Conditions: Pancreatic Ductal Adenocarcinoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this research study is to learn more about a new combination of drugs being given to treat pancreatic cancer. The drugs being tested are BMS-813160, nivolumab, gemcitabine, and nab-paclitaxel. The investigators will be looking at both the side effects and the way the disease responds to treatment.

Detailed description:

Arms:
arm 1: * BMS-813160 300 mg twice per day
* Nivolumab 30-minute intravenous (IV) infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle
* Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle
* Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle
* Post-treatment biopsy at the end of cycle 2
* Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cyclesore cycles arm 2: * Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle
* Post treatment biopsy at the end of cycle 2
* Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles arm 3: * BMS-813160 300 mg twice per day
* Nivolumab 30-minute IV infusion at a flat dose of 480 mg on Day 1 of each 28-day cycle
* Gemcitabine 30-minute IV infusion 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle
* Nab-paclitaxel 30-40-minute IV infusion 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle
* Post-treatment biopsy at the end of cycle 2
* Patients who achieve stable disease, a partial response, or complete response after the first 2 cycles of treatment will continue to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have pseudo-progression will continue to receive treatment for 2 more cycles

Interventions: intervention 1: BMS-813160 intervention 2: Nivolumab intervention 3: Gemcitabine intervention 4: Nab-paclitaxel intervention 5: Biopsy intervention 6: Peripheral blood
Intervention descriptions: intervention 1: BMS-813160 will be supplied by Bristol Myers Squibb intervention 2: Nivolumab will be supplied by Bristol Myers Squibb intervention 3: Gemcitabine will be given as per routine care from commercial supply. intervention 4: Nab-paclitaxel will be given as per routine care from commercial supply. intervention 5: Pre-treatment, end of cycle 2, end of treatment for patients who progress or otherwise do not go to surgery, and surgery for patients who do go to surgery intervention 6: -Cycle 1 Day 1 before treatment begins, after 2 cycles of treatment +/- 3 days of mandatory tumor biopsy, end of treatment for patients who progress or otherwise do not go to surgery, and no more than 24 hours prior to time of surgery (if applicable)

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version: 05/16/2022 – Amendment 7 
 
Page 1 of 83 
 
 
A phase I/II study to evaluate the tolerability and efficacy of BMS-813160 (CCR2/5 inhibitor) with 
nivolumab and gemcitabine and nab-paclitaxel in borderline resectable and locally advanced 
pancreatic ductal adenocarcinoma (PDAC) 
 
Washington University School of Medicine / Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201806007 
Version Date: 05/16/2022 
 
Coordinating Center:  
Washington University School of Medicine 
Principal Investigator:  
Kian-Huat Lim, M.D., Ph.D. 
Phone: (314) 362-6157 
E-mail: kian-huat.lim@wustl.edu  
 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Benjamin Tan, M.D. 
 
 
Washington University  
Medical Oncology 
Katrina Pedersen, M.D.  
 
Washington University  
Medical Oncology 
Rama Suresh, M.D. 
 
 
Washington University  
Medical Oncology 
Haeseong Park, M.D. 
 
 
Washington University  
Medical Oncology 
Nikolaos Trikalinos, M.D. 
 
Washington University  
Medical Oncology 
William Hawkins, M.D.  
 
Washington University  
Surgery 
Ryan Fields, M.D. 
 
 
Washington University  
Surgery 
Maria Majella Doyle, M.D. 
 
Washington University  
Surgery 
Chet Hammill, M.D. 
 
 
Washington University  
Surgery 
Vladimir Kushnir, M.D.  
 
Washington University  
Gastroenterology 
Marianne Ruzinova, M.D., Ph.D. 
Washington University  
Pathology 
David DeNardo, Ph.D.   
 
Washington University  
Tumor Immunology 
Esther Lu, Ph.D. 
 
 
Washington University  
Biostatistics 
 
Study Drug(s):  
 
BMS-813160 
Nivolumab  
Gemcitabine (Gemzar) 
Nab-paclitaxel (Abraxane) 
IND #: 
139562 
ClinicalTrials.gov #: 
NCT03496662 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 


Protocol Version: 05/16/2022 – Amendment 7 
 
Page 2 of 83 
A phase I/II study to evaluate the tolerability and efficacy of BMS-813160 (CCR2/5 
inhibitor) with nivolumab and gemcitabine and nab-paclitaxel in borderline resectable and 
locally advanced pancreatic ductal adenocarcinoma (PDAC) 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
05/29/2018 
Amendment #1 Version 
 
 
 
 
 
 
08/27/2018 
Amendment #2 Version 
 
 
 
 
 
 
04/15/2019 
Amendment #3 Version 
 
 
 
 
 
 
06/05/2019 
Amendment #4 Version 
 
 
 
 
 
 
09/18/2019 
Amendment #5 Version 
 
 
 
 
 
 
03/20/2020 
Amendment #6 Version 
 
 
 
 
 
 
07/28/2021 
Amendment #7 Version 
 
 
 
 
 
 
05/23/2022 
 
 
 


Protocol Version: 05/16/2022 – Amendment 7 
 
Page 3 of 83 
A phase I/II study to evaluate the tolerability and efficacy of BMS-813160 (CCR2/5 
inhibitor) with nivolumab and gemcitabine and nab-paclitaxel in borderline resectable and 
locally advanced pancreatic ductal adenocarcinoma (PDAC) 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 
 


Protocol Version: 05/16/2022 – Amendment 7 
 
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A phase I/II study to evaluate the tolerability and efficacy of BMS-813160 (CCR2/5 
inhibitor) with nivolumab and gemcitabine and nab-paclitaxel in borderline resectable and 
locally advanced pancreatic ductal adenocarcinoma (PDAC) 
 
SCHEMA 
 
 
 


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Part A: Safety Lead-In (Each cycle = 28 days) 
Arm (by 
randomization) 
BMS-813160 (D1-28) 
Nivolumab 
(D1)  
Chemotherapy (D1, 8, 15) 
Dose Level 
Dose 
Dose Level 
Gemcitabine 
Nab-paclitaxel 
Experimental 
(n=9-18) 
0 (starting) 
300 mg BID  
480 mg  
0 (starting) 
1000 mg/m2 
125 mg/m2 
-1 
150 mg BID  
480 mg  
-1 
800 mg/m2 
100 mg/m2 
-2 
150 mg QD  
480 mg  
-2 
600 mg/m2 
75 mg/m2 
Control (n=8) 
N/A 
N/A 
N/A 
0 (starting) 
1000 mg/m2 
125 mg/m2 
N/A 
N/A 
N/A 
-1 
800 mg/m2 
100 mg/m2 
N/A 
N/A 
N/A 
-2 
600 mg/m2 
75 mg/m2 
Part B: Dose Expansion (Each cycle = 28 days) 
Dose expansion 
(N=30*) 
 
Per Part A 
480 mg  
 
Per Part A 
Dose modifications must be made based on toxicities attributed to BMS-813160 or chemotherapy, or both. 
G-CSF not allowed for Cycles 1-2 
* Total of 30 patients includes patients started on and stayed on MTD on experimental arm in Part A 
 
 
 
 
 
 


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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
CAF 
Cancer-associated fibroblast 
CBC 
Complete blood count 
CTL 
Cytotoxic T lymphocyte 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose limiting toxicity 
DSMC 
Data Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
HCC 
Hepatocellular carcinoma 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IM 
Inflammatory monocyte 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSAID 
Non-steroidal anti-inflammatory drug 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PB 
Peripheral blood 
PD 
Pharmacodynamic 
PD 
Progressive disease 
PDAC 
Pancreatic ductal adenocarcinoma 
PFS 
Progression-free survival 
PI 
Principal investigator 


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PR 
Partial response 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
TAM 
Tumor-associated macrophage 
TME 
Tumor microenvironment 
UPN 
Unique patient number 
WUSM 
Washington University School of Medicine 
 
 


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Table of Contents 
SCHEMA ........................................................................................................................................ 4 
1 
BACKGROUND AND RATIONALE .............................................................................. 10 
1.1 
Pancreatic Ductal Adenocarcinoma (PDAC) ................................................................. 10 
1.2 
BMS-813160 .................................................................................................................. 10 
1.3 
Nivolumab (Opdivo) ...................................................................................................... 12 
1.4 
Summary of common or significant side effects for each agent .................................... 13 
1.5 
Study Rationale .............................................................................................................. 13 
1.6 
Correlative Studies Background..................................................................................... 14 
2 
OBJECTIVES .................................................................................................................... 16 
2.1 
Primary Objectives ......................................................................................................... 16 
2.2 
Secondary Objectives (Part B) ....................................................................................... 16 
2.3 
Exploratory Objectives (Parts A and B) ......................................................................... 16 
3 
PATIENT SELECTION .................................................................................................... 17 
3.1 
Inclusion Criteria ............................................................................................................ 17 
3.2 
Exclusion Criteria ........................................................................................................... 18 
3.3 
Inclusion of Women and Minorities............................................................................... 20 
4 
REGISTRATION PROCEDURES ................................................................................... 20 
4.1 
Confirmation of Patient Eligibility ................................................................................. 20 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 21 
4.3 
Assignment of UPN ....................................................................................................... 21 
5 
TREATMENT PLAN ........................................................................................................ 21 
5.1 
Agent Administration ..................................................................................................... 22 
5.2 
Dose De-Escalation Schema – Part A ............................................................................ 23 
5.3 
Definition of MTD, DLT, and Dose Escalation Criteria – Part A ................................. 23 
5.4 
Toxicity, Response, and DLT Evaluations .................................................................... 25 
5.5 
Part B – Dose Expansion ................................................................................................ 26 
5.6 
General Concomitant Medication and Supportive Care Guidelines .............................. 26 
5.7 
Women of Childbearing Potential (WOCBP) ................................................................ 26 
5.8 
Duration of Therapy ....................................................................................................... 27 
5.9 
Duration of Follow-up .................................................................................................... 28 
6 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 28 
6.1 
Dose Modifications for BMS-813160 ............................................................................ 29 
6.2 
Dose Modifications for Nivolumab................................................................................ 30 
6.3 
Dose Modifications for Gemcitabine and Nab-Paclitaxel .............................................. 31 
6.4 
Treatment Beyond Progression ...................................................................................... 33 
7 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 34 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 34 
7.2 
Reporting Requirements for Secondary Sites ................................................................ 38 
8 
PHARMACEUTICAL INFORMATION .......................................................................... 39 
8.1 
BMS-813160 .................................................................................................................. 39 
8.2 
Nivolumab (Opdivo) ...................................................................................................... 40 
8.3 
Gemcitabine (Gemzar) ................................................................................................... 42 
8.4 
Nab-Paclitaxel (Abraxane) ............................................................................................. 44 
9 
CORRELATIVE STUDIES .............................................................................................. 45 
9.1 
Tumor Biopsy ................................................................................................................. 45 


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9.2 
Peripheral Blood ............................................................................................................. 46 
10 
STUDY CALENDAR ....................................................................................................... 48 
11 
DATA SUBMISSION SCHEDULE ................................................................................. 50 
11.1 AE Reporting in the EDC .............................................................................................. 50 
12 
MEASUREMENT OF EFFECT........................................................................................ 50 
12.1 Antitumor Effect – Solid Tumors................................................................................... 50 
12.2 Disease Parameters ......................................................................................................... 51 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 52 
12.4 Response Criteria ........................................................................................................... 54 
13 
DATA AND SAFETY MONITORING ............................................................................ 56 
14 
AUDITING ........................................................................................................................ 58 
15 
STATISTICAL CONSIDERATIONS............................................................................... 58 
15.1 Part A.............................................................................................................................. 58 
15.2 Part B .............................................................................................................................. 59 
15.3 Statistical analysis .......................................................................................................... 59 
16 
MULTICENTER REGULATORY REQUIREMENTS ................................................... 60 
17 
REFERENCES .................................................................................................................. 62 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 65 
APPENDIX B: PATIENT’S MEDICATION DIARY ................................................................. 66 
APPENDIX C: CYP3A4 and P-GP Guidance.............................................................................. 67 
APPENDIX D: MATE Substrates Guidance ................................................................................ 68 
APPENDIX E: Nivolumab Management Algorithms .................................................................. 69 
APPENDIX F: Definitions for Adverse Event Reporting ............................................................ 77 
APPENDIX G: Reporting Timelines ............................................................................................ 79 
APPENDIX H: Washington University Serious Adverse Event Reporting Cover Sheet ............ 83 
 
 


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1 
BACKGROUND AND RATIONALE 
 
1.1 
Pancreatic Ductal Adenocarcinoma (PDAC) 
 
The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is dismal, with 
a 5-year overall survival rate of 8%1. According to the American Cancer Society, an 
estimated 53,670 new cases and 43,090 deaths will occur in the US in 2017. Notably, 
PDAC is projected to be the 2nd leading cause of cancer-related death by 20201. Due to a 
lack of early warning symptoms and effective screening tools, 85-90% of PDAC patients 
are diagnosed at advanced stages when chemotherapy is the only treatment option. The two 
current FDA-approved chemotherapy regimens, FOLFIRINOX and gemcitabine/Nab-
paclitaxel, have improved the median survival of patients with advanced PDAC from about 
6.7 months to 11.1 months and 8.5 months, respectively2, but at the price of significant 
toxicities. Escalating the strength of chemotherapy is unlikely to be tolerated, evidenced 
by a dearth of new, stronger chemotherapy regimens now being tested in clinical trials2. 
Disappointingly, the therapeutic breakthroughs by immune checkpoint blockade in other 
cancer types, such as melanoma, non-small cell lung cancer, and bladder cancer, have not 
yet materialized for PDAC patients3. These challenges are at the forefront of efforts to 
improve the effectiveness of chemotherapy and immunotherapy by overcoming the 
molecular mechanisms that drive the refractory nature of PDAC.  
 
1.2 
BMS-813160 
 
Immunotherapy has emerged as a promising therapeutic modality in cancer treatment. 
Approaches that have shown success in the clinic include immune checkpoint blockade, 
use of chimeric-antigen receptor T cell therapy, instillation of cytotoxic anti-tumor T cells 
and immunostimulatory antibodies. Despite promising results in other cancer types, 
immune-based treatments have not been successful in PDAC. PDAC tumors are 
characterized by a profound desmoplastic tumor microenvironment (TME)4. Major 
components of this TME include a dense fibrotic matrix deposited by cancer-associated 
fibroblasts (CAFs), and significant infiltration of various subsets of immunosuppressive 
myeloid cells, vascular cells, and nerve cells5-7. Targeting the immunosuppressive myeloid 
cells has recently emerged as a promising approach, with multiple strategies now being 
developed and tested. Blocking the CCL2-CCR2 and CCL5-CCR2 axes that drive the 
function of immunosuppressive myeloid cell function are two examples of these 
approaches. Progression of PDAC is accompanied by increased abundance of various 
chemokines including CCL2 and CCL5, which draw and reprograms circulatory myeloid 
cells and regulatory T cells into deterring anti-tumor T cells8,9. CCL2 is secreted by tumors 
and recruits CCR2 positive inflammatory monocytes from the bone marrow to the TME 
where they transform to immuno-suppressive tumor associated macrophages (TAM) and 
prevent effective anti-tumor immunity10-12. Previous studies have shown that the ratio of 
bone marrow to blood inflammatory monocytes is prognostic and inhibition of this axis 
showed responses in preclinical tumor models11,12. Since tumors leverage the CCL2-CCR2 
and CCL5-CCR5 axis to promote tumor growth through Tregs and TAM, blocking of this 
axis may be able to overcome the immunosuppressive TME and 
promote effective anti-tumor immunity. 


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BMS-813160 (developed by Bristol-Myers Squibb) is an equipotent dual antagonist of 
CCR2 and CCR5 that binds potently to both receptors and exhibits potent dual inhibition 
of in vitro receptor-mediated functions, including chemotaxis, calcium flux, non-
hydrolyzable guanosine triphosphate analog (guanosine 5’-3-O- [thio]triphosphate) [GTP-
γS] exchange, and Mac-1 (integrin β) [CD11b] upregulation, as well as CCR5 
phosphorylation and internalization induced by ligand interaction. BMS-813160 is a full 
and reversible antagonist of both receptors and blocks CCR2- and CCR5-dependent 
functions in response to all known ligands. BMS-813160 is also at least 800-fold selective 
against a panel of other chemokine receptors (C-C chemokine receptor 1 [CCR1], C-C 
chemokine receptor 4 [CCR4], C-X-C chemokine receptor 2 [CXCR2], C-X-C chemokine 
receptor 3 [CXCR3], and C-X-C chemokine receptor 5 [CXCR5]) and a panel of G protein-
coupled receptors (GPCRs)/transporters (21 targets). 
 
In CCR2 PD models, BMS-813160 significantly reduced blood monocytes in human 
CCR2 knock-in (hCCR2 KI) mice and increased serum levels of monocyte chemotactic 
protein (MCP)-1 (ligand for CCR2) in hCCR2 KI mice and in monkeys at doses providing 
plasma concentrations that are greater than or equal to the CCR2 binding concentration at 
which 90% inhibition is observed (IC90). The compound also reduced blood monocytes in 
monkeys although the reduction was not statistically significant due to inter-animal 
variability. These data support the use of these 2 measurements, serum MCP-1 and absolute 
monocyte count, as CCR2 PD biomarkers in studies of BMS-813160. In CCR5 
homeostatic models in the mouse, preliminary studies show that BMS-813160 robustly 
inhibited ex vivo-stimulated whole blood (WB) CD11b upregulation at doses providing 
plasma concentrations that are greater than or equal to the mouse CCR5 binding / CD11b 
IC90. When tested in naïve monkeys for its effect on CCR5 phosphorylation with or 
without ex vivo stimulation and CCR5 internalization with ex vivo stimulus, BMS-813160 
significantly inhibited phosphorylation and internalization at plasma concentrations greater 
than or equal to the IC90 of CCR5. When studied in 48-hour thioglycollate (TG) peritonitis 
model using hCCR2 KI mice, BMS-813160 substantially reduced monocyte/macrophage 
influx into the peritoneal cavity, providing an estimated in vivo free plasma concentration 
required to yield 50% of the maximal response (EC50) value of 4.9 nM, which correlated 
well with the in vitro binding IC50 of 5.8 nM (mouse binding to human peripheral blood 
mononuclear cells [hPBMCs]). Maximal inhibition of monocyte/macrophage infiltration 
was achieved with approximately 98% receptor occupancy. 
 
BMS-813160 was previously evaluated and found to be relatively safe and well tolerated 
in both healthy participant studies and in participants with diabetic kidney disease (DKD). 
To date, BMS-813160 has been studied in 4 clinical trials. Altogether, 167 participants 
have received at least one dose of BMS-813160 (108 healthy participants and 59 
participants with diabetic kidney disease). In the single ascending dose study, BMS-813160 
was safe after single dose administrations up to 2000 mg in healthy participants 
(NCT01049165). There were no deaths, serious adverse events (SAEs) or discontinuations 
due to AEs. All reported AEs were mild in intensity. At the 2000 mg dose there was an 
increased incidence of CNS-related AEs (dizziness and euphoric mood). Dizziness 
occurred in 5 participants (7.1%), all receiving BMS-813160, and all but 1 was considered 


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by the investigator to be related to study drug (n = 1 each in the 150 mg and 1200 mg 
groups, and n = 3 in the 2000 mg group). There were 2 participants in the 2000 mg BMS-
813160 group and 1 participant in the placebo group who had AEs of euphoria. Multiple 
doses of BMS-813160 were safe and generally well tolerated in healthy participants across 
the dose range of 10 to 300 mg QD (N=24) and 300 to 900 mg BID (N=18) for 14 days. 
There were no deaths, SAEs, or discontinuations due to AEs in this study. AEs were 
reported by 17 (40.5%) participants receiving any dose of BMS-813160 and in 3 (21.4%) 
participants receiving placebo. There was no apparent dose relationship with respect to 
AEs. One AE of headache in a participant receiving BMS-813160 10 mg QD was 
considered moderate in intensity. All other AEs were considered to be mild in intensity. 
There were concentration-dependent increases in QRS and PR intervals and HR at 600 mg 
BID and 900 mg BID, without any ECG-related AEs or clinical sequalae. The increases in 
PR (mean < 16 msec at peak), QRS (mean < ~10 msec at peak), and HR (< ~10 bpm at 
peak) were not considered clinically significant. Concentration-response assessment 
showed no QTc prolongation. BMS-813160 was generally safe and well-tolerated when 
administered for 12 weeks. 
 
1.3 
Nivolumab (Opdivo) 
 
Nivolumab is a fully human, immunoglobulin G4 (IgG4) [kappa] isotype monoclonal 
antibody that binds to PD-1 with nanomolar affinity (dissociation constant [Kd], 3.06 nM) 
and a high degree of specificity. Nivolumab blocks binding of PD-1 to its ligands PD-L1 
and PD-L2. Nonclinical in vitro testing of nivolumab demonstrated that binding to PD-1 
results in enhanced T-cell proliferation and release of interferon gamma (IFNγ) in vitro in 
mixed lymphocyte reaction and cytomegalovirus assays. Nivolumb is now approved as 
second line treatment for sorafenib-resistant hepatocellular carcinoma (HCC) and 
microsatellite-instability-high (MSI-H) colorectal cancer (CRC).  
 
Combination clinical toxicology studies with BMS-813160 and nivolumab is now being 
evaluated in clinical trial (NCT03184870) for advanced PDAC and CRC. Side effects of 
nivolumab are similar to other anti-PD-1 antibodies and include pulmonary toxicity, renal 
toxicity (including acute renal failure), endocrine abnormalities, GI toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies). There 
is no relationship between the incidence, severity, or causality of AEs and the nivolumab 
dose level. 
 
Nivolumab 480 mg every 4 weeks (Q4W) is currently under active clinical evaluation 
across multiple tumor types (NCT03184870). Using a PPK model, nivolumab 480 mg 
Q4W is predicted to provide average steady-state concentrations (Cavgss) similar to 
nivolumab 3 mg/kg Q2W. Nivolumab 480 mg Q4W is predicted to provide greater 
(approximately 40%) Cmaxss and lower (approximately 20%) trough steady-state 
concentrations (Cminss). Nivolumab has been shown to be safe and well tolerated up to 
doses of 10 mg/kg Q2W and has not demonstrated a clear dose response or exposure-
response safety relationship. Based on these safety findings, the predicted Cmaxss at 480 
mg Q4W is not considered to put patients at increased risk for AEs. The approved doses of 


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3 mg/kg Q2W and 240 mg Q2W have shown survival benefit across multiple tumor types 
compared to respective standards of care. Nivolumab exposure was not a predictor of 
survival in exposure response efficacy analyses conducted for multiple tumor types. 
  
Clinical evaluation of 480mg Q4W is ongoing; as such, summaries of safety information, 
PK, and immunogenicity are not currently available. 
 
1.4 
Summary of common or significant side effects for each agent 
 
BMS-813160: Headache, dizziness, diarrhea, abnormal liver function, impaired wound 
healing, EKG changes (mild prolongation of QRS and PR at > 600mg BID was observed 
but not considered clinically-significant. Not expected to occur at 300mg BID as proposed 
in our study). 
 
Nivolumab: infusion reaction, fatigue, diarrhea, immune-related toxicities including 
pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatitis, encephalitis.  
 
Gemcitabine: infusion reaction, nausea/vomiting, anorexia, flu-like symptoms, fatigue, 
peripheral edema, myelosuppression, abnormal liver function, abnormal kidney function, 
hemolytic uremic syndrome, pneumonitis, capillary leak syndrome, posterior reversible 
encephalopathy syndrome. 
 
Nab-paclitaxel: infusion reaction, hypersensitivity, nausea/vomiting, fatigue, peripheral 
edema, peripheral/sensory neuropathy, abnormal liver function, abnormal kidney function, 
myelosuppression, pneumonitis, abnormal EKG, alopecia, rash, anorexia. 
 
Overlapping toxicities: Pneumonitis, abnormal liver function, abnormal kidney function, 
EKG changes, myelosuppression. 
 
Additional potential toxicities: We expect the majority of the acute side effects to be 
cause by chemotherapy. However, the combination of BMS-813160, nivolumab, 
gemcitabine and nab-paclitaxel may increase the risk for fatigue, diarrhea, pneumonitis and 
abnormal liver function based on overlapping toxicities. These will be monitored for during 
each clinical visit and dose-adjustments will be performed per protocol.  
 
1.5 
Study Rationale 
 
The development of new clinical approaches that are effective against pancreatic ductal 
adenocarcinoma (PDAC) is a significant unmet medical need. One promising way to 
improve outcomes for patients with PDAC is to alter the tumor immune microenvironment 
to support therapeutic responses. Acute immune responses involving CD8+ cytotoxic T 
lymphocytes (CTLs) and/or natural killer cells can effectively restrain tumor development 
and progression. Indeed, the few durable responses to therapy observed in PDAC are often 
associated with maintenance of the anti-tumor CTL activity that kills remnant tumor cells 
following therapy5,13. Unfortunately, to date, immunotherapy has struggled to achieve 
significant clinical benefit when used as a single therapeutic agent in PDAC3. This is likely 


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Page 14 of 83 
due to the presence of an immunosuppressive tumor microenvironment. Critical drivers of 
this immunosuppressive microenvironment are tumor-infiltrating inflammatory monocytes 
(IMs), tumor-associated macrophages (TAMs), and immature granulocytes14-17. In addition 
to instigating immune suppression, these tumor-infiltrating leukocytes impart resistance to 
cytotoxic therapies and promote metastatic dissemination18-20. Thus, high numbers of these 
cells correlate with early metastatic relapse and poor PDAC survival5,21-23. Therefore, 
approaches that reprogram the tumor microenvironment to potentiate protective anti-tumor 
immunity hold significant therapeutic potential. 
 
We and other groups have demonstrated that mobilization and tumor infiltration of IMs 
and TAMs can promote tumor growth, dissemination, local immunosuppression, and 
resistance to cytotoxic therapy5,18,23-25. Signaling through C-C chemokine receptor type 2 
(CCR2) is critical for the mobilization of IMs and their recruitment to inflamed tissues. 
Our recently published reports clearly illustrate that blockade of IM recruitment using 
CCR2 inhibitors (CCR2i), slows tumor progression, improves responses to chemotherapy, 
and prevents metastasis in mouse models of PDAC5,23. Based on these data, we initiated 
an early phase clinical trial targeting the CCR2 signaling pathway in patients with locally 
advanced PDAC. In this trial (NCT01413022), we have observed a remarkable 48.5% 
response rate in the 33 patients treated with CCR2i + FOLFIRINOX. This regimen was 
also well tolerated. Observed clinical responses correlate with a marked reduction in 
CCR2+ IMs and TAMs in patient tumor tissue. In contrast, CCR2i + FOLFIRINOX 
significantly increased effector T cell infiltration and anti-tumor cytokines, suggesting that 
CCR2 inhibition overcomes the suppressive tumor microenvironment. Paralleling these 
clinical data, our published preclinical studies found that CCR2 blockade reinitiates anti-
tumor responses by CD8+ CTLs5,23. Intriguingly, we have discovered that CCR2 blockade 
in both human patients and mouse models leads to the up-regulation of T cell checkpoint 
pathways, including programmed cell death-1 (PD1) and its ligands (PDL1 and PDL2). In 
addition, additional targeting of CCL5-CCR5 should further blunt regulatory T cell 
response thereby further boast the function of cytotoxic T cells9. These data suggest that 
we might find unique therapeutic synergy between dual CCR2/5 inhibition and PD1 
antagonists that could be harnessed to generate durable anti-tumor immunity and improved 
patient survival. 
 
1.6 
Correlative Studies Background 
 
Studying immune infiltrates of pre- and post-treatment PDAC tumor is critical in informing 
the efficacy of tested regimen and potential resistance mechanisms. In this study, all 
enrolled patients will receive restaging radiographic scans after every 2 cycles of treatment 
to determine disease status. Treatment response will be defined by RECIST 1.1 criteria. 
Objective response rate (ORR) is defined as partial response plus complete response. 
Resectability will be assessed by the local treating oncologists, surgeons, and radiologists. 
Because this study enrolled patients with borderline resectable or locally advanced PDAC, 
endoscopic ultrasound-guided tumor biopsies will be performed at two different time 
points: less than 2 weeks before Cycle 1 Day 1 of treatment (pre-treatment), and within 2 
weeks after Cycle 2 Day 15 of treatment (post-treatment).   
 


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Exploratory studies will be performed on the paired biopsied samples and include the 
following:  
 
1. Peripheral and intra-tumoral CCR2 monocytes. Analyses of PB and tumor will be 
performed using flow cytometry as published23. We are particularly interested in changes 
in the number of IMs, which were predictive of survival in our published data23.  
 
 2. Analyses of antigen-specific T lymphocytes in the periphery. Alterations in peripheral 
lymphocyte frequency will be determined with flow cytometry. To assess T lymphocyte 
functionality in PB, we will evaluate proliferation and cytokine profiles following 
polyclonal and/or PMA activation ex vivo. We will compare polyclonal activation of total 
PB (including IMs) to isolated CD4+ and CD8+ T cells. We will also examine the 
responsiveness of T lymphocytes to three common PDAC antigens, including 
mesothelin26,27, MUC128, and CEA29 using peptide stimulation of PBMCs, followed by 
ELISPOT30 and MHC Dextramers responsiveness (IMMUDEX). Results will be compared 
to the non-tumor antigen responses to CMV. Analyses will be performed using a BD 
LSRFortessa-X20 (up to 20-color analysis). Based on the observed reprogramming of the 
tumor microenvironment10, we anticipate that the proposed regimen will improve T cell 
responsiveness and/or cytokine production in response to tumor-specific antigens. If this is 
not observed, we will conclude that CCR2 blockade affects the activity of T cells in the 
tumor microenvironment rather than regulating systemic immune suppression. 
 
3. Changes in the tumor immune microenvironment that facilitate T cell responses. We 
have developed techniques to routinely run both gene expression and flow cytometry on 
very limited amounts of tissue from EUS-guided FNAs or core biopsies. To assess changes 
in the tumor microenvironment, we will employ these techniques on samples from both 
clinical trials to assess how these therapies alter both the cellular immune infiltrate and the 
tumor cytokine microenvironment. 
  
3a Cellular immune infiltrate: Using pre- and post-treatment core biopsies, we will directly 
assess how CCR2i therapies alter tumor-infiltrating immune populations using high-
density flow cytometry. We have optimized these protocols to assess T cells, myeloid cells, 
and DC subsets and activation markers in three 15-color flow cytometry. Using this we fill 
focus on three questions:  
1. How does CCR2i-based therapy impact the number, activation, proliferation, and 
checkpoint expression of tumor-infiltrating T cells?  
2. How does CCR2i-based therapy alter the spectrum of tumor-infiltrating myeloid 
cells, including monocytes, macrophages, and granulocytes? 
3. How does CCR2i-based therapy impact the number and phenotype of tumor-
infiltrating antigen-presenting cells, such as dendritic cells and macrophages? 
4. Does CCR2i-based therapy lead to the upregulation of checkpoint or other 
molecules of immunotherapeutic opportunity (such as LAG3 on T cells or CD40 
on innate immune cells)? 
 
3b Tumor cytokine microenvironment: We will analyze gene expression in tumor tissue 
following pre-amplification using two Taqman-based qRT-PCR arrays. We have designed 


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these arrays to contain 180 cytokines, immune effector, and checkpoints molecules. These 
analyses will yield information regarding alterations in the cytokine microenvironment, 
immunosuppression, and potential new targets for combined immunotherapy.  
 
 
2 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. Part A: To determine the safety of the combination of BMS-813160 plus nivolumab 
plus gemcitabine plus nab-paclitaxel. 
2. Part B: To determine the objective response rate of patients with locally advanced and 
borderline-resectable pancreatic ductal adenocarcinoma treated with the combination 
of BMS-813160 plus nivolumab plus gemcitabine plus nab-paclitaxel. 
 
2.2 
Secondary Objectives (Part B) 
 
1. To determine the percentage of patients with locally advanced and borderline resectable 
pancreatic ductal adenocarcinoma treated with the combination of BMS-813160 plus 
nivolumab plus gemcitabine plus nab-paclitaxel whose disease becomes resectable 
after treatment. 
2. To determine the progression-free survival (PFS) of patients with locally advanced and 
borderline resectable pancreatic ductal adenocarcinoma treated with the combination 
of BMS-813160 plus nivolumab plus gemcitabine plus nab-paclitaxel. 
3. To determine the overall survival (OS) of patients with locally advanced and borderline 
resectable pancreatic ductal adenocarcinoma treated with the combination of BMS-
813160 plus nivolumab plus gemcitabine plus nab-paclitaxel. 
 
2.3 
Exploratory Objectives (Parts A and B) 
 
1. To determine the prevalence and function of inflammatory monocytes in the peripheral 
blood and tumor of patients with locally advanced and borderline resectable pancreatic 
ductal adenocarcinoma before and after treatment with the combination of BMS-
813160 plus nivolumab plus gemcitabine plus nab-paclitaxel. 
2. To compare the difference in the immune cell infiltration and cytokine expression in 
the biopsied tumors of patients with locally advanced and borderline resectable 
pancreatic ductal adenocarcinoma before and after treatment with the combination of 
BMS-813160 plus nivolumab plus gemcitabine plus nab-paclitaxel. 
3. To correlate changes in the immune infiltrate with clinical responses to treatment with 
the combination of BMS-813160 plus nivolumab plus gemcitabine plus nab-paclitaxel 
and survival following treatment with that combination. 
4. To compare results of inflammatory monocyte, analysis, immune cell infiltration and 
cytokine expression analysis, and correlation of immune infiltrate with clinical 
response from patients enrolled to the experimental arm with results of analyses from 
patients enrolled to the control arm (if feasible and depending on the results). 
 


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3 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed locally advanced or borderline resectable 
pancreatic ductal adenocarcinoma. Patients with clinical suspicion of pancreatic 
adenocarcinoma can be enrolled for pre-treatment biopsy, and must be histologically 
confirmed to have adenocarcinoma before being treated on study.  Patients with 
squamous carcinoma, adenosquamous carcinoma or neuroendocrine tumor will be 
excluded. Tumor Biopsy can be omitted, if deemed by PI and treating physician, that 
it may incur immediate, excessive health risks to patients. This determination (rationale 
and discussion with PI and treating physician) should be clearly documented in the 
screening visit notes. 
 
2. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI. 
 
3. At least 18 years of age. 
 
4. ECOG performance status ≤ 1 (see Appendix A) 
 
5. Normal bone marrow and organ function as defined below: 
a. Leukocytes ≥ 2,000/mcL 
b. Absolute neutrophil count ≥ 1,500/mcl 
c. Hemoglobin ≥ 8.5 g/dL 
d. Platelets ≥ 100,000/mcl 
e. Total bilirubin ≤ 1.5 x IULN (except participants with Gilbert’s Syndrome who 
must have normal direct bilirubin) 
f. AST(SGOT)/ALT(SGPT) ≤ 3 x IULN 
g. Serum albumin ≥ 3g/dL 
h. Creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 40 mL/min by Cockcroft-Gault 
for patients with creatinine levels above institutional normal 
 
6. Women of childbearing potential and men must agree to use at least two forms of 
contraception (hormonal, barrier method of birth control, abstinence, and must include 
barrier method) prior to study entry, for the duration of study participation, and through 
5 months (for women) or 7 months (for men) after the last dose of treatment on this 
study.  Should a woman become pregnant or suspect she is pregnant while participating 
in this study, she must inform her treating physician immediately. 
 
7. Able to understand and willing to sign an IRB approved written informed consent 
document. 
 
8. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] v5.0) or baseline before administration of study 


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treatment. Participants with toxicities attributed to prior anti-cancer therapy that are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after 
platinum-based therapy, are permitted to enroll. 
 
3.2 
Exclusion Criteria 
 
1. Prior exposure to chemotherapy or radiation for the disease to be treated on this trial 
not allowed. 
 
2. Previous malignancies (except non-melanoma skin cancers, and in situ bladder, gastric, 
colorectal, endometrial, cervical/dysplasia, melanoma, or breast cancers) unless a 
complete remission was achieved at least 2 years prior to study entry AND no 
additional therapy is required during the study period. Other active malignancy 
requiring concurrent intervention 
 
3. Currently receiving any other investigational agents, or exposure to any investigational 
drug or placebo within 4 weeks of study treatment 
 
4. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to BMS-813160, nivolumab, gemcitabine, paclitaxel, nab-paclitaxel, or 
other agents used in the study. 
 
5. Prior exposure to anti-PD-1, anti-PD-L1, CCR2/5, or anti-CTLA4 antibodies. 
 
6. Taking immunomodulatory agents (including steroids and NSAIDs).  A wash-out 
period of at least 4 weeks or 5 half-lives, whichever is shorter, is required for patients 
receiving immunomodulatory agents at the time of enrollment.  
 
NOTE: daily use of low dose aspirin (e.g. 81 mg PO QD) is not considered an 
immunomodulatory agent and patients are still eligible for enrollment despite taking 
such medication at a low dose. 
 
7. Participants with active, known or suspected autoimmune disease. Participants with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement, euthyroid participants with a history of Grave’s 
disease (participants with suspected autoimmune thyroid disorders must be negative 
for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating 
immunoglobulin prior to first dose of study treatment), psoriasis not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll after discussing with the Principal Investigator 
 
8. Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone or equivalent) or other immunosuppressive medications 
within 14 days of study treatment except for adrenal replacement steroid doses > 10 
mg daily prednisone equivalent in the absence of active autoimmune disease.  Note: 


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treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating study 
treatment is permitted. 
 
9. History of allogeneic organ or stem cell transplant. 
 
10. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry and again within 24 hours prior to first 
treatment. 
 
11. Known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) 
or known active hepatitis C virus (by PCR). 
 
12. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome. Anti-retroviral agents are known to have 
potential adverse pharmacokinetic interactions with nivolumab and/or BMS-813160. 
IN addition, patients not on anti-retroviral agents, regardless of HIV viral load, are at 
increased risk of lethal infections with marrow-suppressive therapy including 
chemotherapy.  Testing for HIV must be performed at sites mandated by local 
requirements. 
 
13. Requires continued use of warfarin for anticoagulation and cannot stop warfarin or be 
safely switched to another anticoagulant. 
 
14. Current or recent (within 3 months of study treatment administration) gastrointestinal 
disease or conditions that could interfere with the swallowing or absorption of study 
medication or inability to tolerate oral medication. 
 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection requiring parenteral anti-bacterial, anti-viral, or anti-fungal therapy ≤ 7 days 
prior to administration of study medication; immunosuppression; autoimmune 
conditions; underlying pulmonary disease; or psychiatric illness/social situations that 
would limit compliance with study requirements.  
 
16. Interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected treatment-related pulmonary toxicity. 
 
17. Uncontrolled or significant cardiovascular disease including, but not limited to, any of 
the following: 
a. Myocardial infarction or stroke/transient ischemic attack within the past 6 months 
b. Uncontrolled angina within the past 3 months 
c. Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or Torsades de pointes) 
d. QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation 
> 480 msec 


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e. History of other clinically significant heart disease (e.g. cardiomyopathy, 
congestive heart failure with NYHA functional classification III-IV, pericarditis, 
significant pericardial effusion, or myocarditis) 
 
18. Major surgery within 28 days prior to the first study treatment.  Participants must have 
recovered from the effects of major surgery or significant traumatic injury at least 14 
days before the first dose of study treatment. 
 
19. Concurrent use of oral or intravenous medications, or food which may interfere with 
BMS-813160 including any strong inhibitors or inducers of CYP3A4 or P-gp is not 
allowed (see Appendix C). These include but are not limited to Class I antiarrhythmics 
(eg, quinidine, procainamide, dysopiramide, lidocaine, phenytoin, mexiletine, 
tocainide, flecainide, propafenone, moricizine), Grapefruit and Seville oranges.  
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
4 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 


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6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email within one business day. Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
 
5 
TREATMENT PLAN 
 
This study will be conducted in two parts.  Part A is the dose safety lead-in phase.  In Part A, 
approximately the first 16 patients will be randomized 1:1 to the control arm (where patients will 
receive chemotherapy only) or the experimental arm (where patients will receive BMS-813160 
plus nivolumab plus chemotherapy).  Randomization will stop after 8 patients have been deemed 
evaluable, as defined by having treated in the control arm, have undergone at least 2 cycles of 
treatment, pre- and post-treatment biopsies, and restaging scan. Therefore, more subjects may be 
randomized to complete 8 evaluable controls. After 8 evaluable patients have been enrolled and 
treated on the control arm, subsequent patients will be enrolled only into the experimental arm (up 
to 18 patients total including the patients previously randomized to the experimental arm) or in the 
expansion phase if MTD (or recommended phase II dose, RP2D) has been determined. These 8 
patients who are enrolled in the control arm will serve as important controls for all analyses 
including toxicities, response rates and exploratory studies when determining the effect of 
gemcitabine plus nab-paclitaxel plus BMS-813160 and nivolumab.  For patients randomized to 
the experimental arm, treatment will start at dose level 0 (refer to Section 5.2). Enrollment in the 
experimental arm will continued until an MTD is determined, which may require up to 18 subjects. 
Enrollment in the experimental arm will be conducted in the standard 3+3 fashion. For the first 3 
subjects, if ≥ 2 subjects experience DLTs, dose de-escalation will be performed, and three new 
subjects will be enrolled. All patients already on the starting dose will resume treatment after 
recovery from previous toxicities, or continue on treatment at the new dose-deescalated level. Nine 
to 18 patients may be needed to determine an MTD if one or more dose de-escalation is warranted.  


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After the MTD of BMS-813160 and chemotherapy has been determined in Part A (or the RP2D), 
more patients will be enrolled at that dose level for a total of 30 patients, including the Part A 
experimental arm patients who were initiated at the MTD and stayed on treatment at that dose 
level.  These patients will all be assessed for efficacy in Part B. 
 
For all patients, a post-treatment biopsy will be performed after 2 cycles of treatment, followed by 
a restaging scan (pancreatic protocol CT or MRI). Patients who have disease progression per 
RECIST 1.1 criteria after the first 2 cycles of treatment will discontinue study treatment, and the 
next treatment option will be decided by the treating physicians.  Patients who achieve stable 
disease, a partial response, or complete response after the first 2 cycles of treatment will continue 
to receive 2 more cycles of treatment followed by a restaging scan. Patients thought to have 
pseudo-progression, as evaluated as per Section 6.4, will continue to receive treatment for 2 more 
cycles. All remaining patients will come off treatment after 4 cycles of treatment. All patients 
treated on control or experimental arms will be followed up every 3-4 months after surgery or the 
last treatment on study for the first two years and per the physician’s discretion beyond two years. 
Participants who withdraw from the study during the DLT evaluation interval for reasons other 
than a DLT may be replaced at the same dose of BMS-813160. 
 
Patients with progressive disease or patients whose disease is not considered resectable after 
treatment will receive other treatments off study as determined by their treating oncologist. If 
deemed appropriate, patients may continue to be treated with gemcitabine and/or nab-paclitaxel.  
Patients whose disease is considered resectable will undergo surgical resection off study (with 
specimens collected as part of this study). 
 
Treatment beyond radiographic disease progression per initial RECIST v 1.1 may be allowed in 
select participants after discussion and agreement with the PI and study supporter that the 
benefit/risk assessment favors continued administration of study treatment. These include: good 
tolerance of study treatment, stable performance status, treatment beyond progression will not 
delay an imminent intervention to prevent serious complications of disease progression (e.g., CNS 
metastases). These are considered investigator-assessed clinical benefit and must be clearly 
documented in clinic notes.  
 
5.1 
Agent Administration 
 
BMS-813160 is an oral drug which will be given at the assigned dose twice (or once) daily 
for patients in Part A assigned to the experimental arm and all patients in Part B.  If a 
patient misses a dose and the next scheduled dose is within the next 8 hours (or within the 
next 16 hours if being taken once daily), s/he should not make up that dose but simply 
resume dosing with the next scheduled dose.  Therefore, patients should make up for the 
missed BMS-813160 dose as long as the next scheduled dose is more than 8 hours away 
(16 hours if once daily). If a patient should vomit within one hour after intake, s/he should 
make up for that dose as long as the next scheduled dose is more than 8 hours away (16 
hours if once daily). Patients will be instructed to bring all unused drug and their medication 
diary (Appendix B) to each study visit for an assessment of compliance. 
 


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Nivolumab will be given as a 30-minute intravenous infusion at a flat dose of 480 mg on 
Day 1 (+/- 2 days) of each 28-day cycle for patients in Part A assigned to the experimental 
arm and all patients in Part B. 
 
Gemcitabine will be given as a 30-minute intravenous infusion at the assigned dose (for all 
patients in Part A) or at the MTD (for all patients in Part B) on Days 1, 8, and 15 of each 
28-day cycle. A window of +/- 2 days is allowed for D1, 8, and 15 of treatment, based on 
blood test results (see Section 6.3) and clinical assessment of patients by treating 
physicians. On days when both nivolumab and gemcitabine are given, a 30-minute rest is 
required between nivolumab and gemcitabine. 
 
Nab-paclitaxel will be given as a 30-40-minute intravenous infusion at the assigned dose 
(for all patients in Part A) or at the MTD (for all patients in part B) on Days 1, 8, and 15 of 
each 28-day cycle.  A window of +/- 2 days is allowed for D1, 8, and 15 of treatment, based 
on blood test results (see Section 6.3) and clinical assessment of patients by treating 
physicians. 
 
5.2 
Dose De-Escalation Schema – Part A 
Part A: Safety Lead-In (Each cycle = 28 days) 
Arm (by 
randomization) 
BMS-813160 (D1-28) 
Nivolumab 
(D1)  
Chemotherapy (D1, 8, 15) 
Dose Level 
Dose 
Dose Level 
Gemcitabine 
Nab-paclitaxel 
Experimental 
(n=9-18) 
0 (starting) 
300 mg BID  
480 mg  
0 (starting) 
1000 mg/m2 
125 mg/m2 
-1 
150 mg BID  
480 mg  
-1 
800 mg/m2 
100 mg/m2 
-2 
150 mg QD  
480 mg  
-2 
600 mg/m2 
75 mg/m2 
Control (n=8) 
N/A 
N/A 
N/A 
0 (starting) 
1000 mg/m2 
125 mg/m2 
N/A 
N/A 
N/A 
-1 
800 mg/m2 
100 mg/m2 
N/A 
N/A 
N/A 
-2 
600 mg/m2 
75 mg/m2 
Part B: Dose Expansion (Each cycle = 28 days) 
Dose expansion 
(N=30*) 
 
Per Part A 
480 mg  
 
Per Part A 
* Total of 30 patients includes patients started on and stayed on MTD on experimental arm in Part A 
  
5.3 
Definition of MTD, DLT, and Dose Escalation Criteria – Part A 
 
5.3.1 Definition of Maximum Tolerated Dose (MTD) 
 
The maximum tolerated dose (MTD) is defined as the dose level at which 2 or less 
of a 6 treated patients experience dose-limiting toxicity during the first cycle (28 
days). Dose de-escalations will proceed until the MTD has been reached. This will 
be the recommended phase II dose (RP2D) for Part B and any future clinical trials.  
 
5.3.2 Dose Limiting Toxicities (DLTs) 
 
For the purpose of guiding dose regimen, DLTs will be defined based on the 
incidence, duration, and grade of AEs for which no alternate cause can be 
identified. Adverse events will be evaluated according to the NCI CTCAE v5.0. 
The incidence of DLT(s) during the first cycle (28 days) of treatment in Part A (the 


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DLT evaluation period) will be used. Every attempt must be made to assign 
relationship to BMS-813160, nivolumab, chemotherapy or to all. Toxicities that are 
well recognized and expected with the chemotherapy backbone, as determined by 
treating physician and PI on the study, will not be counted as dose limiting for the 
entire regimen if the patient is on experimental arm. Also, to meet criteria for dose 
limiting, AEs have to be related to study treatment and not to disease progression 
or known common complications from the disease, be clinically relevant, and be a 
clinically relevant shift from baseline (see Section 6). Consideration will be given 
to a participant’s ability to tolerate the regimen during the safety lead-in phase. 
Participants experiencing a DLT may be treated at one dose reduction of BMS-
813160 and/or chemotherapy as long as they recover from the toxicity and do not 
meet discontinuation criteria, and as long as it is in the best interest of the participant 
per the treating physician, and after discussion with the Principal Investigator and 
Sponsor Participants who withdraw from the study during the DLT evaluation 
interval for reasons other than a DLT may be replaced at the same dose of BMS-
813160. 
 
Continue to monitor all patients for approximately 100 days following 
discontinuation of the study treatment for late immune-related toxicities that have 
been associated with immunotherapy products. Consider any such late toxicities in 
the determination of the maximal tolerated dose and dose schedule to be taken 
forward into the expansion phase of the study. 
 
Hematologic DLT is defined as any of the following that occur during the first cycle 
that are attributed as possibly, probably, or definitely related to the study treatment: 
• Grade 4 neutropenia (ANC < 500 cells/mm3) > 7 consecutive days without 
growth factor support 
• Febrile neutropenia of any duration with temperature ≥ 38.5 °C 
• Grade 4 anemia regardless of duration 
• Grade 2 or above thrombocytopenia (platelets < 75,000/mm3)  
 
Non-hematologic DLT is defined as any possibly, probably, or definitely related 
grade 3 or grade 4 non-hematologic toxicity that occurs during the first cycle with 
the following specific exceptions: 
• Grade 3 diarrhea that responds to optimal antidiarrheal therapy  
• Grade 3 nausea or vomiting that responds to optimal antiemetic therapy 
• Grade 3 prolonged QTc interval on at least two separate ECGs, which are 
corrected by underlying causes including electrolytes abnormalities or 
abnormal fluid status, not complicated by adverse clinical experiences and 
not thought to be related to treatment 
• Grade 3 increase in total bilirubin that improves within 48 hours.  
• Grade 3 electrolyte or laboratory abnormalities that are not complicated by 
associated clinical adverse experiences, last less than 48 hours and either 
resolve spontaneously or respond to conventional medical intervention 
• Isolated Grade 3 or 4 elevation of amylase or lipase not associated with 
clinical or radiographic evidence of pancreatitis 


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Other events that are considered DLTs are: 
• Autoimmune hypophysitis (any grade) 
• Persistent (>4 weeks) unresolved grade≥3 hepatitis not corrected by 
interventions including biliary drainage, adjustment of medications and 
strongly suspected to be related to nivolumab, BMS-8313160 or 
chemotherapy.  
• Pneumonitis (at least grade 2) 
Any toxicity that is possibly, probably, or definitely related to study 
treatment that results in failure to receive at least approximately 75% of the 
planned doses of BMS-813160 during Cycle 1 (e.g. failure to complete at 
least 21 days of treatment in a continuous 28-day regimen) despite maximal 
supportive care measures is also considered a DLT. 
 
5.3.3 Dose De-escalation Criteria 
 
Dose de-escalations will proceed as follows after the occurrence of dose-limiting 
toxicity (DLT). Dose de-escalation of BMS813160 and/or chemotherapy should be 
conducted separately based on consideration of DLTs contributed individually by 
these agents (see Section 6). 
 
Number of Patients 
with DLT at a 
Given Dose Level 
 
De-Escalation Decision Rule 
0 out of 3 
Stop de-escalation. This is defined as RP2D. 
1 out of 3 
Treat 3 more patients at the dose level. 
 
• If 0 of these 3 experiences DLT, then stop de-escalation. 
 
• If 1 or more experience DLT, then proceed to the next dose 
level.  
>=2 out 3 
Treat 3 new patients at the next dose level. 
 
5.4 
Toxicity, Response, and DLT Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 100-day follow up after the 
conclusion of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment due to 
treatment related adverse events(s) prior to completion of Cycle 2 and have not had any 
disease assessment. 
 
A patient is evaluable for DLT assessment only if enrolled to the experimental arm during 
Part A of the study and only during Cycle 1 of treatment.  If the patient is not able to be 
treated on Day 1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and 


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will continue to be evaluated for DLT.  Once the patient has been treated in Cycle 2, s/he 
will no longer be evaluated for DLTs in all subsequent cycles.   
 
5.5 
Part B – Dose Expansion 
 
After the MTD is determined in Part A, additional patients will be enrolled in Part B to 
reach a total of 30 patients treated at the MTD dose level (including part A) 
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive care will be administered as per routine practice. This typically will include 
loperamide as needed for diarrhea, and antiemetic medication for symptoms of nausea or 
emesis. Intravenous fluid support will be provided at the discretion of the treating physician 
for patients who experience significant nausea, emesis, or diarrhea.  For grade 3 or greater 
skin toxicity, dermatology consult is recommended.  Oral antibiotics (such as minocycline 
or doxycycline should be considered at any sign of rash.  Topical cleomycin should also 
be considered at the first sign of rash. 
 
Prohibited and/or restricted medications taken prior to study treatment administration in 
the study are described below. Medications taken within 4 weeks prior to study treatment 
administration must be recorded on the CRF. 
• In vitro, the metabolism of BMS-813160 was primarily mediated via cytochrome 
P450(CYP) 3A4, with some contribution from CYP3A5, and BMS-813160 was 
also a substrate for P-glycoprotein (P-gp). Based on these results, the potential 
exists for drug-drug interaction if BMS-813160 is co-administered with inhibitors 
or inducers of CYP3A or P-gp. Therefore, use of any oral or intravenous strong 
inhibitors or inducers of CYP3A4 or P-gp is not allowed, but topical use is allowed 
(see Appendix C). 
• Grapefruit and Seville oranges and their juices can inhibit CYP3A4 and should not 
be consumed while on study. 
• Caution is warranted with concomitant use of MATE1 substrates with a narrow 
therapeutic index (see Appendix D). 
• Exposure to any investigational drug or placebo within 4 weeks of study treatment 
• administration. 
• Class I antiarrhythmics (eg, quinidine, procainamide, dysopiramide, lidocaine, 
phenytoin, mexiletine, tocainide, flecainide, propafenone, moricizine). 
• In limited circumstances (eg, life threatening illness) the use of the above 
medications may be permitted. 
 
5.7 
Women of Childbearing Potential (WOCBP) 
 
Women of childbearing potential are defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation). A woman is 
considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 


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Page 27 of 83 
salpingectomy, and bilateral oophorectomy. Documentation can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview. A postmenopausal state is defined as 12 months of amenorrhea in a 
woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level> 40 mIU/mL to confirm menopause. WOCBP are required to have a negative 
pregnancy test within 14 days prior to the first day of study treatment, within 24 hours prior 
to first treatment, and every 4 weeks while on treatment  
 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to the following during the treatment and until the end of relevant systemic 
exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the 
need to comply with contraception instructions as directed by the investigator. 
• Male participants are required to use a condom for study duration and until end of 
relevant systemic exposure defined as 7 months after the end of study treatment. 
• Female partners of males participating in the study to consider use of effective 
methods of contraception until the end of relevant systemic exposure, defined as 7 
months after the end of treatment in the male participant. 
• Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile vaginal intercourse or use a male condom during each episode 
of penile penetration during the treatment and until 7 months after the end of study 
treatment. 
• Refrain from donating sperm for the duration of the study treatment and until 7 
months after the end of study treatment. 
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 5 months (for women) or 7 months (for men) following the last dose of study 
treatment. Should a woman become pregnant or suspect she is pregnant while participating 
in this study, she must inform her treating physician immediately. 
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.8 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 


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In the absence of treatment delays due to adverse events, treatment may continue for a total 
of 4 cycles or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.9 
Duration of Follow-up 
 
Patients will be followed every 3 to 4 months after being off treatment for 3 years or until 
death, whichever occurs first.  Patients removed from treatment for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event, or up to 100 
days after the last dose, whichever is later. Patients that did not undergo surgery may be 
contacted via phone for follow-up assessments. 
 
 
6 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Participants will be monitored continuously for AEs while on study therapy. Participants will be 
instructed to notify their physician for any and all AEs. Dose modifications in this section for 
chemotherapy are meant as a general guidance. Modifications should be applied by the 
investigator’s judgment. In case of an AE relationship assignment to chemotherapy alone, dose 
modifications for chemotherapy alone are allowed. In case of doubt, both chemotherapy and BMS-
813160 doses should be modified. Also, in case of assignment of AE relationship to BMS-813160 
alone, dose reduction for chemotherapy is not mandated. Specific algorithms for the management 
of immune-related AEs are provided in Appendix E and are applicable to immune-related AEs for 
all immuno-oncology study treatment combinations. For chemotherapy agents, the package insert 
and local standard of care rules for dose reduction should also be applied. 
 
For an AE requiring dose modification, BMS-813160, chemotherapy, and/or nivolumab should be 
interrupted to allow recovery from the AE. Re-initiation of study treatment cannot occur until the 
AE decreases to ≤ Grade 1 or baseline assessment. In case of delayed recovery to ≤ Grade 1 or 
baseline from treatment-related AEs that result in a delay of treatment for > 28 days, the participant 


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will not receive additional protocol-related therapy and will be removed from study unless 
discussed and agreed upon by the Investigator that it is in the best interest of the participant to 
receive additional therapy with BMS-813160 and/or other study treatments. 
 
6.1 
Dose Modifications for BMS-813160 
 
Please refer to Section 5 for study drug administration guidelines. 
 
Dose Level 
BMS-813160 
0 (starting) 
300 mg BID 
-1 
150 mg BID 
-2 
150 mg QD 
 
• New onset of QTcF intervals > 500 msec or prolongation > 50 msec over baseline, new 
onset QRS intervals > 140 msec, new onset bundle branch block or symptomatic 
bradycardia, Type 2 second or third-degree heart block will require dose interruption 
and restarting at one dose level lower. Any electrolyte abnormalities should be 
corrected and ECG should be repeated with cardiology consultation if clinically 
indicated. 
• Grade 3 non-hematologic toxicity or Grade 4 non-hematologic toxicity attributed to 
BMS-813160 will require immediate discontinuation until recovery to baseline. BMS-
813160 will then be resumed at one dose level reduction. 
• Any Grade 3 laboratory only abnormalities without clinical manifestations or 
electrolyte abnormalities that may be managed with supplementation can be managed 
with dose delay and do not automatically need dose modification. 
• Participants who hold BMS-813160 for 7 days or fewer for reasons other than drug 
toxicity will skip those days and continue on BMS-813160 treatment for the rest of the 
cycle. 
• Participants who hold BMS-813160 for more than 7 days or for drug toxicity will hold 
treatment for the remainder of the cycle and start at a reduced dose for the next cycle. 
• Participants who hold BMS-813160 for more than 7 days due to events deemed 
unlikely or not related to BMS-813160 may resume BMS-813160 at the same dose 
level after discussion with the PI and when it is deemed safe to resume treatment by 
the treating physician. Missed doses will be skipped. 
• If chemotherapy or nivolumab is delayed due to toxicity attributable to chemotherapy 
or nivolumab alone or due to scheduling issues, participants can continue on BMS-
813160 alone. Participants who need a dose reduction for toxicity attributable to BMS-
813160 will continue on the reduced dose of BMS-813160 for the remainder of the 
study. 
• If a participant needs more than 2 dose reductions of BMS-813160 for toxicity, the 
participant will be taken off BMS-813160 and nivolumab, but can continue 
chemotherapy if it is determined to be in the participant’s best interest as per the treating 
investigator. 
• If a participant is off BMS-813160 for more than 28 days, the participant will 
permanently discontinue treatment and be taken off study, unless it is determined to be 
in the participant’s best interest as per the treating investigator. 


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6.2 
Dose Modifications for Nivolumab 
 
No dose modifications allowed.  Doses can be delayed for side effects. Nivolumab will be 
withheld for drug-related toxicities and severe or life-threatening AEs as per the table 
below. 
 
Nivolumab administration should be delayed for the following: 
• Grade 2 non-skin, drug-related AE, with the exception of fatigue 
• Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 
• Grade 3 skin, drug-related AE 
• Grade 3 drug-related laboratory abnormality, with the following exceptions:  
− Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose 
delay 
− Grade ≥ 3 AST, ALT, Total Bilirubin will require dose discontinuation 
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication. 
 
Participants who require delay of nivolumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment criteria 
are met. 
 
Nivolumab treatment should be permanently discontinued for the following: 
• Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment  
• Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the 
following exceptions for laboratory abnormalities, drug-related uveitis, 
pneumonitis, bronchospasm, neurologic toxicity, hypersensitivity reactions, 
infusion reactions, and endocrinopathies: 
− Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
− Grade 3 drug-related endocrinopathies, adequately controlled with only 
physiologic hormone replacement do not require discontinuation. Adrenal 
insufficiency requires discontinuation regardless of control with hormone 
replacement.  
− Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
♦ Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
♦ Grade ≥ 3 drug-related AST, ALT or Total Bilirubin requires 
discontinuation 
♦ Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN 


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• Any Grade 4 drug-related adverse event or laboratory abnormality (including but 
not limited to creatinine, AST, ALT, or Total Bilirubin), except for the following 
events which do not require discontinuation: 
− Grade 4 neutropenia ≤ 7 days 
− Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase 
− Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
− Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or 
hypothyroidism, or glucose intolerance, which resolve or are adequately 
controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the BMS Medical 
Monitor. 
• Any event that leads to delay in dosing lasting > 4 weeks from the previous dose 
requires discontinuation, with the following exceptions: 
− Dosing delays to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed.  
− Dosing delays lasting > 6 weeks from the previous dose that occur for non-
drug-related reasons may be allowed if approved by the Sponsor Investigator.  
 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 4 weeks, the 
Sponsor Investigator must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory 
studies should also continue every 6 weeks or more frequently if clinically indicated during 
such dosing delays. 
 
6.3 
Dose Modifications for Gemcitabine and Nab-Paclitaxel 
 
Dose Level 
Gemcitabine 
Nab-Paclitaxel 
0 (starting) 
1000 mg/m2 
125 mg/m2 
-1 
800 mg/m2 
100 mg/m2 
-2 
600 mg/m2 
75 mg/m2 
If additional dose 
reduction required 
At PI’s discretion 
 
 
 


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Dose Modifications for Hematological Toxicity 
1. Doses held during a cycle (i.e. D8 or D15) will not be made up. 
a. 
If ANC < 500 with C1, re-check CBC within 7 days. If ANC < 500 for 7 days or longer, consult 
with PI and Treating MD to determine if DLT was met (per Section 5.3.2) 
b. If platelets < 75,000 with C1, may be DLT. Consult with PI and Treating MD to determine if 
DLT was met (per Section 5.3.2) 
2. Grade 3-4 Febrile Neutropenia at any point in the cycle (defined as temperature > 101℉ with a neutrophil 
count of < 1000 cells/ml), hold dosing until fever resolution and ANC > 1500 and resume at next lower 
dose level. 
3. Recurrent Grade 3-4 Febrile Neutropenia at any point in the cycle 1 or 2, hold dosing until fever 
resolution and ANC > 1500 and resume at next lower dose level. 
4. Upon recovery of platelets ≥ 75,000 and ANC ≥ 1000, dose reduce 1 level at next scheduled visit 
5. Upon recovery of platelets ≥ 75,000 and ANC ≥ 1000, dose reduce 2 levels at next scheduled visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle Day 
ANC 
(cells/mm3) 
 
Platelet count 
(cells/mm3) 
Dosing 
Adjustment 
Day 1 
< 1500 
OR 
< 100,000 
Delay doses until 
recovery 
Day 8 
< 1000 a, b 
 
OR 
< 75,000 a, b 
Withhold doses 1, 4 
Day 15 
if Day 8 doses were reduced or 
given without modification 
< 1000 a, b 
 
OR 
< 75,000 a, b 
Withhold doses 1, 4 
Day 15 
if Day 8 doses were withheld 
≥ 1000 
OR 
≥ 75,000 
Treat with 1 dose 
level reduction from 
Day 1 
 
< 1000 a, b 
OR 
< 75,000 a, b 
Withhold doses 1, 5 
 
 
 
 


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Dose Modifications for Other Treatment-Related Non-Hematological Toxicities  
Adverse Drug Reaction 
Gemcitabine 
Nab-Paclitaxel 
Peripheral neuropathy (Grade 2) 
No dose reduction 
Dose reduction allowed PI discretion 
Peripheral neuropathy 
(Grade 3 or 4) 
 No dose reduction 
 Withhold until improves to ≤ grade 
1; resume at next lower dose level 
Cutaneous toxicity 
(Grade 2 or 3) 
Reduce to next lower dose level; discontinue treatment if grade 2 or 
3 toxicity persists  
Gastrointestinal toxicity 
(Grade 3 mucositis or diarrhea) 
Withhold until improves to ≤ grade 1; resume at next lower dose 
level 
Unexplained dyspnea or other 
evidence of severe pulmonary 
toxicity 
Discontinue 
No dose reduction 
Grade 3 or 4 hepatic toxicity 
Dose Modification at PI or 
Tx MD Discretion. If 
attributed to Gemcitabine, 
and not recovered to G1 
after 4 weeks, permanently 
discontinue 
Do not administer to patients with 
total bilirubin > 1.5 x IULN or AST 
> 10 x IULN 
Hemolytic-Uremic Syndrome 
Discontinue 
No dose reduction 
Capillary Leak Syndrome 
Discontinue 
No dose reduction 
Posterior Reversible 
Encephalopathy Syndrome 
Discontinue 
No dose reduction 
Other grade 3 or 4 non-
hematological toxicity (except 
nausea or vomiting) 
Withhold or reduce by one dose level either one or both drugs after 
discussion with PI  
 
Grade 3 or 4 nausea and vomiting 
If strongly attributed to chemotherapy, dose reduction at PI’s 
discretion upon resolution to G1 or baseline 
 
6.4 
Treatment Beyond Progression 
 
Pseudoprogression is a possibility for patients who experience actual clinical benefit from 
immunotherapies despite initial radiographic progression (see Section 12). Therefore, 
participants will be permitted to continue treatment beyond initial RECIST v1.1 defined 
PD, assessed by the investigator, as long as they meet the following criteria: 
• Investigator-assessed clinical benefit 
• Tolerance of study treatment 
• Stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (eg, CNS metastases) 
• Participant provides written informed consent prior to receiving additional 
treatment. All other elements of the main consent including description of 
reasonably foreseeable risks or discomforts, or other alternative treatment options 
will still apply. 
 
A radiographic assessment/scan should be performed at the next scheduled scan to 
determine whether there has been a decrease in the tumor size or continued PD. The 
assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued 


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study treatment. If the investigator feels that the participant continues to achieve clinical 
benefit by continuing treatment, the participant should remain on the trial and continue to 
receive monitoring according to the study calendar. For the participants who continue study 
therapy beyond progression, further progression is defined as an additional 10% increase 
in tumor burden with a minimum 5 mm absolute increase from time of initial PD. 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. The tumor burden 
volume from time of initial progression should be used as the reference baseline for 
comparison with the post progression assessment. 
 
New lesions are considered measureable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes which must have a short 
axis of at least 15 mm). Any new lesion considered non-measureable at the time of initial 
progression may become measureable and therefore included in the tumor burden if the 
longest diameter increases to at least 10 mm (except for pathological lymph nodes which 
must have a short axis of at least 15 mm). In situations where the relative increase in total 
tumor burden by 10% is solely due to inclusion of new lesions which become measurable, 
these new lesions must demonstrate an absolute increase of at least 5 mm. 
 
 
7 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix F for definitions and Appendix G for a grid of reporting 
timelines. 
 
Adverse events will be tracked from the time of consent until the date of surgery, or 100 days after 
the last dose of treatment on study if patients do not go for surgery. Patients that did not undergo 
surgery may be contacted via phone for follow-up assessments.  All adverse events must be 
recorded on the toxicity tracking case report form (CRF) with the exception of: 
• 
Baseline adverse events, which shall be recorded on the medical history CRF 
• 
Adverse events related to off-study, non-protocol related therapy 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.  
Reporting requirements for secondary site study teams participating in Washington University-
coordinated research may also be found in Section 7.2. 
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 


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Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change.   
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The Washington University Sponsor-Investigator (or designee) is required to notify 
the QASMC of any unanticipated problems involving risks to participants or others 
occurring at WU or any BJH or SLCH institution that has been reported to and 
acknowledged by HRPO.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submissions to QASMC must include the myIRB 
form and any supporting documentation sent with the form. 
 
For events that occur at secondary sites, the Washington University Sponsor-
Investigator (or designee) is required to notify the QASMC within 10 days of 
Washington University notification via email to qasmc@wustl.edu.  Submission to 
QASMC must include either the myIRB form and supporting documentation or (if 
not submitted to myIRB) the date of occurrence, description of the event, whether 
the event is described in the currently IRB approved materials, the event outcome, 
determination of relatedness, whether currently enrolled participants will be 
notified, and whether the informed consent document and/or any study procedures 
will be modified as a result of this event. 
 
7.1.3 Reporting to Bristol Myers Squibb 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written 
consent to participate in the study through 100 days of discontinuation of dosing 
must be reported to BMS Worldwide Safety, whether related or not related to study 
drug. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (eg, a follow-up skin biopsy). 
 
Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, are collected, including those thought 
to be associated with protocol-specified procedures. The investigator should report 
any SAE occurring after these aforementioned time periods, which is believed to 
be related to study drug or protocol-specified procedure. 
 


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SAEs, whether related or not related to study drug, and pregnancies must be 
reported to BMS within 24 hours \ 1 Business Day of becoming aware of the event. 
SAEs must be recorded on FDA 3500a MedWatch SAE form.   
 
Pregnancies must be reported and submitted to BMS on a MedWatch SAE form. 
  
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) initially 
reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours \ 1 Business Day to BMS using the same procedure used for transmitting the 
initial SAE report.  
 
All SAEs should be followed to resolution or stabilization. 
 
7.1.3.1 Reconciliation 
 
 
The Sponsor will reconcile the clinical database SAE cases (case level only) 
transmitted 
to 
BMS 
Global 
Pharmacovigilance 
(Worldwide.Safety@bms.com). Frequency of reconciliation should be 
every 3 months and prior to the database lock or final data summary. BMS 
GPV&E will email, upon request from the Investigator, the GPV&E 
reconciliation report. Requests for reconciliation should be sent to 
aepbusinessprocess@bms.com. The data elements listed on the GPV&E 
reconciliation report will be used for case identification purposes. If the 
Investigator determines a case was not transmitted to BMS GPV&E, the 
case should be sent immediately to BMS. 
 
7.1.3.2 Early Asset every 3 month AE reporting 
 
Adverse Events that are routinely collected according to GCP shall be 
submitted to BMS every three (3) months by the last working day of the 
third month.   
 
The Adverse Event information required to be sent to BMS is noted in an 
attached ‘Bristol-Myers Squibb Early Asset Investigator Sponsored 
Research (ISR) Import Plan’ which describes the method of collection and 
submission 
to 
BMS 
via 
the 
mailbox: 
MG-RD-GPVE-
PHARMACOVIGILANCE@bms.com 
 
When the file is submitted to BMS, it must be noted the file contains:  


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• 
All Non-serious Adverse Events (only adverse events not previously 
submitted to BMS within the 3 months). 
 
7.1.4 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Washington University principal investigator to report 
to the FDA as follows: 
 
• Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix Ffor definitions) no later than 7 calendar days after 
initial receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix F) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix F) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 


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Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.1.5 Reporting to Secondary Sites 
 
The Washington University Sponsor-Investigator (or designee) will notify the 
research team at each secondary site of all unanticipated problems involving risks 
to participants or others that have occurred at other sites within 10 working days 
of the occurrence of the event or notification of the Sponsor-Investigator or 
designee of the event.  This includes events that take place both at Washington 
University and at other secondary sites, if applicable. Refer to section 16.0 
(Multicenter Management) for more information. 
 
7.2 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University Sponsor-Investigator and designee of all serious adverse events (as described in 
APPENDIX F and G) within 1 working day of the occurrence of the event or notification 
of the secondary site’s PI of the event.  This notification may take place via email if there 
is not yet enough information for a formal written report using FDA Form 3500a 
(MedWatch) form and Washington University’s Cover Sheet (APPENDIX H).   A formal 
written report must be sent to the Washington University Sponsor-Investigator and 
designee within 4 calendar days (for fatal or life-threatening suspected adverse reactions) 
or 11 calendar days (for serious unexpected suspected adverse reactions) of the 
occurrence of the event or notification of the secondary site’s PI of the event 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.  
The research team at Washington University is responsible for reporting all applicable 
events to the FDA and Bristol Myers Squibb as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained prior to 
implementing the change.  Local IRB approval must be obtained as per local guidelines.  
Washington University IRB approval is not required for protocol exceptions occurring at 
secondary sites. 
 
 
 
 
 


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8 
PHARMACEUTICAL INFORMATION 
 
8.1 
BMS-813160 
 
8.1.1 BMS-813160 Description 
 
Molecular Formula: C25H40N8O2 
Molecular Weight: 484.64 
 
8.1.2 Clinical Pharmacology 
 
Inhibition of the CCR2 receptor with BMS-813160 impedes the ability of MCP-1 
to bind to the CCR2 receptor and internalize to activate subsequent signaling 
pathways within the cell. As this internalization of MCP-1 is the main mechanism 
of MCP-1 clearance from the circulation, inhibition of this association and 
internalization would lead to increases in MCP-1 in circulation. Therefore, if BMS-
813160 effectively binds to and inhibits the CCR2 receptor, MCP-1 levels in the 
plasma would increase. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
• The t½ of BMS-813160 in dose groups that had a well characterized terminal 
phase was approximately 12 to 18 hours, which may be amenable for QD 
dosing. 
• Renal excretion (%UR) of BMS-813160 generally increased and CLT/F 
generally decreased with increasing dose, suggesting a dose-related increase in 
the oral bioavailability of BMS-813160. 
• A total of 81.5% of the administered radiolabeled dose was recovered as [14C]: 
the majority in feces (58.7%) and the remaining amount in urine (22.8%). 
• BMS-813160 was the predominant drug-related component in the plasma, and 
BMS-939429 was a prominent metabolite, accounting for 53% and 30% of total 
[14C]. The parent drug, together with selected metabolites that were quantified 
with an exploratory LC-MS/MS assay, comprised approximately 87% of the 
circulating radioactivity. 
 
8.1.4 Supplier(s) 
 
BMS-813160 will be supplied by Bristol Myers Squibb.  At the end of the study 
period, Bristol-Myers Squibb Company will not continue to supply study drug to 
subjects/investigators unless the Sponsor-Investigator chooses to extend their 
study. The investigator is responsible to ensure that the subject receives appropriate 
standard of care or other appropriate treatment in the independent medical 
judgement of the Investigator to treat the condition under study. 
 
8.1.5 Dosage Form and Preparation 
 


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BMS-813160 is available in 150-mg strength capsules for oral administration. 
 
8.1.6 Storage and Stability 
 
BMS-813160 capsules should be stored between 2°C and 25°C (35.6°F and 77°F) 
in a tightly closed container. 
 
8.1.7 Administration 
 
To be taken by mouth on a daily basis as described in Section 5.1. 
 
8.1.8 Special Handling Instructions 
 
None. 
 
8.2 
Nivolumab (Opdivo) 
 
8.2.1 Nivolumab Description 
 
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody indicated 
for the treatment of patients with: 
• BRAF V600 wild-type unresectable or metastatic melanoma, as a single 
agent 
• BRAF V600 mutation positive unresectable or metastatic melanoma, as a 
single agent 
• Unresectable or metastatic melanoma, in combination with ipilimumab 
• Metastatic non-small cell lung cancer and progression on or after platinum-
based chemotherapy 
• Advanced renal cell carcinoma who have received prior anti-angiogenic 
therapy 
• Classical Hodgkin lymphoma that has relapsed or progressed after 
autologous hematopoietic stem cell transplantation and post-transplantation 
brentuximab vedotin 
• Recurrent or metastatic squamous cell carcinoma of the head and neck with 
disease progression on or after a platinum-based therapy 
 
It is a human monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  Nivolumab is an IgG4 kappa immunoglobulin that has 
a calculated molecular mass of 146 kDa. 
 
8.2.2 Clinical Pharmacology 
 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T 
cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 
ligands occurs in some tumors and signaling through this pathway can contribute 
to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human 


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immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor 
and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-
mediated inhibition of the immune response, including the anti-tumor immune 
response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in 
decreased tumor growth. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetics (PK) of nivolumab was studied in patients over a dose range 
of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab 
every 2 or 3 weeks. Nivolumab clearance decreases over time, with a mean 
maximal reduction (% coefficient of variation [CV%]) from baseline values of 
approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance 
(CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered 
clinically relevant. The geometric mean volume of distribution at steady state (Vss) 
(CV%) is 6.8 L (27.3%), and geometric mean elimination half-life is 25 days 
(77.5%).  Steady-state concentrations of nivolumab were reached by 12 weeks 
when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 
approximately 3-fold. The exposure to nivolumab increased dose proportionally 
over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. 
 
8.2.4 Supplier(s) 
 
Nivolumab will be supplied by Bristol Myers Squibb.  At the end of the study 
period, Bristol-Myers Squibb Company will not continue to supply study drug to 
subjects/investigators unless the Sponsor-Investigator chooses to extend their 
study. The investigator is responsible to ensure that the subject receives appropriate 
standard of care or other appropriate treatment in the independent medical 
judgement of the Investigator to treat the condition under study. 
 
8.2.5 Dosage Form and Preparation 
 
Nivolumab is available as a 40 mg/4 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL) 
and 100 mg/10 mL (10 mg/mL) solution in a single-use vial. Each kit will contain 
1 40mg vial and 2 100mg vials. As Nivolumab is administered fixed dose at 480mg, 
each patient will be dispensed 2 kits per dose to achieve the 480mg target. 
 
• Withdraw the required volume of nivolumab and transfer into an 
intravenous container. 
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP, to prepare an infusion with a final concentration 
ranging from 1 mg/mL to 10 mg/mL. 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used vials or empty vials of nivolumab. 
 
8.2.6 Storage and Stability 


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The product does not contain a preservative. 
 
After preparation, store the nivolumab infusion either: 
• at room temperature for no more than 4 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container 
and time for administration of the infusion or 
• under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours 
from the time of infusion preparation. 
 
Do not freeze, Protect from Light 
 
8.2.7 Administration 
 
Administer the infusion over 30 minutes through an intravenous line containing a 
sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer 
to 1.2 micrometer). 
 
Do not coadminister other drugs through the same intravenous line. 
 
Flush the intravenous line at end of infusion. 
 
8.3 
Gemcitabine (Gemzar) 
 
8.3.1 Gemcitabine Description 
 
Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity.  
Gemcitabine HCl is 2’-deoxy-2’,2’-difluorocytidine monohydrochloride (β-
isomer).  The structural formula is as follows: 
 
 
 
The empirical formula for gemcitabine HCl is C9H11F2N3O4·HCl.  It has a 
molecular weight of 299.66. 
 
8.3.2 Clinical Pharmacology 
 
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of 
cells through the G1/S-phase boundary.  Gemcitabine is metabolized by nucleoside 
kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. 
Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible 


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for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA 
synthesis, resulting in reductions in deoxynucleotide concentrations, including 
dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. 
The reduction in the intracellular concentration of dCTP by the action of the 
diphosphate enhances the incorporation of gemcitabine triphosphate into DNA 
(self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, 
only one additional nucleotide is added to the growing DNA strands, which 
eventually results in the initiation of apoptotic cell death. 
 
8.3.3 Pharmacokinetics and Drug Metabolism 
 
Gemcitabine disposition was studied in 5 patients who received a single 1000 
mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% 
of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and 
the inactive uracil metabolite, 2’-deoxy-2’,2’-difluorouridine (dFdU), accounted 
for 99% of the excreted dose. The metabolite dFdU is also found in plasma. 
  
The active metabolite, gemcitabine triphosphate, can be extracted from peripheral 
blood mononuclear cells. The half-life of the terminal phase for gemcitabine 
triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours. 
 
8.3.4 Supplier(s) 
 
Gemcitabine will be given as per routine care from commercial supply. 
 
8.3.5 Dosage Form and Preparation 
 
Gemcitabine for injection, USP, is available in sterile single-use vials individually 
packaged in a carton containing: 200 mg white to off-white lyophilized powder in 
a 10-mL size sterile single use vial or 1 g white to off-white lyophilized powder in 
a 50-mL size sterile single use vial. 
 
8.3.6 Storage and Stability 
 
Unopened vials of gemcitabine are stable until the expiration date indicated on the 
package when stored at controlled room temperature 20°C to 25°C and that allows 
for excursions between 15°C and 30°C. 
 
8.3.7 Administration 
 
Gemcitabine should be given as an intravenous infusion over the course of 30 
minutes. 
 
8.3.8 Special Handling Instructions 
 
No special handling instructions. 


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8.4 
Nab-Paclitaxel (Abraxane) 
 
8.4.1 Nab-Paclitaxel Description 
 
Nab-paclitaxel is an albumin-bound form of paclitaxel with a mean particle size of 
approximately 130 nanometers.  The active agent is paclitaxel, a microtubule 
inhibitor.  The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-
hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-
benzoyl-3-phenylisoserine.  Paclitaxel has the following structural formula: 
 
 
Paclitaxel is a white to off-white crystalline powder with the empirical formula 
C47H51NO14 and a molecular weight of 853.91.  It is highly lipophilic, insoluble in 
water, and melts at approximately 216-217°C. 
 
8.4.2 Clinical Pharmacology 
 
Nab-paclitaxel is a microtubule inhibitor that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization.  This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for vital interphase and 
mitotic cellular functions.  Paclitaxel induces abnormal arrays or “bundles” of 
microtubules throughout the cell cycle and multiple asters of microtubules during 
mitosis. 
 
8.4.3 Pharmacokinetics and Drug Metabolism 
 
Following intravenous administration of nab-paclitaxel, paclitaxel plasma 
concentrations declined in a biphasic manner, the initial rapid decline representing 
distribution to the peripheral compartment and the slower second phase 
representing drug elimination. The terminal half-life was approximately 27 hours. 
 
In vitro studies with human liver microsomes and tissue slices showed that 
paclitaxel was metabolized primarily to 6αhydroxypaclitaxel by CYP2C8; and to 
two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, 
by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was 
inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, 
dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the 


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concentrations used exceeded those found in vivo following normal therapeutic 
doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific 
inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. 
The pharmacokinetics of paclitaxel may also be altered in vivo as a result of 
interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 
and/or CYP3A4. 
 
8.4.4 Supplier(s) 
 
Nab-paclitaxel will be given as per routine care from commercial supply. 
 
8.4.5 Dosage Form and Preparation 
 
It is supplied as a white to yellow, sterile, lyophilized powder for reconstitution 
with 20mL of 0.9% sodium chloride injection, USP prior to intravenous infusion.  
Each single use vial contains 100 mg of paclitaxel (bound to human albumin) and 
approximately 900 mg of human albumin (containing sodium caprylate and sodium 
acetyltryptophanate).  Each milliliter of reconstituted suspension contains 5 mg 
paclitaxel. 
 
8.4.6 Storage and Stability 
 
Store the vials in original cartons at 20°C to 25°C.  Retain the original package to 
protect from bright light. 
 
8.4.7 Administration 
 
Nab-paclitaxel should be given as an intravenous infusion over the course of 30 to 
40 minutes. 
 
8.4.8 Special Handling Instructions 
 
No special handling instructions. 
 
 
9 
CORRELATIVE STUDIES 
 
9.1 
Tumor Biopsy 
 
9.1.1 Collection of Specimens 
 
Collection of tumor core biopsies at the following time points is required: 
• Pre-treatment 
• End of C2 
• End of treatment for patients who progress or otherwise do not go to surgery 
• Surgery for patients who do go to surgery 


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A total of three core biopsies (with a 22-gauge needle) will be taken at each time 
point from each patient.  
 
Tumor Biopsy can be omitted, if deemed by PI and treating physician, that it may 
incur immediate, excessive health risks to patients. This determination (rationale 
and discussion with PI and treating physician) should be clearly documented in visit 
notes. 
 
9.1.2 Handling of Specimens 
 
Both cores are to be cut in half with the top portion placed in 10% formalin buffered 
in PBS and the bottom portion snap frozen in liquid nitrogen.  Follow the processing 
instructions in the lab manual. 
 
9.1.3 Shipping of Specimens 
 
Ship snap frozen specimens on dry ice and samples in ethanol on cold packs, 
Monday through Thursday only, via FedEx to: 
Dr. David DeNardo 
Washington University School of Medicine 
425 S. Euclid Ave. 
Campus Box 8069 
St. Louis, MO 63110 
 
9.2 
Peripheral Blood 
 
9.2.1 Collection of Specimens 
 
Four heparinized green-top tubes each containing 8-10mL of blood will be 
collected at the following time points: 
• Cycle 1 Day 1 before treatment begins 
• after 2 cycles of treatment +/- 3 days of mandatory tumor biopsy 
• End of treatment for patients who progress or otherwise do not go to 
surgery 
• no more than 24 hours prior to time of surgery (if applicable)  
 
9.2.2 Handling of Specimens 
 
Mix all blood tubes and process promptly (within 1 hour) upon receipt.  Follow the 
processing instructions in the lab manual. 
 
9.2.3 Shipping of Specimens 
 
Specimens will be collected by CRA and hand-delivered to the following labs: 
Dr. David DeNardo 


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Washington University School of Medicine 
425 S. Euclid Ave. 
Campus Box 8069 
St. Louis, MO 63110 
 
 
 


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10 
STUDY CALENDAR 
Screening/baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans and x-rays must be done no 
more than 4 weeks prior to the start of the protocol therapy.  There is a +/- 2-day window for D1, D8, and D15 of treatment, all laboratory 
assessments, and +/- 7-day window for radiographic assessments and research tumor biopsies. All lab evaluations will be reviewed with 
regard to dosing timeframe on D1, D8, D15. 
 
Screening 
Pre-
Tx 
Each 28-day cycle2 
End 
of C2 
End of 
C4 
End of 
tx 
Surgery5 
Follow-up9 
D1 
D8 
D15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Physical exam, ECOG PS 
X 
 
X 
X (D8 or D15) 
 
 
 
 
 
CBC plus differential13 
X 
 
X 
X 
X 
 
 
 
 
 
CMP14 
X 
 
X 
X 
X 
 
 
 
 
 
CA19-9 or CEA 
X 
 
X 
 
 
 
 
 
 
 
Pregnancy test1 
X 
X11 
X 
 
 
 
 
 
 
 
CT or MRI 
X 
 
 
 
 
X4 
X 
 
 
X 
EKG 
X 
 
X 
 
 
 
 
 
 
 
Randomization3 
 
X 
 
 
 
 
 
 
 
 
BMS-813160 
 
 
Taken daily6 
 
 
 
 
 
Nivolumab 
 
 
X6 
 
 
 
 
 
 
 
Gemcitabine 
 
 
X 
X 
X 
 
 
 
 
 
Nab-paclitaxel 
 
 
X 
X 
X 
 
 
 
 
 
Research tumor biopsy 
 
X15 
 
 
 
X15 
 
X7,15 
X15 
 
Research blood draw 
 
 
X8 
 
 
X 
 
X7 
X12 
 
AE assessment 
 
X-------------------------------------------------- X10 
 
 
Progression and survival 
 
 
 
 
 
 
 
 
 
X 
1. Women of childbearing potential only 
2. Total of up to 4 cycles 
3. Part A patients only 
4. Patients who progress will discontinue treatment at this point, while patients who achieve SD, PR, or CR will receive 2 more cycles of treatment 
5. Patients whose disease is considered resectable will undergo resection and come off treatment (with specimens collected as part of this study) 
6. To patients randomized to the experimental group in Part A and all patients in Part B 
7. For patients who progress or otherwise do not go to surgery 
8. Before treatment C1D1 only 
9. Q3-4Mo after whipple/EOT tumor collection for the first two years after surgery or until progression, whichever happens first 
10.  For patient proceeding to surgery (i.e .Whipple) at end of study treatment, collect until date of surgery. For patients that do no undergo surgery, collect for 100 
days after last day of treatment. Patient may be contacted by phone for these post study treatment follow-up assessments. 
11. No more than 24 hours prior to the start of treatment 
12. Up to 24 hours prior to surgery 
13. CBC is WBC, Hb, Hct, Plt, MCV, RDW, differential includes neutrophil, lymphocyte, monocyte percentage and absolute counts  


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14. CMP is albumin, BUN, calcium, bicarbonate, chloride, creatinine, glucose, potassium, sodium, total bilirubin, total protein, ALT, AST, and ALP 
15. Tumor Biopsy can be omitted, if deemed by PI and treating physician, that it may incur immediate, excessive health risks to patients. This determination 
(rationale and discussion with PI and treating physician) should be clearly documented in visit notes.


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11 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Research Tissue Form 
Pre-treatment, end of C2, EOT / surgery 
Research Blood Form 
C1D1, end of C2, surgery 
Follow Up Form 
Every 3-4 months after whipple/EOT tumor collection 
for the first two years after surgery and per physician’s 
discretion afterwards 
Tumor Measurement Form 
Baseline, end of C2, end of C4 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
11.1 
AE Reporting in the EDC 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
12 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 


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guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 


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also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
New lesions: New lesions are considered measureable at the time of initial progression if 
the longest diameter is at least 10 mm (except for pathological lymph nodes which must 
have a short axis of at least 15 mm). Any new lesion considered non-measureable at the 
time of initial progression may become measureable and therefore included in the tumor 
burden if the longest diameter increases to at least 10 mm (except for pathological lymph 
nodes which must have a short axis of at least 15 mm). In situations where the relative 
increase in total tumor burden by 10% is solely due to inclusion of new lesions which 
become measurable, these new lesions must demonstrate an absolute increase of at least 5 
mm. 
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment 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 follow-up. Imaging-based 
evaluation is preferred to evaluation by 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 (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If 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).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 


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MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
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, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 


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FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 


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12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.4.3 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. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 


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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. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
12.4.4 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). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
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, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
12.4.6 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert independent 
of the study at the study’s completion.  Simultaneous review of the patients’ files 
and radiological images is the best approach.  
 
 
13 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 


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trial to review toxicity data. A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are 
subject to the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMC must also 
be disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to 
be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring 
Committee (QASMC) semi-annually beginning six months after study activation at Washington 
University (if at least one patient has been enrolled) or one year after study activation (if no patients 
have been enrolled at the six-month mark). 
 
The DSM report will be prepared by the study team with assistance from the study statistician, 
will be reviewed by the DSMB, and will be submitted to the Quality Assurance and Safety 
Monitoring Committee (QASMC).  The DSMB must meet at least every six months beginning six 
months after enrollment of the first patient at a secondary site and no more than one month prior 
to the due date of the DSM report to QASMC.  This report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date, accrual by site, and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities at all participating sites and separated by cohorts with the 
number of dose-limiting toxicities indicated 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMC responsibilities are described in the DSMB charter. 
 


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The study principal investigator and coordinator will monitor for all serious and non-serious 
adverse events on an ongoing basis. Once the principal investigator or coordinator becomes aware 
of an adverse event, the AE will be reported to the HRPO and QASMC according to institutional 
guidelines (please refer to Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/. 
 
 
14 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
• Subject screening and enrollment 
• Reporting of adverse events 
• Maintenance of HIPAA compliance 
• Completeness of regulatory documentation 
• Completeness of participant documentation 
• Acquisition of informed consent 
• IRB documentation 
• Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-
03.31.2015.pdf  
 
 
15 
STATISTICAL CONSIDERATIONS 
 
15.1 
Part A 
 


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Data on the tolerability and toxicity of the combination therapy will be collected for each 
subject, including frequency, type, and severity of adverse events. Based on the treatment 
plan (Section 5.0), 16 patients are randomized to 1:1 to control or experimental arm through 
block randomization without stratification factors. After 8 evaluable patients have been 
enrolled and treated on the control arm, subsequent patients are enrolled only into the 
experimental arm. Up to 18 patients will be enrolled on experimental arm to determine an 
MTD. Due to small sample sizes and dose heterogeneity, no statistical tests of hypotheses 
are planned specifically for this part of the study, but patients who receive MTD will be 
included in Part B for final analyses including ORR, PFS, OS and exploratory studies.   
 
15.2 
Part B 
 
Part B will be conducted subsequently to determine if there is a sufficiently high objective 
response rate (ORR) to warrant further studies.  
 
15.2.1 Sample size calculation 
 
The primary endpoint is ORR and the secondary endpoints include PFS and OS. 
The sample size calculation is based on the primary endpoint only. The objective 
response rate (ORR) of Gem/Abraxane in the MPACT study was 23%31 and the 
disease control rate (DCR) was 48%.. There is interest in pursuing future studies if 
the DCR is greater than 75%. A Simon optimal 2-stage design will test the null 
hypothesis that the true disease control rate (DCR) is less than or equal to 48% 
versus the alternative hypothesis that it exceeds 48% at the type I error rate of 5%. 
In the first stage, 9 patients will be accrued. If the study continues, 19 additional 
patients will be accrued. This design will have at least 80% power to reject the null 
hypothesis when the true DCR is 75%.   
 
The patients treated at the MTD in part A will be included in this expansion cohort.  
 
15.2.2 Stopping rule 
 
If 5 or fewer DCRs are observed out of these 9 patients, the study will be stopped. 
Otherwise, an additional 19 patients will be enrolled in the second stage. If 18 or 
more DCRs are observed out of these 28 patients, we would conclude that 
preliminary evidence for efficacy exists.  
 
15.3 
Statistical analysis 
 
Descriptive statistics will be used to summarize demographic and clinical characteristics, 
as well as the trial results, i.e., statistics for continuous variables may include means, 
medians, ranges and appropriate measures of variability. Qualitative variables will be 
summarized by counts and percentages. All data will be evaluated as observed, and no 
imputation method for missing values will be used.   The primary endpoint ORR and 
toxicity rates, and associated 95% confidence intervals, will be calculated assuming a 
binomial distribution of the number of subjects responding or experiencing toxicity. Due 


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to the possibility of enrollment stopping early based on response, these empirical rates may 
not be exactly unbiased, nor may the confidence intervals achieve exactly the correct 
coverage. These statistical summaries are useful descriptive statistics, however, and will 
still be calculated. The Kaplan-Meier method will be used to calculate the probability of 
OS and PFS. OS is defined as days from date of treatment to date of death within 3 years 
after surgical resection. Patients alive or lost to follow-up are censored at the last treatment 
on study or 3 years after surgical resection, regardless of subsequent treatment received. 
PFS is defined as the days from the date of treatment and death or progression, which 
occurs first. Patients alive without progression or lost to follow-up are censored at the last 
follow-up. For exploratory endpoints, investigations will use Wilcoxon signed-tests and 
paired t-tests to compare the difference of continuous variables before and after treatment, 
and Fisher’s exact tests to compare binary response. 
 
 
16 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show which 
version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
• Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 


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The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 


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17 
REFERENCES 
 
1 Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA Cancer J Clin 67, 7-30, 
doi:10.3322/caac.21387 (2017). 
2 Teague, A., Lim, K. H. & Wang-Gillam, A. Advanced pancreatic adenocarcinoma: a review 
of current treatment strategies and developing therapies. Ther Adv Med Oncol 7, 68-84, 
doi:10.1177/1758834014564775 (2015). 
3 Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally 
advanced or metastatic pancreatic adenocarcinoma. Journal of immunotherapy 33, 828-833, 
doi:10.1097/CJI.0b013e3181eec14c (2010). 
4 Feig, C. et al. The pancreas cancer microenvironment. Clin Cancer Res 18, 4266-4276, 
doi:10.1158/1078-0432.CCR-11-3114 (2012). 
5 Mitchem, J. B. et al. Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating 
Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses. Cancer 
Res, doi:10.1158/0008-5472.CAN-12-2731 (2013). 
6 Goedegebuure, P. et al. Myeloid-derived suppressor cells: general characteristics and 
relevance to clinical management of pancreatic cancer. Curr Cancer Drug Targets 11, 734-
751 (2011). 
7 Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor 
regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer cell 21, 
822-835, doi:10.1016/j.ccr.2012.04.025 (2012). 
8 Goedegebuure, P. et al. Myeloid-derived suppressor cells: general characteristics and 
relevance to clinical management of pancreatic cancer. Curr Cancer Drug Targets 11, 734-
751 (2011). 
9 Tan, M. C. et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor 
growth in a murine model of pancreatic cancer. J Immunol 182, 1746-1755 (2009). 
10 Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in 
combination with FOLFIRINOX in patients with borderline resectable and locally advanced 
pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. 
Lancet Oncol 17, 651-662, doi:10.1016/S1470-2045(16)00078-4 (2016). 
11 Sanford, D. E. et al. Inflammatory monocyte mobilization decreases patient survival in 
pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res 19, 3404-3415, 
doi:10.1158/1078-0432.CCR-13-0525 (2013). 
12 Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating 
cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 
73, 1128-1141, doi:10.1158/0008-5472.CAN-12-2731 (2013). 
13 Loos, M. et al. Expression of the costimulatory molecule B7-H3 is associated with prolonged 
survival in human pancreatic cancer. BMC cancer 9, 463, doi:10.1186/1471-2407-9-463 
(2009). 
14 Porembka, M. R. et al. Pancreatic adenocarcinoma induces bone marrow mobilization of 
myeloid-derived suppressor cells which promote primary tumor growth. Cancer 
immunology, immunotherapy : CII, doi:10.1007/s00262-011-1178-0 (2012). 
15 Qian, B. et al. A distinct macrophage population mediates metastatic breast cancer cell 
extravasation, establishment and growth. PLoS One 4, e6562, 
doi:10.1371/journal.pone.0006562 (2009). 


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16 Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nat Rev Cancer 9, 
239-252, doi:nrc2618 [pii] 
10.1038/nrc2618 (2009). 
17 Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid 
cells by tumours. Nature reviews. Immunology 12, 253-268, doi:10.1038/nri3175 (2012). 
18 DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally 
regulates response to chemotherapy. Cancer Discov 1, 54-67, doi:10.1158/2159-8274.CD-
10-0028 (2011). 
19 Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and 
metastasis. Cell 141, 39-51, doi:S0092-8674(10)00287-4 [pii] 
10.1016/j.cell.2010.03.014 (2010). 
20 Coussens, L. M. & Pollard, J. W. Leukocytes in Mammary Development and Cancer. Cold 
Spring Harb Perspect Biol, doi:cshperspect.a003285 [pii] 
10.1101/cshperspect.a003285 (2010). 
21 Kurahara, H. et al. Significance of M2-polarized tumor-associated macrophage in pancreatic 
cancer. The Journal of surgical research 167, e211-219, doi:10.1016/j.jss.2009.05.026 
(2011). 
22 Kurahara, H. et al. Clinical Significance of Folate Receptor beta-expressing Tumor-
associated Macrophages in Pancreatic Cancer. Annals of surgical oncology, 
doi:10.1245/s10434-012-2263-0 (2012). 
23 Sanford, D. E. et al. Inflammatory Monocyte Mobilization Decreases Patient Survival in 
Pancreatic Cancer: a Role for Targeting the CCL2/CCR2 Axis. Clin Cancer Res, 
doi:10.1158/1078-0432.CCR-13-0525 (2013). 
24 Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour 
metastasis. Nature 475, 222-225, doi:nature10138 [pii] 
10.1038/nature10138. 
25 Zhao, L. et al. Recruitment of a myeloid cell subset (CD11b/Gr1(mid) )via CCL2/CCR2 
promotes thedevelopment of colorectal cancer liver metastasis. Hepatology, 
doi:10.1002/hep.26094 (2012). 
26 Hassan, R. & Ho, M. Mesothelin targeted cancer immunotherapy. Eur J Cancer 44, 46-53, 
doi:10.1016/j.ejca.2007.08.028 (2008). 
27 Leao, I. C., Ganesan, P., Armstrong, T. D. & Jaffee, E. M. Effective depletion of regulatory 
T cells allows the recruitment of mesothelin-specific CD8 T cells to the antitumor immune 
response against a mesothelin-expressing mouse pancreatic adenocarcinoma. Clinical and 
translational science 1, 228-239, doi:10.1111/j.1752-8062.2008.00070.x (2008). 
28 Tang, C. K., Katsara, M. & Apostolopoulos, V. Strategies used for MUC1 immunotherapy: 
human clinical studies. Expert review of vaccines 7, 963-975, doi:10.1586/14760584.7.7.963 
(2008). 
29 Huang, E. H. & Kaufman, H. L. CEA-based vaccines. Expert review of vaccines 1, 49-63, 
doi:10.1586/14760584.1.1.49 (2002). 
30 Bacher, P. et al. Antigen-reactive T cell enrichment for direct, high-resolution analysis of the 
human naive and memory Th cell repertoire. J Immunol 190, 3967-3976, 
doi:10.4049/jimmunol.1202221 (2013). 
31 Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. N Engl J Med 369, 1691-1703, doi:10.1056/NEJMoa1304369 (2013). 


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32 Lacy, J. et al. Interim results of a multicenter phase II trial of nab-paclitaxel (nab-P) plus 
gemcitabine (G) for patients (Pts) with locally advanced pancreatic cancer (LAPC). Journal 
of Clinical Oncology 35, 358-358, doi:10.1200/JCO.2017.35.4_suppl.358 (2017). 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development services. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  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 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: PATIENT’S MEDICATION DIARY 
 
Today’s Date:    
 
 
Agent:  BMS-813160 
Cycle:    
 
Pt #: ________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___capsules) of BMS813160 ________ daily. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forget to take your dose at the right time, you should make up for the missed BMS-813160 dose as long 
as the next scheduled dose is more than ___ hours away. If you should vomit within one hour after intake, you 
should make up for that dose as long as the next scheduled dose is more than ___ hours away and you see 
intact capsule. If your next scheduled dose is less than ___ hours away, do not take that dose.  Restart it with 
the next dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill count 
can be done. 
Day 
Date 
What time was dose taken? 
Comments 
AM dose 
PM dose 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 


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APPENDIX C: CYP3A4 and P-GP Guidance 
 
The lists below are not meant to be all inclusive.  Please consult individual drug labels for further 
information.  Additional information is also available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm 
 
Please note these are not exhaustive lists. Only intravenous and oral therapy for strong 
CYP3A4 inhibitors such as ketoconazole are contraindicated. Topical use of CYP3A4 
inhibitors is allowed.  
 
CYP Enzymes 
Strong Inhibitors 
Moderate Inhibitors 
Weak Inhibitors 
CYP3A 
Boceprevir, 
clarithromycin, 
conivaptan, grapefruit 
juice, indinavir, 
itraconazole, 
ketoconazole, 
lopinavir/ritonavir, 
mibefradil, 
nefazodone, 
nelfinavir, 
posaconazole, 
ritonavir, saquinavir, 
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, 
aprepitant, 
atazanavir, 
ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, 
erythromycin, 
fluconazole, 
fosamprenavir, 
grapefruit juice, 
imatinib, verapamil 
Alprazolam, 
amiodarone, 
amlodipine, 
atorvastatin, 
bicalutamide, 
cilostazol, cimetidine, 
cyclosporine, 
fluoxetine, 
fluvoxamine, ginkgo, 
goldenseal, isoniazid, 
nilotinib, oral 
contraceptives, 
ranitidine, ranolazine, 
tipranavir/ritonavir, 
zileuton 
 
CYP Enzymes 
Strong Inducers 
Moderate Inducers 
Weak Inducers 
CYP3A 
Avasimibe, 
carbamazepine, 
phenytoin, rifampin, 
St. John’s wort 
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin 
Amprenavir, 
aprepitant, 
armodafinil, 
Echinacea, 
pioglitazone, 
prednisone, 
rufinamide 
 
Transporter 
Inhibitors 
P-gp 
Amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, 
ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
verapamil 
 
 


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APPENDIX D: MATE Substrates Guidance 
 
The list below is not meant to be all-inclusive.  Please consult individual drug labels for further 
information. 
 
Transporter 
Substrates 
MATE 
Metformin, cisplatin, oxaliplatin, ganciclovir, acyclovir, procainamide, 
captopril, quinine 
 
 
 


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APPENDIX E: Nivolumab Management Algorithms 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Sponsor Investigator. The guidance applies to all immuno-oncology agents 
and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
 
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. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 
 
 


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APPENDIX F: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can 
be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the adverse event.  “Suspected adverse reaction” 
implies a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at 
immediate risk of death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
 
D. Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in 
the view of the investigator, it results in any of the following outcomes: 
o Death 


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o A life-threatening adverse event  
o Inpatient hospitalization or prolongation of existing hospitalization. The following 
hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life-
threatening event) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy) 
• medical/surgical admission other than to remedy ill health and planned prior 
to entry into the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative reason) 
• admission for administration of anticancer therapy in the absence of any 
other SAEs (applies to oncology protocols) 
o A persistent or significant incapacity or substantial disruption of a person’s ability 
to conduct normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based 
upon appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without 
prospective IRB approval.  The term “research” encompasses all IRB-approved materials 
and documents including the detailed protocol, IRB application, consent form, recruitment 
materials, questionnaires/data collection forms, and any other information relating to the 
research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively 
impact the rights, safety, or welfare of participants or others or the scientific validity of the 
study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, 
or welfare of participants or others or the scientific validity of the study. 
  
 
 


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APPENDIX G: Reporting Timelines 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Bristol Myers-Squibb 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 calendar 
days after it is determined that the 
information qualifies for reporting 
Report to BMS within 24 hours \ 
1 Business Day of becoming 
aware of the event 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 calendar days 
after initial receipt of the 
information 
Report to BMS within 24 hours \ 
1 Business Day of becoming 
aware of the event 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day. 
Report via email after IRB 
acknowledgment 
 
 
Major deviation 
Report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day. 
 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.    
 
 
Protocol exception 
Approval must be obtained 
prior to implementing the 
change 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
that list in the protocol 
or IB 
 
 
Report no later than 15 calendar 
days after it is determined that the 
information qualifies for reporting 
 
Complaints 
If the complaint reveals an 
unanticipated problem 
 
 
 


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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Bristol Myers-Squibb 
involving risks to participants 
or others OR noncompliance, 
report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day.  Otherwise, 
report at the time of continuing 
review. 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant 
poses a safety issue, report 
within 10 working days.   
 
If withdrawing the participant 
does not represent a safety issue 
and the patient will be 
withdrawn, report at continuing 
review. 
 
 
 
Pregnancy 
 
 
 
Report to BMS within 24 hours \ 
1 Business Day of becoming 
aware of the event 
 
 
 
 
 
 
 
 
 
 


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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Bristol Myers-Squibb 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
Pregnancy 
 
 
 
Report to BMS within 24 hours 
\ 1 Business Day of becoming 
aware of the event 
 
 
 
 
 
 


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Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Bristol Myers-Squibb 
Serious AND unexpected 
suspected adverse reaction 
Report no later than 11 calendar days 
after it is determined that the information 
qualifies for reporting. 
Report all applicable 
events to local IRB 
according to local 
institutional guidelines. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to the 
FDA as needed. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to Bristol-
Myers-Squibb as needed. 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
Report no later than 4 calendar days after 
initial receipt of the information. 
Unanticipated problem 
involving risk to participants 
or others 
Report no later than 4 calendar days after 
initial receipt of the information. 
Adverse event or SAE that 
does not require expedited 
reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX H: Washington University Serious Adverse Event Reporting Cover 
Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Event Start Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 Yes 
 
 No 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date