Phase II Multi-Center Study of PARP Inhibitor Rucaparib in Combination With Anti-PD-1 Antibody Nivolumab in Patients With Advanced or Metastatic Biliary Tract Cancer Following Platinum Therapy
Phase: PHASE2
Conditions: Biliary Tract Cancer
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 
2018.044 
     
 
 
 
 
 
 
 
Rucaparib in Combination With Nivolumab in 
Patients With Advanced or Metastatic Biliary Tract 
Cancer Following Platinum Therapy 
    NCT03639935 
 

 
 
UMCC 2018.044 
Phase II Multi-Center Study of PARP inhibitor Rucaparib in Combination with Anti-PD-1 Antibody 
Nivolumab in Patients with Advanced or Metastatic Biliary Tract Cancer Following Platinum 
Therapy  
[CA209-8HY] [338-IIT-090] 
 
Principal Investigator:  
Vaibhav Sahai, MBBS, MS 
 
 
 
 
Division of Hematology/Oncology Department of Internal Medicine 
 
University of Michigan 
 
 
 
 
1500 E. Medical Center Drive 
C412 Med Inn Building 
 
 
 
 
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 
 
Study Drug: 
 
 
Nivolumab (Opdivo®) 
 
 
 
 
Rucaparib (Rubraca®) 
 
 
Initial version:  
 
V 1.0 16Apr2018 
Amended: 
 
 
V 1.1 13May2018 
 
 
 
V 1.2 26June2018 
 
 
 
V 2.0 02July2018 
 
 
 
V 3.0 24April2020 
 
 
 
V 3.1 08June2020 
 
 
 
V 4.0 24November2020 
 
 
NOTE: To effectively manage the COVID-19 pandemic restrictions, 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). These changes are listed in Appendix V of the protocol 
(Study Management during COVID-19). 
 
 
 
 
 
 

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TABLE OF CONTENTS 
STUDY SYNOPSIS ..........................................................................................................6 
1.0 
BACKGROUND AND RATIONALE ............................................................9 
1.1 
Biliary Tract Cancer - Disease Overview ......................................................................... 9 
1.2 
Role of PARP inhibitors in BTC ....................................................................................... 9 
1.3 
Role of Checkpoint Inhibitors in BTC ............................................................................. 10 
1.4 
Rationale ........................................................................................................................ 11 
1.5 
Correlative Studies ........................................................................................................ 11 
2.0 
STUDY OBJECTIVES .................................................................................12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................... 12 
2.3 
Exploratory Objectives ................................................................................................... 12 
2.4 
Endpoints Assessment .................................................................................................. 12 
3.0 
PATIENT ELIGIBILITY ................................................................................12 
3.1 
Eligibility Criteria ............................................................................................................ 12 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES .......14 
5.0 
TREATMENT PLAN.....................................................................................15 
5.1 
Treatment Dosage and Administration .......................................................................... 15 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 15 
5.3 
Management Algorithms for Immuno-Oncology Agents ................................................ 18 
5.4 
Concomitant Medications/Treatments ........................................................................... 18 
5.5 
Other Modalities or Procedures ..................................................................................... 18 
5.6 
Duration of Therapy ....................................................................................................... 18 
5.7 
Off Treatment Criteria .................................................................................................... 19 

Protocol UMCC 2018.044 
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5.8 
Duration of Follow-Up .................................................................................................... 19 
5.9 
Off Study Criteria ........................................................................................................... 19 
5.10 
Patient Replacement ..................................................................................................... 20 
6.0 
STUDY PROCEDURES ..............................................................................20 
6.1 
Screening/Baseline Procedures .................................................................................... 20 
6.2 
Time and Events Table/Schedule of Events/Study Calendar........................................ 20 
7.0 
MEASUREMENT OF EFFECT...................................................................22 
7.1 
Antitumor Effect- Solid Tumors ...................................................................................... 22 
7.2 
Safety/Tolerability .......................................................................................................... 28 
8.0 
ADVERSE EVENTS .....................................................................................28 
8.1 
Adverse Event Reporting Requirements ....................................................................... 28 
8.2 
Definitions ...................................................................................................................... 28 
8.3 
Adverse Event Characteristics ...................................................................................... 31 
8.4 
Serious Adverse Event Reporting Guidelines ............................................................... 32 
8.5 
Routine Reporting .......................................................................................................... 33 
8.6 
Reporting of Unanticipated Problems ............................................................................ 33 
8.7 
Safety Report Reconciliation ......................................................................................... 33 
8.8 
Stopping Rules .............................................................................................................. 34 
9.0 
DRUG INFORMATION ................................................................................34 
9.1 
Rucaparib camsylate ..................................................................................................... 34 
9.2 
Nivolumab ...................................................................................................................... 37 
10.0 
CORRELATIVES/TRANSLATIONAL STUDIES ....................................40 
10.1 
Tissue Collection Guidelines (See Laboratory Manual for details) ............................... 41 
10.2 
Blood Collection Guidelines ........................................................................................... 41 
10.3 
Specimen Banking ......................................................................................................... 42 

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11.0 
STATISTICAL CONSIDERATIONS ..........................................................42 
11.1 
Study Design/Study Endpoints ...................................................................................... 42 
11.2 
Sample Size and Accrual .............................................................................................. 42 
11.3 
Study Populations .......................................................................................................... 42 
11.4 
Data Analyses Plans...................................................................................................... 43 
11.5 
Early Stopping Rules Due to Toxicity ............................................................................ 43 
12.0 
ADMINISTRATIVE PROCEDURES ..........................................................44 
12.1 
Ethics and good clinical practice ................................................................................... 44 
12.2 
Data Management ......................................................................................................... 44 
12.3 
Record Retention ........................................................................................................... 45 
13.0 
DATA AND SAFETY MONITORING ........................................................45 
14.0 
QUALITY ASSURANCE AND AUDITS ...................................................45 
15.0 
CLINICAL MONITORING PROCEDURES ..............................................46 
16.0 
REFERENCES ..............................................................................................48 
17.0 
APPENDICES ...............................................................................................51 
Appendix I 
ECOG Performance Status ................................................................................ 52 
Appendix II 
Child-Pugh Score ............................................................................................... 53 
Appendix III 
Management Algorithms for Immuno-Oncology Agents .................................... 54 
Appendix IV 
Investigator’s Statement ..................................................................................... 62 
Appendix V 
Study Management during COVID-19 ............................................................... 63 

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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 
IDH 
Isocitrate dehydrogenase 
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 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TIL 
Tumor Infiltrating Leukocytes 
UaP 
Unanticipated Problem 
WBC 
White Blood Cells 
 
 
 

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STUDY SCHEMA 
 
 
STUDY SYNOPSIS 
Title 
Phase II Multi-center Study of PARP inhibitor Rucaparib in Combination with Anti-
PD-1 Antibody Nivolumab in Patients with Advanced or Metastatic Biliary Tract 
Cancer Following Platinum Therapy. 
Phase 
Phase II 
Methodology 
Single arm, open-label 
Study Duration 
3 years 
Study Center(s) 
Multi-Center: 3 sites total including lead site: University of Michigan 
Objectives 
Primary objective: 
1. Determine the PFS rate at 4 months in patients with advanced BTC treated 
with rucaparib and nivolumab following 1st line platinum based therapy. 
 
Secondary objectives: 
1. Evaluate the ORR and median PFS and OS as measured from start of study 
treatment and start of initial platinum therapy in patients with advanced BTC. 
2. Evaluate the safety of rucaparib and nivolumab in this patient population. 
3. Evaluate the ORR, median PFS and OS in patients with and without DNA 
damage response (DDR) and isocitrate dehydrogenase (IDH) signatures. 
 
Exploratory objectives: 
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, 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. 
Number of 
Subjects 
32 patients meeting intent-to-treatment guidelines.  Up to 35 patients may be 
enrolled to allow for a small number of patients to be replaced, if necessary. 
Eligibility Criteria 
1. Patients must have a pathologically confirmed adenocarcinoma 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 
of mixed histology are excluded. 
2. Patients must have received 1st line platinum-based chemotherapy for 
advanced BTC for 4-6 months (16-24 weeks) without radiologic or clinical 
progression. Last systemic infusion of 1st line platinum-based therapy may not 
be more than 4 weeks from study informed consent. Prior peri-operative 
chemotherapy is permitted provided it was completed > 6 months from start 
 
Advanced or metastatic 
biliary tract cancer 
(N=32) 
Absence of progression 
after > 4 months on 1st line 
platinum systemic therapy 
Nivolumab 240 mg IV  
day 1, 15 + 
Rucaparib 600 mg BID 
days 1-28 Q28 days 
1o endpoint - PFS rate 4 months 
2 o endpoints – ORR, median PFS & OS 

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of platinum-based therapy for advanced disease. 
3. Prior surgical resection, radiation, chemoembolization, radioembolization or 
other local ablative therapies are permitted if completed ≥ 4 weeks prior to 
enrollment AND if patient has recovered to ≤ grade 1 toxicity. 
4. Patients must have radiographically measurable disease (as per 
RECISTv1.1) in at least one site not previously treated with radiation or liver 
directed therapy (including bland, chemo- or radio-embolization, or ablation) 
either within the liver or in a metastatic site unless the patient has had 
complete response to 1st line platinum-based therapy.  
5. Age ≥18 years 
6. Child-Pugh score of A or B7  
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 obtained ≤2 weeks prior to registration (absolute 
neutrophil count >1500/mm3, hemoglobin >9 g/dL, platelets >100,000/mm3, 
serum creatinine < 1.5 x upper limit normal (ULN), creatinine clearance >= 50 
mL/min, albumin >3.0 g/dL, AST/ALT <3.0 x ULN (<5 x ULN if liver 
metastasis), total bilirubin ≤ 1.5 x upper limit normal. 
12. Must not have a diagnosis of immunodeficiency, or received systemic steroid 
therapy, or any other form of immunosuppressive therapy within 14 days prior 
to trial treatment. 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 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 planned start of the 
study therapy. 
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 rucaparib 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 blood or urine test to rule out pregnancy 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 
6 months (for women) and 7 months (for men) following completion of study 
therapy.  
21. Participants must not have an active, known or suspected autoimmune 
disease which may affect vital organ function, or has/may require systemic 
immunosuppressive therapy for management. Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 

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treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 
22. Participants must not have a condition requiring systemic treatment with either 
corticosteroids 
(>10 
mg 
daily 
prednisone 
equivalent) 
or 
other 
immunosuppressive medications within 14 days of start of treatment. Inhaled 
or topical steroids, and adrenal replacement steroid doses >10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
23. Patients may not have previously received anti PD1/PDL1 antibodies or 
PARP inhibitor for treatment of this cancer. 
Study Product(s), 
Dose, Route, 
Regimen 
Rucaparib 600 mg PO BID days 1-28 
Nivolumab 240 mg IV days 1 and 15 
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 with stable or responding advanced 
disease after at least 4 months of 1st line platinum therapy, and expect a large 
majority of those patients to have previously received between 4 to 6 months of 
platinum therapy. The sample size of this trial is based on the hypothesis that the 
expected proportion of patients surviving without progression after 4 months of 
study treatment will be improved with investigational therapy. We will accrue 32 
evaluable patients to this trial. Evaluable patients are compliant with study 
treatment and observed for progression-free survival events, progression, death, 
or lack of events following up to 4 months of study treatment. Patients non-
complaint with treatment or lost to follow-up will be replaced. Based on the ABC-
02 trial, PFS was estimated to be 72% and 60% at 4 and 6 months after first line 
gemcitabine and cisplatin, similar to the initiation point of our study and PFS was 
51% and 32% at 8 and 10 months, similar to the end of the treatment period for 
the primary outcome assessment in this trial.  Using a conditional probability 
argument, combined with the assumption that patient accrual to this study will 
follow an approximate uniform distribution over the 4 to 6 months of primary 
therapy for the patients accrued, we can accept the average of the PFS estimates 
for each period (4-6 months (66%) and 8-10 months (41.5%)) to correspond to 
our trial time period.  We can then standardize the ABC-02 PFS data so that the 
4-6 month estimate is 100% and the estimate for 4 months thereafter is 63%.  
For our trial, we hope to improve the PFS rate from 63% for these patients to 
85%.  With our proposed sample size of 32 patients this trial will have 80% power 
to detect this difference significantly using a 1-sided test.  
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Biliary Tract Cancer - Disease Overview 
Biliary tract cancer (BTC) develops as a result of malignant transformation of the biliary 
tract mucosa and is anatomically classified as intra-hepatic, extra-hepatic (hilar and 
distal) and gall bladder adenocarcinoma. BTC accounts for 10-15% of all primary liver 
cancer cases worldwide, and its incidence is 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. 
1.2 
Role of PARP inhibitors in BTC 
DNA damage response (DDR) is a broad term describing several complex pathways 
responsible for repairing damaged DNA. These known pathways include base excision 
repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), recombinational 
repair including homologous recombination (HR) and non-homologous end-joining 
(NHEJ), and direct repair mechanisms. BER, NER and MMR are mechanisms 
responsible for repairing single strand breaks (SSB), whereas HR and NHEJ pathways 
are mechanisms involved in repairing double strand breaks (DSB)4–7.  
 
Poly (ADP ribose) polymerase 1 or PARP1 is an abundant nuclear protein heavily 
involved in the repair of SSB8. In the presence of SSB, PARP1 binds to the damaged 
DNA, undergoes conformational change and catalyzes the production of PAR which acts 
as a signal for recruitment of DNA repair factors9.  Under normal conditions the 
dissociation of PARP1 from DNA is required prior to DNA repair completion. In the 
presence of inhibitors, PARP1 remains bound to SSB generating trapped PARP-DNA 
complexes, thus blocking repair and replication9. Unrepaired SSB can produce 
deleterious DSB at the replication forks.  In replicating cells, DSB are repaired via HR and 
NHEJ pathways. However, in cancer cells that are HR deficient (HRD), repair 
mechanisms for DSB fall to more error prone NHEJ pathways which can lead to cell 
death10. Bryant and Farmer separately demonstrated that BRCA1/2 deficient cells, where 
the homologous recombination mechanism is defective, were exquisitely sensitive to 
PARP inhibitors11,12. This has led to many studies investigating the efficacy of PARP 
inhibitors, both as a single agent and in combination with chemotherapy, in various solid 
tumors including ovarian, breast, brain, pancreatic and NSCLC13–20. However, to date, 
HRD signaling and the use of PARPi has not been extensively investigated in BTCs. 
 
Using whole exome-transcriptome sequencing, our pre-clinical data of 53 patients with 
BTCs revealed 14 pts (26.4%) had biallelic DNA damage repair pathway mutations 
(ATM, BAP1, MSH2, BRCA1, BRCA2). Of these, 11 had somatic mutations and 3 had 
germline (MSH2, BRCA1, BRCA2) mutations. Four additional patients were found to 
have mono-allelic mutations with BRCA1 (somatic), PALB2 (somatic) and ATM (familial). 
These monoallelic mutations have been shown to increase the risk of cancer 
development and are involved in DNA DSB repair21–24. 
 
BRCA1 associated protein (BAP1), is a deubiquitinase of histone H2A involved in 
chromatin remodeling and is recruited to DSB sites. BAP1-/- cells are strikingly sensitive 

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to ionizing radiation and PARP inhibition (olaparib) relative to BAP1+/- and BAP1+/+ 
cell25. 
 
In addition, 8 patients had isocitrate dehydrogenase (IDH)1 mutations. Pre-clinical data 
with IDH1 mutant cells demonstrates reduced capacity to repair DSBs which renders 
them highly sensitive to PARP inhibition26,27. This concept is currently being evaluated in 
clinical trial (NCT03212274).  
 
In total, 26 patients (49%) in our cohort had either biallelic somatic and germline (n=14) 
mutations, or monoallelic somatic or germline (n=4) DDR mutations, or IDH1 mutations 
(n=8) and may have potentially benefitted from the use of PARPi. 
 
Rucaparib is a small oral inhibitor of PARP1, PARP2, and PARP3, currently FDA-
approved in patients with ovarian cancer treated with two or more chemotherapy 
regimen28. A phase II ARIEL2 trial evaluating the efficacy of rucaparib at 600 mg twice 
daily, demonstrated greatest response in patients harboring germline or somatic BRCA 
mutations (PFS 12.8 months; 95% CI 9.0-14.7), reduced response rate in those with 
HRD status by high loss of heterozygosity (PFS 5.7 months; 95% CI 5.3-7.6), and least 
response in low loss of heterozygosity (PFS 5.2 months; 95% CI 3.6-5.5)29. Grade ≥3 
adverse events included anemia, elevated ALT or AST, and fatigue. A recent phase III 
clinical trial ARIEL3 of 564 patients demonstrated promising disease control in patients 
with BRCA mutant ovarian cancer30. Median PFS in BRCA mutant arm was 16.6 months 
(95% 13.4-22.9) compared to 5.4 months (95% CI 3.4-6.7) in placebo arm. In patients 
with HRD status, median PFS was 13.6 months (95% CI 10.9-16.2) versus 5.4 months 
(95% CI 5.1-5.6). Similar adverse events were reported in each arm. Rucaparib is 
currently being evaluated in breast, ovarian, as well as prostate cancer with HRD status 
(NCT02505048, NCT02952534, NCT02975934). 
1.3 
Role of Checkpoint Inhibitors in BTC 
The role of cytotoxic immune response against a tumor requires a complex and evolving 
interaction between immune cell subsets. T-cell activation requires dual signaling from 
the T-cell receptor and an additional co-stimulatory molecule31,32. The first signal includes 
binding of the T-cell receptor to antigens presented by antigen presenting cells (APCs). 
Subsequently, the B7 (CD80, CD86) ligand binds to CD28 which is a co-stimulatory 
receptor. This signaling leads to T-cell proliferation, cytokine release and upregulation of 
the immune response. As a result, cytotoxic T lymphocyte antigen 4 (CTLA-4) is 
upregulated and competes with the CD28 receptor for B7 binding. CTLA-4 has higher 
affinity than the CD28 receptor and therefore T-cell response is ultimately down-
regulated. PD-1 is a member of the CD28/CTLA-4 family of T-cell costimulatory receptors 
that includes CD28, CTLA-4, ICOS and BTLA33. PD-1 is expressed on activated T cells, 
B cells and myeloid cells34. 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 occurs35,36. When the 
PD-1 ligand binds to the PD-1 receptor, T-cell activation is blocked. CTLA-4 and PD-1 
are negative regulators of T-cell response that prevent autoimmunity and allows 
tolerance to self-antigens31. If these interactions are interrupted, the 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-L237. 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%. 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 weeks37. Nivolumab is an 

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anti-PD1 antibody that is currently FDA-approved as a single agent and in combination 
with other agents in multiple solid tumors38–42. There is an ongoing phase II clinical trial 
evaluating the efficacy of single agent Nivolumab in advanced biliary tract cancers 
(NCT02829918), the results of which has not been reported yet. Other checkpoint 
inhibitors currently being investigated in this disease group include combination 
checkpoint inhibitors with chemotherapy (NCT03101566) as frontline therapy.  
1.4 
Rationale 
Patients with advanced, unresectable or metastatic BTC have a poor prognosis despite 
systemic chemotherapy. The median PFS with first-line gemcitabine and cisplatin is 
expected to be 8 months2. PARP inhibitors have been shown to be effective when used 
as a single maintenance agent or in combination with conventional chemotherapy in 
patients with BRCA mutations19,20,29,30.  PARP inhibitors affect the cells ability to repair 
single strand breaks and also increase frequency of double strand breaks8. Disruption of 
the DNA damage repair pathways results in increased mutational burden, neoantigens43 
and therefore immunogenicity8 (see Figure 1). This provides a rationale for combining the 
use of PARPi such as rucaparib with a checkpoint inhibitor, nivolumab. Preclinical data 
using combination rucaparib with anti-PD1/ PD-L1 antibodies resulted in greater survival 
benefit and greater tumor response in BRCA1 null syngeneic model as compared to 
monotherapy44. In a separate study, while the use of PARPi in animal models showed 
increased PD-L1 expression, the combination of PARPi with PD-L1/PD-1 checkpoint 
inhibitors showed increased therapeutic efficacy in comparison to each therapy alone45.  
 
 
We therefore hypothesize that following first-line platinum based chemotherapy, 
rucaparib in combination with nivolumab, will improve progression-free survival and 
overall survival in BTC patients. We expect greater efficacy in patients with DDR and IDH 
signatures. These results are expected to have an important positive impact because 
they will provide evidence guided understanding for further evaluation of the use of PARP 
inhibitors with an immune check point inhibitor in BTCs. 
1.5 
Correlative Studies 
We will study the BTC tumor biology, 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, IDH and/or 
immune signatures) that may have clinical efficacy from rucaparib 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 be examined in the context 
of immunologic correlates, tumor biology, and therapeutic efficacy.  
PARP inhibitor 
Loss of one or more DDR 
pathways 
Increased replication 
stress/endogenous DNA 
damage/neoantigens 
Increased immunogenicity 
Figure 1. Potential Synergism of PARP and Immune Checkpoint Inhibition 

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2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
Determine the PFS rate at 4 months in patients with advanced BTC treated with 
rucaparib and nivolumab following 1st line platinum based therapy 
2.2 
Secondary Objectives  
2.2.1 
Evaluate the ORR and the median PFS and OS from start of study treatment and 
start of 1st line platinum therapy in patients with advanced BTC. 
2.2.2 
Evaluate the safety of rucaparib and nivolumab in this patient population. 
2.2.3 
Evaluate the ORR, median PFS and OS in patients with and without DDR and 
IDH signatures. 
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 Endpoint Assessment: For the intent-to-treat population the progression-
free survival (PFS) rate will be defined as the proportion of patients alive and 
without radiological or clinical progression (leading to withdrawal from the study) 
at 4 months and patient replacement as specified in section 5.10. 
 
2.4.2 
Secondary Endpoint Assessment: Overall response rate (ORR) will be 
determined as per the combined RECISTv1.1 and irRECIST criteria. 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. PFS1 will be from start of study 
treatment and will be the primary study endpoint. PFS2 will be from start of 1st 
line platinum therapy. Overall survival (OS) will be defined from the date of 
treatment to either date of death or censoring. OS1 will be from start of study 
treatment. OS2 will be from start of 1st line platinum therapy. Follow-up time will 
be censored at the date of last disease evaluation. Adverse events and 
reportable serious events are defined by the study protocol (NCI Common 
Toxicity Criteria for Adverse Events (CTCAE) v5.0). 
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 adenocarcinoma 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 of mixed 
histology are excluded. 

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3.1.2 
Patients must have received 1st line platinum-based systemic chemotherapy for 
advanced BTC for 4-6 months (16-24 weeks) without radiologic or clinical 
progression. Last systemic infusion of 1st line platinum-based therapy may not be 
more than 4 weeks from study informed consent. Prior peri-operative 
chemotherapy is permitted provided it was completed > 6 months from start of 
platinum-based therapy for advanced disease. 
 
3.1.3 
Prior surgical resection, radiation, chemoembolization, radioembolization or other 
local ablative therapies are permitted if completed > 4 weeks prior to enrollment 
AND if patient has recovered to < grade 1 toxicity. 
 
3.1.4 
Patients must have measurable disease (as per RECISTv1.1) in at least one site 
not previously treated with radiation or liver directed therapy (including bland, 
chemo- or radio-embolization, or ablation) either within the liver or in a metastatic 
site unless the patient has had complete response to 1st line platinum-based 
therapy.  
 
3.1.5 
Age≥18 years 
 
3.1.6 
Child-Pugh score of A or B7 
 
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 obtained ≤ 2 weeks prior to registration  
 
absolute neutrophil count 
≥ 1500/mm3 
hemoglobin 
> 9 g/dL 
platelets 
> 100,000/mm3 
serum creatinine 
≤ 1.5 x ULN 
 
 
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 a diagnosis of immunodeficiency, or received systemic steroid 
therapy, or any other form of immunosuppressive therapy within 14 days prior to 
trial treatment. Short bursts of steroids of 5-7 days (for COPD exacerbation or 
other similar indication) are allowed.   
 
3.1.13 No prior history of solid organ transplantation or brain metastasis (unless treated 
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 

Protocol UMCC 2018.044 
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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) 
 
3.1.17 Must not have received a live vaccine within 30 days of planned start of the study 
therapy. 
 
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 rucaparib 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 
blood or urine test to rule out pregnancy 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 6 months (for 
women) and 7 months (for men) following completion of study therapy 
 
3.1.21 Participants must not have an active, known or suspected autoimmune disease 
which may affect vital organ function, or has/may require systemic 
immunosuppressive therapy for management. 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 must not have a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of start of study treatment. 
Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
 
3.1.23 Patients may not have previously received anti PD1/PDL1 antibodies or PARP 
inhibitor for treatment of this cancer. 
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.    

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A Multi-Site Coordinator of the Coordinating Center, who acts as the registrar, will review the 
submitted documents and process the registration. Sites should inform the Multi-Site Coordinator 
of a potential registration by 5 p.m. on the day prior to registration.  Same day registrations 
cannot be guaranteed.   
 
The registrar will send an email to the requesting site registrar to confirm patient registration and 
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 PARP inhibitor Rucaparib and anti-PD1 
antibody Nivolumab. The safety profile of both agents has been previously evaluated 
individually. 
 
Table 1. Treatment Plan 
Days 
Treatment 
Dose 
Day 1 every 2 weeks 
Nivolumab 
240 mg IV 
Days 1-28 every 28 days 
Rucaparib 
600 mg PO BID 
 
Rucaparib may be taken with or without food. Patients should take rucaparib doses as 
close as possible to 12 hours apart, preferably at the same times every day. If a patient 
misses a dose (i.e., does not take it within 4 hours of the scheduled time), the patient 
should skip the missed dose and resume taking rucaparib with the next scheduled dose 
Missed or vomited doses should not be made up. Patients may continue treatment for 2 
years in absence of disease progression or unacceptable toxicity. 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.2). 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 2. Dose Modifications 
Drug 
Current Dose 
Percentage 
Decrease 
Modified Dose 
Rucaparib 
600 mg PO BID 
~20% 
500 mg PO BID 
500 mg PO BID 
20% 
400 mg PO BID 
400 mg PO BID 
~20% 
300 mg PO BID 
300 mg PO BID 
100% 
Discontinue 
Nivolumab 
240 mg IV  
100% 
Discontinue 

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 If more than one toxicity occurs requiring dose reduction, the dose administered 
should be based on the most severe toxicity. 
 
 Treatment delay of more than 21 days from last intended therapy will result in 
discontinuation from trial, unless otherwise agreed and documented between the 
investigator and the sponsor. 
 
 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. 
 
 Nivolumab cannot be dose reduced and can only be discontinued as per detailed 
algorithms for immune-therapy toxicity management in Appendix III. 
 
Rucaparib Dose Modification Criteria 
Treatment with rucaparib should be held if any of the following are observed and a dose 
reduction should be considered or implemented. 
• 
Grade 3 or 4 hematologic toxicity.  Anemia should be managed as described 
below 
 
• 
Grade 3 or 4 non-hematologic toxicity (except for alopecia, nausea, vomiting, or 
diarrhea adequately controlled with systemic antiemetic/antidiarrheal medication 
administered in standard doses according to the study center routines). Grade 3 
or Grade 4 ALT/AST elevations should be managed as described below 
 
• 
In addition, and at the discretion of the investigator, the dose of rucaparib may be 
held and/or reduced for unremitting Grade 2 toxicity not adequately controlled by 
concomitant medications and/or supportive care. 
 
• 
For patients who meet treatment interruption guidelines above, treatment with 
rucaparib should be held until the toxicity improves to ≤ CTCAE Grade 2. Twice 
daily dosing may then be resumed at either the same dose or a lower dose, 
per investigator discretion. If treatment is resumed at the same dose, and the 
patient experiences the same toxicity, treatment should be interrupted, then 
resumed at a reduced dose following resolution of the event to ≤ CTCAE Grade 
2. If the patient continues to experience toxicity, additional dose reduction steps 
are permitted; however, the investigator should consult with the sponsor’s 
medical monitor before reducing to 300 mg BID. If a patient continues to 
experience toxicity despite dose reduction steps to 300 mg BID, or if dosing with 
rucaparib is interrupted for > 21 consecutive days due to toxicity, treatment 
should be discontinued, unless otherwise agreed and documented between the 
investigator and the sponsor. 
 
Management of Anemia including Evaluation for MDS/AML and Follow-up of 
Patients who Discontinue Treatment with Ongoing Anemia: 
• 
If the patient develops anemia CTCAE Grade ≥ 3, rucaparib treatment should be 
held until the anemia improves to CTCAE Grade ≤ 2 whereupon daily dosing 
may then be resumed at either the same dose or a lower dose, per investigator 
discretion. 
• 
If the duration of dosing is interrupted for > 21 consecutive days due to anemia 
CTCAE Grade ≥ 3, treatment should be permanently discontinued, unless 
otherwise agreed and documented between the investigator and the sponsor or 
designee. 

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• 
In addition, if anemia CTCAE Grade ≥ 3 persists for > 14 consecutive days, or a 
dependence upon blood transfusion occurs, then weekly complete blood counts 
should be performed until resolution of the event. 
• 
If, after 42 days of interruption of rucaparib, the anemia has not improved to 
CTCAE Grade ≤ 1 then the patient should be referred to a hematologist and 
analysis of the bone marrow with cytogenetic studies are recommended 
according to standard hematologic practice. 
• 
The bone marrow analysis may include a bone marrow aspirate (for cellular 
morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for 
bone marrow cellularity). 
 
Management of Rucaparib Treatment-Emergent ALT/AST Elevations: 
• 
Grade 4 ALT/AST elevations: hold rucaparib until values have improved to Grade 
2 or better, then resume rucaparib with a dose reduction. If toxicity is ascribed to 
nivolumab alone then you may resume without a dose reduction. Monitor liver 
function tests weekly for 3 weeks after rucaparib has been restarted. 
• 
Grade 3 ALT/AST elevations, in the absence of other signs of liver dysfunction, 
should be managed as follows: 
o 
Monitor liver function tests weekly until improvement to ≤ Grade 2. 
o 
Continuation of rucaparib with elevation of ALT/AST up to Grade 3 is 
permitted provided bilirubin is < ULN. 
o 
If patient has Grade 3 ALT/AST elevation and continues on rucaparib, 
and levels do not decline within 2 weeks or they continue to rise, 
treatment interruption and resolution to ≤ Grade 2 will be required before 
rucaparib can be resumed, either at the current dose or at a reduced 
dose. 
 
Management of Creatinine Elevation: 
• 
Rucaparib can cause creatinine elevation of any grade in 92% of the patients 
(1% grade 3-4) possibly due to potent inhibition of the MATE1, MATE2-K and 
OCT1 transporters49. The majority of reported grade 1-2 creatinine elevations 
stabilize with continued rucaparib treatment without dose modification. However, 
grade 2 elevation of creatinine can also be due to autoimmune nephritis from 
nivolumab. To help identify whether rucaparib or nivolumab is the underlying 
etiology for the creatinine elevation all subjects will undergo repeat CMP on cycle 
1 day 8. 
o 
Grade 2 creatinine elevation on cycle 1 day 8: Hold rucaparib and re-
check on cycle 1 day 15. If creatinine is improved to grade 1 (<1.5 x 
ULN) on day 15, then resume rucaparib at full dose. 
o 
Grade 3-4 creatinine elevation: Hold rucaparib and consider a dose 
reduction. 
 
Rucaparib Re-treatment Criteria 
Treatment may resume if: 
• 
ANC ≥ 1.0 x 109/L 
• 
Platelet count ≥ 75 x 109/L 
• 
Non-hematologic toxicities have returned to baseline or ≤ CTCAE Grade 1 
severity (or, at the investigator’s discretion, ≤ CTCAE Grade 2 severity if not 
considered a safety risk for the patient). Grade 3 or Grade 4 ALT/AST elevations 
should be managed as described above. 
 

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5.3 
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. 
5.4 
Concomitant Medications/Treatments 
The following concomitant medications or treatments are not permitted while the patient 
is currently receiving therapy on the protocol: 
• 
Other investigational agents 
• 
Concurrent radiation 
 
Effect of Other Drugs on Rucaparib 
Rucaparib is primarily metabolized by CYP2D6 and to a lesser extent by CYP1A2 and 
CYP3A4. Caution should be used for concomitant use of strong CYP3A4 inhibitors or 
inducers. 
 
Effect of Rucaparib on Other Drugs 
Rucaparib reversibly inhibits CYP1A2, CYP2C19, CYP2C9 and CYP3A, and to a lesser 
extent CYP2C8, CYP2D6, and UGT1A1. It is also a potent inhibitor of MATE1 and 
MATE2-K, and a moderate inhibitor of OCT1. Caution should be used for concomitant 
use of CYP substrates with narrow therapeutic index as listed below. 
 
CYP Enzyme 
Substrates with Narrow Therapeutic Index 
CYP1A2 
Tizanidine, theophylline 
CYP2C9 
Warfarin, phenytoin 
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus 
and terfenadine 
 
5.5 
Other Modalities or Procedures 
None 
5.6 
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: 
• 
Disease progression as defined in Section 7.0 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 

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• 
Patient voluntarily withdraws from treatment OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.7 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.6 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.8. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
5.8 
Duration of Follow-Up 
After treatment discontinuation, follow-up for survival and initiation of any other anti-
cancer therapies will be documented every 3 months via telephone or office visit 
documentation for up to 2 years from treatment discontinuation or until death, whichever 
comes first, or 3 years after first date of treatment initiation for those that remain on 
treatment. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.  
5.9 
Off Study Criteria 
Patients can be taken off study 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: 
5.9.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.9.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.9.3 
Patient is unable to comply with protocol requirements; 
5.9.4 
Treating physician judges continuation on the study would not be in the patients 
best interest; 
5.9.5 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.9.6 
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; 
5.9.7 
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; 
5.9.8 
Termination of the study by the Sponsor, the University of Michigan or the FDA; 
5.9.9 
Patient completes protocol treatment and follow-up criteria; 
 
5.9.10 Treatment delay of more than 28 days from last intended therapy; 

Protocol UMCC 2018.044 
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5.9.11 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. 
5.10 
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 (IIT) population. 
   
Patients enrolled on the study will be replaced and not considered a member of the IIT for 
the following reasons 
 
1. Patients who did not receive even one dose of 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 5.9.1 and/or 5.9.3 not secondary to toxicity. 
 
4. Patients meeting off study criteria 5.9.2 and/or 5.9.5 
 
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 to 35 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 

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Table 4. Study Calendar 
Procedures 
Screening1 
Cycle 1 
Cycle X 
EOT 
Visit10 
Follow-Up 
Q3 months 
+/- 1 week11 
Day 1 
Day 8 
Day 15 
Day 1 
Day 15 
Informed Consent 
X 
 
 
 
 
 
 
 
History, Physical 
Examination 
X 
X 
 
X 
X 
 
X 
X 
Weight, BSA 
X 
X 
 
 
X 
 
X 
 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
 
Performance Status 
X 
X 
 
 
X 
 
X 
 
Toxicity 
Evaluations12 
 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
X 
X 
 
X 
X 
X 
 
 
CMP2 
X 
X 
X 
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 
 
 
X 
 
 
 
Scans with Tumor 
Measurements6 
X 
 
 
 
X 
 
 
 
Research Blood7 
 
X 
 
 
X 
 
X 
 
Tissue8 
X 
 
 
 
X 
 
X 
 
Study Drug 
Administration9 
 
X 
 
X 
X 
X 
 
 
Survival Follow-up 
 
 
 
 
 
 
 
X 
 
1. All screening procedures to be completed within 2 weeks of registration, except imaging and informed consent 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 and total protein. 
3. Amylase, lipase, random cortisol, TSH, free T4 and 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 8 weeks, if patient is known to express these tumor markers.

Protocol UMCC 2018.044 
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5. Required for females of childbearing potential. Blood or urine pregnancy test per site 
investigator discretion. Required on C1D1 within 24 hours prior to treatment initiation and 
prior to study drug administration on Day 1 for each subsequent Cycle.  
6. MRI or CT (abdomen/pelvis) with contrast along with CT chest with/without contrast will be 
assessed every 8 + 1 weeks. Imaging assessment of scans at the site should be completed 
by either a radiologist or an imaging core, and not by the oncologist nor via abstraction of 
data from the subjective/clinical radiology report. 
7. Collect 10 ml x 2 Streck® DNA tubes (must be shipped within 48 hours of collection) 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 3 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 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 
11. Patients will be followed every 3 months +/- 1 week after completion of (or early withdrawal 
from) study treatment until death, withdrawal from protocol or 2 years whichever is the 
earliest. 
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. 
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 treatment with study drug. 
 

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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 
and/or randomized 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: 
 
• 
10 mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable)          
• 
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
All tumor measurements must be recorded in millimeters (or decimal fractions of   
centimeters). 
 
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.  
 

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Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor. Pathological nodes 
that are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis of 
these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20 mm x 30 mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the nodal 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
of diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum of diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. If a non-target lymph node grows to 
>15mm after baseline, this node then becomes a new target lesion as per 
irRECIST. The nodal short axis is then added to the sum of diameters, and 
patient response is calculated with the new lesion.  
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required, and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(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 

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thickness is 5 mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  
 
7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Prior to the first PD assessment, patients will be evaluated according the 
following RECISTv1.1 response: 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions (with a minimum absolute increase of 5 mm), taking as 
reference the smallest sum LD recorded since the treatment started, or 
the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking 
as reference the baseline sum LD) nor sufficient increase to qualify for 
PD (taking as reference the smallest sum LD since the treatment 
started). 
 
After the first PD assessment per RECISTv1.1 (=irSD per irRECIST), 
patients will be evaluated for irPD at least 4 weeks apart according to the 
following definition: 
 
Immune-related Progressive Disease (irPD): At least a 20% increase in 
the sum of the LD of target lesions (with a minimum absolute increase of 
5 mm), taking as reference the smallest sum LD recorded since the 
treatment started, or appearance of new lesions since the last 
evaluation. 

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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 5. 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. 
 
 

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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: 
 
• 
Investigator determined clinical benefit 
• 
Tolerance of study drug 
• 
Stable performance status 
• 
Treatment beyond progression will not delay an imminent intervention to 
prevent serious complications of disease progression (e.g., CNS 
metastases) 
• 
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. 

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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: 
• 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
• 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration through 100 days following the 
last dose of the study treatment must be recorded as an adverse event in the patient’s 
source documents and on the CRF regardless of frequency, severity (grade) or assessed 
relationship to the study treatment or intervention.  
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.  

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• 
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. 
• 
Anticipated fluctuations of pre-existing conditions, including the disease 
under study, that don’t represent a clinically significant exacerbation or 
worsening, are not considered 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: 
• 
Previously planned (prior to signing the informed consent form) surgeries 
should not be reported as SAEs unless the underlying medical condition 
has worsened during the course of the study.  
• 
Preplanned hospitalizations or procedures for preexisting conditions that 
are already recorded in the patient’s medical history at the time of study 
enrollment should not be considered SAEs.  
• 
Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other 
protocol-required procedure) should not be considered SAEs. However, 
if the preexisting condition worsened during the course of the study, it 
should be reported as an SAE. 

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• 
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, or the administration of other drug(s) known to 
be hepatotoxic. 
 
While treatment is interrupted, the patient should be evaluated for the presence 
of confounding factors including malignant disease in the liver, co-administration 
of other suspect drugs, cholestasis, and viral or autoimmune hepatitis that could 
have caused the laboratory abnormalities. Other laboratory investigations of liver 
function such as international normalized ratio (INR) should be implemented as 
indicated. If no alternative cause is identified, rucaparib must be permanently 
discontinued. 
 
All cases of possible DILI should be followed until all abnormalities have returned 
to normal, returned to baseline levels, or an alternative cause is found to explain 
the combination of the increased transaminases and total bilirubin. 
 
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. 
 
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: 
• 
Myelodysplastic Syndrome and Acute Myeloid Leukemia 
• 
Pneumonitis 
 
 

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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.  
 
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: 
• 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
• 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
• 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug 
under study. 
8.2.7 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. 

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8.4 
Serious Adverse Event Reporting Guidelines  
8.4.1 Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless 
of causality to study drug, will be reported to the Principal Investigator and also to 
the Coordinating Center.  All SAEs and UPs must be reported to the Coordinating 
Center within 24 hours of first awareness of the event.  Events should be reported 
using the Coordinating Center’s SAE form as available in the study database.  A 
copy of the SAE form as available in the study database should be sent to the 
Coordinating Center via fax at 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 must also be reported within 24 hours of receipt of the 
information by the investigator. 
 
All SAEs and UPs will be reported to the IRB per current institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to 
the participating sites within 5 days of review of the information by the Coordinating 
Center’s Principal Investigator (or designee in the event of extended absence) only 
in the case that the event(s) is believed to be related (i.e., possibly, probably, or 
definitely) to the study drug. The Coordinating Center will be responsible for 
reporting of events to the FDA and supporters, as appropriate (outlined below). 
8.4.2 
Reporting procedures to BMS 
All Serious Adverse Events (SAEs) occurring from the initial study treatment 
administration through 100 days following the last dose of the study treatment will 
be reported by the Coordinating Center to BMS Worldwide safety.  Any SAEs 
occurring after 100 days following the last dose of the study treatment that are 
believed to be related to study drug will also be reported to BMS Worldwide 
safety.  
The Coordinating Center will send the initial completed SAE Form within 24 
hours of receipt via email to BMS Worldwide Safety 
(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 Clovis 
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 Clovis.  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 Clovis. All AESIs 
will be collected and reported to Clovis throughout the subject’s participation in 
the study.  
The Coordinating Center will send the initial completed SAE Form within 24 
hours of receipt via email to Clovis (drugsafety@clovisoncology.com; Fax: 303-
261-8319).   
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 

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available, a follow-up report will be generated and sent to Clovis 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 
Assistance Program (MIAP) will assist the Sponsor in submitting 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 must report it to the IRB within 14 calendar days 
of the study team becoming aware of the problem. 
 
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 Clovis 
Oncology (drugsafety@clovisoncology.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@clovisoncology.com.  The data elements listed on the reconciliation report 
will be used for identification purposes.  If the Investigator determines a report was not 
transmitted to BMS GPV&E, and/or Clovis the report should be sent immediately as 
appropriate.   

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8.8 
Stopping Rules  
See section 11.5 for Early Stopping Rules Due to Toxicity. In addition, 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. 
9.0 
DRUG INFORMATION 
9.1 
Rucaparib camsylate 
9.1.1 
Other Names 
Rubraca, CO-338; formerly known as PF-01368338-BW and AG-014447 
9.1.2 
Classification 
RUBRACA is a poly (ADP-ribose) polymerase (PARP) inhibitor. 
9.1.3 
Mechanism of Action 
Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, 
including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro 
studies have shown that rucaparib-induced cytotoxicity may involve inhibition 
of PARP enzymatic activity and increased formation of PARP-DNA complexes 
resulting in DNA damage, apoptosis, and cell death. Increased rucaparib-induced 
cytotoxicity was observed in tumor cell lines with deficiencies in BRCA1/2 and 
other DNA repair genes. Rucaparib has been shown to decrease tumor growth in 
mouse xenograft models of human cancer with or without deficiencies in BRCA. 
9.1.4 
Pharmacokinetics 
All pharmacokinetics of rucaparib were characterized in patients with cancer. 
Rucaparib demonstrated linear pharmacokinetics over a dose range from 240 to 
840 mg twice daily with time-independence and dose-proportionality. The mean 
steady-state rucaparib Cmax was 1940 ng/mL (54% coefficient of variation [CV]) 
and AUC0-12h was 16900 h⋅ng/mL (54% CV) at the approved recommended 
dosage. Accumulation was 3.5 to 6.2 fold. Median terminal half-life (T1/2) was 17 
hours following a single intravenous dose of 12 to 40 mg rucaparib. 
 
1. Absorption: The median Tmax at steady state was 1.9 hours at the approved 
recommended dosage (600 mg BID). The mean absolute bioavailability of 
rucaparib immediate release tablet was 36% with a range from 30% to 45%. 
Following a high-fat meal, the Cmax was increased by 20% and AUC 0-24h 
was increased by 38%, and Tmax was delayed by 2.5 hours, as compared to 
dosing under fasted conditions. 
 
2. Distribution: Rucaparib had a steady-state volume of distribution of 113L to 
262L following a single intravenous dose of 12 mg to 40 mg rucaparib. In 
vitro, the protein binding of rucaparib was 70% in human plasma at 
therapeutic concentrations. Rucaparib was preferentially distributed to red 
blood cells with a blood-to-plasma concentration ratio of 1.83. 
 
3. Metabolism: In vitro, rucaparib was metabolized primarily by CYP2D6 and to 
a lesser extent by CYP1A2 and CYP3A4. 
 
4. Elimination: The mean terminal T1/2 of rucaparib was 17-19 hours, following a 
single oral dose of 600 mg rucaparib. The apparent clearance ranged from 
15.3 to 79.2 L/hour, following continuous 600 mg rucaparib orally twice daily. 

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The clearance ranged from 13.9 to 18.4 L/hour, following a single 
intravenous dose of rucaparib 12 mg to 40 mg. 
9.1.5 
Storage, Preparation and Stability 
Refer to the current FDA-approved package insert for storage, stability and 
special handling information. Rucaparib is supplied as 200, 250 and 300 mg 
strength tablets. All tablets are provided in high-density polyethylene (HDPE) 
bottles (or equivalent) with child-resistant caps and should be stored in the 
provided containers between 20°-25° C (68° to 77° F); excursion permitted 
between 15° to 30° C (59° to 86° F) (see USP Controlled Room Temperature). 
Patients may be dispensed 1 or more strengths depending on their current dose 
of rucaparib. The number of bottles of each strength dispensed will be sufficient 
to supply 28 days of treatment (plus a 2-day overage) until the next rucaparib 
dispensation visit. Bottles containing rucaparib tablets will be labeled according 
to national regulations for investigational products. 
9.1.6 
Dosing and Administration 
See Section 5.1 
 
The starting dose of rucaparib as a continually administrated oral monotherapy 
will be 600 mg twice daily.  
 
Patients may take rucaparib with or without food. Each dose should be taken with 
approximately 8 oz (240 mL) of room temperature water. Tablets should be 
swallowed whole without crushing or chewing.  
 
Patients should take rucaparib doses as close as possible to 12 hours apart, 
preferably at the same times every day. If a patient misses a dose (i.e., does not 
take it within 4 hours of the scheduled time), the patient should skip the missed 
dose and resume taking rucaparib with the next scheduled dose. Missed or 
vomited doses should not be made up.  
9.1.7 
Availability 
Clovis Oncology will supply the study drug in 200 mg, 250 mg and 300 mg 
tablets with 60 tablets per bottle. 
9.1.8 
Handling and Disposal 
Handling and disposal of rucaparib should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents. 
9.1.9 
Adverse Effects 
1. Side Effects: Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. Most 
common adverse reactions (≥ 20%) were nausea, fatigue (including 
asthenia), vomiting, anemia, abdominal pain, dysgeusia, constipation, 
decreased appetite, diarrhea, thrombocytopenia, and dyspnea. Most 
common laboratory abnormalities (≥ 35%) were increase in creatinine, 
increase in ALT, increase in AST, decrease in hemoglobin, decrease in 
lymphocytes, increase in cholesterol, decrease in platelets, and decrease in 
absolute neutrophil count. The following adverse reactions have been 
identified in < 20% of the 377 patients treated with Rubraca 600 mg twice 
daily: dizziness (17%), neutropenia (15%), rash (includes rash, rash 
erythematous, rash maculopapular and dermatitis) (13%), pyrexia (11%), 
photosensitivity reaction (10%), pruritus (includes pruritus and pruritus 

Protocol UMCC 2018.044 
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generalized) (9%), Palmar-plantar erythrodysesthesia syndrome (2%), and 
febrile neutropenia (1%). 
 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are 
considered adverse events of special interest (AESIs), as these events have 
been observed in patients exposed to cytotoxic chemotherapy (e.g., platinum 
and anthracyclines) used for treatment of ovarian cancer as well as with 
PARP inhibitors, including rucaparib. Patients in rucaparib clinical studies 
diagnosed with MDS or AML had significant confounding risk factors 
including prior cytotoxic chemotherapy, as well as a deleterious BRCA 
mutation (8, 9). Based on these confounding factors, there is insufficient 
scientific evidence to conclude that MDS and AML are causally related to 
rucaparib. Clovis has added these potential risks to all Informed Consent 
Forms (ICFs) / Patient Information Sheets (PISs). AESI’s (both serious and 
non-serious) will be reported to Clovis within 48 hours of awareness and will 
continue to be reported to Clovis under SAE reporting requirements. More 
information on AESIs for rucaparib is provided in the rucaparib IB. 
 
Photosensitivity has been observed in patients treated with rucaparib. 
Patients should avoid spending time in direct sunlight because they burn 
more easily during treatment with rucaparib. When outdoors, patients should 
use typical precautions such as applying sunscreen (sun protection factor 50 
or greater) and/or covering exposed skin with clothing and wearing a hat and 
sunglasses. 
 
2. Pregnancy and Lactation: Based on findings from animal studies and its 
mechanism of action, Rubraca can cause fetal harm when administered to 
pregnant women. There are no available data in pregnant women to inform 
the drug-associated risk. In an animal reproduction study, administration of 
rucaparib to pregnant rats during organogenesis resulted in embryo-fetal 
death at maternal exposure that were 0.04 times the AUC 0-24h in patients 
receiving the recommended dose of 600 mg twice daily. Women of 
reproductive potential should use highly-effective contraception during 
therapy and for at least 6 months after treatment has been discontinued. Men 
receiving rucaparib and who are sexually active with women of child bearing 
potential should adhere to contraception for a period of 6 months after the 
last dose of nivolumab. Male patients must not make semen donations 
during treatment and for 6 months following the last dose of rucaparib.  
Patients should be instructed to notify the investigator if pregnancy is 
discovered either during or within 6 months of completing treatment with 
rucaparib 
 
There is no information regarding the presence of rucaparib in human milk, 
or on its effects on milk production or the breast-fed infant. Because of the 
potential for serious adverse reactions in breast-fed infants from Rubraca, 
advise lactating women not to breastfeed during treatment with Rubraca and 
for 2 weeks after the final dose. 
 
3. Drug Interactions:  
Effects of Other Drugs on Rucaparib: In vitro, rucaparib had a low metabolic 
turnover rate in human liver microsomes, and was metabolized primarily by 
CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. In vitro, rucaparib 
was shown to be a substrate of P-gp and BCRP, but not a substrate of renal 
uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters 
OATP1B1 and OATP1B3. Concomitant treatment with proton pump inhibitors 
has no clinically meaningful change in steady-state exposures.  

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Effect of Rucaparib on Other Drugs: Effect of rucaparib on other drugs has 
not been studied in humans. Rucaparib reversibly inhibited CYP1A2, 
CYP2C19, CYP2C9, and CYP3A, and to a lesser extent CYP2C8, CYP2D6, 
and UGT1A1. Rucaparib induced CYP1A2, and down regulated CYP2B6 
and CYP3A4 in human hepatocytes at clinically relevant exposures. 
Rucaparib was a potent inhibitor of MATE1 and MATE2-K, and a moderate 
inhibitor of OCT1. Weak inhibition was observed at ultra-therapeutic 
concentration (300 µM) of rucaparib for MRP4, OATP1B1, OATP1B3, OAT1, 
and OAT3. No inhibition was observed for MRP2, MRP3, or BSEP. 
Rucaparib was an inhibitor of BCRP and P-gp efflux transporters with IC50 of 
55 μM and 283 μM, respectively. Rucaparib is a weak inhibitor of CYP2C9 in 
vivo. Caution should be used for concomitant use of CYP substrates with 
narrow therapeutic index as listed below. 
 
CYP Enzyme 
Substrates with Narrow Therapeutic Index 
CYP1A2 
Tizanidine, theophylline 
CYP2C9 
Warfarin, phenytoin 
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus and terfenadine 
 
 
9.2 
Nivolumab 
9.2.1 
Other Names 
 
 
Opdivo, BMS-936558, MDX-1106, ONO-4538 
9.2.2 
Classification 
 
 
Immunomodulatory; checkpoint inhibitor 
9.2.3 
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. 
9.2.4 
Pharmacokinetics 
1. Distribution: Nivolumab has linear pharmacokinetics after single and multiple 
dosing within the range 0.1 mg/kg to 10 mg/kg. The volume distribution (Vd) 
is 8L. 2.  
2. Elimination: Clearance is independent of dose in the range 0.1 mg/kg to 10 
mg/kg. The total body clearance is 9.5 mL/hr, and the elimination half-life of 
is approximately 26.7 days. Body weight normalized dosing showed 
approximately constant trough concentrations over a wide range of body 
weights.  
9.2.5 
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 (5 vials of 100 mg/10 mL). 
 

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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. Dilute with either NS or D5W to a final concentration of 1 to 10 mg/mL. 
 
Mix by gentle inversion; do not shake. 
 
Care must be taken to assure sterility of the prepared solution as the product 
does not contain any anti-microbial preservative or bacteriostatic agent. No 
incompatibilities between nivolumab and polyvinyl chloride (PVC), non-PVC/non-
DEHP (di(2-ethylhexyl)phthalate) IV components, or glass bottles have been 
observed. 
 
The administration of undiluted and diluted solutions of nivolumab must be 
completed within 24 hours of preparation. If not used immediately, the infusion 
solution may be stored up to 24 hours in a refrigerator at 2°- 8°C (36°-46°F) and 
a maximum of 8 hours of the total 24 hours can be at room temperature (20°-
25°C, 68°-77°F) and room light. The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period.  
9.2.6 
Dose and Administration 
See Section 5.1 
Nivolumab is to be administered as a 30 (± 10 minute) intravenous infusion (or as 
per current standard of care), 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. 
9.2.7 
Availability 
Bristol Myers Squibb (BMS) will provide the study drug. 
9.2.8 
Handling and Disposal 
Handling and disposal of nivolumab should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents. Nivolumab disposal will 
be conducted at individual sites and will not be returned to BMS. Recommended 
safety measures for preparation and handling of nivolumab include laboratory 
coats and gloves. 
9.2.9 
Adverse Effects 
1. Adverse Effects: The Comprehensive Adverse Events and Potential Risks list 
(CAEPR) provides a single list of reported and/or potential adverse events 
(AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs 
(SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applicatio 
ns/docs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 2069 patients. Below is the CAEPR for BMS- 936558 (Nivolumab, 
MDX-1106). 
 

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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:  
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)  

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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, 
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 6 
months after treatment has been discontinued. Men receiving nivolumab and 
who are sexually active with women of child bearing potential should adhere 
to contraception for a period of 7 months after the last dose of nivolumab. 
 
Lactation: It is not known if nivolumab is excreted into breast milk. Due to the 
potential for serious adverse reactions in the nursing infant, the manufacturer 
recommends women to discontinue breastfeeding during treatment with 
nivolumab. 
 
3. Drug Interactions: Nivolumab is not expected to have any effect on 
cytochrome P450 or other drug metabolizing enzymes in terms of inhibition 
or induction, and is, therefore, not expected to induce these types of PK-
based drug interactions. No incompatibilities between nivolumab injection 
and polyvinyl chloride (PVC), non-PVC/non-DEHP (di(2-ethylhexyl)phthalate) 
IV components, or glass bottles have been observed. 
 
10.0 
CORRELATIVES/TRANSLATIONAL STUDIES 

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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 rucaparib will be the 
overarching goal of this translational science. Tumor from core biopsies will be examined 
histologically by immunohistochemistry (IHC), immunofluorescence (IF), and RNA analysis. Post-
treatment biopsy tissue will be separated into sections for paraffin embedding, fresh frozen in 
OTC, and fresh frozen in RNAlater. Whole genomic DNA will be evaluated for mutational 
analysis). Biologic readouts for PD-1 and CTLA4 response biomarkers will be assessed along 
with specific markers of tumor infiltrating leukocytes (TILs). TILs and their subsets will be 
assessed using markers by IHC (e.g. CD4, CD8, FoxP3 (Treg), CD14 or CD68 (TAMs), CD11c 
(DCs)).  Response biomarkers will be determined by IHC or IF (e.g. B7-H1 (PD-1L), CD80, CD86, 
B7-H4, B7-HDC (PD-L2), CTLA4, CD28, LAG3, Tim-3, CD40, OX40)46,47.  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)48 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 markers46 
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:  
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: Screening 
2. On-treatment: Cycle 4 Day 1 
3. Post-treatment: 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 3 Day 1 
3. Post-treatment: EOT  
 
Blood will be collected, processed and shipped to the University of Michigan as detailed in 
the lab manual. 
 
 

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10.3 
Specimen Banking 
Patient samples collected for this study will be retained at University of Michigan. 
Specimens will be stored indefinitely or until they are used up. If future use is denied or 
withdrawn by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens. 
 
All CT scans should be de-identified using trial patient and site IDs and shipped to the 
University of Michigan for banking and exploratory endpoint assessment. 
 
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 at 
least 4 months of platinum-based front-line systemic chemotherapy with last dose within 
4 weeks of informed consent. The primary endpoint is PFS rate at 4 months following the 
initiation of study treatment. Secondary endpoints include the calculation of the ORR, 
median PFS and OS (from start of study treatment and 1st line platinum-based therapy), 
and the incidence of adverse events.  
11.2 
Sample Size and Accrual 
The investigators hope to enroll patients after 4-6 months of first line platinum therapy 
without progression. The sample size of this trial is based on the hypothesis that we will 
improve upon the expected proportion of patients surviving without progression after 4 
months of investigational therapy. We will accrue 32 evaluable patients to this trial.  
Evaluable patients are compliant with study treatment and observed for progression-free 
survival events, progression (requiring study discontinuation), death, or lack of events at 
4 months. Patients non-complaint with study treatment or lost to follow-up (either not 
secondary to toxicity) will be replaced. Based on the ABC-02 trial, PFS was estimated at 
72% and 60% after 4 and 6 months of first line gemcitabine and cisplatin, similar to the 
initiation point of our study.  PFS was 51% and 32% at 8 and 10 months, similar to the 
end of the treatment period for the primary outcome assessment in this trial.  Using a 
conditional probability argument, combined with the assumption that patient accrual to 
this study will follow an approximate uniform distribution over the 4 to 6 months of primary 
therapy for the patients accrued, we can accept the average of the PFS estimates for 
each period (4-6 months (66%) and 8-10 months (41.5%)) to correspond to our trial time 
period.  We can then standardize the ABC-02 PFS data so that the 4-6 month estimate is 
100% to correspond to the start point for patients in this trial and the estimate for 4 
months thereafter, 63% (0.415/0.66).  For our trial, we hope to improve the PFS rate from 
63% for these patients to 85%.  With our proposed sample size of 32 patients this trial will 
have 80% power to detect this difference significantly, with 5% type 1 error, using a 1-
sided test  
 
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 5.10. 

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11.4 
Data Analyses Plans 
The primary endpoint is the progression-free survival proportion measured after 4 months 
of study treatment for patients in the IIT population.  This endpoint is defined as the 
proportion of evaluable patients alive and progression-free after 4 months of study 
treatment in the event of no loss to follow-up and/or early patient discontinuation.  The 
outcome is expected to be observed for each patient.  In the event that either loss to 
follow-up or early discontinuation occurs (either not secondary to toxicity), the 4-month 
PFS will be estimated using the product-limit method of Kaplan and Meier.  Follow-up 
time will be defined as time from the date of first study treatment (PFS1) and 1st line 
platinum-based therapy (PFS2) until the date of radiological (as per combined RECIST 
v1.1 and irRECIST criteria) or clinical progression (leading to withdrawal from the study 
treatment), or loss to follow-up due to toxicity or non-compliance with study procedures, 
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. In order to adjust for the patient’s exposure to 
primary platinum-based therapy, a secondary analysis will utilize the Cox proportional 
hazards model with exposure time entered as an adjustment covariate as either a 
continuous covariate or as 4 months of exposure versus more than 4 months of 
exposure. OS will be similarly estimated and summarized with follow-up time calculated 
from the date of first study treatment (OS1) and 1st line platinum-based therapy (OS2) 
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. 
11.5 
Early Stopping Rules Due to Toxicity 
In order to protect patients from potential undue severe toxicity of this regimen, we have 
implemented stopping rules for documented SAE events that are at least possibly 
attributable to the study regimen.  Using data from study of rucaparib monotherapy as 
maintenance therapy in ovarian cancer (phase 3 ARIEL3 trial; Coleman RL et al. Lancet. 
2017 Oct 28;390(10106):1949-1961) as a guide, which had a SAE rate of 21% - defined 
as the percentage of patients experiencing at least one SAE during study treatment. In 
addition, the investigation of nivolumab in hepatocellular carcinoma (CHECKMATE-040 
trial; El-Khoueiry AB et al. Lancet. 2017 Jun 24;389(10088):2492-2502) had a SAE rate 
of 4%. During the conduct of this proposed study, if we become confident from 
accumulating study data that the SAE rate, defined in the same way, involves more than 
30% patients, then we will halt accrual on the trial in order to convene the data safety 
monitoring board (DSMB). The DSMB will review types and outcome of toxicity events 
and to recommend study closure or changes that could improve the trial.   
 
To operationalize this stopping rule we have used a Bayesian sequential stopping rule 
under the beta-binomial relationship between prior expectation of toxicity and 
accumulating toxicity data.  We have used a pessimistic and slightly informative prior, the 
uniform, to suggest that prior to study data we believe the percentage of SAE is equally 
like between 0 and 100%, with an average of 50%.  If the posterior probability after study 
data is 80% or greater that the SAE probability per patient is 30% or greater, we will halt 
the trial.  The following table lists the number of patients accrued and the number of 
patients experiencing an SAE to trigger stopping the trial.  The rule is implemented after 5 
patients are accrued. 
 
Number of patients 
on study treatment 
Number 
experiencing SAE 
1 – 5 
No rule to apply – 

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too early 
6 – 10 
6 
11 – 12 
7 
13 – 14 
8 
15 – 16 
9 
17 – 18 
10 
19 – 20 
11 
20 – 22 
12 
23 – 24 
13 
25 – 26 
14 
27 – 28 
15 
29 – 30 
16 
31 – 32 
17 
 
Under this rule, if the true probability of SAE was 20%, 30%, 40%, 50%, or 60% the trial 
would stop early <1%, 8%, 30%, 62%, and 71%, respectively.  And the expected sample 
size for the trial would be 32, 31, 27, 21, and 19 patients, respectively. 
 
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:  
• 
At the time of registration   
o 
Subject entry into the EDC 
 
Subject Status 
 
Demographics 
• 
During study participation 
o 
All data should be entered online within 10 business days of data acquisition. 
[Information on dose limiting toxicity events must be entered within one 
business day.] Information on Serious Adverse Events must be entered 
within the reporting timeframe specified in Section 8.5 of the protocol.  
  
 

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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 quarterly 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: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (SAE reporting, unanticipated problems) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 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.  
 
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 quarterly 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 

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authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 
15.0 
CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by the University of Michigan 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 first treatment cycle.  The study site 
will send the de-identified source documents to the Coordinating Center for monitoring.  
‘Centralized’ monitoring may be requested by the Coordinating Center if an amendment requires 
changes to the protocol procedures. The site will send in pertinent de-identified source 
documents, as defined by the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first.  The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and samples collected 
 
Proper storage, dispensing and inventory of study medication 
 
Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review.  At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner.  For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 
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 

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Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit. 
 
 

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16.0 
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Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet 
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O’Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell. 2015;60(4):547-560. 
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Plummer R, Jones C, Middleton M, et al. Phase I Study Of The Poly ( ADP-Ribose ) Polymerase 
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Fong P, Boss D, Yap T, et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA 
Mutation Carriers. N Engl J Med. 2009:123-134. 
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Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib 
in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept 
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Tutt A, Robson M, Garber J, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients 
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de Murcia J, Niedergang C, Trucco C, et al. Requirement of poly ( ADP-ribose ) polymerase in 
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18.  
Rajan A, Carter CA, Kelly RJ, et al. A phase I combination study of olaparib with cisplatin and 
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doi:10.1158/1078-0432.CCR-11-2425. 
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Oza AM, Cibula D, Benzaquen AO, et al. Olaparib combined with chemotherapy for recurrent 
platinum-sensitive ovarian cancer: A randomised phase 2 trial. Lancet Oncol. 2015;16(1):87-97. 
doi:10.1016/S1470-2045(14)71135-0. 
20.  
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-
sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by 
BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861. 
doi:10.1016/S1470-2045(14)70228-1. 
21.  
Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a 
breast cancer susceptibility gene. Nat Genet. 2007;39(2):165-167. doi:10.1038/ng1959.PALB2. 
22.  
Rahman N, Scott RH. Cancer genes associated with phenotypes in monoallelic and biallelic 
mutation carriers: New lessons from old players. Hum Mol Genet. 2007;16(R1):60-66. 
doi:10.1093/hmg/ddm026. 
23.  
Stankovic T, Kidd AM, Sutcliffe A, et al. ATM mutations and phenotypes in ataxia-telangiectasia 

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families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and 
breast cancer. Am J Hum Genet. 1998;62(2):334-345. doi:10.1086/301706. 
24.  
Wong MW, Nordfors C, Mossman D, et al. BRIP1, PALB2, and RAD51C mutation analysis reveals 
their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res 
Treat. 2011;127(3):853-859. doi:10.1007/s10549-011-1443-0. 
25.  
Yu H, Pak H, Hammond-Martel I, et al. Tumor suppressor and deubiquitinase BAP1 promotes 
DNA double-strand break repair. Proc Natl Acad Sci. 2014;111(1):285-290. 
doi:10.1073/pnas.1309085110. 
26.  
Lu Y, Kwintkiewicz J, Liu Y, et al. Chemosensitivity of IDH1-mutated gliomas due to an impairment 
in PARP1-mediated DNA repair. Cancer Res. 2017;77(7):1709-1718. 
doi:10.1016/j.cell.2016.05.007.Mapping. 
27.  
Sulkowski PL, Corso CD, Robinson ND, et al. 2-Hydroxyglutarate produced by neomorphic IDH 
mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci 
Transl Med. 2017;9(375):1-32. doi:10.1126/scitranslmed.aal2463.2-Hydroxyglutarate. 
28.  
Kohn EC, Lee J, Ivy SP. The HRD decision--which PARP inhibitor to use for whom and when. Clin 
Cancer Res. 2017:clincanres.2186.2017. doi:10.1158/1078-0432.CCR-17-2186. 
29.  
Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian 
carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 
2017;18(1):75-87. doi:10.1016/S1470-2045(16)30559-9. 
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Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian 
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Peggs KS, Quezada SA, Korman AJ, Allison JP. Principles and use of anti-CTLA4 antibody in 
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Robert C, Ghiringhelli F. What Is the Role of Cytotoxic T Lymphocyte-Associated Antigen 4 
Blockade in Patients with Metastatic Melanoma? Oncologist. 2009:848-861. 
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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. 
34.  
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. 
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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. 
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Carter LL, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T 
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4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9. 
37.  
Bang YJ, Doi T, De Braud F, et al. Safety and Efficacy of Pembrolizumab (MK-3475) in Patients 
With Advanced Biliary Tract Cancer: Interim Results of KEYNOTE-028. European Cancer 
Congress. 2015. Vienna, Austria. 
38.  
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-
Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665. 
39.  
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous 
Non–Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-1639. 
doi:10.1056/NEJMoa1507643. 
40.  
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34. 
doi:10.1056/NEJMoa1504030. 
41.  
Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after 
platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 
2017;18(3):312-322. doi:10.1016/S1470-2045(17)30065-7. 
42.  
Robert C, Long G V., Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF 
Mutation. N Engl J Med. 2015;372(4):320-330. doi:10.1056/NEJMoa1412082. 
43.  
Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of BRCA1/2-
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PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016;7(12):13587-13598. 
doi:10.18632/oncotarget.7277. 
44.  
Robillard L, Nguyen M, Loehr A, et al. Preclinical evaluation of the PARP inhibitor rucaparib in 
combination with PD-1 and PD-L1 inhibition in a syngeneic BRCA1 mutant ovarian cancer mode. 
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45.  
Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances 
cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711-3720. 
doi:10.1158/1078-0432.CCR-16-3215. 
46.  
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. 
47.  
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 
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doi:10.1158/1078-0432.CCR-15-1434. 
48.  
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: A knowledge-based 
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49. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488752/ 
 
 
 

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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 
 
 
 

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

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Appendix II 
Child-Pugh Score 
 
 
Measure 
1 point 
2 points 
3 points 
Total Bilirubin mg/dL 
<2 
2-3 
>3 
Serum Albumin g/dL 
>3.5 
2.8-3.5 
<2.8 
PT Time 
• 
PT >ULN 
• 
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: R.N.H. Pugh, I.M. Murray-Lyon, J.L. Dawson, M.C. Pietroni, Roger Williams. Transection of 
the esophagus for bleeding esophageal varices. British Journal of Surgery. Volume 60. Issue 8, 
pages 646-649, August 1973. 

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

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Appendix IV 
Investigator’s Statement 
 
1. I have carefully read this protocol entitled “Phase II Study of PARP inhibitor Rucaparib in 
Combination with Anti-PD-1 Antibody Nivolumab in Patients with Advanced or Metastatic Biliary 
Tract Cancer Following Platinum Therapy”, Version 4.0 dated 11/24/2020 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:  
____________\______________\_____________ 
 
 
 

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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).  
 
1. COVID-19 Testing:  
a. 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. 
b. 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.  
c. Per study Supporters [Clovis and Bristol-Myers Squibb] additional reporting requirements, 
it is requested that the Medical Monitor is to be immediately informed in the event that a 
trial participant exhibits or reports symptoms consistent with COVID-19 (whether or not 
confirmed by a positive test result). Depending on the investigational product being 
administered and the patient’s clinical presentation, dosing may be withheld, until such 
time as symptoms resolve. This decision should be made by the site PI, determining what 
is the best course of action for the patient, in consultation with the Medical Monitor. In 
some cases, the PI and/or Medical Monitor may request a participant be retested before 
dosing of the investigational product is resumed. 
 
2. Study Visit Schedule: 
a. 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). 
b. 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. 
c. Where participants cannot be seen at the site or by home visit, the use of telemedicine 
and adaptation of schedule of assessments can be implemented, where feasible to 
ensure patient safety. 
d. 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. 
 
3. Laboratory Assessments: 
a. Pre-Treatment, Cycle 4 Day 1 (UM Only) & End of Treatment (EOT) biopsy samples will 
be obtained, if applicable/possible, and will be retained at site until further notification. 
b. Cycle 1 Day 1, Cycle 3 Day 1 and End of Treatment blood samples 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. 
 
4. Study Medications: 

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a. Adjustments for alternate drug administration have been permitted by the Supporters 
(Clovis and Bristol-Myers Squibb) and Sponsor-Investigator.  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.  
b. The patient may remain on study without receiving drug for more than 28 days if the 
drug(s) are held due to COVID-19. 
c. If a patient does not receive investigational regimen (both Nivolumab and Rucaparib) 
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. 
d. Nivolumab or Rucaparib may be held independent of the other drug if drug infusion or 
intake not considered possible or safe due to COVID-19. 
e. Sites may ship Rucaparib (Oral Medication) with drug diary directly to subjects via an 
overnight, traceable courier.