absence of disease progression or unacceptable toxicity. 
Statistical 
Methodology 
The trial is sized to compare each randomized treatment arm to a historical value 
for PFS in this patient population receiving standard treatment. The PFS 
proportion in this patient population at 6 months is 59%. Using this value as the 
null hypothesis, we hope to see an increase in the proportion of alive, 
progression-free patients to 80% or above in each of the combination arms.  
Thirty-two patients evaluable for the 6-month PFS endpoint are required to test 
this hypothesis with >80% power and at most 5% type I error (1-sided).  A 
maximum of 64 evaluable patients will be enrolled. 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Biliary Tract Cancer - Disease Overview 
Biliary tract cancer (BTC) develops as a result of malignant transformation of the biliary 
tract mucosa and is anatomically classified as intra-hepatic, extra-hepatic (hilar and 
distal) and gall bladder adenocarcinoma. BTC accounts for 10-15% of all primary liver 
cancer cases worldwide, and its incidence is rising (Shaib, Davila et al. 2004).  Advanced 
BTCs are aggressive tumors with median survival time from diagnosis of less than 12 
months (Valle, Wasan et al. 2010), and five-year overall survival (OS) of ~5% despite 
therapy (Nathan, Pawlik et al. 2007). The options for systemic chemotherapy for patients 
with advanced BTC remains limited with only a few meaningful improvements made over 
the past few decades. Valle et al randomly assigned 410 patients with locally advanced 
or metastatic BTC to receive gemcitabine with or without cisplatin in the phase III ABC-02 
trial (Valle, Wasan et al. 2010). Patients on the gemcitabine cisplatin arm demonstrated 
an improvement in OS (11.7 versus 8.1 months; hazard ratio (HR), 0.64; 95% CI, 0.52 to 
0.80; p>0.001) as compared to the gemcitabine alone arm. The following clinically 
relevant grade 3 and 4 adverse events were noted in the gemcitabine/cisplatin arm: 
neutropenia (25.3%), anemia (7.6%), thrombocytopenia (15.7%), abnormal liver function 
(16.7%), fatigue (18.7%), nausea (4%), vomiting (5.1%), impaired renal function (1.5%), 
infection (18.2%), deep vein thrombosis (2%), and thromboembolic event (3.5%). This 
result established the gemcitabine and cisplatin combination as a standard first line 
regimen for patients with advanced BTC. 
1.2 
Role of Checkpoint Inhibitors in BTC 
T-cell activation requires dual signaling from the T-cell receptor and an additional co-
stimulatory molecule (Peggs, Quezada et al. 2006, Robert and Ghiringhelli 2009). The 
first signal includes binding of the T-cell receptor to antigens presented by antigen 
presenting cells (APCs). Subsequently, the B7 (CD80, CD86) ligand binds to CD28 which 
is a co-stimulatory receptor. This signaling leads to T-cell proliferation, cytokine release 
and upregulation of the immune response. As a result, cytotoxic T lymphocyte antigen 4 
(CTLA-4) is upregulated and competes with the CD28 receptor for B7 binding. CTLA-4 
has higher affinity than the CD28 receptor and therefore T-cell response is ultimately 
down-regulated. PD-1 is a member of the CD28/CTLA-4 family of T-cell costimulatory 
receptors that includes CD28, CTLA-4, ICOS and BTLA (Freeman, Long et al. 2000). PD-
1 is expressed on activated T cells, B cells and myeloid cells (Nishimura and Honjo 
2001). There are 2 ligands, PD-L1 and PD-L2 that are specific for PD-1. Once they bind 
to PD-1, down-regulation of T-cell activation occurs (Latchman, Wood et al. 2001, Carter, 
Fouser et al. 2002). When the PD-1 ligand binds to the PD-1 receptor, T-cell activation is 
blocked. CTLA-4 and PD-1 are negative regulators of T-cell response that prevent 
autoimmunity and allows tolerance to self-antigens (Peggs, Quezada et al. 2006). If these 
interactions are interrupted, the checkpoint is turned off which can lead to enhanced 
antitumor T-cell activation. 
 
Nivolumab (Opdivo™), a fully human immunoglobulin G4 programmed death-1 (PD-1) 
immune checkpoint inhibitor antibody, binds with high affinity to PD-1 receptors on T 
cells, blocking their interaction with PD ligands 1 and 2 (PD-L1/PD-L2) and restoring T-
cell antitumor function (Rizvi, Hellmann et al. 2016). Twenty-three PD-L1 positive patients 
with advanced BTC were enrolled in the KEYNOTE-028 phase 1b trial of pembrolizumab 
(another anti-PD-1 antibody) monotherapy.  Within this cohort of heavily pretreated 
patients, an ORR of 17.4% (N=4; 95% CI, 5.0-38.8) was demonstrated and an additional 
4 patients had stable disease for a disease control rate of 35% (Bang, Doi et al. 2015). At 
the time of this report, the median response duration had not yet been reached (range, 
5.4+ to 9.3+ weeks). Adverse events were generally consistent with previously reported 
safety data for pembrolizumab. There were no treatment-related deaths. Five patients, 


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including all responders, remain on treatment more than 40 weeks (Bang, Doi et al. 
2015).  
 
Ipilimumab (Yervoy™) is a fully human monoclonal immunoglobulin (Ig) G1κ specific for 
human CTLA-4. Ipilimumab binds to CTLA-4 and inhibits its interaction with B7 ligands 
(CD80, CD86) on APCs which can augment T-cell activation and proliferation, including 
the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 
signaling can also reduce T-regulatory cell function, which may contribute to a general 
increase in T cell responsiveness, including the anti-tumor immune response (Ipilimumab 
Investigator Brochure, 2015). While the toxicity and clinical responses overlap, 
mechanisms of immune activation and range of responses appear to be different for 
ipilimumab and nivolumab. Preclinical data suggests the combination of nivolumab and 
ipilimumab enhances T-cell antitumor activity. This combination is FDA approved in 
patients with melanoma, and is being currently investigated in patients with non-small cell 
lung cancer (NCT02477826), bladder cancer (NCT02553642), advanced solid tumors 
(NCT01928394), pancreatic cancer (NCT01928394) and hepatocellular carcinoma 
(NCT01658878). 
 
Melanoma. The combination of nivolumab plus ipilimumab was investigated in a phase III 
clinical trial in untreated melanoma and showed improved median progression-free 
survival (11.5 months; 95% CI, 8.9 to 16.7 months) compared to nivolumab or ipilimumab 
alone (P<.001) [12]. The most frequent treatment-related select adverse events of grade 
3 or 4 were diarrhea (in 2.2% of patients in the nivolumab group, 9.3% of those in the 
nivolumab-plus-ipilimumab group, and 6.1% of those in the ipilimumab group), colitis (in 
0.6%, 7.7%, and 8.7%, respectively), and increased alanine aminotransferase level (in 
1.3%, 8.3%, and 1.6%, respectively) (Larkin, Chiarion-Sileni et al. 2015).  
 
Small cell lung cancer (SCLC). CheckMate-032 is a phase 1/2 open-label trial, evaluating 
the safety and efficacy of nivolumab monotherapy, or nivolumab combined 
with ipilimumab, in advanced or metastatic solid tumors at different doses and schedules. 
The CheckMate-032 SCLC cohort included 180 patients with progressive disease after 
one or more prior lines of therapy, including a first-line platinum-based chemotherapy 
regimen. In this analysis, patients received nivolumab monotherapy 3 mg/kg 
administered intravenously every two weeks, or nivolumab 1 mg/kg plus ipilimumab 3 
mg/kg, every three weeks for four cycles followed by nivolumab 3 mg/kg every two 
weeks. All patients were treated until disease progression or unacceptable toxicity. The 
confirmed objective response rate (primary objective) was 31% (n=14/45) in patients who 
received nivolumab plus ipilimumab and was 13% (n=7/55) with nivolumab alone. Grade 
3–4 treatment-related adverse events (TRAEs) occurred in 11% of pts in nivolumab alone 
arm, and 32% of patients in the nivolumab 1mg/kg + ipilimumab 3mg/kg arm; 5% and 
13% discontinued due to TRAEs, respectively. One TR death due to myasthenia gravis 
occurred in the combination arm (Antonia, Lopez-Martin et al. 2016). 
 
Renal cell cancer (RCC). In the CheckMate-016 study, patients with metastatic RCC 
were randomized to either nivolumab 3 mg/kg + ipilimumab 1mg/kg (n=47) or nivolumab 
1 mg/kg + ipilimumab 3 mg/kg (n=47). After a median follow-up of 22 months, the overall 
response rate was 40% in each arm, with median PFS of 6.6 months with nivolumab 3 + 
ipilimumab 1 and 9.1 months with nivolumab 1 + ipilimumab 3. Less frequent grade 3/4 
treatment-related adverse effects were reported with nivolumab 3 + ipilimumab 1 
compared with nivolumab 1 + ipilimumab 3 (38% vs 62%). The most common 
were ↑ lipase (15% vs 28%), ↑ ALT (4% vs 21%), diarrhea (4% vs 15%), ↑ AST (4% vs 
13%), and colitis (0% vs 15%) respectively. The most common grade 3–4 select 
treatment-related AEs were gastrointestinal (4% vs 23%) and hepatic (6% vs 21%) 
respectively. High dose ipilimumab showed dose-related toxicity, which further supports 
development of nivolumab 3 mg/kg + ipilimumab 1mg/kg in the first-line setting 
(Hammers, Plimack et al. 2016). 


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1.3 
Role of Chemotherapy in Conjunction with Checkpoint Inhibitors 
Chemotherapy has been shown to lead to the upregulation of PD-L1 expression (Peng, 
Hamanishi et al. 2015). In addition, chemotherapy can enhance tumor antigen 
presentation by upregulating the production of tumor neoantigens, or expression of the 
MHC class I molecules to which these antigens bind. Alternatively, chemotherapy may 
upregulate co-stimulatory molecules (e.g. B7-1) or downregulate co-inhibitory molecules 
(e.g. PD-L1/B7-H1 or B7-H4) expressed on the tumor cell surface, enhancing the 
strength of effector T-cell activity. Chemotherapy may also render tumor cells more 
sensitive to T cell–mediated lysis through fas-, perforin-, and Granzyme B–dependent 
mechanisms (Emens and Middleton 2015). Gemcitabine is an example of an 
immunomodulatory chemotherapeutic agent with pleiotropic immune effects. 
Gemcitabine induces tumor cell apoptosis and enhances cross-priming of CD8+ T cells in 
animal models (Nowak, Lake et al. 2003). It also reverses defective cross-presentation of 
tumor antigens by tumor-infiltrating dendritic cells (McDonnell, Lesterhuis et al. 2015). 
Cisplatin is another immunomodulatory chemotherapeutic agent that has been showed to 
stimulate tumor infiltration of inflammatory APCs expressing relatively high levels of T-cell 
so-stimulatory ligands (e.g. B7). 
 
The immunogenic properties of conventional chemotherapy and rapid emergence of 
chemotherapy resistance provide a good rationale for combining gemcitabine plus 
cisplatin with immunotherapy, particularly immune checkpoint inhibitors. CheckMate 012, 
a phase I, multicohort study, was conducted to explore the safety and efficacy of 
nivolumab as monotherapy or combined with current standard therapies in first-line 
advanced non-small cell lung cancer. Patients (n = 56) received nivolumab plus platinum-
doublet concurrently every 3 weeks for four cycles followed by nivolumab alone until 
progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus 
gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 
5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to 
assess safety and tolerability. Secondary objectives included objective response rate and 
24-week progression-free survival rate. The objective response rates for nivolumab 10 
mg/kg plus gemcitabine-cisplatin was 33% along with progression-free and overall 
survival rates of 51% and 25% at 2 years, respectively (Rizvi, Hellmann et al. 2016).  
1.4 
Rationale 
Patients with advanced, unresectable or metastatic BTC have a poor prognosis despite 
systemic chemotherapy. The median PFS with first-line gemcitabine and cisplatin is 
expected to be 8 months. The immunogenic properties of conventional chemotherapy 
and rapid emergence of chemotherapy resistance provide a good rationale for combining 
chemotherapy with immunotherapy, particularly immune checkpoint inhibitors (Rizvi, 
Hellmann et al. 2016). Monotherapy with pembrolizumab, another anti PD-1 antibody, 
has demonstrated activity in patients with heavily pre-treated, advanced BTC. 
Additionally, inhibition of CTLA-4 signaling via ipilimumab can also reduce T-regulatory 
cell function, and the combination of nivolumab and ipilimumab has been shown to 
improve clinical efficacy in several solid cancers in comparison with anti PD-1 alone. 
 
Therefore, we hypothesize that PD-1 receptor inhibition in combination with systemic 
chemotherapy, or ipilimumab will improve the progression-free and overall survival in this 
population without increasing toxicity. These results are expected to have an important 
positive impact because they will provide a strong evidence-guided understanding of BTC 
microenvironment and identification of potential biomarkers of response (and resistance) 
to inform a phase III clinical trial of immunotherapy in BTC.  
1.5 
Correlative Studies 
We will study the BTC tumor microenvironment through the use of pre-treatment tissue 
(all sites) as well as on-treatment (for patients at University of Michigan) and post-


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treatment (optional for patients enrolled at all sites) tumor biopsies. In addition, blood will 
be collected as detailed in the schedule of events/study calendar. Identification of 
important biologic subsets of BTC patients that may have clinical efficacy from nivolumab 
and ipilimumab will be the overarching goal of these translational studies along with 
developing biologic insights for future therapeutic development. Biologic readouts for PD-
1 and CTLA4 response biomarkers will be assessed along with specific markers of tumor 
infiltrating leukocytes (TILs). Biologic markers and RNA expression will be examined in 
the context of immunologic correlates, tumor biology, and therapeutic efficacy.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
Determine the PFS rate at 6 months in patients with advanced BTC treated with 
nivolumab, gemcitabine and cisplatin, or nivolumab and ipilimumab 
2.2 
Secondary Objectives  
2.2.1 
Evaluate the ORR, median PFS and OS of patients with advanced BTC. 
 
2.2.2 
Evaluate the safety of nivolumab in combination with gemcitabine and cisplatin, 
or ipilimumab in this patient population. 
2.3 
Exploratory Objectives 
2.3.1 
To explore predictors of biomarker response and mechanisms of resistance 
based on the exploratory analysis of tumor tissue obtained through serial 
biopsies and blood. 
a) Levels of PD-L1 (B7-H1), PD-L2, CTLA-4, T cell subset, myeloid-derived 
cell subset infiltration by immunohistochemistry (IHC) at baseline (for all 
patients), at 2 months and progression (for patients enrolled at University 
of Michigan) 
b) Whole exome genomic and transcriptomic (RNAseq) analysis for tumor 
biology and immune signature at baseline and progression  
c) PBMC collection for immune cell subset analysis including serum for 
future biomarker analysis 
2.4 
Endpoints Assessment 
2.4.1 
Primary Endpoint Assessment: The progression-free survival (PFS) will be 
defined as time from date of treatment to date of radiological or clinical 
progression (leading to withdrawal from the study), or death from any cause, 
whichever comes first. Follow-up time will be censored at the date of last disease 
evaluation. 
 
2.4.2 
Secondary Endpoint Assessment: Overall response rate (ORR) will be 
determined as per the combined RECISTv1.1 and irRECIST criteria. Overall 
survival (OS) will be defined from the date of treatment to either date of death or 
censoring. Adverse events and reportable serious events are defined by the 
study protocol (NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
v4.03). 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the eligibility criteria to be enrolled to the study. Study treatment may 
not begin until a subject is enrolled. 
 


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3.1 
Eligibility Criteria 
 
3.1.1 
Patients must have a pathologically confirmed adenocarcinoma of the biliary tract 
(intra-hepatic, extra-hepatic (hilar, distal) or gallbladder) that is not eligible for 
curative resection, transplantation, or ablative therapies. Tumors of mixed 
histology are excluded.  
 
3.1.2 
Patients may not have received prior systemic treatment (chemotherapy or 
targeted therapy) for advanced BTC. Prior adjuvant chemotherapy is permitted 
provided it was completed > 6 months from registration. 
 
3.1.3 
Patients may have received prior radiation, chemoembolization, 
radioembolization or other local ablative therapies or hepatic resection if 
completed ≥ 4 weeks prior to registration AND if patient has recovered to ≤ grade 
1 toxicity. Extrahepatic palliative radiation is permitted if completed ≥ 2 weeks 
prior to enrollment AND if patient has recovered to ≤ grade 1 toxicity 
 
3.1.4 
Patients must have radiographically measurable disease (as per RECISTv1.1) in 
at least one site not previously treated with radiation or liver directed therapy 
(including bland, chemo- or radio-embolization, or ablation) either within the liver 
or in a metastatic site.  
 
3.1.5 
Must be ≥ 18 years of age. 
 
3.1.6 
Must have a Child-Pugh score of A.  
 
3.1.7 
Must have an ECOG performance status of 0-1. 
 
3.1.8 
Ability to understand and willingness to sign IRB-approved informed consent. 
 
3.1.9 
Willing to provide archived tissue, if available, from a previous diagnostic biopsy. 
 
3.1.10 Must be able to tolerate CT and/or MRI with contrast.  
 
3.1.11 Must have adequate organ function obtained ≤ 2 weeks prior to registration:  
 
absolute neutrophil count 
≥ 1500/mm3 
hemoglobin 
≥ 9 g/dL 
platelets 
≥ 100,000/mm3 
serum creatinine 
≤ 1.5 x ULN 
creatinine clearance 
≥ 50 mL/min 
albumin 
≥ 3.0 g/dL 
AST/ALT  
≤ 3.0 x ULN (≤5 x ULN if liver metastasis) 
total bilirubin 
≤ 1.5 x ULN 
INR 
≤ 1.5 ULN 
 
3.1.12 Must not have a diagnosis of immunodeficiency, or have received systemic 
steroid therapy, or any other form of immunosuppressive therapy within 7 days 
prior to trial treatment. Short bursts of steroids of 5-7 days (for COPD 
exacerbation or other similar indication) are allowed.   
 
3.1.13 Must not have known Hepatitis B, Hepatitis C, or HIV seropositivity. Testing is not 
required in absence of clinical suspicion. 
 
3.1.14 Must not have prior history of organ transplantation or brain metastasis. 


Protocol UMCC 2017.026 
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3.1.15 Must not have undergone a major surgical procedure < 4 weeks prior to 
registration. 
 
3.1.16 Must not have an active second malignancy other than non-melanoma skin 
cancer or cervical carcinoma in situ. Patients with history of malignancy are 
eligible provided primary treatment of that cancer was completed > 1 year prior to 
registration and the patient is free of clinical or radiologic evidence of recurrent or 
progressive malignancy. 
 
3.1.17 Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours off 
antibiotics) 
 
3.1.18 Must not have received a live vaccine within 30 days of planned start of the study 
therapy. 
 
3.1.19 Must not have a psychiatric illness, other significant medical illness, or social 
situation which, in the investigator’s opinion, would limit compliance or ability to 
comply with study requirements. 
 
3.1.20 Women must not be pregnant or breastfeeding since study drugs may harm the 
fetus or child. All females of childbearing potential (not surgically sterilized and 
between menarche and 1 year post menopause) must have a negative screening 
pregnancy test. 
 
3.1.21 Women of child-bearing potential and men must agree to use 2 methods of 
adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence 
prior to study entry, for the duration of study participation and for 5 months (for 
women) and 7 months (for men) following completion of study therapy.  
 
3.1.22 Participants with an active, known or suspected autoimmune disease which may 
affect vital organ function, or has/may require systemic immunosuppressive 
therapy for management are excluded. Participants with type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, skin disorders (such as 
vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
 
3.1.23 Participants must not have a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 7 days of start of study treatment. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Patient registration and randomization for this trial will be centrally managed by the Oncology 
Clinical Trials Support Unit (i.e. the Coordinating Center) of The University of Michigan 
Comprehensive Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the Coordinating Center. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Coordinating Center. After patient eligibility has been 


Protocol UMCC 2017.026 
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determined, a copy of the completed Eligibility Worksheet together with all the pertinent de-
identified source documents will be submitted by the requesting site to the Coordinating Center, 
by email to 
    
 
A Multi-Site Coordinator of the Coordinating Center, who acts as the registrar, will review the 
submitted documents and process the registration. Sites should inform the Multi-Site Coordinator 
of a potential registration by 5 p.m. on the day prior to registration.  Same day registrations 
cannot be guaranteed.   
 
The registrar will send an email to the requesting site registrar to confirm patient registration and 
randomization and to provide the study identification number and randomization number assigned 
to the patient. In addition, a copy of the completed Eligibility Worksheet signed and dated by the 
registrar will be sent back to the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 calendar days of randomization otherwise the 
patient will be taken off study. Re-screening is allowed. 
5.1.1 
Arm A: Nivolumab once every 3 weeks in combination with gemcitabine and 
cisplatin was evaluated in the CheckMate 012 trial in non-small cell lung cancer 
(Rizvi, Hellmann et al. 2016). The safety profile of nivolumab plus gemcitabine 
and cisplatin is consistent with that expected for individual agents. Nivolumab 
360 mg every 3 week dose has/is being investigated in multiple clinical trials in 
combination with chemotherapy for ease of administration (NCT02967133, 
NCT02864251 and NCT02434081). 
 
TABLE 1. Arm A – Regimen Description
Agent 
Prophylaxis 
Dose 
Route2
Schedule3 
Cycle 
Length 
Gemcitabine 
per 
institutional 
policy 
1000 mg/m2 
per 
commercial 
package 
insert 
IV over 25 – 
35 minutes 
before 
cisplatin 
Cycles 1 through 8 
Days 1 and 8 
3 weeks (21 
days)  
Cisplatin 
25 mg/m2 
per 
commercial 
package 
insert 
IV over 25 – 
65 minutes 
after 
gemcitabine 
Days 1 and 8 
Nivolumab1 
360 mg per 
commercial 
package 
insert 
IV over 25 – 
65 minutes 
after 
cisplatin 
Day 1 
240 mg per 
commercial 
package 
insert 
IV over 25 – 
65 minutes  
Day 1 
240 mg per 
commercial 
package 
insert 
IV over 25 – 
65 minutes 
Day 1 of Cycles 9+ 
2 weeks (14 
days) 
 
1 If both gemcitabine and cisplatin are discontinued prior to 8 cycles of protocol treatment, then 
nivolumab may be continued alone at 240 mg IV every 2 weeks. If the patient has stable disease 
on imaging after 8 cycles, then they will discontinue gemcitabine and cisplatin, and continue 
single agent nivolumab at 240 mg IV every 2 weeks, in absence of disease progression or 
unacceptable toxicity. 
2 Infusion times may be extended as needed for safety (e.g. infusion reaction occurs). These 
instances should be documented in the patient medical records. 
3 As per section 5.6, patients may not be treated on study for longer than 2 years. 
 
 
 
 
 
 


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5.1.2 
Arm B. Nivolumab and ipilimumab combination has been studied in multiple 
cancers and is FDA approved for melanoma. The safety profile of nivolumab plus 
ipilimumab is consistent with that expected for individual agents (Larkin, 
Chiarion-Sileni et al. 2015). Nivolumab 240 mg every 2 week dose is FDA 
approved for use in renal cell carcinoma, metastatic melanoma and non-small 
cell lung cancer. 
 
TABLE 2. Arm B – Regimen Description1
Agent 
Prophylaxis 
Dose 
Route2
Schedule3 
Cycle 
Length 
Nivolumab 
per 
institutional 
policy 
240 mg per 
commercial 
package 
insert 
IV over 25 – 
65 minutes 
before 
ipilimumab 
Day 1 of each Cycle 
2 weeks 
(14 days)  
Ipilimumab 
1 mg/kg per 
commercial 
package 
insert 
IV over 25 – 
65 minutes 
after 
nivolumab 
Day 1 of every 3rd 
Cycle 
 
1 The patient can continue nivolumab every 2 weeks and ipilimumab every 6 weeks, in absence 
of disease progression or unacceptable toxicity. 
2 Infusion times may be extended as needed for safety (e.g. infusion reaction occurs). These 
instances should be documented in the patient medical records. 
3 As per section 5.6, patients may not be treated on study for longer than 2 years. 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.4). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0.3. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
Table 3: Dose Modifications 
Arm A 
Gemcitabine 
Current Dose 
Percentage Decrease 
Modified Dose 
1000 mg/m2 
20% 
800 mg/m2 
800 mg/m2 
20% 
640 mg/m2 
640 mg/m2 
100% 
Discontinue 
Cisplatin 
25 mg/m2 
20% 
20 mg/m2 
20 mg/m2 
20% 
16 mg/m2 
16 mg/m2 
100% 
Discontinue 
Nivolumab 
360 mg 
100% 
Discontinue 
240 mg 
100% 
Discontinue 
Arm B 
Nivolumab 
240 mg 
100% 
Discontinue 
Ipilimumab 
1 mg/kg 
100% 
Discontinue 
 


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5.2.1 
All dose reductions will be permanent unless otherwise noted. 
5.2.2 
If more than one toxicity occurs requiring dose reduction, the dose administered 
should be based on the most severe toxicity. 
5.2.3 
Treatment delay of more than 28 days from last intended therapy will result in 
treatment discontinuation. 
5.2.4 
If one of the drugs is discontinued due to toxicity attributed to that agent, the 
patient will be allowed to continue a modified regimen with the remaining study 
arm agent/s. For Arm A however, monotherapy with cisplatin is not permitted, 
though monotherapy with gemcitabine is allowed. Additionally, if both 
gemcitabine and cisplatin are held, then also hold nivolumab. If both gemcitabine 
and cisplatin are discontinued, then nivolumab may be continued alone at 240 
mg. 
5.2.5 
Nivolumab and/or ipilimumab cannot be dose reduced in response to toxicity, 
and can only be discontinued as per detailed algorithms for immune-therapy 
toxicity management in Appendix III.  
5.2.6 
Patients on Arm B may be allowed to continue nivolumab monotherapy if toxicity 
is deemed related to ipilimumab and deemed safe to continue as per the treating 
investigator. 
5.2.7 
Investigators should consider dose re-calculation of gemcitabine and/or cisplatin 
with change in BSA as per standard of care/institutional guidelines. However, a 
change in BSA by 10% or more should lead to a dose re-calculation. 
5.2.8 
Investigators should consider dose re-calculation of ipilimumab with change in 
weight as per standard of care/institutional guidelines. However, a change in 
weight by 10% or more should lead to a dose re-calculation. 
5.2.9 
Missed Dose: If the regimen held or missed was to be given on Day 1 then that 
next cycle will not be considered to start until the day the first dose is actually 
administered. Held doses of either or both gemcitabine and cisplatin on Day 8 
will be considered omitted. 
 
 


Protocol UMCC 2017.026 
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TABLE 4. Day 1 Dose Modifications for Hematologic Toxicity for Gemcitabine and Cisplatin in Arm A 
Hematologic Toxicity 
Dose Adjustment for Gemcitabine and/or Cisplatin 
ANC1 ≥ 1000/mm3 
AND 
Platelets ≥ 100,000/mm3 
Treat as scheduled 
ANC1 < 1000/mm3 
OR/AND 
Platelets < 100,000/mm3 
Hold both gemcitabine and cisplatin up to a maximum of 28 days until ANC ≥ 1000/mm3 AND platelets 
≥ 100,000/mm3 then resume at next lower dose level for either or both gemcitabine and cisplatin as 
detailed in Table 3. If not resolved, then discontinue all treatment. 
1Note: Growth factors may be added for low ANC BEFORE a dose reduction is instituted at the treating physician’s discretion. 
 
Table 5: Day 8 Dose Modifications for  Hematologic Toxicity for Gemcitabine and Cisplatin in Arm A 
Hematologic Toxicity 
Dose Adjustment for Gemcitabine 
Dose Adjustment for Cisplatin 
ANC1 >1000/mm3 
AND 
Platelets ≥ 75,000/mm3 
No change in dose 
No change in dose 
ANC1 500-999/mm3 
OR 
Platelets 50,000-74,999/mm3 
Decrease Day 8 dose by 1 dose level for this cycle 
Consider decrease Day 1 & 8 by 1 dose level for 
subsequent cycles 
Decrease Day 8 dose by 1 dose level for this cycle 
Consider decrease in Day 1 & 8 dose by 1 dose level for 
subsequent cycles 
ANC1 <500/mm3 
OR 
Platelets <50,000/mm3 
Hold Day 8 treatment 
Decrease Day 1 & 8 by 1 dose level for subsequent 
cycles 
Hold Day 8 treatment 
Decrease in Day 1 & 8 dose by 1 dose level for 
subsequent cycles 
 
Table 6: Day 1 & 8 Dose Modifications for  Non-Hematologic Toxicity for Gemcitabine and Cisplatin in Arm A 
Non-Hematologic Toxicity 
Dose Adjustment for Gemcitabine 
Dose Adjustment for Cisplatin 
Alopecia, anemia, venous 
thromboembolism 
No modification to doses 


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Grade >3 Nausea and 
vomiting (ongoing after 
maximal anti-emetic therapy) 
Consider decrease or discontinuation of cisplatin 
No change in dose 
Grade >2 Hyperbilirubinemia 
Hold both gemcitabine and cisplatin up to a maximum of 28 days until toxicity resolves to Grade ≤ 1, then resume 
at same doses as before. If not resolved, then discontinue all treatment. Doses will not be modified for cholangitis 
attributable to biliary obstruction/stent occlusion unless this occurs in the setting of >grade 3 neutropenia 
Grade >3 possibly 
attributable to cytotoxic 
treatment 
Hold all protocol treatment and monitor toxicity weekly. If toxicity resolves to ≤ Grade 1 within 4 weeks, treatment 
may be resumed with one dose level reduction gemcitabine and cisplatin. 
>Grade 3 Peripheral 
neuropathy 
No change in dose 
 
Hold cisplatin up to a maximum of 28 days until toxicity 
resolves to Grade ≤ 2, then resume at same dose or 
next lower dose level. 
>Grade 2 Creatinine increase 
(>1.5 x ULN) 
No change in dose 
Hold cisplatin and assess hydration and general medical 
status of the patient. Cisplatin may be resumed if 
creatinine improves to <1.5 x ULN with 1 dose level 
reduction. 
 
Note: Laboratory abnormalities that are not directly attributable to treatment (i.e., hyperglycemia) or not clinically relevant (i.e., lymphopenia) do not 
require modification of dosing. All dose adjustments for toxicity of gemcitabine and/or cisplatin will be described in the clinical record. 


Protocol UMCC 2017.026 
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5.3 
Management Algorithms for Immuno-Oncology Agents 
Nivolumab and ipilimumab are associated with immune related adverse events 
secondary to the unrestrained T cell activation. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of 
adverse events: 
 
Gastrointestinal 
Renal 
Pulmonary 
Hepatic 
Endocrinopathies 
Skin 
Neurological 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All 
occurrences of potential DILIs, meeting the defined criteria in Appendix III must be 
reported as SAEs.  
 
Please refer to Appendix III for algorithm details. 
5.4 
Concomitant Medications/Treatments 
The following concomitant medications or treatments are not permitted while the patient 
is currently receiving therapy on the protocol: 
 
Other investigational agents 
 
Immunosuppressive medications, including systemic corticosteroids, excluding 
prophylactic use of steroids per institutional protocol. 
 
Concurrent radiation 
5.5 
Other Modalities or Procedures 
None 
5.6 
Duration of Therapy 
Treatment may continue for a total of 2 years (discontinue gemcitabine/cisplatin in Arm A 
after 8 cycles) or until one of the following criteria apply: 
 
Disease progression as defined in Section 7.0 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient voluntarily withdraws from treatment OR 
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.7 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.6 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.8. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 


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5.8 
Duration of Follow-Up 
After treatment discontinuation, follow-up for survival and initiation of any other anti-
cancer therapies will be documented every 3 months via telephone or office visit 
documentation for up to 2 years from treatment discontinuation or until death, whichever 
comes first, or 3 years after first date of treatment initiation for those that remain on 
treatment. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.  
5.9 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
5.9.1 
Patient withdraws consent (termination of treatment and follow-up);  
5.9.2 
Patient becomes pregnant;  
5.9.3 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.9.4 
Termination of the study by the Sponsor-Investigator, or the FDA; 
5.9.5 
Patient completes protocol treatment and follow-up criteria; 
5.10 Patient Replacement 
All patients who receive at least one dose of study therapy will be considered evaluable.   
 
Patients enrolled in the study will be considered non-evaluable under the following case 
scenarios and replaced by additional patients: 
 
1. Patients who received no investigational therapy. 
 
2. Patients who withdrew consent for study therapy prior to first response evaluation. 
 
3. Patients meeting off study criteria 5.9.2 and 5.9.3.  
 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
6.2 
Time and Events Table/Schedule of Events/Study Calendar 
 
 


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Table 7. Study Calendar 
Procedures 
Screening1
Arm A 
Arm B 
EOT 
Visit8 
Follow-Up 
Q3 months 
+/- 1 week9 
Cycle 1 
Cycle X 
Cycle 1 
Cycle X 
Day 1 
Day 8 
Day 1 
Day 1 
Day 1 
Informed Consent 
X 
 
 
 
 
 
 
 
History, Physical 
Examination 
X 
X 
 
X12 
X 
X13 
X 
 
Weight, BSA 
X 
X 
 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status 
X 
X 
 
X12 
X 
X13 
X 
 
Toxicity Evaluations 
 
X 
X 
X12 
X 
X13 
 
 
Scans with Tumor 
Measurements 
X 
 
 
X5 
 
X5 
 
 
CBC with differential 
X 
X 
X 
X12 
X 
X13 
 
 
CMP2 
X 
 
X 
X12 
X 
X13 
 
 
TSH, free T4, free 
T3, random cortisol, 
lipase 
X 
 
 
X11 
 
X11 
 
 
CA 19-9, CEA 
X 
X 
 
X10 
X 
X10 
X 
 
PT, PTT 
X 
 
 
 
 
 
 
 
Pregnancy Test3 
X 
X 
 
 
 
 
 
 
Concomitant 
Medication Review 
X 
X 
 
X12 
X 
X13 
 
 
ECG 
X 
 
 
 
 
 
 
 
Research Blood4 
 
X 
 
X 
X 
X 
X 
 
Tissue6 
X 
 
 
X 
 
X 
X 
 
Study Drug 
Administration7 
 
X 
X 
X 
X 
X 
 
 
Survival Follow-up 
 
 
 
 
 
 
 
X 
 
1. All screening procedures to be completed within 2 weeks of registration, except imaging which should be ≤ 4 weeks. 
2. Comprehensive metabolic panel includes BUN/creatinine, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, 
ALT, total bilirubin and total protein. 
3. Required for females of childbearing potential. Serum or urine pregnancy test per site investigator discretion. 


Protocol UMCC 2017.026 
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4. Specimens will be collected prior to administration of initial dose, prior to Cycle 4 Day 1 drug administration, and at time of EOT 
(drawn only once per time point). Refer to the lab manual for sample collection and processing details. 
5. MRI or CT (abdomen/pelvis) with contrast along with CT chest with/without contrast will be assessed every 8 + 1 weeks. Imaging 
assessment of scans at the site should be completed by either a radiologist or an imaging core, and not by the oncologist nor via 
abstraction of data from the subjective/clinical radiology report. 
6. Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery. Procurement of tissue is mandatory 
for enrollment however, all biopsies are optional. If tissue from initial biopsy is not available, a repeat biopsy is NOT required and patient 
will be eligible for enrollment. Cycle X Day 1 biopsies will only be collected for patients enrolled at the University of Michigan, and should 
be completed after at least 4 cycles of treatment and prior to the 9th cycle of treatment. Refer to the lab manual for sample collection 
and processing details.  
7. See Section 5.1 for details. Study drug administration with associated labs will have a window of + 3 days. 
8. End of treatment (EOT) visit should be completed within 30 days of last treatment. And if possible, biopsy should be collected prior to 
start of subsequent therapy. 
9. Patients will be followed every 3 months via telephone or office visit documentation for up to 2 years from treatment discontinuation or 
until death, whichever comes first, or 3 years after first date of treatment initiation for those that remain on treatment. 
10. Check CA 19-9 and CEA every 6 +/- 1 weeks prior to infusion. May be delayed if infusion is not scheduled within the window. 
11. Check TSH, free T3, free T4, and lipase every 6 +/ - 1 weeks prior to infusion. May be delayed if infusion is not scheduled within the 
window. Random cortisol is required only at baseline. 
12. Required every CXD1 for cycles 1 through 8, and every even cycle thereafter (e.g. cycles 10, 12, 14, etc.). 
13. Required every odd cycle (e.g. cycles 3, 5, 7, etc.).   


Protocol UMCC 2017.026 
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7.0 
MEASUREMENT OF EFFECT 
7.1 
Antitumor Effect- Solid Tumors 
Immunotherapy drugs such as nivolumab and ipilimumab can initially cause inflammation 
in the early stages of treatment. Immune-related RECIST (irRECIST) utilizes RECISTv1.1 
but considers an inflammatory response (or “pseudo-progression”) as normal. The main 
difference between RECISTv1.1 and irRECIST is that patients can stay on trial after the 
first progressive disease (PD) assessment (as per RECISTv1.1) if using immune-related 
RECIST criteria. This PD per RECISTv1.1 is then re-labeled as immune related stable 
disease (irSD) per irRECIST and requires addition of unidimensional measurements of all 
new lesions (that meet the definition of target lesion) to be added to the sum of longest 
diameters (SLD) calculation for response assessment. Importantly, immune-related 
progression (irPD) must be confirmed by a follow-up scan at least 4 weeks (within 4-8 
weeks) following the initial PD/irSD assessment in order to take the patient off the trial.  
 
Subjects that are deemed to have clinical progression and unstable should not be 
continued on therapy after PD (per RECISTv1.1) and are therefore not required to have 
repeat tumor imaging for confirmation as per irPD definition. It is at the discretion of the 
site investigator whether to continue a subject on study treatment until repeat imaging is 
obtained. This clinical judgment decision by the site investigator should be based on the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. 
 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for primary endpoint, PFS at 6 months.  All patients that receive at 
least one dose of study therapy will be considered evaluable.  Patients enrolled 
and/or randomized to therapy but that never receive study therapy will be 
replaced. 
 
Evaluable for objective response. All enrolled patients who received at least 1 
cycle(s) of therapy, and had their disease re-evaluated will be considered 
evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
 
10 mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
 
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable)          
 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
All tumor measurements must be recorded in millimeters (or decimal fractions of   
centimeters). 
 


Protocol UMCC 2017.026 
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Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm 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. 
 
Note: Tumor lesions that are situated in a previously irradiated area will only be 
considered measurable, if they have had subsequent progression by at least 5 
mm.  
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm using CT scan), are considered non-
measurable disease. Bone lesions without measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed 
by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their 
size (non-nodal lesions with the longest diameter), be representative of all 
involved organ(s), but in addition should be those that lend themselves to 
reproducible repeated measurements. If a non-nodal lesion is either not present 
or is initially measured with longest diameter <10mm as a non-target then grows 
to >10mm after baseline, this lesion then becomes a new target lesion as per 
irRECIST criteria. The non-nodal longest diameter is then added to the sum of 
diameters, and patient response is calculated with the new lesion.  
 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor. Pathological nodes 
that are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis of 
these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20 mm x 30 mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the nodal 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
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 
of diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum of diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. If a non-target lymph node grows to 
>15mm after baseline, this node then becomes a new target lesion as per 
irRECIST. The nodal short axis is then added to the sum of diameters, and 
patient response is calculated with the new lesion.  
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required, and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 


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(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start date and never more than 4 weeks before the 
beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
subsequent follow-up studies. Imaging-based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  
 


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7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Prior to the first PD assessment, patients will be evaluated according the 
following RECISTv1.1 response: 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions (with a minimum absolute increase of 5 mm), taking as 
reference the smallest sum LD recorded since the treatment started, or 
the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking 
as reference the baseline sum LD) nor sufficient increase to qualify for 
PD (taking as reference the smallest sum LD since the treatment 
started). 
 
After the first PD assessment per RECISTv1.1 (=irSD per irRECIST), 
patients will be evaluated for irPD at least 4 weeks apart according to the 
following definition: 
 
Immune-related Progressive Disease (irPD): At least a 20% increase in 
the sum of the LD of target lesions (with a minimum absolute increase of 
5 mm), taking as reference the smallest sum LD recorded since the 
treatment started, or appearance of new lesions since the last 
evaluation. 
7.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All 
lymph nodes should be non-pathological in size (<10 mm short axis) 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
 
Although a clear progression on non-target lesions in absence of stable 
target lesions is exceptional, the opinion of the treating physician should 
prevail in such circumstances.  
7.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 
 
 
 
Evaluation as per combined RECISTv1.1/irRECIST 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
per 
RECISTv1.1
Overall 
Response 
per 
irRECIST 
Confirmed Response 
for this Category 
Requires: 
CR 
CR 
No 
CR 
NA 
>4 wks. confirmation 
CR 
CR 
Non-CR/PD 
No 
PR 
NA 
>4 wks. confirmation 
PR 
CR 
Non-CR/PD 
No 
SD 
CR 
Non-CR/PD 
No 
SD 
NA 
Documented at least 
once >4 wks. from 
baseline 
PD 
Any 
Any 
PD 
irSD 
>4 wks. confirmation 
Any 
PD* 
Any 
Any 
Any 
Yes 
PD 
Any 
Any 
NA 
irPD 
No further confirmation 
required 
Any 
PD* 
Any 
Any 
Any 
Yes 
* 
Only in exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
         NA=not applicable 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
 
7.1.4.4 Treatment Beyond Progression 
Accumulating evidence indicates a minority of subjects treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD. 
 
Subjects treated on either Arm A or B will be permitted to continue study 
treatment beyond initial RECISTv1.1 defined PD, assessed by the 
investigator, as long as they meet the following criteria: 
 
 
Investigator determined clinical benefit 
 
Tolerance of study drug 
 
Stable performance status 
 
Treatment beyond progression will not delay an imminent 
intervention to prevent serious complications of disease 
progression (e.g., CNS metastases) 
 
A radiographic assessment/ scan should be performed within 4-8 weeks 
of initial investigator-assessed progression to determine whether there 
has been a decrease in the tumor size or continued PD (termed irPD). 
The assessment of clinical benefit should be balanced by clinical 
judgment as to whether the subject is clinically deteriorating and unlikely 
to receive any benefit from continued treatment. 
 


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If the investigator feels that the subject continues to achieve clinical 
benefit by continuing treatment, the subject should remain on the trial 
and continue to receive monitoring according to the Study Calendar (see 
Table 7). 
 
Immune-related Progressive Disease (irPD): For the subjects who 
continue study therapy beyond progression, further progression is 
defined as an additional 10% increase in tumor burden with a minimum 5 
mm absolute increase from time of initial PD, unequivocal worsening of 
NT lesions, or appearance of new lesions since the last evaluation. This 
includes an increase in the sum of diameters of all target lesions and/ or 
the diameters of new measurable lesions compared to the time of initial 
PD. Study treatment should be discontinued permanently upon 
documentation of further progression (i.e. irPD). 
 
 
7.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
7.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
7.2 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.0.3 for reporting of non-hematologic 
adverse events (http://ctep.cancer.gov/reporting/ctc.html).  
 
 
 
8.0 
ADVERSE EVENTS 
 
8.1 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of the initial study treatment administration through 100 days after the last dose 
of study treatment. Any serious adverse event that occurs more than 100 days after the 
last study treatment and is considered related to the study treatment or intervention must 
also be reported. Serious Adverse Events (SAEs) will continue to be followed until: 


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 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration through 100 days following the 
last dose of the study treatment must be recorded as an adverse event in the patient’s 
source documents and on the CRF regardless of frequency, severity (grade) or assessed 
relationship to the study treatment or intervention. However, with regards to laboratory 
and vital sign abnormalities, only those which require protocol treatment to be modified or 
treatment to be rendered should be reported as AEs or SAEs. 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event. However, anticipated fluctuations of pre-existing 
conditions, including the disease under study, that don’t represent a clinically significant 
exacerbation or worsening, need not be reported as AEs.  
8.2 
Definitions 
8.2.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
 
 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it 
meets the definition of an adverse event unless it is a pre-existing (prior 
to protocol treatment) condition. 
8.2.2 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator 
or sponsor-investigator, it results in any of the following outcomes: 
  
 
Death. Note, if death results from (progression of) the disease, the 
disease should be reported as event (SAE) itself. 
 
A life-threatening adverse event. An adverse even is considered ‘life-
threatening’ if, in the view of either the investigator [or sponsor], its 
occurrence places the patient or subject at immediate risk of death. It 


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does not include an adverse event that, had it occurred in a more severe 
form, might have caused death.  
 
Inpatient hospitalization or prolongation of existing hospitalization for > 
24 hours. 
 
A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 
A congenital anomaly/birth defect. 
 
An important medical event. Any event that may not result in death, be 
life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize 
the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition of “Serious Adverse Event”. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse.  
 
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
8.2.3 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event. All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs. 
Potential drug induced liver injury is defined as:  
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to 
be hepatotoxic. 
 
8.2.4 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  


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 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug 
under study. 
8.2.5 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, or in the protocol.  
8.3 
Adverse Event Characteristics 
8.3.1 
CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.3. A copy of the CTCAE version 4.0.3 can be 
down loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.3.2 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
RELATED 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
UNRELATED 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study 
treatment/intervention. 
8.4 
Serious Adverse Event Reporting Guidelines  
8.4.1 
Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless 
of causality to study drug, will be reported to the Principal Investigator and also to 
the Coordinating Center.  All SAEs and UPs must be reported to the Coordinating 
Center within 24 hours of first awareness of the event.  Events should be reported 
using the Coordinating Center’s SAE form as available in the study database.  A 
copy of the SAE form as available in the study database should be sent to the 
Coordinating Center via fax at 
 or via email to 
within 24 hours of the site’s knowledge of the event.  
 
Follow-up information must also be reported within 24 hours of receipt of the 
information by the investigator. 
 
All SAEs and UPs will be reported to the IRB per current institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to 
the participating sites within 5 days of review of the information by the Coordinating 
Center’s Principal Investigator (or designee in the event of extended absence) only 
in the case that the event(s) is believed to be related (i.e., possibly, probably, or 
definitely) to the study drug. The Coordinating Center will be responsible for 
reporting of events to the FDA and supporters, as appropriate (outlined below). 


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8.4.2 
Reporting procedures to BMS 
All Serious Adverse Events (SAEs) occurring from the initial study treatment 
administration through 100 days following the last dose of the study treatment will 
be reported by the Coordinating Center to BMS Worldwide safety.  Any SAEs 
occurring after 100 days following the last dose of the study treatment that are 
believed to be related to study drug will also be reported to BMS Worldwide 
safety.  
The Coordinating Center will send the initial completed SAE Form within 24 
hours of receipt via email to BMS Worldwide Safety 
).   
If only limited information is initially available or an ongoing SAE changes in its 
intensity or relationship to the study drug, or if new information becomes 
available, a follow-up report will be generated and sent to BMS Worldwide Safety 
within 24 hours of receipt.   
8.4.3 
Reporting procedures to FDA 
In this trial, serious, unexpected adverse events believed to be definitely, 
probably or possibly related to the study treatment will be reported to the Food 
and Drug Administration via the MedWatch 3500A Form. The Michigan IND/IDE 
Assistance Program (MIAP) (University of Michigan) will assist the IND Sponsor 
in reporting SAEs to the FDA that meet the reporting requirements in 21 CFR 
312.32.  This reporting could include the initial report and follow-up reports when 
appropriate for the event.  
8.5 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
8.6 
Reporting of Pregnancy 
Pregnancies that occur during study participation or within 5 months of last study dose 
should be reported to the Coordinating Center via e-mail at CTSU-Oncology-
Multisite@med.umich.edu immediately upon site’s knowledge of the event.  
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 


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If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 14 calendar days 
of the study team becoming aware of the problem. 
8.8 
Safety Report Reconciliation  
The Sponsor will reconcile the clinical database SAE reports transmitted to BMS Global 
Pharmacovigilance 
.  Frequency of reconciliation should 
be every 3 months and prior to the database lock or final data summary.  BMS GPV&E 
will email, upon request from the Investigator, the GPV&E reconciliation report.  Requests 
for reconciliation should be sent to 
  The data elements 
listed on the GPV&E reconciliation report will be used for identification purposes.  If the 
Investigator determines a report was not transmitted to BMS GPV&E, the report should 
be sent immediately to BMS.   
8.9 
Stopping Rules  
The DSMC comprised of the principal investigator, co-investigators at University of 
Michigan, study statistician, and multi-site coordinator will be responsible for the 
continuous monitoring of the study for treatment tolerability and efficacy.  During the 
monthly meetings current study data will be reviewed and the decision to continue, hold, 
or stop accrual to either treatment arm of this study will be formally considered. There are 
no formal stopping rules for this study. 
 
 
9.0 
DRUG INFORMATION 
9.1 
Gemcitabine 
9.1.1 
Other Names 
 
 
Gemzar 
9.1.2 
Classification 
Gemcitabine (difluorodeoxycytidine) is a pyrimidine antimetabolite, which is an 
analogue of deoxycytidine. It was initially synthesized as a potential antiviral drug 
but selected for anticancer development because of its activity in in-vivo and in 
vitro tumors. Gemcitabine is approved for the treatment of patients with BTC and 
will be obtained commercially. 
9.1.3 
Mechanism of Action 
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of 
cells through the G1/S-phase boundary. Gemcitabine is metabolized by 
nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) 
nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an 
enzyme responsible for catalyzing the reactions that generate deoxynucleoside 
triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide 
concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP 
for incorporation into DNA. The reduction in the intracellular concentration of 
dCTP by the action of the diphosphate enhances the incorporation of 
gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine 
nucleotide is incorporated into DNA, only one additional nucleotide is added to 
the growing DNA strands, which eventually results in the initiation of apoptotic 
cell death. 


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9.1.4 
Pharmacokinetics 
1. Distribution: Gemcitabine plasma protein binding is negligible. The volume of 
distribution is increased with the infusion length. In a pharmacokinetics study 
of patients with various solid tumors, the volume of distribution of 
gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long 
infusions (70 to 285 minutes), the volume of distribution rose to 370 L/ m2. 
 
2. Metabolism: Gemcitabine is metabolized intracellularly to form active 
gemcitabine di- and tri-phosphates. The gemcitabine di- and triphosphates 
do not appear to circulate in plasma in measurable amounts. Gemcitabine is 
metabolized by the liver to form the inactive uracil derivative, 2'-deoxy-2',2'-
difluorouridine (dFdU). The inactive metabolite does not appear to 
accumulate with weekly dosing; however, it is excreted by the kidneys and 
may accumulate in patients with decreased renal function. 
 
3. Elimination: Following a single 1,000 mg/m2 /30 min [14C]-gemcitabine 
infusion, 92% to 98% of the dose was recovered within 1 week after 
gemcitabine administration. Urinary excretion of the parent drug and the 
dFdU metabolite accounted for 99% of the excreted dose, and less than 1% 
of the dose was excreted in feces. The renal clearance of gemcitabine is less 
than 10%; therefore, the parent drug appears to be almost completely 
metabolized to the inactive dFdU. 
 
Clearance of gemcitabine is affected by age and gender and is lower in 
women and the elderly. Differences in either clearance or volume of 
distribution based on patient characteristics or the duration of infusion result 
in changes in half-life and plasma concentrations. Studies showed that 
gemcitabine half-life for short infusions ranged from 42 to 94 minutes, for 
long infusions it varied from 245 to 638 minutes, depending on age and 
gender, reflecting a greatly increased volume of distribution with longer 
infusions. The terminal phase half-life for the active metabolite, gemcitabine 
triphosphate, in mononuclear cells ranges from 1.7-19.4 hours. 
9.1.5 
Storage, Preparation and Stability 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
9.1.6 
Dosing and Administration 
See Section 5.1 
9.1.7 
Availability 
Gemcitabine is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert for the most comprehensive and up to date 
information. 
9.1.8 
Handling and Disposal 
Handling and disposal of gemcitabine should be per institutional guidelines for 
the handling and disposal of biologic and cytotoxic agents. Recommended safety 
measures for preparation and handling of gemcitabine include laboratory coats 
and gloves. 
9.1.9 
Adverse Effects 
1. Side Effects: Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. Adverse 


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effects reported in >20% to 100% of subjects treated with gemcitabine 
include: flu-like symptoms, nausea, vomiting, rash, alopecia, infection, 
myelosuppression including anemia, leukopenia, neutropenia, and 
thrombocytopenia, muscle weakness, hematuria, paresthesia, sensory 
neuropathy, fatigue, somnolence, hearing loss, peripheral edema. Adverse 
effects reported in 4% to 20% of subjects include: diarrhea, constipation, 
stomatitis, dyspnea, capillary leak syndrome, posterior reversible 
encephalopathy syndrome (PRES). Adverse effects reported in 3% or less of 
subjects include: arrhythmias, supraventricular arrhythmias, congestive heart 
failure, myocardial infarction, desquamation and bullous skin eruptions, 
gangrene, cerebrovascular accident, hepatic failure, adult respiratory distress 
syndrome (ARDS), anaphylaxis, renal failure, pulmonary fibrosis, pulmonary 
edema, and, Interstitial, pneumonitis. Grade 3 and 4 adverse events in 
combination with cisplatin for BTC from the phase trial are as listed in Table 
2 of the publication (Valle, Wasan et al. 2010).  
 
2. Pregnancy and Lactation: Category D. Gemcitabine may cause fetal harm 
when administered to a pregnant woman. This agent has produced 
teratogenic effects in mice and rabbits when administered at a dose of < 2 
mg/m2. Adverse effects included decreased fetal viability, weight and 
morphologic defects. There is no data on gemcitabine administration during 
human pregnancy, and it is not currently known if metabolites are excreted in 
human milk. However, many drugs are excreted in human milk, and there is 
a potential for adverse effects in nursing infants. Therefore, the use of 
gemcitabine should be avoided in pregnant or nursing women because of the 
potential hazard to the fetus or infant. 
3. Drug Interactions: Per gemcitabine package insert, no formal drug interaction 
studies have been performed to date. When gemcitabine was administered 
with cisplatin there was minimal or no effect on the pharmacokinetics of the 
studied drugs. 
9.2 
Cisplatin 
9.2.1 
Other Names 
CDDP, Platinol, NSC-119875 
9.2.2 
Classification 
Cisplatin is an alkylating agent, which inhibits DNA synthesis by producing cross-
linking of parent DNA strands (cell-cycle phase-nonspecific). Cisplatin is 
approved for the treatment of patients with BTC and will be obtained 
commercially. 
9.2.3 
Mechanism of Action 
 
 
Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a 
central platinum atom surrounded by two chloride atoms and two ammonia 
molecules in the cis position. It is water soluble and acts as a bifunctional 
alkylating agent with cell cycle nonspecific characteristics. The intra-strand cross-
links, in particular with guanine and cytosine, change DNA conformation and 
inhibit DNA synthesis leading to the cytotoxic and anti-tumor effects of cisplatin. 
Although cisplatin seems to act as an alkylating agent, there are data to indicate 
that its mode and sites of action are different from those of nitrogen mustard and 
the standard alkylating agents and that cisplatin does not exhibit cross-resistance 
with other alkylating agents or nitrosoureas. 


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9.2.4 
Pharmacokinetics 
1. Absorption: Following rapid IV injection of cisplatin over up to one hour, peak 
plasma drug and platinum concentrations occur immediately. When cisplatin 
is administered by IV infusion over 6 or 24 hours, plasma concentrations of 
total platinum increase gradually during the infusion and peak immediately 
following the end of the infusion. 
 
2. Distribution: Following intravenous dosing, cisplatin distributes rapidly into 
tissues, with highest concentrations in the liver, prostate and kidney. Plasma 
levels of cisplatin decay in a biphasic mode with an initial half-life of 25 to 49 
minutes, and a secondary phase ranging from 58 to 73 hours. This prolonged 
phase is due to protein binding, which exceeds 90%. Cisplatin penetrates 
poorly into the CNS. 
 
3. Metabolism: Cisplatin is non-enzymatically transformed to one or more 
metabolites that are extensively protein bound and have minimal cytotoxic 
activity. The non-protein bound (unchanged) fraction is cytotoxic. 
 
4. Elimination: Urinary excretion is incomplete. Following bolus injection or 
infusion over a dose range of 40-140 mg/m2 varying in length from 1-24 
hours, from 10 to about 40% of the administered platinum is excreted in the 
urine in 24 hours. Renal clearance of free platinum exceeds the glomerular 
filtration rate, indicating that cisplatin or other platinum containing molecules 
are actively secreted by the kidneys. Renal clearance of free platinum is 
nonlinear and variable, and is dependent on dose, urine flow rate, and 
individual variability in the extent of active secretion and possible tubular 
reabsorption. 
9.2.5 
Storage, Preparation and Stability 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
9.2.6 
Dose and Administration 
 
 
See Section 5.1 
9.2.7 
Availability 
Cisplatin is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
9.2.8 
Handling and Disposal 
Handling and disposal of cisplatin should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents. Recommended safety 
measures for preparation and handling of gemcitabine include laboratory coats 
and gloves. 
9.2.9 
Adverse Effects 
1. Side Effects: Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. Adverse 
effects reported in >20% to 100% of subjects treated with cisplatin include: 
nausea, vomiting, myelosuppression, anemia, leucopenia, thrombocytopenia, 
nephrotoxicity (acute renal failure and chronic renal insufficiency), and 
ototoxicity. Adverse effects reported in 4% to 20% of subjects include: 
alopecia, dysgeusia, diarrhea, hypersensitivity reaction, confusion, vestibular 


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dysfunction, peripheral neuropathy, blurred vision or altered color perception. 
Adverse effects reported in 3% or less of subjects include: secondary 
malignancy and seizure. Other published literature suggests risk of 
thromboembolic events. 
 
2. Pregnancy and Lactation: Category D. Cisplatin can cause fetal harm when 
administered to a pregnant woman. In mice, cisplatin is teratogenic and 
embryotoxic. This drug has been found to be excreted in human milk and 
because of the potential for serious adverse reactions in nursing infants, 
patients receiving cisplatin should not breast feed. 
 
3. Drug Interactions: During cisplatin therapy, plasma levels of anticonvulsant 
agents (valproic acid, phenytoin, and carbamazepine) may become sub-
therapeutic and should be monitored. Concomitant use with 
aminoglycosides, tacrolimus, and amphotericin B increase risk of 
nephrotoxicity. Concomitant use with loop diuretics and aminoglycosides 
increase risk of ototoxicity. Concurrent use with lithium may result in reduced 
lithium plasma concentration. Concurrent use with warfarin may result in 
increased INR. Concurrent use with thioctic acid may result in decreased 
cisplatin effectiveness and should be avoided. 
9.3 
Nivolumab 
9.3.1 
Other Names 
 
 
Opdivo, BMS-936558, MDX-1106, ONO-4538 
9.3.2 
Classification 
 
 
Immunomodulatory; checkpoint inhibitor 
9.3.3 
Mechanism of Action 
 
Nivolumab is a fully human IgG4 programmed death 1 (PD-1) immune 
 
checkpoint inhibitor antibody that selectively blocks the interaction between PD-
 
1, which is expressed on activated T cells, and PD-1 ligand 1 (PD-L1) and 2 (PD-
 
L2), which are expressed on immune cells and tumor cells. 
9.3.4 
Pharmacokinetics 
1. Distribution: Nivolumab has linear pharmacokinetics after single and multiple 
dosing within the range 0.1 mg/kg to 10 mg/kg. The volume distribution (Vd) 
is 8L. 2.  
2. Elimination: Clearance is independent of dose in the range 0.1 mg/kg to 10 
mg/kg. The total body clearance is 9.5 mL/hr, and the elimination half-life of 
is approximately 26.7 days. Body weight normalized dosing showed 
approximately constant trough concentrations over a wide range of body 
weights.  
9.3.5 
Storage, Preparation and Stability 
Nivolumab is supplied a sterile solution (Opdivo Intravenous) which comes in 
vials of 100 mg/10 mL (10 mL). Nivolumab vials must be stored at a temperature 
of 2*C to 8*C and should be protected from light. If stored in a glass front 
refrigerator, vials should be stored in the carton. 
 
 
For details on prepared drug storage and use time of nivolumab under room 
 
temperature/light and refrigeration, please refer to the Investigator Brochure 
 
section for “Recommended Storage and Use Conditions” and/or pharmacy 


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reference sheets. Briefly, withdraw the required volume and transfer into an IV 
 
container. Dilute with either NS or D5W to a final concentration of 1 to 10 mg/mL. 
 
Mix by gentle inversion; do not shake. 
 
Care must be taken to assure sterility of the prepared solution as the product 
does not contain any anti-microbial preservative or bacteriostatic agent. No 
incompatibilities between nivolumab and polyvinyl chloride (PVC), non-PVC/non-
DEHP (di(2-ethylhexyl)phthalate) IV components, or glass bottles have been 
observed. 
 
The administration of undiluted and diluted solutions of nivolumab must be 
completed within 24 hours of preparation. If not used immediately, the infusion 
solution may be stored up to 24 hours in a refrigerator at 2°- 8°C (36°-46°F) and 
a maximum of 4 hours of the total 24 hours can be at room temperature (20°-
25°C, 68°-77°F) and room light. The maximum 4-hour period under room 
temperature and room light conditions includes the product administration period.  
9.3.6 
Dose and Administration 
See Section 5.1 
Nivolumab is to be administered as a 30 (± 5 minute) intravenous infusion, using 
a pump with a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. It is 
not to be administered as an IV push or bolus injection. At the end of the infusion, 
flush the line with a sufficient quantity of 0.9% sodium chloride Injection or 5% 
Dextrose Injection. 
9.3.7 
Availability 
Bristol Myers Squibb (BMS) will provide the study drug. 
9.3.8 
Handling and Disposal 
Handling and disposal of nivolumab should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents. Recommended safety 
measures for preparation and handling of nivolumab include laboratory coats and 
gloves. 
9.3.9 
Adverse Effects 
1. Adverse Effects: The Comprehensive Adverse Events and Potential Risks list 
(CAEPR) provides a single list of reported and/or potential adverse events 
(AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applicatio 
ns/docs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 2069 patients. Below is the CAEPR for BMS- 936558 (Nivolumab, 
MDX-1106). 
 
Please refer to the Investigator Brochure Addendum for the 
Comprehensive Adverse Events and Potential Risks (CAEPR) List. 
 
Adverse events reported on BMS-936558 (Nivolumab, MDX- 1106) trials, but 
for which there is insufficient evidence to suggest that there was a 


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reasonable possibility that BMS- 936558 (Nivolumab, MDX-1106) caused the 
adverse event:  
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; 
Heart failure; Pericarditis; Ventricular arrhythmia  
 
EAR AND LABYRINTH DISORDERS - Vestibular disorder  
 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune 
thyroiditis); Endocrine disorders - Other (hypopituitarism)  
 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder  
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; 
Enterocolitis; Flatulence; Gastrointestinal disorders - Other (mouth sores); 
Mucositis oral; Vomiting  
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Chills; Edema limbs; Malaise; Pain  
 
HEPATOBILIARY DISORDERS - Bile duct stenosis; Hepatobiliary disorders 
- Other (autoimmune hepatitis) IMMUNE SYSTEM DISORDERS - 
Anaphylaxis; Immune system disorders - Other (limbic encephalitis)  
 
INFECTIONS AND INFESTATIONS - Bronchial infection; Encephalitis 
infection; Lung infection; Sepsis; Upper respiratory infection  
 
INVESTIGATIONS - Alkaline phosphatase increased; CPK increased; GGT 
increased; Investigations - Other (blood LDH increased); Investigations - 
Other (CRP increased); Investigations - Other (eosinophil count increased); 
Investigations - Other (protein total decreased); Investigations - Other 
(thyroxine free increased); Investigations - Other (triiodothyronine free 
decreased); Investigations - Other (WBC count increased); Lymphocyte 
count increased; Weight loss; White blood cell decreased  
 
METABOLISM AND NUTRITION DISORDERS - Dehydration;  
Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hyponatremia; 
Hypophosphatemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; 
Back pain; Musculoskeletal and connective tissue disorder - Other 
(musculoskeletal pain); Musculoskeletal and connective tissue disorder - 
Other (polymyalgia rheumatica); Myalgia; Pain in extremity  
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts 
and polyps) - Other (histiocytic necrotizing lymphadenitis)  
 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial 
hemorrhage; Nervous system disorders - Other (autoimmune neuropathy); 
Stroke  
 
PSYCHIATRIC DISORDERS - Insomnia  
 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary 
disorders - Other (nephritis); Renal and urinary disorders - Other 
(tubulointerstitial nephritis)  
 


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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchospasm; Cough; Dyspnea; Hypoxia; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (interstitial lung disease); 
Respiratory, thoracic and mediastinal disorders - Other (lung infiltration); 
Wheezing  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Pain of skin; Periorbital edema; Photosensitivity; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (rosacea); Toxic 
epidermal necrolysis  
 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
Note: BMS-936558 (Nivolumab, MDX-1106) in combination with other agents 
could cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never 
previously associated with either agent. Adverse events occurring in < 1%, 
post marketing, and/or case reports: Hemophagocyticlymphohistiocytosis, 
rhabdomyolysis and polymyositis have been reported in patients received 
more than one dose of combination therapy (nivolumab 3 mg/kg and 
ipilimumab 1 mg/kg every 3 weeks) for the treatment of metastatic gastric 
adenocarcinoma and advanced bladder cancer, respectively. 
 
2. Pregnancy and Lactation: Pregnancy: Adverse events were observed in 
animal reproduction studies. Nivolumab may be expected to cross the 
placenta; effects to the fetus may be greater in the second and third 
trimesters. Based on its mechanism of action, nivolumab is expected to 
cause fetal harm if used during pregnancy. Women of reproductive potential 
should use highly-effective contraception during therapy and for at least 5 
months after treatment has been discontinued. Men receiving nivolumab and 
who are sexually active with women of child bearing potential should adhere 
to contraception for a period of 7 months after the last dose of nivolumab. 
 
Lactation: It is not known if nivolumab is excreted into breast milk. Due to the 
potential for serious adverse reactions in the nursing infant, the manufacturer 
recommends women to discontinue breastfeeding during treatment with 
nivolumab. 
 
3. Drug Interactions: Nivolumab is not expected to have any effect on 
cytochrome P450 or other drug metabolizing enzymes in terms of inhibition 
or induction, and is, therefore, not expected to induce these types of PK-
based drug interactions. No incompatibilities between nivolumab injection 
and polyvinyl chloride (PVC), non-PVC/non-DEHP (di(2-ethylhexyl)phthalate) 
IV components, or glass bottles have been observed. 
9.4 
Ipilimumab 
9.4.1 
Other Names 
(BMS-734016, MDX-010, YERVOY®) (NSC 732442) (IND-119672) 
9.4.2 
Classification  
Immunomodulatory; checkpoint inhibitor 
9.4.3 
Mechanism of Action 
Cytotoxic T-lymphocyte antigen-4 CTLA-4 is a negative regulator of T-cell 
activity. Ipilimumab is a full human monoclonal immunoglobin (lg) antibody that 
binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, 


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CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation 
and proliferation, including the activation and proliferation of tumor infiltrating T-
effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell 
function, which may contribute to a general increase in T cell responsiveness, 
including the anti-tumor immune response. 
9.4.4 
Pharmacokinetics 
1. Absorption: No formal pharmacokinetic drug interaction studies have been 
conducted with ipilimumab. Ipilimumab is not expected to have 
pharmacokinetic drug-drug interactions, since it is not metabolized by 
CYP450 or other drug metabolizing enzymes. 
2. Distribution: Ipilimumab is confined mainly to the extracellular fluid. Peak 
concentration (Cmax), trough concentration (Cmin), and area under the 
plasma concentration versus time curve (AUC) of ipilimumab increased dose 
proportionally within the dose range examined ipilimumab is confined mainly 
to the extracellular fluid. Peak concentration (Cmax), trough concentration 
(Cmin), and area under the plasma concentration versus time curve (AUC) of 
ipilimumab increased dose proportionally within the dose range examined. 
Based on population pharmacokinetic analysis, the mean volume of 
distribution (% coefficient of variation) at steady state was 7.47 liters (10%). 
3. Metabolism: Not applicable. Monoclonal antibodies are usually degraded into 
amino acids and small peptides, independently from CYP450 or other drug-
metabolizing enzymes. 
4. Elimination: Clearance increased with body weight, but no dose adjustment 
is required with dosing on a mg/kg basis. Upon repeated dosing every 3 
weeks, the clearance (CL) of ipilimumab was found to be time-invariant, and 
systemic accumulation was 1.5-fold or less. The mean value (% coefficient of 
variation) generated through population pharmacokinetic analysis for the 
terminal half-life (t1/2) was 15.4 days (34%) and for CL was 16.8 mL/h 
(38%).  
9.4.5 
Storage, Preparation and Stability 
Ipilimumab injection is supplied as 200 mg/40 mL (5 mg/mL). It is formulated as a 
clear to slightly opalescent, colorless to pale yellow, sterile, non-pyrogenic, 
single-use, isotonic aqueous solution that may contain particles. Each vial is a 
Type I flint glass vial with gray butyl stoppers and sealed with aluminum seals. 
 
1. Store intact vials of ipilimumab refrigerated at (2 to 8 °C), protected from 
light. Do not freeze. 
2. Ipilimumab is given undiluted or further diluted in 0.9% NaCl Injection, USP 
or 5% Dextrose Injection, USP in concentrations between 1 mg/mL and 4 
mg/mL. Ipilimumab is stable in a polyvinyl chloride(PVC), non-PVC/non 
DEHP (di-(2-ethylhexyl) phthalate) IV bag or glass container up to 24 hours 
refrigerated at (2 to 8 °C) or at room temperature/room light. 
3. The product may be infused using a pump at the protocol-specific dose(s) 
and rate(s) through a PVC IV solution infusion set with an in-line, sterile, 
nonpyrogenic, low-proteinbinding filter (pore size of 0.2 micrometer to 1.2 
micrometer). 
4. Do not administer ipilimumab as an IV push or bolus injection. 
5. Stability of prepared IV ipilimumab solution is stable up to 24 hours 
refrigerated at (2 to 8 °C) or at room temperature/ room light.  
6. Partially used vials or empty vials of ipilimumab injection should be discarded 
at the site according to appropriate drug disposal procedures. 


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9.4.6 
Dose and Administration 
 
 
See Section 5.1 
Ipilimumab injection is to be administered as an infusion with an in-line, sterile, 
nonpyrogenic, low-protein-binding filter (pore size of 0.2 micrometer to 1.2 
micrometer). Do not administer as IV push or bolus injection. 
9.4.7 
Availability 
Bristol Myers Squibb (BMS) will provide the study drug. 
9.4.8 
Handling and Disposal 
Handling and disposal of ipilimumab should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents. Recommended safety 
measures for preparation and handling of ipilimumab include laboratory coats 
and gloves. 
9.4.9 
Adverse Effects 
1. Side Effects: The Comprehensive Adverse Events and Potential Risks list 
(CAEPR) provides a single list of reported and/or potential adverse events 
(AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applicatio 
ns/docs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 2678 patients. Below is the CAEPR for Ipilimumab (MDX-010). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER. If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Please refer to the Investigator Brochure Addendum for the 
Comprehensive Adverse Events and Potential Risks (CAEPR) List. 
 
2. Pregnancy and Lactation: There are no adequate and well controlled studies 
of Ipilimumab in pregnant women. Use of Ipilimumab during pregnancy only if 
the potential benefit justifies the potential risk to the fetus. Human IgG1 is 
known to cross the placental barrier and ipilimumab is an IgG1; therefore, 
ipilimumab has the potential to be transmitted from the mother to the 
developing fetus. It is not known whether ipilimumab is secreted in human 
milk. Because many drugs are secreted in human milk and because of the 
potential for serious adverse reactions in nursing infants from ipilimumab, a 
decision should be made whether to discontinue nursing or to discontinue 
ipilimumab, taking into account the importance of ipilimumab to the mother. 
 
3. Drug Interactions: No formal pharmacokinetic drug interaction studies have 
been conducted with ipilimumab. Ipilimumab is not expected to have 
pharmacokinetic drug-drug interactions, since it is not metabolized by 
CYP450 or other drug metabolizing enzymes 
 
 


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10.0 
CORRELATIVES/TRANSLATIONAL STUDIES 
We will study the BTC tumor microenvironment through the use of pre-treatment tissue collection 
(at all sites) as well as on-treatment (for patients at University of Michigan) and post-treatment 
(optional for patients enrolled at all sites) tumor biopsies. Identification of important biologic 
subsets of BTC patients that may have clinical efficacy from nivolumab and ipilimumab will be the 
overarching goal of this translational science. Tumor from core biopsies will be examined 
histologically by immunohistochemistry (IHC), immunofluorescence (IF), and RNA analysis. Post-
treatment biopsy tissue will be separated into sections for paraffin embedding, fresh frozen in 
OTC, and fresh frozen in RNAlater. Whole genomic DNA will be evaluated for mutational 
analysis). Biologic readouts for PD-1 and CTLA4 response biomarkers will be assessed along 
with specific markers of tumor infiltrating leukocytes (TILs). TILs and their subsets will be 
assessed using markers by IHC (e.g. CD4, CD8, FoxP3 (Treg), CD14 or CD68 (TAMs), CD11c 
(DCs)).  Response biomarkers will be determined by IHC or IF (e.g. B7-H1 (PD-1L), CD80, CD86, 
B7-H4, B7-HDC (PD-L2), CTLA4, CD28, LAG3, Tim-3, CD40, OX40) (Wu, Kryczek et al. 2009, 
Lou, Diao et al. 2016).  Cytokine signaling representative of Th1, Th2, and other immune pathway 
signature gene expression will be determined by transcriptomic assessment (RNAseq) and 
analyzed using Gene Set Enrichment Analysis software (GSEA) (Subramanian, Tamayo et al. 
2005, Eichler 2012) at the University of Michigan.  Furthermore, we will study peripheral blood for 
the presence of peripheral blood mononuclear cell subsets following Ficoll separation and 
multiplex FACS analysis for T cell subset markers and co-stimulatory/inhibitory markers (Wu, 
Kryczek et al. 2009). Biologic markers and RNA expression will be examined in the context of 
patient efficacy.  
10.1 Tissue Collection 
Tissue will be collected at the time points specified in section 6.2 Study Calendar. A 
FFPE block or 10 unstained and 1 H&E slide should be submitted as per the lab manual. 
Please refer to the lab manual for additional sample collection and processing details.  
 
A CLIA certified targeted gene panel will be run on the post-treatment tissue without 
additional cost to the patient, and the report will be released to the treating investigator to 
inform future therapy options. 
10.2 Blood Collection 
Blood samples will be collected at the time points specified in section 6.2 Study Calendar. 
Please refer to the lab manual for sample collection and processing details.  
10.3 Centralized Imaging 
All baseline and response imaging studies will be de-identified and shipped to the 
University of Michigan for banking and exploratory endpoint assessment. Please see the 
lab manual for data format and shipping details. 
10.4 Specimen Banking 
Patient samples collected for this study will be retained at University of Michigan. 
Specimens will be stored indefinitely or until they are used up. If future use is denied or 
withdrawn by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are 
subject to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories. 
 
11.0 
STATISTICAL CONSIDERATIONS 


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11.1 Study Design/Study Endpoints 
This protocol will randomize patients with advanced unresectable BTC equally (1:1) to 
one of two novel treatment regimens. The randomization will be stratified for locally 
advanced versus metastatic cancers. The primary endpoint is PFS at 6 months following 
the initiation of treatment. Comparisons will be limited between each novel treatment 
regimen and the historical control value and not directly between treatments. Secondary 
endpoints include the calculation of the overall response rate, median PFS, overall 
survival, and the incidence of adverse events for each treatment regimen separately.  
11.2 Sample Size and Accrual 
The trial is sized to compare each randomized treatment arm to a historical value for PFS 
in this patient population receiving standard treatment. The PFS proportion in this patient 
population at 6 months is 59% (Valle, Wasan et al. 2010). Using this value as the null 
hypothesis, we hope to see an increase in the proportion of alive, progression-free 
patients to 80% or above in each of the combination arms. Thirty-two patients evaluable 
for the 6-month PFS endpoint are required to test this hypothesis with >80% power and 
at most 5% type I error (1-sided).  A maximum of 64 evaluable patients (per Section 
7.1.1) will be enrolled. 
11.3 Data Analyses Plans 
PFS will be estimated using the product-limit method of Kaplan and Meier. Follow-up time 
will be defined as time from date of first study treatment until the date of radiological or 
clinical progression (leading to withdrawal from the study), or death from any cause, 
whichever comes first.  Follow-up time will be censored at the date of last disease 
evaluation.  Estimates for the median and 75th percentiles with 95% confidence intervals 
will be reported.  OS will be similarly estimated and summarized with follow-up time 
calculated from the date of first study treatment until date of death or censoring.  Other 
safety data (e.g., laboratory safety parameters, vital signs, concomitant medications and 
new physical examination findings) will be summarized descriptively by reporting counts 
and percentages, with exact binomial confidence intervals where appropriate. ORR will 
be determined as per the RECISTv1.1 guidelines.  Adverse events will be reported per 
the NCI CTCAE v4.03. There are no formal stopping rules for this study. 
 
 
12.0 
ADMINISTRATIVE PROCEDURES 
12.1 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and be consistent with 
Good Clinical Practice (GCP), as defined by the International Conference on 
Harmonization (ICH), WHO and any local directives. 
 
The protocol, any amendments, and the subject informed consent will receive Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion 
before initiation of the study.  
12.2 Data Management 
All information will be recorded locally and entered into Case Report Forms (CRFs) on 
the web-based electronic data capture (EDC) system of the University of Michigan. 
Online access will be provided to each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits 
and prior to and between visits. Discrepant, unusual and incomplete data will be queried 
by the MSC. The investigator or study coordinator will be responsible for providing 


Protocol UMCC 2017.026 
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resolutions to the data queries, as appropriate. The investigator must ensure that all data 
queries are dealt with promptly.  
 
The data submission schedule is as follows:  
 
At the time of registration   
o 
Subject entry into the EDC 
 
Subject Status 
 
Demographics 
 
During study participation 
o 
All data should be entered online within 10 business days of data acquisition. 
[Information on dose limiting toxicity events must be entered within one 
business day.] Information on Serious Adverse Events must be entered 
within the reporting timeframe specified in Section 8.5 of the protocol.  
  
All study information should be recorded in an appropriate source document (e.g. clinic 
chart). 
12.3 Record Retention 
The Investigators must retain all study records and source documents for the maximum 
period required by applicable regulations and guidelines, or institution procedures, 
whichever is longer. 
 
13.0 
DATA AND SAFETY MONITORING 
The Data and Safety Monitoring Committee (DSMC) of The University of Michigan 
Comprehensive Cancer Center (UMCCC) is the DSMC for this study.  This committee is 
responsible for monitoring the safety and data integrity of the trial. 
 
At each site the study team is required to meet quarterly to discuss matters related to: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
These meetings are to be documented by the site data manager or study coordinator using the 
Protocol Specific Data and Safety Monitoring Report (DSMR), signed by the site principal 
investigator or co-investigator.  Each site is required to submit the completed DSMR to the Multi-
Site Coordinator at the University of Michigan Coordinating Center on a quarterly basis together 
with other pertinent documents. 
 
Similarly, protocol deviations are to be documented using the Notice of Protocol Deviation Form 
and requires the signatures of both the sites data manager or study coordinator and the site 
principal investigator or co-investigator. These reports are to be sent to the University of Michigan 
Coordinating Center within 7 calendar days of awareness of the event and on a quarterly basis 
with the Protocol Specific Data and Safety Monitoring Report. 
 
The Coordinating Center is responsible for collating all the Data and Safety Monitoring Reports 
from all the participating sites, and providing the information to the Data Safety Monitoring 
Committee. 
14.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of 
the trial if the committee identifies a need for a more rigorous evaluation of study-related issues.  


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A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 
15.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by The University of Michigan Comprehensive Cancer Center 
(UMCCC) must be conducted in accordance with the ethical principles that are consistent with 
Good Clinical Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the UMCCC. 
Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted 
by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and his study 
staff should make every effort in attending the site initiation meeting. Study–related questions or 
issues identified during the site initiation meeting will be followed-up by the appropriate UMCCC 
personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents 
at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first ‘Centralized’ 
visit should occur after the first subject enrolled completes [first treatment cycle/course].  The 
study site will send the de-identified source documents to the Coordinating Center for monitoring.  
‘Centralized’ monitoring may be requested by the Coordinating Center if an amendment requires 
changes to the protocol procedures. The site will send in pertinent de-identified source 
documents, as defined by the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first.  The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and samples collected 
 
Proper storage, dispensing and inventory of study medication 
 
Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review.  At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner.  For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 


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Participating site will also undergo a site close-out upon completion, termination or cancellation of 
a study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit. 
 
 


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16.0 
REFERENCES 
1. Antonia, S., J. Lopez-Martin, J. Bendell, Ott PA, Taylor MH, Eder JP, Jäger D, Le DT, De Braud 
FG, Morse M, Ascierto PA, Horn L, Amin A, Pillai RN, Evans TR, Harbison CT, Lin C, Tschaika 
M and C. E (2016). Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) 
for the treatment of recurrent small cell lung cancer (SCLC). 2016 ASCO Annual Meeting, J 
Clin Oncol. 34: abstr 100. 
2. Bang, Y., T. Doi, F. de Braud, S. Piha-Paul, A. Hollebecque, A. Razak, C. Lin, P. Ott, A. He, S. 
Saraf, M. Koshiji, A. Siegel and R. Aggarwal (2015). Safety and Efficacy of Pembrolizumab 
(MK-3475) in Patients With Advanced Biliary Tract Cancer: Interim Results of KEYNOTE-028. 
European Cancer Congress, Vienna, Austria. 
3. Carter, L., L. A. Fouser, J. Jussif, L. Fitz, B. Deng, C. R. Wood, M. Collins, T. Honjo, G. J. 
Freeman and B. M. Carreno (2002). "PD-1:PD-L inhibitory pathway affects both CD4(+) and 
CD8(+) T cells and is overcome by IL-2." Eur J Immunol 32(3): 634-643. 
4. Eichler, G. S. (2012). "Bioinformatics/biostatistics: microarray analysis." Methods Mol Biol 823: 
347-358. 
5. Emens, L. A. and G. Middleton (2015). "The interplay of immunotherapy and chemotherapy: 
harnessing potential synergies." Cancer Immunol Res 3(5): 436-443. 
6. Freeman, G. J., A. J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L. J. Fitz, N. 
Malenkovich, T. Okazaki, M. C. Byrne, H. F. Horton, L. Fouser, L. Carter, V. Ling, M. R. 
Bowman, B. M. Carreno, M. Collins, C. R. Wood and T. Honjo (2000). "Engagement of the PD-
1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of 
lymphocyte activation." J Exp Med 192(7): 1027-1034. 
7. Hammers, H., E. R. Plimack, J. R. Infante, B. I. Rini, D. McDermott, L. Lewis, M. H. Voss, P. 
Sharma, S. K. Pal, A. Razak, C. K. Kollmannsberger, D. Heng, J. Spratlin, B. McHenry, P. 
Gagnier and A. Amin (2016). "Updated results from a phase I study of nivolumab (Nivo) in 
combination with ipilimumab (Ipi) in metastatic renal cell carcinoma (mRCC): The CheckMate 
016 study." Annals of Oncology 27(suppl 6). 
8. Larkin, J., V. Chiarion-Sileni, R. Gonzalez, J. J. Grob, C. L. Cowey, C. D. Lao, D. Schadendorf, 
R. Dummer, M. Smylie, P. Rutkowski, P. F. Ferrucci, A. Hill, J. Wagstaff, M. S. Carlino, J. B. 
Haanen, M. Maio, I. Marquez-Rodas, G. A. McArthur, P. A. Ascierto, G. V. Long, M. K. 
Callahan, M. A. Postow, K. Grossmann, M. Sznol, B. Dreno, L. Bastholt, A. Yang, L. M. Rollin, 
C. Horak, F. S. Hodi and J. D. Wolchok (2015). "Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma." N Engl J Med 373(1): 23-34. 
9. Latchman, Y., C. R. Wood, T. Chernova, D. Chaudhary, M. Borde, I. Chernova, Y. Iwai, A. J. 
Long, J. A. Brown, R. Nunes, E. A. Greenfield, K. Bourque, V. A. Boussiotis, L. L. Carter, B. M. 
Carreno, N. Malenkovich, H. Nishimura, T. Okazaki, T. Honjo, A. H. Sharpe and G. J. Freeman 
(2001). "PD-L2 is a second ligand for PD-1 and inhibits T cell activation." Nat Immunol 2(3): 
261-268. 
10. Lou, Y., L. Diao, E. R. Cuentas, W. L. Denning, L. Chen, Y. H. Fan, L. A. Byers, J. Wang, V. A. 
Papadimitrakopoulou, C. Behrens, J. C. Rodriguez, P. Hwu, Wistuba, II, J. V. Heymach and D. 
L. Gibbons (2016). "Epithelial-Mesenchymal Transition Is Associated with a Distinct Tumor 
Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune 
Checkpoints in Lung Adenocarcinoma." Clin Cancer Res 22(14): 3630-3642. 
11. McDonnell, A. M., W. J. Lesterhuis, A. Khong, A. K. Nowak, R. A. Lake, A. J. Currie and B. W. 
Robinson (2015). "Tumor-infiltrating dendritic cells exhibit defective cross-presentation of 
tumor antigens, but is reversed by chemotherapy." Eur J Immunol 45(1): 49-59. 
12. Nathan, H., T. M. Pawlik, C. L. Wolfgang, M. A. Choti, J. L. Cameron and R. D. Schulick (2007). 
"Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER 
database analysis." J Gastrointest Surg 11(11): 1488-1496; discussion 1496-1487. 
13. Nishimura, H. and T. Honjo (2001). "PD-1: an inhibitory immunoreceptor involved in peripheral 
tolerance." Trends Immunol 22(5): 265-268. 
14. Nowak, A. K., R. A. Lake, A. L. Marzo, B. Scott, W. R. Heath, E. J. Collins, J. A. Frelinger and 
B. W. Robinson (2003). "Induction of tumor cell apoptosis in vivo increases tumor antigen 
cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells." 
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15. Peggs, K. S., S. A. Quezada, A. J. Korman and J. P. Allison (2006). "Principles and use of anti-
CTLA4 antibody in human cancer immunotherapy." Curr Opin Immunol 18(2): 206-213. 
16. Peng, J., J. Hamanishi, N. Matsumura, K. Abiko, K. Murat, T. Baba, K. Yamaguchi, N. 
Horikawa, Y. Hosoe, S. K. Murphy, I. Konishi and M. Mandai (2015). "Chemotherapy Induces 
Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-kappaB to Foster an 
Immunosuppressive Tumor Microenvironment in Ovarian Cancer." Cancer Res 75(23): 5034-
5045. 
17. Rizvi, N. A., M. D. Hellmann, J. R. Brahmer, R. A. Juergens, H. Borghaei, S. Gettinger, L. Q. 
Chow, D. E. Gerber, S. A. Laurie, J. W. Goldman, F. A. Shepherd, A. C. Chen, Y. Shen, F. E. 
Nathan, C. T. Harbison and S. Antonia (2016). "Nivolumab in Combination With Platinum-
Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung 
Cancer." J Clin Oncol 34(25): 2969-2979. 
18. Rizvi, N. A., M. D. Hellmann, J. R. Brahmer, R. A. Juergens, H. Borghaei, S. Gettinger, L. Q. 
Chow, D. E. Gerber, S. A. Laurie, J. W. Goldman, F. A. Shepherd, A. C. Chen, Y. Shen, F. E. 
Nathan, C. T. Harbison and S. Antonia (2016). "Nivolumab in Combination With Platinum‐
Based Doublet Chemotherapy for First-Line Treatment of Advanced Non–Small-Cell Lung 
Cancer." Journal of Clinical Oncology 34(25): 2969-2979. 
19. Robert, C. and F. Ghiringhelli (2009). "What is the role of cytotoxic T lymphocyte-associated 
antigen 4 blockade in patients with metastatic melanoma?" Oncologist 14(8): 848-861. 
20. Shaib, Y. H., J. A. Davila, K. McGlynn and H. B. El-Serag (2004). "Rising incidence of 
intrahepatic cholangiocarcinoma in the United States: a true increase?" J Hepatol 40(3): 472-
477. 
21. Subramanian, A., P. Tamayo, V. K. Mootha, S. Mukherjee, B. L. Ebert, M. A. Gillette, A. 
Paulovich, S. L. Pomeroy, T. R. Golub, E. S. Lander and J. P. Mesirov (2005). "Gene set 
enrichment analysis: a knowledge-based approach for interpreting genome-wide expression 
profiles." Proc Natl Acad Sci U S A 102(43): 15545-15550. 
22. Valle, J., H. Wasan, D. H. Palmer, D. Cunningham, A. Anthoney, A. Maraveyas, S. 
Madhusudan, T. Iveson, S. Hughes, S. P. Pereira, M. Roughton, J. Bridgewater and A. B. C. 
T. Investigators (2010). "Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer." 
N Engl J Med 362(14): 1273-1281. 
23. Wu, K., I. Kryczek, L. Chen, W. Zou and T. H. Welling (2009). "Kupffer cell suppression of 
CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 
interactions." Cancer Res 69(20): 8067-8075. 
 
 
 


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17.0 
APPENDICES 
 
Appendix I 
ECOG Performance Status 
Appendix II 
Child-Pugh Status 
Appendix III 
Management Algorithms for Immuno-Oncology Agents 
Appendix IV 
Investigator’s Statement 
 
 
 


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Appendix I 
ECOG Performance Status 
 
 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature e.g. light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
Source: Eastern Cooperative Oncology Group 
 
 
 


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Appendix II 
Child-Pugh Score 
 
 
Measure 
1 point 
2 points 
3 points 
Total Bilirubin mg/dL 
<2 
2-3 
>3 
Serum Albumin g/dL 
>3.5 
2.8-3.5 
<2.8 
PT Time 
 
PT 
 
INR 
 
1-3 
<1.8 
 
4-6 
1.8-2.3 
 
>6 
>2.3 
Ascites 
Absent 
Slight 
Moderate to Severe 
Hepatic 
Encephalopathy 
None 
Grade 1-2 
(or suppressed with 
medication) 
Grade 3-4 (or 
refractory) 
 
Source: R.N.H. Pugh, I.M. Murray-Lyon, J.L. Dawson, M.C. Pietroni, Roger Williams. Transection of 
the esophagus for bleeding esophageal varices. British Journal of Surgery. Volume 60. Issue 8, 
pages 646-649, August 1973. 


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Appendix III 
Management Algorithms for Immuno-Oncology Agents 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all immuno-
oncology agents and regimens. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids.


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Appendix IV 
Investigator’s Statement 
 
1. I have carefully read this protocol entitled “A Randomized Phase II Study of Nivolumab in 
Combination with either Gemcitabine/Cisplatin or Ipilimumab as First Line Therapy for Patients with 
Advanced Unresectable Biliary Tract Cancer”, Version dated 02/28/2018 and agree that it contains 
all the necessary information required to conduct the study. I agree to conduct the study as outlined 
in the protocol.  
 
2. I agree to conduct this study according to the moral, ethical and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, the principles of Good Clinical Practice 
(GCP) as described in 21 Code of Federal Regulations (CFR) and any applicable local 
requirements.  
 
3. I understand that this trial and any subsequent changes to the trial will not be initiated without 
approval of the appropriate Institutional Review Board, and that all administrative requirements of 
the governing body of the institution will be complied with fully.  
 
4. Informed written consent will be obtained from all participating patients in accordance with 
institutional and Food and Drug Administration (FDA) requirements as specified in Title 21, CFR, 
Part 50.  
 
5. I understand that my signature on the electronic Case Report Form (eCRF) indicates that I have 
carefully reviewed each page and accept full responsibility for the contents thereof.  
 
6. I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior consent 
from University of Michigan unless this requirement is superseded by the FDA. 
 
 
 
Site PI Name: 
 
________________________________________ 
 
Site Name:  
 
________________________________________ 
 
Signature of Site PI:  
________________________________________ 
 
Date of Signature:  
____________\______________\_____________