A Single Arm Phase Ib/II Multi-Center Study of Nivolumab in Combination With Nanoliposomal-Irinotecan, 5-Fluorouracil, and Leucovorin as Second Line Therapy for Patients With Advanced Biliary Tract Cancer
Phase: PHASE1
Conditions: Biliary Tract Cancer
Sponsor: University of Michigan Rogel Cancer Center

UMCC 2018.101 
 
Phase Ib/II Trial of Nal-Irinotecan and Nivolumab as Second-Line Treatment in Patients 
With Advanced Biliary Tract Cancer 
 
NCT03785873 

UMCC 2018.101
A Single Arm Phase Ib/II Multi-Center Study of Nivolumab in Combination with 
nanoliposomal-Irinotecan, 5-Fluorouracil, and Leucovorin as Second Line 
Therapy for Patients with Advanced Biliary Tract Cancer [CA209-8LF]
Principal/Sponsor Investigator:
Vaibhav Sahai, MBBS, MS
Division of Hematology/Oncology 
Department of Internal Medicine 
University of Michigan
1500 E. Medical Center Drive 
Ann Arbor, MI 48109
Phone: 734-936-4991
Fax: 734-936-4940
Email: vsahai@med.umich.edu
Biostatistician:
Kent Griffith, MPH, MS 
University of Michigan
Center for Cancer Biostatistics, School of Public Health 
Email: kentg@med.umich.edu
Coordinating Center
University of Michigan
Experimental Drugs:
Nanoliposomal-Irinotecan (Onivyde ) 
Nivolumab (Opdivo®)
IND#:
141994
Initial version:
FINAL v. 1.1 24Oct2018
Revised:
v.2.1: 11Dec2018
v.3.0: 22Mar2019
v.4.0: 14Jun2019
v.4.1: 02Apr2020 (COVID-19 Appendix)
v.4.2: 08Jun2020
v.5.0: 11Nov2020
v.6.0: 11Jul2023
NOTE: To effectively manage the COVID-19 pandemic restrictions, changes to protocol-required item were 
made to minimize or eliminate immediate hazards or to protect the life and well-being of research participants 
(e.g., to limit exposure to COVID-19). These changes are listed in Appendix V of the protocol (Study 
Management during COVID-19).

Protocol UMCC 2018.101 
 
Page 2 of 64 
 
Table of Contents 
 
ABBREVIATIONS ............................................................................................................................................. 5 
1.0     STUDY SYNOPSIS……………………………………………………………………………………………...6 
1.1 
Biliary Tract Cancer - Disease Overview .................................................................................... 9 
1.2 
Role of Irinotecan in BTC ............................................................................................................ 9 
1.3 
Role of Immune Checkpoint Inhibitors in BTC .......................................................................... 10 
1.4 
Role of Chemotherapy in Conjunction with Immune Checkpoint Inhibitors in BTC .................. 10 
1.5 
Rationale ................................................................................................................................... 11 
1.6 
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 ........................................................................................................................ 12 
4.0     SUBJECT SCREENING AND REGISTRATION PROCEDURES ....................................................... 15 
5.0     TREATMENT PLAN ............................................................................................................................. 15 
5.1 
Treatment Dosage and Administration ..................................................................................... 15 
5.2 
Dose Limiting Toxicities (DLTs) ................................................................................................ 16 
5.3       Toxicities and Dosing Delays/Dose Modifications ..................................................................... 16 
5.4 
Management Algorithms for Immuno-Oncology Agents ........................................................... 19 
5.5 
Concomitant Medications/Treatments....................................................................................... 20 
5.6 
Other Modalities or Procedures ................................................................................................ 20 
5.7 
Duration of Therapy................................................................................................................... 20 
5.8 
Off-Treatment Criteria ............................................................................................................... 21 
5.9 
Duration of Follow-Up ............................................................................................................... 21 

Protocol UMCC 2018.101 
 
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5.10 
Off-Study Criteria ....................................................................................................................... 21 
5.11 
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 ............................................................................................................. 24 
7.1 
Antitumor Effect- Solid Tumors ................................................................................................. 24 
7.2 
Safety/Tolerability ...................................................................................................................... 30 
8.0     ADVERSE EVENTS .............................................................................................................................. 30 
8.1 
Adverse Event Reporting Requirements ................................................................................... 30 
8.2 
Definitions .................................................................................................................................. 30 
8.3 
Adverse Event Characteristics .................................................................................................. 33 
8.4 
Serious Adverse Event Reporting Guidelines ........................................................................... 33 
8.5 
Routine Reporting ..................................................................................................................... 35 
8.6 
Reporting of Unanticipated Problems ....................................................................................... 35 
8.7 
Safety Report Reconciliation ..................................................................................................... 35 
8.8 
Stopping Rules .......................................................................................................................... 35 
9.0     DRUG INFORMATION ......................................................................................................................... 36 
9.1 
Nanoliposomal-Irinotecan ......................................................................................................... 36 
9.2 
5-Fluorouracil (5-FU) ................................................................................................................. 39 
9.3 
Leucovorin (LV) ......................................................................................................................... 39 
9.4 
Nivolumab ................................................................................................................................. 40 
10.0     CORRELATIVES/TRANSLATIONAL STUDIES ................................................................................ 43 
10.1 
Tissue Collection Guidelines (See Laboratory Manual for details) ........................................... 44 
10.2 
Blood Collection Guidelines ...................................................................................................... 44 
10.3 
Specimen Banking .................................................................................................................... 44 
11.0     STATISTICAL CONSIDERATIONS ................................................................................................... 45 
11.1 
Study Design/Study Endpoints .................................................................................................. 45 

Protocol UMCC 2018.101 
 
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11.2 
Sample Size and Accrual .......................................................................................................... 45 
11.3 
Study Populations ..................................................................................................................... 46 
11.4 
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 ............................................................................................. 48 
15.0     CLINICAL MONITORING PROCEDURES ......................................................................................... 49 
16.0     REFERENCES .................................................................................................................................... 50 
17.0     APPENDICES ..................................................................................................................................... 52 
Appendix I 
ECOG Performance Status ................................................................................................. 53 
Appendix II 
Child-Pugh Score ................................................................................................................ 54 
Appendix III        Management Algorithms for Immuno-Oncology Agents ...................................................... 55 
Appendix IV        Investigator’s Statement ...................................................................................................... 62 
Appendix V         Study Management during COVID-19…………………………………………………………..63 
 

Protocol UMCC 2018.101 
Page 5 of 64 
 
 
ABBREVIATIONS: 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
APC 
Antigen Presenting Cells 
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 
DDR 
DNA Damage Response 
DILI 
Drug-Induced Liver Injury 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
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 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TIL 
Tumor Infiltrating Leukocytes 
UaP 
Unanticipated Problem 
WBC 
White Blood Cells 

Protocol UMCC 2018.101
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STUDY SCHEMA
STUDY SYNOPSIS
Title
A Single Arm Phase Ib/II Multi-Center Study of Nivolumab in Combination with 
nanoliposomal-Irinotecan, 5-Fluorouracil, and Leucovorin as Second Line 
Therapy for Patients with Advanced Biliary Tract Cancer
Phase
Phase Ib/II
Methodology
Single arm, open-label
Study Duration
3 years
Study Center(s)
Multi-Center: up to 6 sites total including lead site University of Michigan
Objectives
Primary objective:
1.
Phase Ib: Determine the recommended phase 2 dose (RP2D) and dose-
limiting toxicities (DLTs) of nanoliposomal-Irinotecan, 5-Fluorouracil, 
Leucovorin and Nivolumab
2.
Phase II: Determine the median PFS
Secondary objectives:
1.
Evaluate the safety and toxicity of this drug combination in this patient 
population.
2.
Evaluate the ORR and median OS
Exploratory objectives:
To explore biomarkers of 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 only).
b) Whole exome genomic and transcriptomic (RNAseq) analysis for tumor 
biology, DDR and immune signature profiling at baseline and progression.
c) PBMC collection for immune cell subset analysis including serum for future 
biomarker analysis (for patients enrolled at University of Michigan only).
Number of 
Subjects
30-40 evaluable
Eligibility Criteria
1. Patients must have a pathologically confirmed carcinoma of the biliary tract 
(intra-hepatic, extra-hepatic (hilar, distal) or gall bladder) that is not eligible for 
curative resection, transplantation, or ablative therapies. Tumors with mixed 
hepatocellular and cholangiocarcinoma histology are excluded.
Advanced or 
metastatic biliary 
tract cancer after 
progression on
1st line systemic 
therapy*
Experimental
nanoliposomal-
Irinotecan + 
Leucovorin +
5-Fluorouracil + 
Nivolumab
Day 1 Q14 days
Phase Ib
(N=10-20)
Phase II
(N=20)
0
1 endpoint: RP2D
0
2 endpoints: Safety &
toxicity, ORR, 
median PFS and OS
0
1 endpoint: Median PFS
0
2 endpoints: Safety &
toxicity, ORR, 
median OS
*No prior Irinotecan 
or PD-1 Ab

Protocol UMCC 2018.101 
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2. Patients must have received one and only one prior systemic therapy for 
advanced disease. Prior therapies must have not included Irinotecan or PD- 
1/PD-L1 antibody. Patient should have either progressed on or within 6 
months of first-line systemic therapy or deemed intolerant of that therapy. 
3. Prior surgical resection, radiation, chemoembolization, radioembolization or 
other local ablative therapies are permitted if completed ≥ 4 weeks prior to 
registration 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 lesion. 
5. Age ≥18 years 
6. Child-Pugh score less than 7 
7. ECOG performance status of 0-1 
8. Ability to understand and willingness to sign IRB-approved informed consent 
9. Available archived tissue (FFPE block or 20 unstained slides from prior core 
biopsy or surgery) 
10. Must be able to tolerate CT and/or MRI with contrast 
11. Adequate organ function assessed ≤2 weeks prior to registration (absolute 
neutrophil count ≥1500/mm3, hemoglobin ≥9 g/dL, platelets ≥75,000/mm3, 
serum creatinine ≤ 1.5 x upper limit normal (ULN), 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. 
12. Must not have received systemic steroid therapy, or any other form of 
immunosuppressive therapy within 14 days prior to registration. Short bursts 
of steroids of 5-7 days (for COPD exacerbation or other similar indication) are 
allowed. 
13. No prior history of solid organ transplantation or brain metastasis (unless 
treated, asymptomatic and stable). 
14. Must not have undergone a major surgical procedure < 4 weeks prior to 
registration. 
15. 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. 
16. Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours 
off antibiotics). 
17. Must not have received a live vaccine within 30 days of registration. 
18. 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. 
19. Women must not be pregnant or breastfeeding since 5-Fluorouracil, 
nanoliposomal-Irinotecan and/or Nivolumab 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 pregnancy test (blood or 
urine) within 2 weeks prior to registration. 
20. 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. 
21. 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, 

Protocol UMCC 2018.101 
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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. 
22. Participants with a condition requiring systemic treatment with either 
corticosteroids 
(>10 
mg 
daily 
prednisone 
equivalent) 
or 
other 
immunosuppressive medications within 14 days of registration are excluded. 
Inhaled, ocular, intra-articular, intra-nasal or topical steroids, and adrenal 
replacement steroid doses >10 mg daily prednisone equivalent, are permitted 
in the absence of active autoimmune disease. 
23. No known UGT1A1* variants or Gilbert’s syndrome 
24. Prisoners or subjects who are involuntarily incarcerated, or compulsorily 
detained for treatment of either a psychiatric or physical (e.g. infectious 
disease) illness would be excluded. 
25. No known hypersensitivity to 5-Fluorouracil, Leucovorin, Irinotecan, and/or 
Nivolumab. 
26. Must not have ongoing bowel obstruction. 
27. No known HIV, Hepatitis B or Hepatitis C infection that is untreated and/or 
with a detectable viral load. 
28. Patients must not have uncontrolled intercurrent illness including, but not 
limited to, interstitial lung disease, symptomatic congestive heart failure, 
unstable angina pectoris, uncontrolled cardiac arrhythmia. 
29. No known medical condition (e.g. a condition associated with uncontrolled 
diarrhea such as ulcerative colitis or acute diverticulitis) that, in the 
investigator’s opinion, would increase the risk associated with study 
participation or interfere with the interpretation of safety results. 
30. Patients must not be on warfarin, strong CYP3A4 inducers (such as 
phenytoin, phenobarbital, primidone, carbamazepine, rifampin, rifabutin, 
rifapentine or St. John’s Wort), strong CYP3A4 inhibitors (such as 
ketoconazole, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole), and strong UGT1A1 
inhibitors (such as atazanavir, gemfibrozil, indinavir and ketoconazole). 
 
Study Product(s), 
Dose, Route, 
Regimen 
Starting Dose Level (cycle length is 14 days) 
nanoliposomal-Irinotecan 70 mg/m2 IV day 1 
5-Fluorouracil 2400 mg/m2 IV continuous infusion for 46 hours 
Leucovorin 400 mg/m2 IV day 1 
Nivolumab 240 mg IV day 1 
Duration of 
Administration 
Patients may continue treatment for 2 years in absence of disease progression or 
unacceptable toxicity. 
 
 
 
 
 
 
Statistical 
Methodology 
The investigators intend to enroll patients who have either progressed or are 
deemed intolerant of 1st line systemic therapy for advanced biliary tract cancer. 
A limited phase 1b trial will be implemented to assure that dose levels 
suggested for this combination are safe. Because toxicity across the combined 
agents is expected to be additive rather than synergistic and in light of the poor 
prognosis for this patients, we are willing to tolerate up to but not exceeding 30% 
DLT toxicity proportion during the first 4 weeks of therapy. To investigate this, 
we will enroll up to 10 patients to the phase Ib portion of this trial at dose level 0. 
If >4 patients of the first 5 to 10 patients enrolled into this cohort have a DLT 
during the first 4 weeks of therapy, then accrual at dose level 0 will halt if yet to 
reach 10. Dose level will be abandoned in favor of dose level -1. If the toxicity 
boundary of 4 is crossed at dose level 0, up to an additional 10 patients will be 
accrued at dose level -1 and the same rules applied. If at dose level -1 more 
than 4 patients experience DLT, then the trial will be stopped and the 
combination abandoned. However, if either the 10 patient cohort at dose level 0 

Protocol UMCC 2018.101 
Page 9 of 64 
 
 
 
 
or level -1 conclude without tripping the toxicity rule, then that dose level will be 
declared the recommended phase 2 dose (RP2D) with an additional 20 patients 
enrolled at that dose level for the Phase 2 assessment of efficacy as measured 
by the median PFS. The median PFS of second line treatment of 
cholangiocarcinoma is expected to be 2.9 months (null) and we expect that the 
median PFS will be 5.0 months (alternate hypothesis) for this study’s 
combination. We anticipate that we can accrue 1.7 patients per month for 18 
months (between phase 1b and phase 2); we will follow all patients for 
progression and survival for 12 months following the accrual of the last patient. 
This will afford 83% power to detect the hypothesized difference in median PFS 
time, using a two-sided test with at most 5% type one error. Patients on the 
phase Ib portion of this trial treated at the RP2D will be included in the 
population for the analysis of the primary endpoint of the phase II portion of the 
trial. 
 
 
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 rising1. Advanced BTCs are aggressive 
tumors with median survival time from diagnosis of less than 12 months2, and five-year 
overall survival (OS) of ~5% despite therapy3. The options for systemic chemotherapy for 
patients with advanced BTC remain limited with few meaningful improvements over the 
past 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 
trial2. 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. This result established the gemcitabine and 
cisplatin combination as a standard first line regimen for patients with advanced BTC. 
Durable response rates are infrequent however, and a substantial number of patients 
progress quickly. Additional strategies and subsequent lines of therapy remain largely 
investigational, with no clear standard at present. 
 
1.2 
Role of Irinotecan in BTC 
Irinotecan (Camptosar©, CPT-11) is a camptothecin derivative that inhibits 
topoisomerase I, an enzyme that induces reversible single-stranded DNA breaks to 
relieve torsional strain in DNA through its active metabolite, SN-38. The combination of 
Irinotecan plus 5-Fluorouracil (5-FU)/Leucovorin (LV) (FOLFIRI) has shown activity in the 
first and second line settings in multiple GI cancers. Studies in biliary cancer have 
revealed modest activity, although these are small studies (Table 1). 
 
Table 1. Use of Irinotecan and/or 5-FU/capecitabine in 2nd line management of 
biliary tract cancer 
 
No. 
 
Regimen 
N 
Overall 
response 
rate, N (%) 
Progression 
free survival, 
months 
Overall 
survival, 
months 
1 
FOLFIRI4 
24 
NA 
2.9 
NR 
2 
Irinotecan5 
13 
1 (7.7) 
1.8 
6.7 
3 
Irinotecan6 
25 
2 (8%) 
NR 
10 
4 
Capecitabine or 5-FU/LV7 
26 
2 (10%) 
2.8 
8.0 

Protocol UMCC 2018.101 
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Nanoliposomal-Irinotecan (nanoliposomal-IRI) is a nanoliposomal encapsulated form of 
Irinotecan that Drummond et al. demonstrated in animal studies to have significantly 
longer circulation times when bound to triethylammonium salts or polyphosphates when 
compared to free drug formulations. At 24 hours, 23.2% of an injected dose of 
nanoliposomal-IRI remained without detectable conversion of the encapsulated prodrug 
to its inactive or active metabolite form as compared to only 2% of the free drug 
formulation remaining after 30 minutes with 35% of injected free drug present in the 
inactive carboxylate form. Antitumor activity in breast and colon xenografts were 
significantly higher with nanoliposomal-IRI as compared to free Irinotecan with a fourfold 
reduction of drug toxicity in mice without reaching the maximum tolerated dose (MTD)8,9. 
Maximum tolerated doses of nanoliposomal-IRI have been established in several phase I 
studies in advanced solid tumors refractory to chemotherapy with recommended dosing 
of 120 mg/m2 every 3 weeks as monotherapy and 70 mg/m2 combined with 5-FU/LV 
every two weeks10. 
 
The combination of nanoliposomal-IRI plus 5-FU/LV has been shown to be both safe and 
effective following gemcitabine-based treatment in advanced pancreatic cancer in the 
NAPOLI-1 trial. The combination of nanoliposomal-IRI demonstrated improvements in 
progression free (PFS) (3.1 vs 1.5 months; P<0.001) and OS (6.2 vs 4.1 months; 
P=0.038) as compared to 5-FU/LV10. 
 
1.3 
Role of Immune Checkpoint Inhibitors in BTC 
Programmed death (PD)-1 is a member of the CD28/CTLA-4 family of T-cell 
costimulatory receptors that includes CD28, CTLA 4, ICOS and BTLA11. PD-1 is 
expressed on activated T cells, B cells and myeloid cells12. 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,13,14. When a PD-1 ligand binds to the PD-1 receptor, T-cell activation is 
blocked. PD-1 is a negative regulator of T-cell response that prevents autoimmunity and 
allows tolerance to self-antigens. If PD-1/ligand interactions are interrupted, this 
checkpoint is turned off which can lead to enhanced antitumor T-cell activation. 
 
One of the first agents studied in this disease group was pembrolizumab, a humanized 
monoclonal antibody against PD-1 that is designed to block the interaction between PD-1 
and its ligands PD-L1 and PD-L2. Twenty-three PD-L1 positive patients with advanced 
BTC were enrolled in the KEYNOTE-028 phase 1b trial of pembrolizumab 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%15. Adverse events were generally consistent with previously reported 
safety data for pembrolizumab. There were no treatment-related deaths. Five patients, 
including all responders, remained on treatment more than 40 weeks15. Nivolumab is an 
anti-PD1 antibody that is currently FDA-approved as a single agent and in combination 
with other agents in multiple solid tumors at 240 mg dose every 2 weeks, and more 
recently at 480 mg dose every 4 weeks. A few ongoing studies utilizing PD-1 blockade in 
advanced BTCs refractory to 1st line therapy include Nivolumab monotherapy 
(NCT02829918), pembrolizumab plus capecitabine and oxaliplatin (NCT03111732), and 
atezolizumab plus cobimetinib (NCT03201458)16. 
 
1.4 
Role of Chemotherapy in Conjunction with Immune Checkpoint Inhibitors in BTC 
Chemotherapy has been demonstrated to lead to upregulation of PD-L1 expression17. 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 

Protocol UMCC 2018.101 
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through fas-, perforin-, and Granzyme B–dependent mechanisms18. 5-FU, a pyrimidine 
analog antimetabolite which works by inhibition of thymidylate synthase, has 
demonstrated in vivo a major decrease in myeloid-derived suppressor cells (MDSCs) and 
induction of MDSC apoptotic death with net increase in IFNγ (interferon gamma) 
production by tumor-specific CD8(+) T Cells19. Irinotecan is also an example of an 
immunomodulatory chemotherapeutic agent with pleiotropic immune effects, and when 
combined with 5-FU/LV (FOLFIRI), demonstrated increased T-helper 1 and cytotoxic T- 
cell response, including secretion of IL-2 and IFNγ through down regulation of MDSCs 
and regulatory T-cells (TREG)20. The immunomodulatory properties of conventional 
chemotherapy and properties of these specific agents provide a good rationale for 
combining 5-FU and nanoliposomal-IRI with immunotherapy, particularly immune 
checkpoint inhibitors. 
 
The PembroPlus trial (NCT02331251), a phase Ib, multicohort study, evaluated the 
safety and efficacy of pembrolizumab with gemcitabine (G), G+Docetaxel, G+nab- 
paclitaxel, G+vinorelbine, Irinotecan, or liposomal doxorubicin in advanced solid tumors. 
Forty-nine patients were enrolled. Specific to our study, pembrolizumab (2 mg/kg) was 
given in combination with Irinotecan (300mg/m2) every 21 days with an acceptable safety 
profile. All patients experienced grade 1-4 treatment-emergent adverse events (AEs), 
although only 3 of 12 enrolled patients experienced grade 3-4 toxicity, only one of which 
required a dose reduction21. 
 
1.5 
Rationale 
There is a clear and urgent need for an effective second line treatment in BTC. The 
immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to 
the upregulation of PD-L1 expression17 rendering tumor cells more sensitive to T cell- 
mediated lysis and neoantigen production18, rapid emergence of chemotherapy 
resistance, and known modest efficacy of single agent PDL1 antibody in BTC provides a 
rationale for combining chemotherapy and immunotherapy. 
 
We hypothesize that the combination of a PD-1 targeted antibody with 5-FU and 
nanoliposomal-Irinotecan chemotherapy will increase objective response rates. 
Nanoliposomal-Irinotecan with 5-FU/LV is an attractive cytotoxic option based upon 
favorable side effect profile and proven effectiveness following gemcitabine based 
therapy in advanced pancreas cancer. In colon and pancreatic ductal adenocarcinoma, 
the combination of Nivolumab plus capecitabine and Irinotecan is currently being 
investigated in a phase Ib/II (NCT02423954) study with phase I results suggesting an 
acceptable safety profile22. We anticipate the combination of nanoliposomal-Irinotecan 
with 5FU/LV and Nivolumab will be well tolerated. Additionally, we hypothesize that this 
combination of nanoliposomal-IRI, 5-FU/LV, and Nivolumab will prolong PFS in patients 
with advanced biliary tract cancer treated previously with systemic chemotherapy with 
commensurate improvements in survival and other meaningful patient outcomes. 
 
1.6 
Correlative Studies 
We will study the BTC tumor biology, DNA damage response (DDR) and immune 
signatures through the use of pre-treatment tissue (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. In addition, blood will be collected as detailed in the schedule of 
events/study calendar. Identification of important biologic subsets of BTC patients (such 
as DDR and/or immune signatures) that may have clinical efficacy from nanoliposomal- 
Irinotecan and Nivolumab will be the overarching goal of these translational studies along 
with developing biologic insights for future therapeutic development. Biologic readouts for 
PD-1 and other immune response biomarkers will be assessed along with specific 
markers of tumor infiltrating leukocytes (TILs). Biologic markers and RNA expression will 

Protocol UMCC 2018.101 
Page 12 of 64 
 
 
be examined in the context of immunologic correlates, tumor biology, and therapeutic 
efficacy. 
 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
2.1.1 
Phase Ib: Determine the recommended phase 2 dose (RP2D) and dose limiting 
toxicities (DLTs) of nanoliposomal-Irinotecan, 5-Fluorouracil, Leucovorin and 
Nivolumab in subjects with advanced biliary cancer 
2.1.2 
Phase II: Determine the median PFS 
 
2.2 
Secondary Objectives 
2.2.1 
Evaluate the safety and toxicity of this drug combination in this patient population 
2.2.2 
Evaluate the ORR and median OS 
 
2.3 
Exploratory Objectives 
2.3.1 
To explore biomarkers of 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, DDR 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 Endpoints Assessment: The primary endpoint of the phase 1b portion of 
this trial is to evaluate the incidence of DLTs at different dose levels to identify 
the RP2D. 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 Endpoints Assessment: Adverse events and reportable serious 
events are defined by the study protocol (NCI Common Toxicity Criteria for 
Adverse Events (CTCAE) v5.0). 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. 
Follow-up time will be censored at the date of last disease evaluation. 
 
 
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. 
 
3.1 
Eligibility Criteria 
3.1.1 
Patients must have a pathologically confirmed carcinoma of the biliary tract (intra- 
hepatic, extra-hepatic (hilar, distal) or gall bladder) that is not eligible for curative 
resection, transplantation, or ablative therapies. Tumors with mixed hepatocellular 
and cholangiocarcinoma histology are excluded. 

Protocol UMCC 2018.101 
Page 13 of 64 
 
 
3.1.2 
Patients must have received one and only one prior systemic therapy for advanced 
disease. Prior therapies must have not included Irinotecan or PD-1/PD-L1 
antibody. Patient should have either progressed on or within 6 months of first-line 
systemic therapy or deemed intolerant of that therapy. 
 
3.1.3 
Prior surgical resection, radiation, chemoembolization, radioembolization or other 
local ablative therapies are permitted if completed ≥ 4 weeks prior to registration 
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 lesion. 
 
3.1.5 
Age ≥18 years 
 
3.1.6 
Child-Pugh score of less than 7. 
 
3.1.7 
ECOG performance status of 0-1. 
 
3.1.8 
Ability to understand and willingness to sign IRB-approved informed consent. 
 
3.1.9 
Available archived tissue (FFPE block or 20 unstained slides from prior core biopsy 
or surgery). 
 
3.1.10 Must be able to tolerate CT and/or MRI with contrast. 
 
3.1.11 Adequate organ function assessed ≤2 weeks prior to registration: 
absolute neutrophil count 
≥ 1500/mm3 
hemoglobin 
> 9 g/dL 
platelets 
> 75,000/mm3 
serum creatinine 
≤ 1.5 x upper limit of normal (ULN) 
albumin 
≥ 3.0 g/dL 
AST/ALT 
≤ 3.0 x ULN (< 5 x ULN if liver metastasis) 
total bilirubin 
≤ 1.5 x ULN 
 
3.1.12 Must not have received systemic steroid therapy, or any other form of 
immunosuppressive therapy within 14 days prior to registration. Short bursts of 
steroids of 5-7 days (for COPD exacerbation or other similar indication) are 
allowed. 
 
3.1.13 No prior history of solid organ transplantation or brain metastasis (unless treated, 
asymptomatic and stable). 
 
3.1.14 Must not have undergone a major surgical procedure < 4 weeks prior to 
registration. 
 
3.1.15 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. 
 
3.1.16 Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours off 
antibiotics). 

Protocol UMCC 2018.101 
Page 14 of 64 
 
 
3.1.17 Must not have received a live vaccine within 30 days of registration. 
 
3.1.18 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. 
 
3.1.19 Women must not be pregnant or breastfeeding since 5-Fluorouracil, 
nanoliposomal-Irinotecan and/or Nivolumab 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 pregnancy test (blood or urine) within 2 
weeks prior to registration. 
 
3.1.20 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. 
 
3.1.21 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. 
 
3.1.22 Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days of registration are excluded. Inhaled, ocular, intra- 
articular, intra-nasal or topical steroids, and adrenal replacement steroid doses 
>10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 
 
3.1.23 No known UGT1A1* variants or Gilbert’s syndrome 
 
3.1.24 Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained 
for treatment of either a psychiatric or physical (e.g. infectious disease) illness 
would be excluded. 
 
3.1.25 No known hypersensitivity to 5-Fluorouracil, Leucovorin, Irinotecan, and/or 
Nivolumab. 
 
3.1.26 Must not have ongoing bowel obstruction. 
 
3.1.27 No known HIV, Hepatitis B or Hepatitis C infection that is untreated and/or with a 
detectable viral load. 
 
3.1.28 Patients must not have uncontrolled intercurrent illness including, but not limited 
to, interstitial lung disease, symptomatic congestive heart failure, unstable angina 
pectoris, uncontrolled cardiac arrhythmia. 
 
3.1.29 No known medical condition (e.g. a condition associated with uncontrolled 
diarrhea such as ulcerative colitis or acute diverticulitis) that, in the investigator’s 
opinion, would increase the risk associated with study participation or interfere 
with the interpretation of safety results. 
 
3.1.30 Patients must not be on warfarin, strong CYP3A4 inducers (such as phenytoin, 
phenobarbital, primidone, carbamazepine, rifampin, rifabutin, rifapentine or St. 

Protocol UMCC 2018.101 
Page 15 of 64 
 
 
John’s Wort), strong CYP3A4 inhibitors (such as ketoconazole, clarithromycin, 
indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telaprevir, voriconazole), and strong UGT1A1 inhibitors (such as atazanavir, 
gemfibrozil, indinavir and ketoconazole). 
 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Patient registration for this trial will be centrally managed by the Oncology Clinical Trials Support 
Unit (i.e. the Coordinating Center) of the University of Michigan Rogel 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 a Screening and 
Enrollment Log. 
 
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 
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 CTSU-Oncology-Multisite@med.umich.edu. 
 
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. EST 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 
to provide the study identification 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. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 calendar days of enrollment to the study 
otherwise the patient will be taken off-study. Re-screening is allowed. 
 
Patients will receive combination therapy with nanoliposomal-Irinotecan, 5-Fluorouracil, 
Leucovorin and Nivolumab. Prophylaxis/pre-medications per institutional policy. The 
safety profile of nanoliposomal-Irinotecan, 5-Fluorouracil, Leucovorin agents in 
combination has been previously evaluated. The safety profile of Nivolumab has been 
previously evaluated as well. 
 
Patients will begin phase Ib dosing at dose level 0 and up to 10 patients will be treated at 
this level. If toxicity limits are not exceeded as per section 11.2, dose level 0 will be 
declared the recommended phase 2 dose and 20 additional patients will be treated on 
the phase II study. 

Protocol UMCC 2018.101 
Page 16 of 64 
 
 
 
Table 2. Treatment Plan (Day 1 Q14 days) 
 
Dose 
Level 
 
Leucovorin 
(IV over 90 min) 
nanoliposomal- 
Irinotecan 
(IV over 90 min) 
5-FU continuous 
infusion 
(IV over 46 hours) 
Nivolumab 
(IV over 30 min) 
0 
400 mg/m2 
70 mg/m2 
2400 mg/m2 
240 mg 
-1 
200 mg/m2 
70 mg/m2 
2000 mg/m2 
240 mg 
 
Infusion times (+/- 10 min except 5-FU pump which would be per manufacturer 
guidelines) may be extended as needed for safety (e.g. infusion reaction occurs) but 
these instances should be documented in the patient medical records. The Leucovorin 
and nanoliposomal-Irinotecan will be infused concurrently, followed by Nivolumab and 
then the 5-FU continuous infusion. Pre-medications per institutional policy. Patients may 
continue treatment for 2 years in absence of disease progression or unacceptable 
toxicity. 
 
5.2 
Dose Limiting Toxicities (DLTs) 
A DLT will be any of the following occurring during the first 4 weeks of therapy attributed 
(possibly, probably, or definitely) to the drug combination following day 1 treatment and 
occurring in the 28-day interval as assessed using the NCI CTCAE v5.0. 
1. Grade 4 or greater hematological toxicity with the exception of uncomplicated grade 4 
leukopenia/ neutropenia lasting <7 days) 
2. Grade 3 or higher thrombocytopenia with bleeding 
3. Grade 3 or greater febrile neutropenia per CTCAE v5.0 criteria. 
4. Grade 3 or greater non-hematological toxicity, except nausea, vomiting, diarrhea, 
(lasting <3 days or without supportive care measures), hyperbilirubinemia (secondary 
to biliary obstruction), alopecia, fatigue, and hypersensitivity reaction 
5. Any death not clearly due to the underlying disease or extraneous causes. 
6. Any hepatic adverse event meeting the criteria for Hy’s Law 
7. Grade 3 or higher electrolyte abnormality that lasts >72 hours, or is clinically 
complicated, or does not resolve spontaneously or with conventional medical 
interventions. 
 
With completion of cycle 1 and 2, and following DLT determination (yes vs. no), cycle 3 
may begin. 
5.3 
Toxicities and Dosing Delays/Dose Modifications 
General Considerations 
1. Subsequent cycles of therapy may begin when ANC > 1,000, platelets > 75K and all 
toxicity attributable to treatment has resolved to < grade 1 (except as noted in section 
5.3.3). 
2. Doses will not be modified for cholangitis attributable to biliary obstruction/stent 
occlusion unless this occurs in the setting of > grade 3 neutropenia. 
3. 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. 
4. Efforts to attribute toxicity experienced to a single component or some combination of 
the cytotoxic agents will be made by treating investigator and doses of the 
accountable agent(s) will be modified or held according to that judgment. Dose 
adjustments for toxicity will be described in the clinical record. 
5. Doses that are reduced for toxicity will not be subsequently increased. 
6. If a patient experiences neutropenic fever at any point in the treatment cycle, 
chemotherapy will be delayed until ANC > 1,000 and antibiotic treatment of the event 

Protocol UMCC 2018.101 
Page 17 of 64 
 
 
is completed. When treatment resumes, consider one dose level reduction as per 
Table 2 for one/more agents. 
7. If a chemotherapy treatment is not given on day 1 of any cycle due to toxicity per 
Table 4 or5, one or more drugs will require dose modification as per Table 3. 
8. Treatment delay of more than 28 days from last intended therapy will result in 
discontinuation from trial, unless otherwise agreed and documented between the 
investigator and the sponsor-investigator. 
9. Investigators should consider dose re-calculation 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. 
10. If more than one toxicity occurs requiring dose reduction, the dose administered 
should be based on the most severe toxicity. 
11. If one of the drugs is held or discontinued due to toxicity attributed to that agent, 
the patient will be allowed to continue the rest of the combination therapy. 
12. Nivolumab cannot be dose reduced and can only be held or discontinued as per 
detailed algorithms for immune-therapy toxicity management in Appendix III. 
13. If the regimen held or missed was to be given on Day 1 then that cycle will not be 
considered to start until the day the first dose is actually administered. 
 
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/Study Calendar (Section 6.2). 
 
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 5.0. Dose adjustments should be made according to the 
system showing the greatest degree of toxicity. 
 
 
Table 3. Dose Modifications 
Drug 
Current Dose 
Percentage 
Decrease 
Modified Dose 
 
nanoliposomal- 
Irinotecan 
70 mg/m2 
20% 
55 mg/m2 
55 mg/m2 
20% 
45 mg/m2 
45 mg/m2 
100% 
Discontinue 
Leucovorin 
400 mg/m2 
50% 
200 mg/m2 
 
200 mg/m2 
100% 
Discontinue 
5-Fluorouracil 
2400 mg/m2 
20% 
2000 mg/m2 
 
2000 mg/m2 
20% 
1600 mg/m2 
 
1600 mg/m2 
100% 
Discontinue 
Nivolumab 
240 mg IV 
100% 
Discontinue 

Page 18 of 64 
 
 
Protocol UMCC 2018.101 
 
 
Table 4. Dose Modifications for Hematologic Toxicity for 5-Fluorouracil, Leucovorin and nanoliposomal-Irinotecan 
Hematologic Toxicity 
Dose Adjustment for 5-Fluorouracil, Leucovorin and nanoliposomal-Irinotecan 
ANC1 ≥ 1000/mm3 
AND 
Platelets ≥ 75,000/mm3 
Treat as scheduled 
ANC1 < 1000/mm3 
OR/AND 
Platelets < 75,000/mm3 
Hold all drugs up to a maximum of 28 days from expected date of treatment until ANC ≥ 1000/mm3 
AND platelets ≥ 75,000/mm3 then resume at next lower dose level for either or all drugs 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: Dose Modifications for Non-Hematologic Toxicity for 5-Fluorouracil, Leucovorin and nanoliposomal-Irinotecan 
Non-Hematologic Toxicity 
Dose Adjustment for 5-Fluorouracil/Leucovorin 
Dose Adjustment for nanoliposomal-Irinotecan 
Alopecia, anemia, venous 
thromboembolism 
No modification to doses 
Grade >3 nausea and 
vomiting (ongoing after 
maximal anti-emetic therapy) 
Consider decrease 
 
Consider decrease 
Grade >2 hyperbilirubinemia 
Hold 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 of one or more drugs. 
 
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 will be described in the clinical record. 

Protocol UMCC 2018.101 
Page 19 of 64 
 
 
5.4 
Management Algorithms for Immuno-Oncology Agents 
Nivolumab is 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 and consider the following criteria. 
 
x 
Dosing delays to allow for prolonged steroid tapers to manage Nivolumab-related 
AEs are allowed. Prior to initiating treatment in a subject with a dosing delay 
lasting >4 weeks starting from date of missed/due dose, the sponsor-investigator 
must be consulted. 
x 
Delay Nivolumab dosing for grade 2 non-skin, drug-related AE, with the 
exception of fatigue, constipation, hypertension 
x 
Delay Nivolumab dosing for grade 3 drug-related laboratory abnormality, with the 
exception of lymphopenia, asymptomatic amylase or lipase. 
x 
Discontinue Nivolumab for grade 2 drug-related uveitis, eye pain or blurred vision 
that does not respond to topical therapy and does not improve to grade 2 severity 
within the re-treatment period, or requires systemic treatment. 
x 
Discontinue Nivolumab for any grade 3 non-skin, drug-related AE lasting >7 days 
or recurs, with the following exceptions for laboratory abnormalities, drug-related 
uveitis, pneumonitis, bronchospasm, neurologic toxicity, hypersensitivity 
reactions, infusions reactions and endocrinopathies. 
o 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic 
toxicity, myocarditis, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation. 
o 
Grade 3 drug-related endocrinopathies, adequately controlled with only 
physiologic hormone replacement do not require discontinuation. Adrenal 
insufficiency requires discontinuation regardless of control with hormone 
replacement. 
o 
Grade 3 drug-related laboratory abnormalities do not require 
discontinuation except: 
 
Grade 3 drug-related thrombocytopenia lasting >7 days or 
associated with bleeding requires discontinuation 
 
Grade >3 or higher drug-related AST, ALT or total bilirubin 
management as per Hepatic AE Management Algorithm in 
Appendix III. 
x 
Discontinue Nivolumab for any grade 4 drug-related AE or laboratory abnormality 
(including, but not limited to creatinine, AST, ALT, or total bilirubin), except for the 
following events which do not require discontinuation: 
o 
Grade 4 neutropenia < 7 days 
o 
Grade 4 lymphopenia, leukopenia, asymptomatic amylase or lipase 

Protocol UMCC 2018.101 
Page 20 of 64 
 
 
o 
Isolated grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72 hours of onset 
o 
Grade 4 drug-related endocrinopathy AE, such as hyper- or 
hypothyroidism, or glucose intolerance, which resolve or are adequately 
controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones, or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with the sponsor-investigator. 
x 
Discontinue Nivolumab for any adverse event, laboratory abnormality or 
intercurrent illness which, in the judgment of the investigator present a 
substantial clinical risk to the subject with continued Nivolumab dosing. 
 
Subjects may resume treatment with Nivolumab when the drug-related AE(s) resolve to 
grade <1 or baseline value, with the following exceptions: 
 
x 
Subjects may resume treatment in the presence of grade 2 fatigue 
x 
Subjects who have not experienced a grade 3 drug-related skin AE may resume 
treatment in the presence of grade 2 skin toxicity 
x 
Subjects with grade 2 AST, ALT and/or total bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline, and management with 
corticosteroids (if needed) is complete. 
x 
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to 
baseline before treatment is resumed. Participants with persistent grade 1 
pneumonitis after completion of a steroid taper over at least 1 month may be 
eligible for retreatment if discussed with and approved by sponsor-investigator, 
x 
Subjects with drug-related endocrinopathies controlled with only physiologic 
hormone replacement may resume treatment. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
 
5.5 
Concomitant Medications/Treatments 
The following concomitant medications or treatments are not permitted while the patient 
is currently receiving therapy on the protocol: 
x 
Other investigational agents 
x 
Immunosuppressive medications, including systemic corticosteroids 
x 
Concurrent radiation 
x 
Warfarin 
x 
Strong CYP3A4 inducers (such as phenytoin, phenobarbital, primidone, 
carbamazepine, rifampin, rifabutin, rifapentine or St. John’s Wort) and 
inhibitors (such as ketoconazole, clarithromycin, indinavir, itraconazole, 
lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole). 
Please refer to the FDA package insert for nanoliposomal-Irinotecan for 
details. 
x 
Strong UGT1A1 inhibitors (such as atazanavir, gemfibrozil, indinavir and 
ketoconazole). Please refer to the FDA package insert for nanoliposomal- 
Irinotecan for details. 
 
5.6 
Other Modalities or Procedures 
None 
 
5.7 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 2 
years until one of the following criteria apply: 
x 
Disease progression as defined in Section 7.0 
x 
Treatment delay of more than 28 days from last intended therapy 
x 
Inter-current illness that prevents further administration of treatment 

Protocol UMCC 2018.101 
Page 21 of 64 
 
 
x 
Unacceptable adverse event(s) 
x 
Patient voluntarily withdraws from treatment OR 
x 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
5.8 
Off-Treatment Criteria 
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.7 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 5.9. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
 
5.9 
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. 
 
5.10 
Off-Study Criteria 
Patients can be taken off study treatment 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 treatment/study participation will be 
documented and may include: 
 
5.10.1 Patient withdraws consent (termination of treatment and follow-up); 
 
5.10.2 Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
 
5.10.3 Patient is unable to comply with protocol requirements; 
 
5.10.4 Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
 
5.10.5 Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
 
5.10.6 Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
 
5.10.7 Lost to Follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented; 
 
5.10.8 Termination of the study by the Sponsor, the University of Michigan or the FDA; 
 
5.10.9 Patient completes protocol treatment and follow-up criteria; 
 
5.10.10 Patient has confirmed progressive disease as per RECISTv1.1/irRECIST criteria 
and/or, at the discretion of the treating physician, exhibits clinical 
progression which warrants removal from the study. 

Protocol UMCC 2018.101 
Page 22 of 64 
 
 
5.11 
Patient Replacement 
All patients that receive at least one dose of study therapy will be considered evaluable 
for toxicity and will be considered a member of the intent-to-treat (ITT) population. 
 
Patients enrolled on the study will be replaced and not considered a member of the ITT 
for the following reasons 
 
1. Patients who received no investigational therapy on study. 
 
2. Patients that withdraw consent for study therapy prior to first response evaluation not 
secondary to toxicity. 
 
3. Patients meeting off-study criteria 5.10.1 and/or 5.10.3 not secondary to toxicity. 
 
4. Patients meeting off-study criteria 5.10.2 and/or 5.10.5 
 
We expect the proportion of patients needed to be replaced to be extremely small for this 
clinical trial, at or less than 10% of those enrolled. Maximum enrollment to this trial will 
be increased from 30 to 35 and from 40 to 44 patients if the necessity to replace patients 
is encountered. 
 
 
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 

Page 23 of 64 
 
 
Protocol UMCC 2018.101 
 
 
Table 6. Study Calendar 
Procedures 
Screening1 
*Cycle 1 
Cycle 2+ 
 
EOT Visit10 
Follow-Up 
Q3 months +/- 
1 week11 
Day 1 
Day 1 
Informed Consent 
X 
 
 
 
 
History, Physical 
Examination 
X 
X 
X13 
X 
X 
Weight, BSA 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
 
Performance Status 
X 
X 
X13 
X 
 
Toxicity Evaluations12 
 
X 
X13 
X 
X 
CBC with differential 
X 
X 
X 
 
 
CMP2 
X 
X 
X 
 
 
Other labs3 
 
X 
X 
 
 
CA 19-9 (or CEA)4 
X 
X 
X 
X 
 
PT, PTT 
X 
 
 
 
 
Pregnancy Test5 
X 
X 
X 
 
 
Concomitant 
Medication Review 
X 
X 
X13 
 
 
Scans with Tumor 
Measurements6 
X 
 
X 
 
 
Research Blood7 
 
X 
X 
X 
 
Tissue8 
X 
 
X 
X 
 
Study Drug 
Administration9 
 
X 
X 
 
 
Survival Follow-up 
 
 
 
 
X 
*Cycle = 2 weeks 
 
1. All screening procedures to be completed within 2 weeks of registration, except imaging which should be ≤ 4 weeks. Protocol 
treatment is to begin <14 calendar days of registration. 
2. Comprehensive metabolic panel includes BUN/creatinine, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, 
ALT, total bilirubin, total protein and albumin. 
3. Amylase, lipase, random cortisol, TSH, free T4 and free T3 on cycle 1 day 1, and then day 1 of every odd-numbered cycle. 
4. Check CA 19-9 (or CEA, if CA 19-9 not expressed) every odd-numbered cycle, if patient is known to express these tumor markers. 

Protocol UMCC 2018.101 
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5. Required for females of childbearing potential. Serum or urine pregnancy test per site 
investigator discretion. Must be completed prior to every odd numbered cycle. 
6. MRI or CT (abdomen/pelvis) with contrast along with CT chest with/without contrast will be 
assessed as follows: at Screening <4 weeks prior to study enrollment; C2 + performed at 
every 8 + 1 week from C1D1.  Subsequent scans should be performed 8 +1 week from the 
date of last scan. 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. 
7. See Section 10.1 for details. Cycle 1 Day 1 specimens will be collected pre-treatment and 
Cycle X Day 1 specimens will only be collected on Cycle 5 Day 1 prior to drug administration. 
8. Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or 
surgery. Formalin-Fixed Paraffin-Embedded (FFPE) block(s) (preferred), or 20 FFPE slides 
plus H&E slide is required. Procurement of tissue is mandatory for enrollment. On-treatment 
biopsies will only be collected at/after cycle 4 day 1 for patients enrolled at the University of 
Michigan. Post-treatment biopsies on progression are optional (see Section 10.1). 
9. See Section 5.1 for details. Study drug administration with associated labs will have a window 
of + 3 days. 
10. 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. 
11. Patients will be followed every 3 months +/- 1 week after completion of (or early withdrawal 
from) study treatment 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. 
12. 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. 
13. Cycle 2, 3, and then every odd-numbered cycle 
 
 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 
Antitumor Effect- Solid Tumors 
Immunotherapy drugs such as Nivolumab 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 study treatment. 

Protocol UMCC 2018.101 
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Evaluable for primary endpoint, PFS at 4 months. All patients that receive at 
least one dose of study therapy will be considered evaluable. Patients enrolled 
to therapy but that never receive study therapy will be replaced. 
 
Evaluable for objective response. All enrolled patients who have measurable 
disease at registration, receive at least 1 cycle(s) of therapy, and have 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 be considered progressive disease.) 
 
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: 
 
x 
10 mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
x 
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non- 
measurable) 
x 
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). 
 
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 

Protocol UMCC 2018.101 
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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’ 
(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 >10 mm 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 5 mm or less. When CT scans have slice thickness greater than 5 

Protocol UMCC 2018.101 
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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. 
 
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 disease 
progression per RECIST 1.1, or appearance of new lesions since the last 
evaluation. 

Protocol UMCC 2018.101 
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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. 
 
 
Table 7. Evaluation as per combined RECISTv1.1/irRECIST 
 
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. 

Protocol UMCC 2018.101 
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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 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: 
 
x 
Investigator determined clinical benefit 
x 
Tolerance of study drug 
x 
Stable performance status 
x 
Treatment beyond progression will not delay an imminent 
intervention to prevent serious complications of disease 
progression (e.g., CNS metastases) 
x 
Tumor markers are stable/improving, if expressed 
 
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. 
 
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 6.2). 
 
For the subjects who continue study therapy beyond progression, further 
progression is defined as an additional 20% increase in tumor burden 
with a minimum 5 mm absolute increase from time of initial PD. 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. 

Protocol UMCC 2018.101 
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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 5.0 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. Adverse Events of Special Interest as defined in section 8.2.4 will be 
collected throughout the subject’s participation in the study. Serious Adverse Events 
(SAEs) will continue to be followed until: 
 
x 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
x 
There is satisfactory explanation other than the study treatment for the changes 
observed; or 
x 
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. 
 
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. 
 
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 or vital sign finding which requires protocol treatment to be 
modified), symptom, or disease temporally associated with the use of an 
experimental intervention, whether or not related to the intervention. 

Protocol UMCC 2018.101 
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x 
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. 
x 
Anticipated fluctuations of pre-existing conditions, including the disease 
under study, that don’t represent a clinically significant exacerbation or 
worsening, do not need to be reported as AEs. 
 
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: 
 
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the 
investigator [or sponsor investigator], its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event that, 
had it occurred in a more severe form, might have caused death. 
 
o 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours 
 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o 
A congenital anomaly/birth defect 
o 
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. 
 
Events or outcomes not qualifying as SAEs: 
x 
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. 
x 
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. 
x 
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. 

Protocol UMCC 2018.101 
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x 
Events of progression of the patient’s underlying cancer as well as 
events clearly related to progression of the patient’s cancer (signs and 
symptoms of progression) should not be reported as an SAE unless the 
outcome is fatal within the safety reporting period. 
 
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, progression of liver metastasis, or the 
administration of other drug(s) known to be hepatotoxic. 
 
8.2.4 Adverse Events of Special Interest (AESI) 
AESIs (serious or non-serious) are defined as AEs of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be 
appropriate. Such an event might warrant further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid 
communication by the trial sponsor to other parties (e.g., regulators) might also 
be warranted. 
 
These events may differ from those caused by non-immunotherapies and may 
require immunosuppression as part of their management. 
 
All AESIs must be reported as SAEs and will be collected throughout the 
subject’s participation in the study. 
 
The AESI(s) for this trial are: 
x 
Demyelination, 
x 
Encephalitis, 
x 
Guillain-Barré syndrome, 
x 
Myasthenic syndrome, 
x 
Uveitis. 
 
8.2.5 Pregnancy or drug exposure during pregnancy 
If a patient becomes pregnant during the course of the study, dosing should be 
discontinued immediately. 
 
All pregnancies occurring during study participation or within 6 months of last 
dosing must be reported to the Coordinating Center within the same timelines as 
for an SAE. 

Protocol UMCC 2018.101 
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All pregnancies should be followed through to outcome whenever possible. The 
Coordinating Center should be notified once the outcome of a pregnancy is 
known. 
 
The Coordinating Center will be responsible for reporting pregnancy information to 
the FDA and supporters, as appropriate (outlined below). 
 
8.2.6 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
x 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Inserts (Labels). 
x 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochures. 
x 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document. See 
section 9 for the list of expected adverse events related to the drug under 
study. 
x 
The “expectedness” of an event is defined only in relation to the study 
drug(s) and does not relate to it being “anticipated” due to the disease or 
population under study. 
 
8.2.7 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in the protocol, or in the informed 
consent document. 
 
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 5.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 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. 
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. 
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 

Protocol UMCC 2018.101 
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Coordinating Center via fax at 734-232-0744 or via email to CTSU-Oncology-
Multisite@med.umich.edu within 24 hours of the site’s knowledge of the event. 
 
Follow-up information should also be reported within 24 hours of receipt of the 
information by the investigator. 
 
Participating sites should report all SAEs and UPs to their local IRB per current 
local 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). 
 
8.4.2 
Reporting procedures to BMS 
All Serious Adverse Events (SAEs and events of pregnancy) 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. All AESIs will be collected and reported to 
BMS throughout the subject’s participating in the study. 
The Coordinating Center will send the initial completed SAE Form within 24 
hours of receipt via email to BMS Worldwide Safety 
(Worldwide.Safety@bms.com; Fax: 609-818-3804). 
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 Ipsen 
All Serious Adverse Events (SAEs and events of pregnancy) 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 Ipsen. 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 Ipsen. All AESIs 
will be collected and reported to Ipsen throughout the subject’s participating in 
the study. 
The Coordinating Center will send the initial completed SAE Form within 24 
hours of receipt via email to Ipsen (drugsafety.USA@ipsen.com). 
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 Ipsen within 24 hours 
of receipt. 
 
8.4.4 
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. The Michigan IND/IDE 

Protocol UMCC 2018.101 
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Assistance Program (MIAP) will be responsible for reporting SAEs to the FDA 
that meet the reporting requirements in 21 CFR 312.32. 
 
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 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. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator should report it to the Coordinating Center within 
24 hours of awareness and to their local IRB per local guidelines. 
 
8.7 
Safety Report Reconciliation 
The Sponsor-Investigator, or designee will reconcile the clinical database SAE reports 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com and Ipsen 
Oncology (drugsafety.USA@ipsen.com). Frequency of reconciliation should be as 
outlined in the clinical study agreements. BMS GPV&E will email, upon request from the 
Sponsor-Investigator, or designee, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to aepbusinessprocess@bms.com and 
drugsafety.USA@ipsen.com. 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, and/or Ipsen the report should be sent immediately as 
appropriate. 
 
8.8 
Stopping Rules 
There are no formal stopping rules for this study; however, the Data and Safety 
Monitoring Committee (DSMC) of the University of Michigan Rogel Cancer Center is the 
DSMC for this study and will be responsible for monitoring the safety and data integrity of 
the trial as outlined in Section 13. 

Protocol UMCC 2018.101 
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9.0 
DRUG INFORMATION 
 
9.1 
Nanoliposomal-Irinotecan 
 
9.1.1 
Other Names 
Onivyde

9.1.2 
Classification 
nanoliposomal-Irinotecan is formulated with Irinotecan hydrochloride trihydrate, a 
topoisomerase I inhibitor, into a liposomal dispersion for intravenous use. 
 
9.1.3 
Mechanism of Action 
Irinotecan liposome injection is a topoisomerase 1 inhibitor encapsulated in a 
lipid bilayer vesicle or liposome. Topoisomerase 1 relieves torsional strain in 
DNA by inducing single-strand breaks. Irinotecan and its active metabolite SN-38 
bind reversibly to the topoisomerase 1-DNA complex and prevent re-ligation of 
the single-strand breaks, leading to exposure time-dependent double-strand DNA 
damage and cell death. In mice bearing human tumor xenografts, Irinotecan 
liposome administered at Irinotecan HCl-equivalent doses 5-fold lower than 
Irinotecan HCl achieved similar intratumoral exposure of SN-38. 
 
9.1.4 
Pharmacokinetics 
The pharmacokinetic parameters of total Irinotecan and total SN-38 following the 
administration of nanoliposomal-Irinotecan 70mg/m2 as a single agent or part of 
combination chemotherapy are presented in Table 4 of the package insert. Over 
the dose range of 50 to 155 mg/m2, the Cmax and AUC of total Irinotecan 
increases with dose. Additionally, the Cmax of total SN-38 increases 
proportionally with dose; however, the AUC of total SN-38 increases less than 
proportionally with dose. 
 
1. Distribution: 
Direct measurement of Irinotecan liposome showed that 95% of Irinotecan 
remains liposome-encapsulated, and the ratios between total and 
encapsulated forms did not change with time from 0 to 169.5 hours post- 
dose. The mean volume of distribution is summarized in Table 4 of the 
package insert. Plasma protein binding is <0.44% of the total Irinotecan in 
nanoliposomal-Irinotecan. 
 
2. Metabolism: 
The metabolism of Irinotecan liposome has not been evaluated. Irinotecan is 
subject to extensive metabolic conversion by various enzyme systems, 
including esterases to form the active metabolite SN-38, and UGT1A1 
mediating glucuronidation of SN-38 to form the inactive glucuronide 
metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative 
metabolism to several inactive oxidation products, one of which can be 
hydrolyzed by carboxylesterase to release SN-38. In the population 
pharmacokinetic analysis using the results of a subset with UGT1A1*28 
genotypic testing, in which the analysis adjusted for the lower dose 
administered to patients homozygous for the UGT1A1*28 allele, patients 
homozygous (N=14) and non-homozygous (N=244) for this allele had total 
SN-38 average steady-state concentrations of 1.06 and 0.95 ng/mL, 
respectively. 
 
3. Elimination: 

Protocol UMCC 2018.101 
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The disposition of nanoliposomal-Irinotecan has not been elucidated in 
humans. Following administration of Irinotecan HCl, the urinary excretion of 
Irinotecan is 11 to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The 
cumulative biliary and urinary excretion of Irinotecan and its metabolites (SN- 
38 and SN-38 glucuronide), over a period of 48 hours following 
administration of Irinotecan HCl in two patients, ranged from approximately 
25% (100 mg/m2) to 50% (300 mg/m2). 
 
9.1.5 
Storage, Preparation and Stability 
Refer to the current Investigator Brochure for storage, stability and special 
handling information. 
9.1.6 
Dosing and Administration 
See Section 5.1 
nanoliposomal-Irinotecan injection should be administered as a 90 (± 10 minute) 
intravenous infusion without the use of an in-line filter. 
 
9.1.7 
Availability 
Ipsen pharmaceuticals will provide the study drug. 
 
9.1.8 
Handling and Disposal 
The investigator will be instructed by the Coordinating Center on the return or 
destruction of unused nanoliposomal-Irinotecan. If any nanoliposomal-Irinotecan 
is lost or damaged, its disposition should be documented in the source 
documents. nanoliposomal-Irinotecan supplies will be retained at the clinical site 
pending instructions for disposition by the Coordinating Center. 
 
If instructed to do so, unused supplies of nanoliposomal-Irinotecan should be 
destroyed according to institutional policies. Destruction will be documented in 
the drug accountability forms. 
 
9.1.9 
Drug accountability 
The investigator or designee is responsible for taking an inventory of each 
shipment of nanoliposomal-Irinotecan received, and comparing it with the 
accompanying form. Accurate records will be kept in the source documentation 
of all drug administration (including dispensing and dosing). 
 
9.1.10 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. 
The safety data described below are derived from patients with metastatic 
adenocarcinoma of the pancreas previously treated with gemcitabine-based 
therapy who received any part of protocol-specified therapy in Study 1, an 
international, randomized, active-controlled, open-label trial. Protocol- 
specified therapy consisted of nanoliposomal-Irinotecan70 mg/m2 with 
Leucovorin 400 mg/m2 and Fluorouracil 2400 mg/m2 over 46 hours every 2 
weeks (nanoliposomal-Irinotecan/5-FU/LV; N=117), nanoliposomal- 
Irinotecan 100 mg/m2 every 3 weeks (N=147), or Leucovorin 200 mg/m2 and 
Fluorouracil 2000 mg/m2 over 24 hours weekly for 4 weeks followed by 2- 
week rest (5-FU/LV; N=134). Serum bilirubin within the institutional normal 
range, albumin ≥ 3 g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were 
required for study entry. The median duration of exposure was 9 weeks in 
the nanoliposomal-Irinotecan/5-FU/LV arm, 9 weeks in the nanoliposomal- 
Irinotecan monotherapy arm, and 6 weeks in the 5-FU/LV arm. 

Protocol UMCC 2018.101 
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The most common adverse reactions (≥ 20%) of nanoliposomal-Irinotecan 
were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, 
stomatitis, and pyrexia. The most common, severe laboratory abnormalities 
(≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most common 
serious adverse reactions (≥ 2%) of nanoliposomal-Irinotecan were diarrhea, 
vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, 
dehydration, septic shock, pneumonia, acute renal failure, and 
thrombocytopenia. 
 
Adverse reactions led to permanent discontinuation of nanoliposomal- 
Irinotecan in 11% of patients receiving nanoliposomal-Irinotecan/5-FU/LV; 
the most frequent adverse reactions resulting in discontinuation of 
nanoliposomal-Irinotecan were diarrhea, vomiting, and sepsis. Dose 
reductions of nanoliposomal-Irinotecan for adverse reactions occurred in 
33% of patients receiving nanoliposomal-Irinotecan/5-FU/LV; the most 
frequent adverse reactions requiring dose reductions were neutropenia, 
diarrhea, nausea, and anemia. nanoliposomal-Irinotecan was withheld or 
delayed for adverse reactions in 62% of patients receiving nanoliposomal- 
Irinotecan/5-FU/LV; the most frequent adverse reactions requiring 
interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and 
thrombocytopenia. 
 
2. Pregnancy 
Risk Summary - Based on animal data with Irinotecan HCl and the 
mechanism of action of nanoliposomal-Irinotecan, nanoliposomal-Irinotecan 
can cause fetal harm when administered to a pregnant woman. There are no 
available data in pregnant women. Embryotoxicity and teratogenicity were 
observed following treatment with Irinotecan HCl, at doses resulting in 
Irinotecan exposures lower than those achieved with nanoliposomal- 
Irinotecan 70 mg/m2 in humans, administered to pregnant rats and rabbits 
during organogenesis [see Data]. Advise pregnant women of the potential 
risk to a fetus. In the U.S. general population, the estimated background risk 
of major birth defects and miscarriage in clinically recognized pregnancies is 
2-4% and 15-20%, respectively. 
 
Data - Animal Data No animal studies have been conducted to evaluate the 
effect of Irinotecan liposome on reproduction and fetal development; 
however, studies have been conducted with Irinotecan HCl. Irinotecan 
crosses the placenta of rats following intravenous administration. Intravenous 
administration of Irinotecan at a dose of 6 mg/kg/day to rats and rabbits 
during the period of organogenesis resulted in increased post-implantation 
loss and decreased numbers of live fetuses. In separate studies in rats, this 
dose resulted in an Irinotecan exposure of approximately 0.002 times the 
exposure of Irinotecan based on area under the curve (AUC) in patients 
administered nanoliposomal-Irinotecan at the 70 mg/m2 dose. Administration 
of Irinotecan HCl resulted in structural abnormalities and growth delays in 
rats at doses greater than 1.2 mg/kg/day (approximately 0.0002 times the 
clinical exposure to Irinotecan in nanoliposomal-Irinotecan based on AUC). 
Teratogenic effects included a variety of external, visceral, and skeletal 
abnormalities. Irinotecan HCl administered to rat dams for the period 
following organogenesis through weaning at doses of 6 mg/kg/day caused 
decreased learning ability and decreased female body weights in the 
offspring. 

Protocol UMCC 2018.101 
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3. Lactation: 
Risk Summary - There is no information regarding the presence of Irinotecan 
liposome, Irinotecan, or SN-38 (an active metabolite of Irinotecan) in human 
milk, or the effects on the breastfed infant or on milk production. Irinotecan is 
present in rat milk [see Data below]. Because of the potential for serious 
adverse reactions in breastfed infants from nanoliposomal-Irinotecan, advise 
a nursing woman not to breastfeed during treatment with nanoliposomal- 
Irinotecan and for one month after the final dose. 
Data - Radioactivity appeared in rat milk within 5 minutes of intravenous 
administration of radiolabeled Irinotecan HCl and was concentrated up to 65- 
fold at 4 hours after administration relative to plasma concentrations. 
 
4. Drug Interactions: 
In a population pharmacokinetic analysis, the pharmacokinetics of total 
Irinotecan and total SN-38 were not altered by the co-administration of 
Fluorouracil/Leucovorin. Following administration of Irinotecan HCl, 
dexamethasone, a moderate CYP3A4 inducer, does not alter the 
pharmacokinetics of Irinotecan. In vitro studies indicate that Irinotecan, SN- 
38 and another metabolite, aminopentane carboxylic acid (APC), do not 
inhibit cytochrome P-450 isozymes. 
 
Strong CYP3A4 Inducers Following administration of non-liposomal 
Irinotecan (i.e., Irinotecan HCl), exposure to Irinotecan or its active 
metabolite, SN-38, is substantially reduced in adult and pediatric patients 
concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants 
phenytoin and strong CYP3A4 inducers. Avoid the use of strong CYP3A4 
inducers (e.g., rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, 
phenobarbital, St. John’s Wort) if possible. Substitute non-enzyme inducing 
therapies at least 2 weeks prior to initiation of Onivyde therapy. 7.2 Strong 
CYP3A4 or UGT1A1 Inhibitors Following administration of non-liposomal 
Irinotecan (i.e., Irinotecan HCl), patients receiving concomitant ketoconazole, 
a CYP3A4 and UGT1A1 inhibitor, have increased exposure to Irinotecan and 
its active metabolite SN-38. Co-administration of nanoliposomal-Irinotecan 
with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, 
lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, 
voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil, indinavir) may 
increase systemic exposure to Irinotecan or SN-38. Avoid the use of strong 
CYP3A4 or UGT1A1 inhibitors if possible. 
 
9.2 
5-Fluorouracil (5-FU) 
5-FU will be supplied from commercially available product obtained through the local 
hospital pharmacy or licensed distributor in accordance with local guidelines. For 
complete details on drug preparation, administration, storage conditions, clinical 
pharmacology, pharmacokinetics, known precautions, warnings and adverse reactions 
please see the 5-FU package insert. 
 
9.3 
Leucovorin (LV) 
Leucovorin will be supplied from commercially available product obtained through the 
local hospital pharmacy or licensed distributor in accordance with local guidelines. For 
complete details on drug preparation, administration, storage conditions, clinical 
pharmacology, pharmacokinetics, known precautions, warnings and adverse reactions 
please see the Leucovorin package insert. Note, Leucovorin should not be mixed in the 
same infusion as 5-Fluorouracil, since this may lead to the formation of a precipitate. 

Protocol UMCC 2018.101 
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9.4 
Nivolumab 
 
9.4.1 
Other Names 
Opdivo, BMS-936558, MDX-1106, ONO-4538 
 
9.4.2 
Classification 
Immunomodulatory; checkpoint inhibitor 
 
9.4.3 
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. 
 
9.4.4 
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. 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. 
 
9.4.5 
Storage, Preparation and Stability 
Nivolumab is supplied as 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. Do not freeze or shake. 
 
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 
reference sheets. Briefly, withdraw the required volume and transfer into an IV 
container or dilute with either NS or D5W to protein concentration as low as 
0.35mg/mL. The total volume of infusion must not exceed 160mL and for patients 
with body weight of less than 40 kg it must not exceed 4mL/kg of body weight. 
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), polyolefin 
containers and infusion sets, 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 8 hours of the total 24 hours can be at room temperature (up to 
25°C, 77°F) and room light. The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period. 
 
9.4.6 
Dose and Administration 
See Section 5.1 

Protocol UMCC 2018.101 
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Nivolumab is to be administered as a 30 (± 10 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. 
 
9.4.7 
Availability 
Bristol-Myers Squibb (BMS) will provide the study drug. 
 
9.4.8 
Handling and Disposal 
The investigator will be instructed by the Coordinating Center on the destruction 
of unused Nivolumab. If any Nivolumab is lost or damaged, its disposition should 
be documented in the source documents. Nivolumab disposal will be conducted 
at individual sites and will not be returned to BMS. Nivolumab supplies will be 
retained at the clinical site pending instructions for disposition by the 
Coordinating Center. Recommended safety measures for preparation and 
handling of Nivolumab include laboratory coats and gloves. 
 
When instructed to do so, unused supplies of Nivolumab should be destroyed 
according to institutional policies. Destruction will be documented in the drug 
accountability forms. 
 
9.4.9 
Drug accountability 
The investigator or designee is responsible for taking an inventory of each 
shipment of Nivolumab received, and comparing it with the accompanying form. 
Accurate records will be kept in the source documentation of all drug 
administration (including dispensing and dosing). 
 
9.4.10 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). 
 
The most common adverse reaction (≥20%) in patients with melanoma was 
rash. The most common adverse reactions (≥20%) in patients with 
advanced squamous non-small cell lung cancer were fatigue, dyspnea, 
musculoskeletal pain, decreased appetite, cough, nausea, and constipation. 
 
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 
reasonable possibility that BMS- 936558 (Nivolumab, MDX-1106) caused the 
adverse event: 

Protocol UMCC 2018.101 
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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) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchospasm; Cough; Dyspnea; Hypoxia; Respiratory failure; Respiratory, 

Protocol UMCC 2018.101 
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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 5 months (for women) and 7 months (for 
men) 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. 
 
 
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 nanoliposomal- 
Irinotecan 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 RNA later. 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- 

Protocol UMCC 2018.101 
Page 44 of 64 
 
 
1L), CD80, CD86, B7-H4, B7-HDC (PD-L2), CTLA4, CD28, LAG3, Tim-3, CD40, OX40)23,24. 
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)25 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 markers23 (for patients at University of Michigan). Biologic markers and RNA 
expression will be examined in the context of patient efficacy. 
 
10.1 
Tissue Collection Guidelines (See Laboratory Manual for details) 
 
Pre- and Post-treatment (for patient at all sites excluding University of Michigan): 
1. Pre-treatment: Screening: 
Formalin-fixed paraffin-embedded (FFPE) diagnostic tumor tissue block(s) is preferred to 
allow IHC and genomic/immune profiling. If not, then up to 20 FFPE 5 micron slides plus 
a H&E slide from a core biopsy block will be required for IHC. Procurement of tissue is 
mandatory to complete correlative studies. 
 
2. Post-treatment biopsy for research (optional): 
Tissue should be collected, processed and shipped to University of Michigan as detailed 
in the lab manual. 
 
Pre-, On- and Post-treatment (for patients enrolled at University of Michigan): 
1. Pre-treatment tissue collection: Screening 
2. On-treatment biopsy for research: Cycle 4 Day 1 
3. Post-treatment biopsy for research (optional): EOT 
Please refer to the lab manual for 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. 
 
10.2 
Blood Collection Guidelines 
Blood samples will be collected at three different time-points for each patient as detailed 
below: 
1. Pre-treatment: Cycle 1 Day 1 
2. On-treatment: Cycle 5 Day 1 
3. Post-treatment: EOT 
 
Blood will be collected, processed and shipped to the University of Michigan as detailed in 
the lab manual. 
 
10.3 
Specimen Banking 
Patient blood and tissue samples collected for this study will be retained at University of 
Michigan for optional unspecified future research. 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. 
 
All CT scans should be de-identified and coded using trial patient and site IDs and 
submitted to the University of Michigan for banking and exploratory endpoint assessment. 
Refer to Lab Manual for details. 

Protocol UMCC 2018.101 
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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 
 
11.1 
Study Design/Study Endpoints 
This protocol will enroll patients with advanced unresectable BTC who have received one 
and only one prior systemic therapy (not including Irinotecan or PD-1 antibody) and have 
either progressed or deemed intolerant to at front-line systemic therapy. The primary 
endpoint of phase Ib portion of the trial is determination of RP2D and DLTs and the 
primary endpoint of the phase II portion is median PFS following the initiation of study 
treatment. Secondary endpoints include the calculation of the ORR, median OS (from 
start of study treatment and 1st line therapy), and the incidence of adverse events. 
 
11.2 
Sample Size and Accrual 
A limited phase 1b trial will be implemented to assure that dose levels suggested for this 
combination are safe. Because toxicity across the combined agents is expected to be 
additive rather than synergistic and in light of the poor prognosis for this patients, we are 
willing to tolerate up to but not exceeding 30% DLT toxicity proportion during the first 4 
weeks of therapy. To investigate this, we will enroll up to 10 patients to the phase Ib 
portion of this trial at dose level 0. If>4 patients of the first 5 to 10 patients enrolled into 
this cohort have a DLT during the first 4 weeks of therapy then accrual at dose level 0 will 
halt if yet to reach 10. Dose level will then be abandoned in favor of dose level -1. The 
operating characteristics for this schema for different values for the true probability of 
DLT are given in the table 3 below. 
 
Table 8. Operating Characteristics for Trial Schema 
Probability of 
DLT 
Probability 
of early 
stopping 
Probability 
declaring level 
not safe 
Expected 
sample 
size 
Expected number 
of patient 
experiencing DLT† 
0.20 
0.007 
0.032 
10 
2.0 
0.25 
0.020 
0.075 
10 
2,5 
0.30 
0.050 
0.149 
9.9 
3.0 
0.35 
0.100 
0.250 
9.8 
3.4 
0.40 
0.167 
0.371 
9.7 
3.8 
0.45 
0.263 
0.500 
9.4 
4.1 
0.50 
0.379 
0.623 
9.1 
4.4 
†Mean number of patients experiencing toxicity for each trial, whether stopped early or 
complete accrual. 
 
If the toxicity boundary of 4 is crossed at dose level 0, up to an additional 10 patients will 
be accrued at dose level -1 and the same rules applied. If at dose level -1 more than 4 
patients experience DLT, then the trial will be stopped and the combination abandoned. 
However, if either the 10-patient cohorts at dose level 0 or level -1 conclude without 
tripping the toxicity rule then that dose level will be declared the recommended phase 2 
dose (RP2D) with an additional 20 patients enrolled at that dose level for the Phase 2 
assessment of efficacy as measured by the median PFS. The median PFS of second line 
treatment of cholangiocarcinoma is expected to be 2.9 months (null) and we expect that 
the median PFS will be 5.0 months (alternate hypothesis) for this study’s combination. 
We anticipate that we can accrue 1.7 patients per month for 18 months (between phase 
1b and phase 2); we will follow all patients for progression and survival for 12 months 
following the accrual of the last patient. This will afford 83% power to detect the 

Protocol UMCC 2018.101 
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hypothesized difference in median PFS time, using a two-sided test with at most 5% type 
one error. Patients on the phase Ib portion of this trial treated at the RP2D will be 
included in the population for the analysis of the primary endpoint of the phase II portion 
of the trial. 
 
During the phase 2 portion of the trial, we will continue to monitor patients for toxicity, 
identically as during the first 4-weeks of therapy as for the phase I patients. If at any 
point during the conduct of the phase 2 portion of this trial, the observed proportion of 
first-cycle dose-limiting toxicity is 45% or above at the RP2D then we will halt new accrual 
to the trial. The DSMB for this trial will then reconsider the appropriate level for the RP2D 
in light of the proportion, type, severity, and reversibility of DLTs. 
 
11.3 
Study Populations 
The evaluable population for the primary, secondary, and safety endpoints is the intent- 
to-treat (IIT) population as defined in section 5.11. 
 
11.4 
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 treatment), 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. ORR will 
be determined as per the irRECIST guidelines for the IIT population. Other safety data 
(e.g., laboratory safety parameters, vital signs, and new physical examination findings) 
will be summarized descriptively for the IIT population by reporting counts and 
percentages, with exact binomial confidence intervals where appropriate. Adverse events 
will be reported per the NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
version 5.0. 
 
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 
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: 
x 
At the time of registration 

Protocol UMCC 2018.101 
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o 
Subject entry into the EDC 
 
Subject Status 
 
Demographics 
x 
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 8.4 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 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center 
Data and Safety Monitoring Committee (DSMC). 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring of 
data and patient safety in this trial and conduct regular data review with participating sites. 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate 
will review data and patient safety issues with participating sites per a defined monthly meeting 
cadence. Depending on the protocol activity, the meeting cadence may be more frequent. This 
data review meeting may be achieved via a teleconference or another similar mechanism to 
discuss matters related to: 
 
¾ Enrollment rate relative to expectations, characteristics of participants 
¾ Safety of study participants (SAE reporting, unanticipated problems) 
¾ Adherence to protocol (protocol deviations) 
¾ Completeness, validity and integrity of study data 
¾ Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion. 
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the 
review period and their site’s data are in alignment with the data reported in the database. 
Written confirmation is to be provided to the Project Manager/Delegate within the timeline 
requested to retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to 
be retained in the Trial Master File.  
 
The Project Manager/Delegate is responsible for collating the data from all participating sites 
and completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to 
document the data review meeting discussion.  

Protocol UMCC 2018.101 
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The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a monthly basis for independent 
review. 
 
14.0 
QUALITY ASSURANCE AND AUDITS 
The DSMC 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. 
 
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. 

Protocol UMCC 2018.101 
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15.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by the University of Michigan Rogel Cancer Center 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 University of 
Michigan Rogel Cancer Center. 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 
Coordinating Center 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 Cycle 2. 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: 
 
¾ 
Adherence to the protocol 
¾ 
Completeness and accuracy of study data and samples collected 
¾ 
Proper storage, dispensing and inventory of study medication 
¾ 
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. 
 
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. 

Protocol UMCC 2018.101 
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16.0 
REFERENCES 
1. 
Shaib Y, El-Serag HB. The Epidemiology of Cholangiocarcinoma. Semin Liver Dis. 
2004;24(2):115-125. doi:10.1055/s-2004-828889. 
2. 
Valle J, Wasan H, Palmer D, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract 
cancer. N Engl J Med. 2010;4(4):395-397. doi:10.1586/egh.10.45. 
3. 
Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after 
surgery for cholangiocarcinoma: A 30-Year population-based SEER database analysis. J 
Gastrointest Surg. 2007;11(11):1488-1497. doi:10.1007/s11605-007-0282-0. 
4. 
Sebbagh. Effects of the sequential administration of GEMOX followed by FOLFIRI in 
cholangiocarcinoma. J Clin Oncol. 2014;(32):suppl3; abstr 348. 
5. 
Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary 
cancer: a systematic review. Ann Oncol. 2014;25(12):2328-2338. doi:10.1093/annonc/mdu162. 
6. 
Sanz-Altamira PM, O’Reilly E, Stuart KE, et al. A phase II trial of Irinotecan (CPT-11) for 
unresectable biliary tree carcinoma. Ann Oncol. 2001;12(4):501-504. 
doi:10.1023/A:1011135014895. 
7. 
Kim RD. SWOG S1310: Randomized phase II trial of single agent MEK inhibitor trametinib vs. 5- 
Fluorouracil or capecitabine in refractory advanced biliary cancer. J Clin Oncol. 2017;(35):suppl; 
abstr 4016. 
8. 
Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly active 
nanoliposomal Irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 
2006;66(6):3271-3277. doi:10.1158/0008-5472.CAN-05-4007. 
9. 
Passero FC, Grapsa D, Syrigos KN, Saif MW. The safety and efficacy of Onivyde (Irinotecan 
liposome injection) for the treatment of metastatic pancreatic cancer following gemcitabine-based 
therapy. Expert Rev Anticancer Ther. 2016;16(7):697-703. doi:10.1080/14737140.2016.1192471. 
10. 
Chen L-T, Wang-Gillam A, Li C-P, et al. Final results of NAPOLI-1: A phase 3 study of 
nanoliposomal-IRI (MM-398) ± 5-Fluorouracil and Leucovorin (5-FU/LV) vs 5-FU/LV in metastatic 
pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. Ann Oncol. 
2016;27(suppl_6):622PD-622PD. doi:10.1002/ijc.29210. 
11. 
Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the Pd-1 Immunoinhibitory Receptor by a 
Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. J Exp Med. 
2000;192(7):1027-1034. doi:10.1084/jem.192.7.1027. 
12. 
Nishimura H, Honjo T. PD-1: An inhibitory immunoreceptor involved in peripheral tolerance. 
Trends Immunol. 2001;22(5):265-268. doi:10.1016/S1471-4906(01)01888-9. 
13. 
Carter LL, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T 
cells and is overcome by IL-2. Eur J Immunol. 2002;32(3):634-643. doi:10.1002/1521- 
4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9. 
14. 
Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell 
activation. Nat Immunol. 2001;2(3):261-268. doi:10.1038/85330. 
15. 
Bang YJ, Doi T, Braud F De, et al. 525 Safety and efficacy of pembrolizumab (MK-3475) in 
patients (pts) with advanced biliary tract cancer: Interim results of KEYNOTE-028. Eur J Cancer. 
2015;51:S112. doi:10.1016/S0959-8049(16)30326-4. 
16. 
ClinicalTrial.Gov. 2017. 
17. 
Peng J, Hamanishi J, Matsumura N, et al. Chemotherapy induces programmed cell death-ligand 1 
overexpression via the nuclear factor-κBto foster an immunosuppressive tumor microenvironment 
in Ovarian Cancer. Cancer Res. 2015;75(23):5034-5045. doi:10.1158/0008-5472.CAN-14-3098. 
18. 
Emens LA, Middleton G. The Interplay of Immunotherapy and Chemotherapy: Harnessing 
Potential Synergies. Cancer Immunol Res. 2015;3(5):436-443. doi:10.1158/2326-6066.CIR-15- 
0064. 
19. 
Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid- 
derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 
2010;70(8):3052-3061. doi:10.1158/0008-5472.CAN-09-3690. 
20. 
Kim HS, Park HM, Park JS, et al. Dendritic cell vaccine in addition to FOLFIRI regimen improve 
antitumor effects through the inhibition of immunosuppressive cells in murine colorectal cancer 
model. Vaccine. 2010;28(49):7787-7796. doi:10.1016/j.vaccine.2010.09.046. 
21. 
Weiss GJ, Waypa J, Blaydorn L, et al. A phase Ib study of pembrolizumab plus chemotherapy in 
patients with advanced cancer (PembroPlus). Br J Cancer. 2017;117(1):33-40. 

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doi:10.1038/bjc.2017.145. 
22. 
Khemka V, Haire P, Waypa J, Weiss G. P-278Phase Ib/II study of Nivolumab plus CAPIRI: Initial 
results of metastatic colon cancer and pancreatic adenocarcinoma patients. Ann Oncol. 
2016;27(suppl 2):ii80-ii81. doi:10.1093/annonc/mdw199.268. 
23. 
Ke W, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human 
hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 
2009;69(20):8067-8075. doi:10.1158/0008-5472.CAN-09-0901. 
24. 
Lou Y, Diao L, Cuentas ERP, et al. 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. 2016;22(14):3630-3642. 
doi:10.1158/1078-0432.CCR-15-1434. 
25. 
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: A knowledge-based 
approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 
2005;102(43):15545-15550. doi:10.1073/pnas.0506580102. 

Protocol UMCC 2018.101 
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17.0 
APPENDICES 
 
Appendix I 
ECOG Performance Status 
Appendix II 
Child-Pugh Score 
Appendix III 
Management Algorithms for Immuno-Oncology Agents 
Appendix IV 
Investigator’s Statement 
  Appendix V       Study Management during COVID-19

Protocol UMCC 2018.101 
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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 

Protocol UMCC 2018.101 
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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 
Prothrombin Time 
x PT >ULN 
x INR 
 
1-3 
<1.7 
4-6 
1.7-2.3 
>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: Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The Liver and 
Portal Hypertension. Philadelphia: Saunders; 1964. pp. 50–58. 

Protocol UMCC 2018.101 
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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 (I-O) 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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Protocol UMCC 2018.101 
 
 
Appendix IV 
Investigator’s Statement 
 
1. I have carefully read this protocol entitled “A Single Arm Phase Ib/II Multi-Center Study of 
Nivolumab in combination with nanoliposomal-Irinotecan, 5-Fluorouracil, and Leucovorin as 
Second Line Therapy for Patients with Advanced Biliary Tract Cancer”, version 5.0 dated 
11Nov2020 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: 
  
\ 
 \  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 63 of 64 
 
Protocol UMCC 2018.101 
 
 
Appendix V       Study Management during COVID-19 
Due to ongoing government and clinical changes necessary to effectively manage the COVID-19 
pandemic, the following changes to protocol-required items were made to minimize or eliminate 
immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure 
to COVID-19).  
 
A. COVID-19 Testing:  
x 
COVID-19 is not currently being added to the protocol as part of the screening requirements, but 
may be done as part of the clinical assessment, as needed during the course of the pandemic. 
x 
COVID-19 tests/results will be recorded in the subject’s source documents but will only be added 
as an Adverse/ Serious Adverse Event in the eCRF should the test yield a COVID-19 positive 
result.  
 
B. Study Visit Schedule: 
x 
For individual instances where assessments cannot be made and/or data are not able to be 
collected, the reasons for failing to obtain the data should be documented (e.g., identifying the 
specific limitation imposed by COVID-19 leading to the inability to perform the protocol-specified 
assessment). 
x 
Ongoing participants who are unable or unwilling to attend protocol-specified trial visits and 
procedures, may continue in the trial if the Principal Investigator (PI) deems it appropriate and for 
as long as the patient continues to consent to participation and where patient safety can be 
monitored. 
x 
Where participants cannot be seen at the site or by home visit, the use of telemedicine and 
adaptation of schedule of assessments will be implemented, where feasible to ensure patient 
safety. 
x 
Adjustments to the protocol imaging visit window (8 ±1 week) are permitted by the Sponsor-
Investigator if on-schedule visits are not possible due to COVID-19. 
 
C. Laboratory Assessments: 
x 
Screening tissue & End of Treatment (EOT) biopsy samples – will be obtained only at approved 
sites, if applicable/possible, and will be retained at site until further notification. 
x 
Cycle 1 Day 1, Cycle 5 Day 1 and EOT – blood will be obtained if possible and will be processed 
and shipped per the study lab manual.  If the research lab closes and is unavailable to accept 
samples, this will be communicated out to the study team.   
x 
Cycle 4 Day 1 – biopsy sample will be obtained if possible.  If the research lab closes and is 
unavailable to accept biopsy samples this will be communicated out to the study team. 
 
D. Study Medications: 
x 
Adjustments for alternate drug administration have been permitted by the Supporters (Ipsen and 
Bristol-Myers Squibb) and Sponsor-Investigator, stating that ongoing participants who are unable 
or unwilling to attend protocol-specified trial visits and procedures, may continue in the trial if the 
site PI deems it appropriate and for as long as the patient continues to consent to participation and 
where patient safety can be monitored.  
x 
The patient may remain on study without receiving drug for more than 28 days if the drug(s) are 
held due to COVID-19. 
x 
If a patient does not receive investigational regimen consecutively for 4 weeks from last intended 
dose between consecutive CT scans due to COVID-19, then the patient may continue on treatment 
despite progression on CT scan.