Conditions: Pancreatic Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
A multi-institutional, single arm phase II study of nivolumab, cabiralizumab and stereotactic body radiotherapy (SBRT) in patients with LAUPC. The purpose of this study is to determine the safety and tolerability of combined cabiralizumab, nivolumab and radiotherapy in the treatment of locally advanced pancreatic cancer. Investigators will also estimate the surgical resection rate following treatment with combined cabiralizumab, nivolumab and radiotherapy in subjects with locally advanced unresectable pancreatic cancer.

Detailed description:

Arms:
arm 1: Subjects will be enrolled into this study following completion of 2-6 months of multi agent chemotherapy with documentation of stable or responsive disease.

Interventions: intervention 1: Nivolumab + Cabiralizumab intervention 2: Stereotactic Body Radiotherapy (SBRT)
Intervention descriptions: intervention 1: Will be administered on Day 1 and Day 14; Subjects will continue treatment every 2 weeks with subsequent imaging every 8 weeks. intervention 2: Patients will be simulated supine with the addition of a 4D C T if appropriate. A stereotactic immobilization device with abdominal compression will be used.

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
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authorized in writing by the study sponsor 
 
Page 1 
 
 
 
 
 
 
 
 
 
A phase II multi-institutional study of nivolumab, cabiralizumab, and stereotactic 
body radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer 
 
Version Date: January 28, 2020 
 
 
Principal  Investigator: 
Deirdre Cohen, MD 
NYU Perlmutter Cancer Center 
160 East 34th Street, NYC 10016 
deirdre.cohen@nyumc.org 
212-731-5656 
Additional Investigators:  
Kevin Du, MD PhD 
Department of Radiation Oncology 
NYU Perlmutter Cancer Center 
160 East 34th Street, NYC 
Kevin.du@nyumc.org 
212-731-5003 
Benjamin Medina, MD 
Co-Principal Translational Investigator:  
NYU School of Medicine  
Benjamin.medina@nyumc.org 
 
George Miller, MD 
Co-Principal Translational Investigator 
NYU School of Medicine 
George.Miller@nyumc.org 
 
Cristina Hajdu, MD 
Department of Pathology 
NYU School of Medicine 
Cristina.hajdu@nyumc.org 
NYULHStudy  Number: 
s17-01430 
Sponsor Study Number: 
CA025-008 
Funding Sponsor: 
Bristol Myers Squibb  
IND/IDE Number: 
138964 
Regulatory  Sponsor: 
Perlmutter Cancer Center at NYU Health 
160 East 34th Street, NYC 10016 
deirdre.cohen@nyumc.org 
212-731-5656 
Study Product: 
Nivolumab- Opdivo 
Carbiraluzumab 
ClinicalTrials.gov Number 
NCT03599362 ClinicalResearchProtocolPerlmutterCancerCenter
 


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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other 
applicable US government research regulations, and institutional research policies and procedures. The 
International Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) 
(sometimes referred to as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with 
FDA and DHHS regulations. The Principal Investigator will assure that no deviation from, or changes to 
the protocol will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects Protection 
Training 
 
 
 


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PROTOCOL APPROVAL SIGNATURES 
 
 
Protocol Title: A phase II multi-institutional study of nivolumab, cabiralizumab, and stereotactic body 
radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer 
 
Protocol Number: s17-01430 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use guidelines for current Good Clinical Practice, and applicable 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
Date 


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Table of Contents 
 
   
Statement of Compliance .................................................................................................................................. 3 
Table of Contents ......................................................................................................................................... 5 
List of Abbreviations........................................................................................................................................ 7 
Protocol Summary ........................................................................................................................................... 9 
Schematic of Study Design ...............................................................................................................................11 
1 
Key Roles ..............................................................................................................................................12 
2 
Introduction, Background Information and Scientific Rationale ................................................................13 
2.1 
Background Information and Relevant Literature ................................................................................................................ 13 
2.2 
Cabiralizumab ................................................................................................................................................................ 17 
2.3 
Nivolumab ..................................................................................................................................................................... 27 
2.4 
Sterotactic Body Radiation Therapy (SBRT) ...................................................................................................................... 32 
2.5 
Rationale........................................................................................................................................................................ 34 
2.6 
Potential Risks & Benefits ................................................................................................................................................ 39 
3 
Objectives and Purpose ..........................................................................................................................43 
3.1 
Primary Objectives .......................................................................................................................................................... 43 
3.2 
Secondary Objectives ...................................................................................................................................................... 43 
3.3 
Exploratory Objectives .................................................................................................................................................... 43 
4 
Study Design and Endpoints ...................................................................................................................43 
4.1 
Description of Study Design ............................................................................................................................................. 43 
4.2 
Study Endpoints .............................................................................................................................................................. 44 
5 
Study Enrollment and Withdrawal ..........................................................................................................45 
5.1 
Inclusion Criteria ............................................................................................................................................................ 45 
5.2 
Exclusion Criteria ........................................................................................................................................................... 46 
5.3 
Inclusion of Women and Minorities ................................................................................................................................... 48 
5.4 
Vulnerable Subjects ......................................................................................................................................................... 48 
5.5 
Strategies for Recruitment and Retention ........................................................................................................................... 48 
5.6 
Registration Procedures ................................................................................................................................................... 49 
5.7 
Duration of Study Participation ......................................................................................................................................... 50 
5.8 
Total Number of Participants and Sites .............................................................................................................................. 51 
5.9 
Participant Withdrawal or Termination .............................................................................................................................. 51 
5.10 
Premature Termination or Suspension of Study ................................................................................................................... 52 
6 
Study Agents .........................................................................................................................................53 
6.1 
Cabiralizumab ................................................................................................................................................................ 53 
6.2 
Nivolumab ..................................................................................................................................................................... 54 
6.3 
Study Agent Accountability Procedures ............................................................................................................................. 55 
7 
Treatment Plan ......................................................................................................................................55 
7.1 
Cabiralizumab and Nivolumab Administration.................................................................................................................... 55 
7.2 
SBRT ............................................................................................................................................................................ 56 
7.3   Definition of Unacceptable Toxicity .......................................................................................................................................... 57 
8 
Dosing Delays/Dose Modifications ...........................................................................................................58 
8.1 
Cabiralizumab and Nivolumab Dose Adjustments ............................................................................................................... 58 
8.2 
Management Algorithms for Cabiralizumab and Nivolumab ................................................................................................. 59 
8.3 
Dose Discontinuation Criteria for Cabiralizumab and Nivolumab .......................................................................................... 59 
8.4 
Criteria to Resume Treatment with Cabiralizumab and Nivolumab ........................................................................................ 60 
8.5 
Treatment of Cabiralizumab and Nivolumab Infusion Reactions ........................................................................................... 60 
8.6   Radiation Dose Adjustments ..................................................................................................................................................... 61 
9 
Study Procedures and Schedule ...............................................................................................................62 
9.1 
Laboratory Procedures/Evaluations ................................................................................................................................... 62 
9.2 
Study Schedule ............................................................................................................................................................... 64 
9.3 
Concomitant Medications, Treatments, and Procedures ........................................................................................................ 67 
9.4 
Participant Access to Study Agent at Study Closure............................................................................................................. 67 
10 
Assessment of Safety ..............................................................................................................................67 


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10.1 
Specification of Safety Parameters .................................................................................................................................... 67 
10.2 
Classification of an Adverse Event .................................................................................................................................... 69 
10.3 
Time Period and Frequency for Event Assessment and Follow-Up ........................................................................................ 70 
10.4 
Reporting Procedures – Notifying the IRB ......................................................................................................................... 71 
10.5 
Reporting Procedures – Notifying the Study Sponsor ........................................................................................................... 75 
10.6 
Reporting Procedures – Notifying the FDA ........................................................................................................................ 78 
10.7 
Reporting Procedures – Participating Investigators .............................................................................................................. 79 
10.8 
Safety Oversight ............................................................................................................................................................. 79 
11 
Clinical Monitoring ................................................................................................................................80 
12 
Statistical Considerations........................................................................................................................80 
12.1 
Statistical and Analytical Plans (SAP)................................................................................................................................ 80 
12.2 
Statistical Hypotheses ...................................................................................................................................................... 82 
12.3 
Analysis Datasets ............................................................................................................................................................ 82 
12.4 
Description of Statistical Methods ..................................................................................................................................... 82 
12.5 Sample Size ............................................................................................................................................................................ 83 
13 
Source Documents and Access to Source Data/Documents .........................................................................84 
14 
Quality Assurance and Quality Control ...................................................................................................84 
14.1 
Subsite QC monitoring .................................................................................................................................................... 83 
15 
Ethics/Protection of Human Subjects .......................................................................................................84 
15.1 
Ethical Standard .............................................................................................................................................................. 84 
15.2 
Institutional Review Board ............................................................................................................................................... 84 
15.3 
Informed Consent Process ................................................................................................................................................ 84 
15.4 
Participant and Data Confidentiality .................................................................................................................................. 85 
15.5 Future Use of Stored Specimens ................................................................................................................................................ 86 
16 
Data Handling and Record Keeping ........................................................................................................88 
16.1 
Data Collection and Management Responsibilities .............................................................................................................. 88 
16.2 
Study Records Retention .................................................................................................................................................. 88 
16.3 
Protocol Deviations ......................................................................................................................................................... 89 
16.4 
Publication and Data Sharing Policy .................................................................................................................................. 90 
17 
Study Finances ......................................................................................................................................91 
17.1 
Funding Source ............................................................................................................................................................... 91 
18 
Study Administration .............................................................................................................................91 
18.1 
Study Leadership............................................................................................................................................................. 91 
19 
Conflict of Interest Policy .......................................................................................................................91 
20 
Schedule of Events .................................................................................................................................92 
21 
References.............................................................................................................................................93 
Appendix 1:..............................................................................................................................................96 
Appendix 2:..............................................................................................................................................96 
Appendix 3: ............................................................................................................................................................................ 98 
 
 
 
 
 


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List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
ALP 
Alkaline phosphatase 
ALT 
Alanine  Aminotransferase 
AST 
Aspartate  Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTO 
Clinical Trials Office 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMFS 
Distant metastasis free survival rate 
DSMC 
Data Safety Monitoring Committee 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
LAUPC 
Locally advanced unresectable pancreatic cancer 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
National Cancer Institute Common Terminology Criteria for Adverse Events, version 
NCI-CTCAE 
5.0 
NIH 
National Institutes of Health 
NYULH 
New York University Langone Health 


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OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
OS 
Overall Survival 
PCC 
Perlmutter Cancer Center 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PR 
Partial Response 
QA 
Quality Assurance 
QC 
Quality Control 
RECIST 
Response Evaluation Criteria in Solid Tumors     
SAE 
Serious Adverse Event/Serious Adverse Experience 
US 
United States 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 


 
 
 
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Protocol Summary 
 
Title 
A phase II study of nivolumab, cabiralizumab, and stereotactic body 
radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer 
Brief Summary 
A multi-institutional, single arm phase II study of nivolumab, cabiralizumab and 
SBRT in patients with LAUPC. 
Phase 
Phase II 
Objectives 
Primary Objectives: 
• 
To determine the safety and tolerability of combined cabiralizumab, 
nivolumab and radiotherapy in the treatment of locally advanced 
pancreatic cancer. 
• 
To estimate the surgical resection rate following treatment with 
combined cabiralizumab, nivolumab and radiotherapy in subjects with 
locally advanced unresectable pancreatic cancer. 
Secondary  Objectives: 
• 
To evaluate preliminary anti-tumor activity of combined cabiralizumab, 
nivolumab and radiotherapy in subjects with locally advanced 
unresectable pancreatic cancer. 
• 
To evaluate the pharmacodynamic (PD) effect of the combination 
regimen on biomarkers in peripheral blood samples and tumor biopsy 
specimens. 
Methodology 
Multi-center, open-label, single arm, phase II study 
Endpoint 
Co-Primary  Endpoints 
• 
Rate of unacceptable toxicity  
• 
R0 resection rate 
Secondary  Endpoints 
• 
Overall response rate (ORR), progression free survival rate (PFS), 
overall survival rate (OS), and distant metastasis free survival rate 
(DMFSR) 
Exploratory  Endpoints 
• 
Nonclassical CD16+ monocyte and CSF1 levels in peripheral blood 
and tissue. 
• 
Immune changes within blood and tissue following treatment and 
correlate with clinical endpoints 
Study Duration 
The duration of this follow-up is up to 2 years following the last dose of study 
treatment, although a longer follow-up period could be considered in selected cases if 
an efficacy signal is apparent. Tumor assessment scans, for participants who have 
ongoing clinical benefit beyond the 2-year period following the first dose of study 
treatment, may continue to be collected as part of standard-of-care treatment. 
Subsequent therapies will also be recorded in this survival follow-up periodtreatment, 
although a longer follow-up period could be considered in selected cases if an 
efficacy signal is apparent. Tumor assessment scans, for participants who have 
ongoing clinical benefit beyond the 2-year period following the first dose of study 
treatment, may continue to be collected as part of standard-of-care treatment. 
Subsequent therapies will also be recorded in this survival follow-up period 


 
 
 
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Participant Duration 
Up to 2 years 
Enrollment Period 
4 weeks 
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Duration of IP 
administration 
Up to 2 years 
Study Centers/Sites 
Multicenter: 
1) Perlmutter Cancer Center (PCC) at NYU Langone Health 
2) TBD 
3)TBD 
Number of participants 
20 participants with 10-12 accrued at NYU Langone Health over 2 years 
Description of Study 
Agent/Procedure 
Cabiralizumab 4mg/kg IV every two weeks 
Nivolumab flat dose 240mg IV every two weeks 
SBRT: 6.6 Gy for 5 days 
Key Procedures 
Tumor biopsy and blood draws 
Statistical Analysis 
Safety will be evaluated by tabulating the type and severity of all unacceptable 
toxicities and adverse events. If more than two of the first six patients 
experience an unacceptable toxicity, accrual will be temporarily halted while 
the study team investigates potential dose modifications. The rate of R0 
resection will be calculated as the proportion of enrolled patients who achieve 
R0 resection. The rate of R0 resection will be estimated with its associated 
exact 95% confidence interval. If the lower bound of the confidence interval 
exceeds the null rate of 5%, the therapy will be deemed worthy of further 
investigation. 
Overall response will be tabulated according to RECIST criteria. PFS, OS, and 
DMFS will be estimated using the Kaplan-Meier method. 


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Version: 2.0 
 
Schematic of Study Design 
 
 
 


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1 Key Roles 
Principal Investigator: 
Deirdre Cohen, MD 
NYU Perlmutter Cancer Center 
160 East 34th Street, NY 10016  
Deirdre.cohen@nyumc.org 
212-731-5656 
 
Co-Principal Translational Investigator:  
Benjamin Medina, MD 
NYU Langone School of Medicine   
Benjamin.medina@nyumc.org 
 
Co-Principal Translational Investigator 
George Miller. MD 
NYU Langone School of Medicine 
George.Miller@nyumc.org 
 
Pathologist: 
Cristina Hajdu, MD 
Department of Pathology 
NYU School of Medicine 
Cristina.hajdu@nyumc.org 
 
Radiation Oncologist: 
Kevin Du, MD PhD 
Department of Radiation Oncology 
NYU Perlmutter Cancer Center 
160 East 34th Street, NYC 
Kevin.du@nyumc.org 
212-731-5003 
 
Biostatistician:   
Andrea B. Troxel, Sc.D 
Professor of Population Health and Director of the Division of Biostatistics 
650 First Avenue 
Fifth Floor, 521   
New York, NY 10016 
212-263-6527 
 
Clinical Research Coordinator: 
Benson Joseph 
NYU Perlmutter Cancer Center 
160 East 34th Street, NY 10016 
212-731-5076 
 
Data Manager: 
Dunbar Sharpe 
Senior GI Research Coordinator 
One Park Avenue 
New York, NY 10016 
212-263-4419 
 
 
 
 


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2 Introduction, Background Information and Scientific Rationale 
2.1 Background Information and Relevant Literature 
The incidence and mortality rate from pancreatic cancer continues to rise in the United States, with an 
estimated 53,670 new cases expected in 2017 and 43,090 deaths.[1] Surgery remains the cornerstone of 
curative intent treatment; however, only 10-20% of patients present with resectable disease. The majority 
of the patients present with advanced disease, with 30-40% having locally advanced disease with 
involvement of adjacent vascular structures and the remainder of patients with distant metastases.[2] 
 
For those patients with LAPC, treatment is not well defined, but most typically involves either 
chemotherapy alone or combined with radiation therapy (RT). However, the actual contribution of RT to 
survival in LAPC remains controversial despite five published randomized clinical trials.[3-7] Initial studies 
conducted in the 1980’s demonstrated conflicting results. An Eastern Cooperative Oncology Group 
(ECOG) study randomized 91 LAPC patients to treatment with either weekly bolus 5-Fluorouracil (5FU) 
alone or initial concurrent chemoradiation with 5FU followed by weekly bolus 5FU.[5] There was no 
significant difference in outcome with median overall survival of 8.2 months in the chemotherapy arm 
versus 8.3 months in the chemoradiation arm. In contrast, the Gastrointestinal Tract Cancer Group 
(GITSG) randomized 43 patients to treatment with chemotherapy with streptozosin, mitomycin and 5FU 
(SMF) or initial chemoradiation with 5FU followed by SMF. While the study was terminated prematurely 
due to poor accrual, there was a one year survival of 41% with the addition of radiation versus 19% in the 
chemotherapy only arm.[3] Twenty years later, two additional studies were undertaken with the use of 
more modern RT methods and newer chemotherapeutics, however, once again there were inconsistent 
findings. The French group, FFCD/SFRO, randomized 119 patients to induction chemoradiation with 5FU 
and cisplatin followed by gemcitabine versus gemcitabine alone. A significantly decreased median 
overall survival was noted with RT compared to chemotherapy only (8.6 vs 13 months).[4] In contrast, the 
ECOG 4201 study demonstrated an improved median overall survival of 11.1 months with concurrent RT 
and gemcitabine compared to 9.2 months with gemcitabine alone.[6] Finally, the most recently reported 
study, LAP 07, did not show a survival benefit for the use of consolidative chemoradiation with 
capecitabine following 4 months of gemcitabine-based chemotherapy compared with 6 months of 
gemcitabine based chemotherapy alone.[7] Collectively, these data demonstrate the overall limited 
efficacy of standard therapies for LAPC (see table 1). While RT may provide some benefit when used at 
selected doses, fractionations or with certain chemotherapy combinations, its effect thus far is modest 
and in some cases may even be detrimental.  
 
Table 1: Results from randomized studies of radiation therapy in LAPC 


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At this time, NCCN recommendations for LAPC include either chemotherapy or chemoradiotherapy, with 
emphasis on enrollment in clinical trial as the preferred treatment option. 
 
Survival rates for patients with LAPC remain low with the most recently completed randomized phase III 
LAP07 study demonstrating a median overall survival with combined modality therapy of 15-16.5 
months[7]. In this study, single agent gemcitabine was compared to gemcitabine followed by 
chemoradiotherapy with capecitabine. Only 4% of patients underwent curative-intent resection. Since this 
study was conducted, both FOLFIRINOX and gemcitabine plus nab-paclitaxel have demonstrated 
superiority compared to single agent gemcitabine in patients with metastatic disease.[8, 9] As a result, 
there have been several subsequent retrospective and single arm prospective reports suggesting such 
combination regimens are appropriate neoadjuvant treatment in patients with locally advanced pancreatic 
cancer who have good functional status[10-14] However, to date, no randomized clinical trial has been 
published. 
 
A meta-analysis including over 4000 pancreatic cancer patients, found that survival rates for LAPC 
patients  receiving  neoadjuvant  therapy  (of  whom  93.7%  received  neoadjuvant  radiotherapy)  and 
subsequent surgical resection had median survival of 20.5 months, which is within the range of pancreatic 
cancer patients with primary resection and adjuvant therapy[15] (see figure 1). 
 
 
 
Figure 1: Summary overview of survival and resection percentages of different groups of patients 
with pancreatic cancer 
 


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In another meta-analysis which included over 5000 non-metastatic pancreatic cancer patients, the role 
and outcomes of neoadjuvant therapy (in which radiotherapy was given in 79.2% of patients) were 
examined(see figure 2)[16].In this review, a similar survival rate was noted for LAPC patients receiving 
neoadjuvant therapy followed by resection (18.7 months) compared to the survival rate for all initially 
resectable patients who underwent neoadjuvant therapy +/- surgical resection (18.2 months). This again 
demonstrates the value of upfront therapy for this challenging patient population. While survival is the 
main intent of neoadjuvant therapy, R0 resection rate is a secondary goal as positive resection margins 
have repeatedly been shown to be associated with worse survival.[17-19] Typically R0 resection rate for 
patients with LAPC is very low. In the most recently reported randomized trial looking at neoadjuvant 
chemoradiotherapy compared to chemotherapy alone, the overall R0 resection rate was 2.5%.[7] In this 
study, chemotherapy administered was with single agent gemcitabine. Higher R0 rates have been 
reported when combination chemotherapy is administered. In a systematic review and patient-level 
meta-analysis of FOLFIRINOX with or without radiation therapy for LAPC, the R0 resection rate was 
reported to be 18%. Similarly, in another meta-analysis, R0 rate was found to be 23% following 
chemotherapy +/- radiation.[16] 
 
 
Figure 2: Summary of outcomes after neoadjuvant therapy among non-metastatic pancreatic 
patients. 
 
 


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While the optimal treatment paradigm for LAPC has yet to be defined, there is good rationale for the 
further study of RT. First, local tumor progression contributes to significant morbidity and mortality in this 
disease. As more effective systemic treatments evolve and are incorporated into practice, the 
complications related to local disease progression are predicted to increase and more commonly limit 
long-term survival.  Currently, it is estimated based on clinical and autopsy data that approximately 30% 
or more of patients die from complications related to local disease progression.[20]  Second, because 
complete surgical resection continues to be a necessary component to cure pancreatic cancer, the focus 
on improving local treatment modalities is essential. If a LAPC patient can be “downstaged” and 
converted to a resectable state, then higher cure rates may be possible 
 
Given the poor outcomes in patients with LAPC, there is a clear need for improved therapy. Current 
clinical trials focused on RT in LAPC investigate the effects of intensifying radiation regimens (RTOG 
1201), optimizing combinations with systemic agents(SCALOP-2 and CONKO-007), and  improving 
patient selection(RTOG 1201). However, none of these strategies takes into account the fact that despite 
the direct and well known tumoricidal effects of radiation on malignant epithelial cells, its clinical efficacy 
in pancreatic cancer may be limited by its promotion of innate and adaptive immune suppression. 


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2.2 Cabiralizumab 
 
Cabiralizumab is a recombinant, humanized Immunoglobulin G4 (IgG4) monoclonal antibody that binds to 
human colony stimulating factor 1 receptor (CSF1R; c-fms). Binding of cabiralizumab to CSF1R 
antagonizes binding of CSF1 and IL34, the two ligands to CSF1R, thereby preventing activation of  
CSF1R. Cabiralizumab contains a single amino acid substitution in the hinge region to prevent hemi-  
dimer exchange. 
 
CSF1R signaling plays a fundamental role in the differentiation, maintenance, trafficking, and function of 
monocytic lineage cells including monocytes, macrophages, and osteoclasts.[21] Two ligands have been 
identified for CSF1R: CSF1 and IL34 (reviewed in ([22]). Cabiralizumab blocks the binding of these 
ligands to CSF1R, thus inhibiting downstream functions such as development and survival of monocytic 
lineage cells. 
 
The tumor microenvironment, composed of non-cancer cells and stroma, is recognized as a major factor 
influencing the growth of tumor cells. Tumor-associated macrophages (TAMs) are particularly abundant in 
the tumor microenvironment and are thought to play a key role in promoting tumor growth. TAMs can 
promote angiogenesis (blood vessel formation in tumors), tumor survival, and metastasis, and may confer 
resistance to current therapies. TAMs are also immunosuppressive and through the release of soluble 
factors and cell surface T cell checkpoint inhibitors can suppress anti-tumor T cell responses. In the 
majority of tumors increased numbers of TAMs correlate with poor clinical outcome,[23] supporting TAMs 
as an attractive therapeutic target. Immunosuppressive TAMs are dependent on CSF1 for survival; a drug 
that inhibits CSF1R could limit the influence of TAMs on the tumor microenvironment and could be 
complementary and augment current cancer therapies (e.g., checkpoint-based immunotherapies such as 
antibodies that target the PD1 or CTLA4 pathways). 
 
 
2.2.1 
Preclinical Data 
 
2.2.1.1 
Pharmacokinetics 
 
Cabiralizumab binds to CSF1 in cynomolgus monkeys and humans with similar affinity. Therefore, 
pharmacokinetics (PK) and toxicokinetics (TK) of cabiralizumab were characterized in cynomolgus 
monkeys following single IV bolus administration or weekly repeat IV infusion administration, respectively. 
The duration of the IV infusion was 30 minutes. 
 
Four PK/TK studies were conducted in cynomolgus monkeys to support clinical development of 
cabiralizumab (Table 2). A ligand binding enzyme-linked immunosorbent assay (LBA) was used to 
measure cabiralizumab plasma concentration. Antibodies against cabiralizumab were measured in 
cynomolgus monkey plasma using an electrochemiluminescent bridging immunoassay (ECLA) method. 


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Table 2: Nonclinical Pharmacokinetic and Toxicokinetic Studies 
 
Study 
Number 
GLP Study 
Type 
Species and Number of Subjects per Group 
Dose 
(mg/kg) 
Route 
Dose Regimen 
0787- 
11180 
No PK 
Cynomolgus monkey n=1/sex/group 
3, 10, 30, 
150 
IV 
Single 
0787- 
11287 
No TK 
Cynomolgus monkey n=1/sex/group 
3, 10, 150 30 min IV 
infusion 
4 doses, given 
weekly 
0787- 
12002 
Yes TK 
Cynomolgus monkey, n=3/sex/group for 
Terminal Sacrifice n=2/sex group for Recovery 
Sacrifice 
50 and 150 30 min IV 
infusion 
4 doses, given 
weekly 
0787- 
13315 
Yes TK 
Cynomolgus monkey n=4/sex/group for 
Terminal Sacrifice n=2/sex group for Recovery 
Sacrifice 
20, 50, and 
100 
30 min IV 
infusion 
13 doses, 
given weekly 
 
• 
When given as a single IV bolus dose, cabiralizumab exhibited target-mediated clearance in the 
dose range of 3–150 mg/kg. Maximum observed serum concentration (Cmax) increased 
proportionally to dose at all dose levels tested. Area under plasma concentration curve 
extrapolated to infinity (AUCinf) increases were greater than dose proportional from 3 mg/kg to 10 
mg/kg and were dose proportional from 10 mg/kg to 150 mg/kg. The total clearance is 
approximately 0.21 mL/h/kg (5.0 mL/day/kg) in the dose range of 10–150 mg/kg. Since all eight 
animals were anti-cabiralizumab antibody (ADA) positive and the presence of ADA affects the total 
exposure for some animals, the relative attribution of non-specific clearance to target-       
mediated clearance or to ADA-mediated clearance is unknown. 
 
• 
When given as weekly repeat IV infusion administration in three toxicology studies in the dose 
range of 3–150 mg/kg, the TK profile following the first dose was similar to what was observed in 
the single-dose PK study. Cmax increased proportionally to dose at all dose levels tested. AUC 
increased dose proportionally from 10 mg/kg to 150 mg/kg, but less than dose proportionally from 
3 mg/kg to 10 mg/kg, suggesting that there was a limited contribution of target-mediated clearance 
to the total clearance at higher dose levels. The mechanism of prolonged exposure following 
last dose in comparison to PK data from the single dose is unknown, but is likely caused by the 
decreases in target-mediated clearance due to the reduction of CSF1R expressing cells of 
the 
monocyte/macrophage lineage in the presence of cabiralizumab (Figure 3 and Figure 4). 
Target-mediated clearance of cabiralizumab was caused by these CSF1R expressing cells. 
Estimated clearance at steady state (CLss) was 8.74, 2.78, and 5.34 day* g/mL for ADA-negative 
cynomolgus monkeys dosed at 20, 50, and 100 mg/kg, respectively, based on the data from the 
13-week repeat-dose GLP toxicology study. A nearly 2-fold accumulation was observed between 
the first and last dose for Cmax and AUC except the ones affected by ADAs. 
 
 
 
Figure 3: Individual Plasma Cabiralizumab Concentration-Time Profile in Cynomolgus Monkeys 
after 4-Week Repeat Dosing 


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Figure 4: Group Mean (+SD) Plasma Cabiralizumab Concentration-Time Profile in Cynomolgus 
Monkeys after 13-Week Repeat Dosing 
 
 
• 
ADAs were detected in the toxicity studies for animals administered cabiralizumab (4 out of 4, 6 
out of 20, and 20 out of 36 positive for the samples tested for the 4-week pilot toxicity study, the 
4-week GLP toxicity study, and 13-week GLP toxicity study, respectively). In general, the 
presence of ADAs was associated with lower plasma concentrations of cabiralizumab (Figure 3 
and Figure 4). However, the TK data supported that the adequate exposure was observed for 
most of the animals in two GLP toxicity studies. 
 
• 
Cabiralizumab concentration-dependent PD effect was observed for CD16+ monocytes reduction 
in cynomolgus monkeys. The lowest plasma concentration of cabiralizumab with maximum 
reduction of CD16+ monocytes in cynomolgus monkeys after weekly 
repeat IV infusion of cabiralizumab is approximately 10 μg/mL. Based on the findings from 
cynomolgus monkeys, the cabiralizumab concentration-effect for the reduction of CD16+ 
monocytes in humans was evaluated as an exploratory PD marker. 
 
• 
The starting dose for the first-in-human single IV administration in healthy volunteers was 0.2 
mg/kg based on evaluation of the minimum anticipated biological effect level (MABEL). 
 
2.2.1.2 
Distribution, Metabolism, and Excretion 


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The expected consequence of metabolism of biotechnology-derived pharmaceuticals such as 
cabiralizumab is the degradation to small peptides and individual amino acids following receptor-mediated 
endocytosis. Therefore, the metabolic pathways are generally understood. 
 
Following a single administration of cabiralizumab at 0.2, 1, 3, and 10 mg/kg, total clearance decreased 
with increasing dose and ranged from 1.60 to 0.105 mL/h/kg in healthy volunteers. The total clearance of 
0.105 mL/h/kg at 10 mg/kg is within the range for a typical human IgG monoclonal antibody. Following 
multiple dose administration of cabiralizumab in different populations, the accumulation of cabiralizumab 
exposure was observed for doses 2 mg/kg with every two week dosing 
 
2.2.1.3 
Toxicology 
 
Cabiralizumab was generally well-tolerated in the toxicology studies in cynomolgus monkeys. Test article- 
related findings included clinical observations, hematology and clinical chemistry changes, and 
histopathologic changes. The majority of these observations were considered non-adverse. The most 
prominent clinical observation was reversible periorbital edema, seen after prolonged exposure to 
cabiralizumab. The onset of edema did not show a clear relationship to exposure levels; however edema 
resolved after systemic clearance of the drug. Periorbital edema is a known side effect with drugs 
affecting the CSF1 pathway.[24] The main hematologic change was a decrease in circulating CD16+ 
monocytes, which was considered a PD effect, and the decreased cell numbers normalized with clearance 
of cabiralizumab from circulation. Cabiralizumab-related clinical chemistry effects included reversible 
increased ALT, AST, CK, and LDH values. These laboratory abnormalities were not associated 
with 
evidence of tissue injury or histopathologic changes and were attributed to decreased clearance of the 
ALT, AST, CK, and LDH molecules from serum due to a decreased number of liver macrophages 
(Kupffer cells). Kupffer cells are the cells responsible for clearance of short-lived serum enzymes such as 
ALT, AST, CK, and LDH. The connection between elevated serum enzymes, inhibition of CSF1R, and 
reduction of Kupffer cell numbers have been previously demonstrated in nonclinical studies.[25] Similar 
findings of increased serum enzymes have been reported for several CSF1R pathway antagonists, for 
example, PD-0360324, which is a human IgG2 monoclonal antibody to CSF1. During preliminary safety 
studies of this antibody in humans, dose-related increases in the levels of AST and CK were observed in 
the absence of other liver or muscle injury markers. These serum enzyme elevations were also attributed 
to reductions in Kupffer cell numbers. Accordingly, the ALT, AST, CK, and LDH elevations are considered 
non-toxic and an indirect PD effect of cabiralizumab exposure. 
 
The most noteworthy necropsy findings in both pivotal studies was the histopathological observation of 
reversible expansion of the submucosal collagen fibers by clear space and varying amounts of a blue, 
granular ECM. This was most abundantly seen in the esophagus but was also present in a large variety 
of other tissues. This change was not associated with inflammatory cells or with any sign of degeneration 
or other alteration of the collagen fibers, fibroblasts, or the smooth muscle cells within the area of 
expansion. Most likely the reduction of tissue macrophages causes the observed accumulation of ECM 
due to a decreased clearance of glycosaminoglycans, especially hyaluronic acid, that are prominent in 
connective tissue and are normally catabolized by macrophages. A similar observation was also seen in 
op/op mice that lack functional CSF1.[25] This change is considered an indirect effect of cabiralizumab. 
There was no evidence that the accumulation of the blue granular ECM was adverse. There were no 
correlative clinical observations or organ weight changes, and the findings were fully reversible during a 
drug-free recovery period. Therefore, these observations were not considered adverse. 
 
The no-observable-adverse-effect level (NOAEL) was determined to be 100 mg/kg for cynomolgus 
monkey, when administered for 13 weekly doses. 
 
No reproductive or developmental toxicity studies have been conducted with cabiralizumab at this stage. 
Examinations of the reproductive organs in the 4-week and 13-week toxicology studies have shown no 
evidence of reproductive target toxicity. Male fertility assessment at the end of the dosing phase in the 13- 
week toxicity study did not show any effect of cabiralizumab on male fertility. 


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2.2.1.4 
Pharmacodynamics 
 
Cabiralizumab binds specifically to the extracellular domain (ECD) of human and cynomolgus monkey 
CSF1R as determined by direct binding enzyme-linked immunosorbent assay (ELISA) and Biacore 
analysis. Cabiralizumab binds in a dose-dependent manner to the ECD of human CSF1R fused to IgG1 
Fc (CSF1R-Fc) and to cynomolgus monkey CSF1R-Fc with comparable half-maximal response (EC50) 
values. Cabiralizumab binds to human and cynomolgus monkey CSF1R-Fc with KD values in the low 
nanomolar (nM) range. 
 
Cabiralizumab  did  not  bind  to  human  c-Kit-Fc  or  to  human  PDGFR-Fc  in  direct  binding  ELISAs, 
demonstrating specificity of cabiralizumab for CSF1R. cKit and PDGFR are proteins with  the closest 
amino acid sequence homology to CSF1R in their ECDs. 
 
Cabiralizumab blocks binding interactions between CSF1R and its two known ligands, CSF1 and IL34, as 
determined by competitive binding ELISAs. Cabiralizumab IC50 values were similar for both CSF1 and 
IL34 in these assays, indicating cabiralizumab blocks binding of both ligands with equal potency. 
 
Cabiralizumab inhibited both CSF1 and IL34-induced CSF1R phosphorylation in a recombinant cell line 
engineered to overexpress CSF1R (CHO-CSF1R) in cell-based assays, demonstrating cabiralizumab 
blocks the activation of ligand-induced CSF1R signaling pathways. Cabiralizumab also inhibits CSF1 and 
IL34-induced proliferation/survival of peripheral blood IL34 signaling pathways, but also the subsequent 
physiologic responses of primary human monocytes to these ligands. 
 
To assess the activation potential of cabiralizumab, CHO-CSF1R cells were incubated with cabiralizumab 
in the absence of CSF1 or IL34, and CSF1R phosphorylation was quantified from cell lysates using a 
phospho-CSF1R ELISA. To test if cross-linking of cabiralizumab could result in CSF1R activation, in 
some studies cell bound cabiralizumab was cross-linked with a secondary antibody or with a biotinylated 
secondary antibody followed by tertiary avidin cross- linking. Under no condition tested was the induction 
of CSF1R phosphorylation observed, consistent with a lack of cabiralizumab agonist activity. In 
conclusion, the data from both the recombinant cell line and primary monocytes suggest that 
cabiralizumab lacks the potential to activate CSF1R signaling either directly or when cross-linked. 
 
To further assess the activation potential of cabiralizumab, freshly isolated peripheral blood monocytes 
were incubated with cabiralizumab in the absence of CSF1 or IL34, and its effects on monocyte 
proliferation/survival were assessed. In this case, cabiralizumab cross-linking may be facilitated by Fc 
receptors expressed on monocytes themselves. Under no condition tested did cabiralizumab induce 
monocyte proliferation/survival, consistent with a lack of cabiralizumab agonist activity. 
 
Effect on CD16+ Monocytes in Cynomolgus Monkeys 
 
CD16+ monocytes were reduced in monkeys receiving four weekly IV infusions of 50 mg/kg or 150 mg/kg 
cabiralizumab, consistent with CSF1R pathways being necessary to support the growth and maintenance 
of this monocyte subpopulation in vivo. CD16+ monocyte inhibition occurred within one week of dosing 
and was sustained throughout the dosing and exposure period. The CD16+ monocytes were restored to 
normal baseline levels after cabiralizumab cleared with no evidence of a rebound effect. The CD16- 
monocyte subpopulation remained unaffected by administration of cabiralizumab. 
 
Effect on CSF1 Serum Levels in Cynomolgus Monkeys 
 
Plasma levels of CSF1 are a measure of cabiralizumab target engagement. CSF1 is cleared from 
circulation under normal physiological conditions by macrophages (primarily liver Kupffer cells) via 
CSF1R-mediated endocytosis and intracellular degradation (Bartocci 1987). Cabiralizumab binds to and 
blocks CSF1R, resulting in a large, rapid increase in circulating CSF1 concentration, after which CSF1 
levels reach a new steady state. The data (for Day 8 and Day 15) show that a minimum biological effect 
occurred  at  5  μg/mL,  and  a  half-maximal  response  (EC50)  was  8  μg/mL  cabiralizumab.  While 


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cabiralizumab elevates CSF1, FivePrime believes that these elevations  will have no consequence 
because: 
• 
The receptor through which CSF1 signals is blocked by cabiralizumab. 
• 
The levels of CSF1 fall dramatically once cabiralizumab is cleared. 
• 
In the presence of cabiralizumab, when CSF1 is elevated, the potential for extremely high 
concentrations of CSF1 to displace cabiralizumab from the CSF1R receptor was evaluated in the 
cabiralizumab   cell   potency   assay.   The   data   showed   that   concentrations   as   high   as 
10 μg/mL CSF1 had no impact on cabiralizumab potency or maximal inhibition of CSF1R 
signaling. 
 
Cabiralizumab Effect on Bone Resorption in Cynomolgus Monkeys 
 
Treatment with cabiralizumab will potentially decrease the osteoclastic activity in RA that contributes to 
bone destruction. Plasma and urine markers of bone resorption were evaluated in monkeys following 
repeat dosing with cabiralizumab. Urine Collagen-type I N-terminal telopeptide (NTx) and plasma CTx, 
NTx, and Trap5b were all decreased at Day 28 after four weekly doses in the male monkeys. A similar 
trend was observed in the female monkeys, but the result was not statistically significant. At the recovery 
termination on Day 245, urinary NTx was restored to baseline in all monkeys. 
 
2.2.1.5 
Efficacy in Human Disease Tissues 
 
The ability of cmFPA008 to enhance anti-PD1 efficacy was studied in an orthotopic pancreatic tumor 
model. KRasG12D/Ink4a-/- pancreatic ductal adenocarcinoma (PDAC) cells were surgically implanted 
into the pancreas of immunocompetent mice. To determine the effect of CSF1R blockade on 
macrophages, tumor bearing mice were treated with cmFPA008 alone for eight days at which point 
tumors were excised and analyzed by flow cytometry. Murine PDAC tumors contain a distinct subset of 
immunosuppressive TAMs identified as CD206Hi and a subset of immunostimulatory TAMs identified as 
CD206Low. Quantification of CD206Hi and CD206Low TAM subsets revealed that cmFPA008 led to a 
significant reduction of CD206Hi immunosuppressive TAMs whereas CD206Low immunostimulatory 
TAMs were less affected. To determine the effect of CSF1R blockade on the T cell checkpoint blockade, 
tumor cells were analyzed for PDL1 expression. cmFPA008 treatment increased the number of 
PDL1+ 
tumor cells. Taken together, these results suggest that although cmFPA008 
reprograms the TAM 
compartment towards immune stimulation, this reprogramming also leads to upregulation of PDL1 on 
tumors cells which could limit an anti-tumor T cell response. 
 
 
 
To test the effects of CSF1R blockade on anti-PD1 efficacy, mice bearing established tumors were 
treated with cmFPA008, anti-PD1, or the combination together with gemcitabine (GEM). Anti-PD1 or 


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cmFPA008 alone showed only limited efficacy at decreasing the progression of established tumors. In 
contrast, the combination of cmFPA008 and anti-PD1 significantly reduced tumor progression. Similar 
results were seen in KRasG12Dp53-/- tumors. These data suggest that CSF1R blockade can reprogram 
the immunosuppressive TAM compartment and significantly enhance anti-PD1 therapy. 
 
 
 
2.2.2    Clinical Data to Date 
 
2.2.2.1   Pharmacokinetics 
 
The PK and ADA of cabiralizumab were characterized in three studies: FPA008-001, FPA008- 002, and 
FPA008-003. These data are described in detail in the Investigator’s Brochure. The cabiralizumab serum 
concentrations were quantitatively measured by a validated enzyme-linked immunosorbent assay 
(ELISA). PK parameters were estimated for each patient using noncompartmental analysis (NCA) by 
Phoenix® WinNonlin® (Version 6.3, Certara L.P., St. Louis, MO). The pharmacokinetic (PK) profile of 
cabiralizumab is characterized by linear and nonlinear clearance 
pathways, with the latter likely 
mediated by binding to CSF1R on cells. As monocyte and macrophage cells are dependent on CSF1R 
for viability, these target-bearing cells are reduced in number following cabiralizumab treatment, resulting 
in a decrease of target-mediated clearance. Once target-mediated 
clearance is saturated at high or 
repeat doses, cabiralizumab clearance is similar to other human IgG antibodies.  
 
Following a single administration of cabiralizumab at 0.2, 1, 3, and 10 mg/kg, total clearance decreased 
with increasing dose and ranged from 1.60 to 0.105 mL/h/kg in healthy volunteers. The total clearance of 
0.105 mL/h/kg at 10 mg/kg is within the range for a typical human IgG monoclonal antibody. Following 
multiple dose administration of cabiralizumab in different populations, the accumulation of cabiralizumab 
exposure was observed for doses 2 mg/kg with every two week dosing. The PK characteristics observed 
in healthy volunteers and patients with RA, PVNS, and cancer support dosing of cabiralizumab every two 
weeks or less frequently. 
 
In Phase 1a, patients with cancer were administrated cabiralizumab at doses of 2, 4, and 6 mg/kg every 
two weeks as monotherapy and at 1, 2, 4 mg/kg every two weeks in combination with 3 mg/kg nivolumab 
every two weeks. Cabiralizumab serum concentration vs nominal time data is displayed in Figure 5.  
 
 
 
 
 
 
 
 
Figure 5: Mean (±SD) Cabiralizumab Serum Concentration vs. Time in Patients with Solid Tumor 
following First Dose Administration 
 
 


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Based on preliminary analyses, following the first dose in patients with cancer at 2, 4, and 6 mg/kg as 
monotherapy or at 1, 2, and 4 mg/kg in combination with nivolumab, Cmax increased dose proportionally 
while AUC and Cmin increased more than dose proportionally, suggesting target-mediated clearance. 
Accumulation was observed for Cmax and Cmin ZLWK 2 mg/kg every two week dosing. Exposure was 
similar at 4 mg/kg for cabiralizumab as monotherapy and in combination with nivolumab.(see figure 6) 
Furthermore, exposure with cabiralizumab 4mg/kg in the presence of nivolumab was similar in the 
pancreatic cancer cohort compared to other tumor types (see figure 7) The PK of cabiralizumab was similar 
among patients with pancreatic cancer and other cancers. [26] 


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Figure 6: Pharmacokinetic Parameters of Cabiralizumab +/- Nivolumab 
 
Figure 7: Pharmacokinetic Parameters of Cabiralizumab 4mg/kg + Nivolumab in pancreatic cohort 
vs other solid tumors 
 
 
 
 
2.2.2.2 
Pharmacodynamics 
 
Three pharmacodynamic (PD) biomarkers correlate with cabiralizumab exposure in nonclinical studies: 
CSF1 serum levels, circulating CD16-positive peripheral blood monocytes (CD16+ monocytes), and 
serum markers of bone resorption. 
 
CSF1 and IL34 Ligands 
Cabiralizumab blocks binding interactions between CSF1R and its two ligands, CSF1 and IL34. In 
nonclinical studies, cabiralizumab dosing resulted in a rapid and sustained increase in serum CSF1 that 
was readily reversible. The consequences of extremely high CSF1R ligand levels have been considered 
and are not anticipated to cause any adverse effects. Both CSF1 and IL34 were measured in the serum 
from all subjects in Parts 1, 2 (healthy volunteers) and Part 3 (patients with RA) of the study using 
commercially available ELISAs. The results were comparable to what was observed in nonclinical studies, 
marked by a rapid and sustained elevation of serum CSF1R ligands that was restored to baseline upon 


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clearance of cabiralizumab. The data prove that both CSF1R ligands have high turnover in humans and 
that CSF1R is a dominant mechanism of ligand clearance. 
 
Effects on CD16+ Monocytes 
• 
Human peripheral blood monocytes can be divided into three subgroups based on surface 
expression of CD14 and CD16; classical monocytes (CD14++CD16-), intermediate monocytes 
(CD14++CD16+), and nonclassical monocytes (CD14+CD16++). Nonclassical CD16+ monocytes 
are dependent on CSF1R signaling for survival and/or differentiation and are reduced upon 
CSF1R inhibition. Nonclassical CD16+ monocyte levels in peripheral blood have been or are 
being assessed in all three clinical studies described above as pharmacodynamic markers of 
CSF1R inhibition; FPA008-001 in healthy volunteers and patients with RA, FPA008-002 in 
patients with PVNS, and FPA008-003 in patients with advanced cancer. In general across all 
three studies, cabiralizumab treatment results in a transient increase in nonclassical CD16+ 
monocytes at four hours followed by complete reduction, to the limits of the assay, by 72 hours. 
The duration of nonclassical CD16+ monocyte reduction is dose and concentration dependent 
and levels return to normal once drug has decreased below approximately 10 μg/mL. 
Cabiralizumab 4 mg/kg Q2W was the minimal dose required to consistently deplete circulating 
nonclassical monocytes throughout the dosing interval; results were similar with cabiralizumab 4 
mg/kg + nivolumab.(see figure 10). These decreases in levels of nonclassical monocytes were 
similar in the pancreatic cancer cohort as compared to other tumor types. Cabiralizumab does not 
reduce classical CD16- monocyte levels. 
 
Figure 8: Cabiralizumab-mediated Reduction of Nonclassical CD16+ Monocytes in Patients with 
Cancer in Study FPA008-003 
 
 
 
 
Bone Turnover Markers 
Cabiralizumab may be of therapeutic benefit in patients with RA by targeting pro-inflammatory 
monocytes/macrophages and bone-destructive osteoclasts. A surrogate marker for inhibition of osteoclast 
activity is the measurement of bone resorption markers such as NTx, CTx and Trap5b in serum or urine. 
A decrease in urine NTx and plasma CTx, NTx and Trap5b was observed in monkeys following repeat 
dosing of cabiralizumab. A dose-dependent reversible decrease in urinary NTx was a reported 
pharmacodynamics (PD) effect of PD- 0360324, a neutralizing monoclonal antibody to CSF1, in healthy 
volunteers (Sadis 2009). CTx and Trap5b were measured by ELISA in serum samples collected from 
healthy volunteers following dosing with placebo or cabiralizumab in Parts 1 and 2 of study FPA008-001 
and from patients with RA dosed with cabiralizumab in Part 3. A decrease in both serum CTx and Trap5b 
was observed at 3 mg/kg and 10 mg/kg in healthy volunteers. There was no statistically significant 
change in either marker following one or two doses of 1 mg/kg cabiralizumab in healthy volunteers 
(placebo subjects not shown). In Part 3 of this study, eighteen patients with RA were enrolled into five 
cohorts: 1 mg/kg for two doses, 3 mg/kg for two doses, 3 mg/kg for three doses, 6 mg/kg for two doses, 


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and 6 mg/kg for three doses. Data is available for the first three cohorts in Part 3. A dose-dependent 
decrease in both serum CTx and Trap5b was observed with cabiralizumab in patients with RA. 
 
 
2.2.2.3 
Safety and Efficacy 
 
The clinical summary of safety and efficacy is based on three clinical studies: 
1. Study FPA008-001 evaluated the safety of cabiralizumab as single or double ascending doses in 
48 healthy volunteers (36 received cabiralizumab and 12 received placebo). This study also 
evaluated the safety and efficacy of cabiralizumab administered as two or three doses, 14 days 
apart, in 18 rheumatoid arthritis (RA) subjects. This study has been completed. 
2. Study  FPA008-002  is  evaluating  the  safety  and  efficacy  of cabiralizumab  monotherapy  for 
6 months in approximately 40 subjects with pigmented villonodular synovitis (PVNS). 
3. Study FPA008-003 is evaluating the safety and efficacy of cabiralizumab as monotherapy and in 
combination with nivolumab in approximately 295 subjects with advanced cancers. 
 
Study FPA008-001 – Healthy Volunteers and Rheumatoid Arthritis 
Thirty six healthy volunteers and 18 RA subjects received cabiralizumab in Study FPA008-001. No dose- 
limiting toxicities (DLTs) were reported and no unexpected treatment-related adverse events (AEs) have 
been reported from RA subjects treated with three doses up to 6 mg/kg. 
 
In healthy volunteers and patients with RA, adverse events related to treatment with cabiralizumab have 
included edema, skin findings and elevations in circulating levels of certain enzymes. The edema 
described is mostly facial and periorbital (including eyelid) edema; the onset and duration of the edema 
varies, and does not appear to correlate with the serum concentration of cabiralizumab. Edema has been 
reported in other compounds targeting CSF1R pathway. Skin findings include pruritus and rash. Enzyme 
elevations include CK, lactate dehydrogenase (LDH) and AST. These enzyme elevations have been 
noted in a majority of patients, but have been reversible and clinically asymptomatic without evidence of 
other underlying organ dysfunction in most patients. 
 
Study FPA008-002 – Pigmented Villonodular Synovitis 
 
Study FPA008-002 is currently ongoing and is evaluating cabiralizumab as monotherapy in subjects with 
PVNS. Details relating to safety are included in the latest version of the cabiralizumab IB (FivePrime, 
2017) 
 
Study FPA008-003 – Advanced Cancers (Cabiralizumab/Nivolumab) 
 
As of 01-Aug-2017, cabiralizumab-related AEs were reported in 169 of 195 subjects (87%) treated Q2W 
in Phase 1b of Study FPA008-003. The AEs reported in more than 10% of the subjects included: CK 
increased (77 subjects, 40%); periorbital edema (73 subjects, 73%); AST increased (65 subjects, 33%); 
fatigue (61 subjects, 31%); ALT increased and pruritus (32 subjects each, 16%); amylase increase and 
rash (30 subjects each, 15%); lipase increase (29 subjects, 15%); nausea (27 subjects, 14%); and LDH 
increased (20 subject, 10%). 
 
Cabiralizumab-related  Grade 3 AEs in Phase 1b were predominantly enzyme elevations of CK  
(14 Grade 3 and 14 Grade 4 events), LDH (one Grade 3 and one Grade 4 event), Alkaline phosphate 
([ALP] two Grade 3 events), ALT (two Grade 3 events), and AST (10 Grade 3 events). Other related 
AEs that were  Grade 3 and reported in 2 or subjects ( 1%) included 13 events of amylase 
increased (12 Grade 3 and one Grade 4), 15 events of Grade 3 lipase increased (14 Grade 3 and one 
Grade 4), 11 events of Grade 3 Fatigue, and three events of Grade 3 hypertension. 
 
Twenty-six of 195 subjects (13%) experienced a cabiralizumab-related SAE in Phase 1b. The SAEs 
reported in two or more subjects ( 1%) included: CK increased (three subjects, 3%), brain  edema 


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pneumonitis, hyponatremia (two subjects each, 1%). Also SAEs included one event of Grade 4 CK 
increased (related to cabiralizumab and nivolumab), one event of Grade 3 autoimmune colitis (related to 
nivolumab), and one event of Grade 3 hypopituitarism (related to cabiralizumab and nivolumab). 
 
Two Grade 5 SAEs prior to study treatment discontinuation have occurred in Phase 1a of Study FPA008- 
003: one subject had a Grade 5 pulmonary embolus (not related) and a Grade 5 pneumonitis (related to 
both drugs) and the other subject had a Grade 5 hypoxic respiratory failure secondary to pneumonia (not 
related). Six Grade 5 SAEs prior to study treatment discontinuation were reported in Phase 1b of this 
study. These included 1 sudden cardiac death (unrelated), 1 death due to tumor thrombus blocking a 
major blood  vessel (unrelated), 2  patients with  respiratory failure (unrelated), 1 patient with acute 
respiratory distress (related), and 1 patient with acute respiratory failure (related). 
 
Between 15 December 2016 and 15 February 2017, an additional 34 patients have been enrolled in the 
pancreatic tumor expansion phase of FPA008-003. The type, incidence, and severity of all AEs and AEs 
leading to discontinuation in these additional patients were generally consistent with the expected safety 
profile. All cabiralizumab-related AEs in Phase 1b were Grade 1 or 2, with the exception of: six Grade 4 
CK increases, one Grade 4 LDH increase, three Grade 3 CK increases, three Grade 3 AST increases, 
three Grade 3 lipase increases, three Grade 3 hypertension, one Grade 3 diarrhea, one Grade 3 
hypopituitarism. SAEs related to cabiralizumab were reported in six additional patients (for a total of eight 
treatment- related SAEs) in these additional patients. The new treatment-related SAEs reported in one 
patient each were pneumonitis, dyspnea, hypopituitarism, hyperbilirubinemia, hyponatremia, and seizure. 
 
The study is still ongoing in the Phase 1b dose expansion and efficacy data for both phases of the study 
are preliminary. In this heavily pretreated pancreatic cancer population durable clinical benefit was 
observed in 5 of 31 (16%) evaluable patients.[27] All 4 confirmed responses were in patients with 
microsatellite stable tumors and were accompanied by steep declines in levels of the pancreatic 
tumor marker CA19-9 over baseline. 
   
  2.2.3 
Dose Rationale 
 
Cabiralizumab 4mg/kg dose was selected based on preliminary analyses. Following the first dose in 
patients with cancer at 2, 4, and 6 mg/kg as monotherapy or at 1, 2, and 4 mg/kg in combination with 
nivolumab, Cmax increased dose proportionally while AUC and Cmin increased more than dose 
proportionally, suggesting target-mediated clearance. Accumulation was observed for Cmax and Cmin 
with ≥ 2 mg/kg every two week dosing. Exposure was similar at 4 mg/kg for cabiralizumab as 
monotherapy and in combination with nivolumab (limited data, Cabiralizumab Investigator’s Brochure 
Version 4 May 2017). Furthermore, the 4mg/kg every 2 week dose achieved the concentration (>10 
g/mL) necessary for maximum reduction of nonclassical CD16+ monocytes between dose intervals in a 
majority of patients when overall tolerability and safety allowed. 
 
 
2.3 
Nivolumab 
 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-
1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative 
regulatory molecule expressed by activated T and B lymphocytes.[28] Binding of PD-1 to its ligands, 
programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte 
activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as 
self-antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration. 
 
 
 


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The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided transformative 
information on the nature of the immune system and cancer. An emerging picture suggests that 
endogenous immune responses can mediate effective tumor regression and/or improved survival even in 
patients with large volume tumors resistant to other forms of therapy. Some of the unique features of this 
type of therapy, based largely on experience in advanced melanoma, include: improved overall survival 
(OS) with or without radiographic responses or improved progression-free survival (PFS); responses that 
may be delayed or occur after radiographic disease progression; combinations of immune modulators  
with enhanced or novel activities (in the example of ipilimumab and nivolumab); and toxicity that is almost 
exclusively immune or inflammatory in nature. It is not yet clear what factors determine responses and 
which components of the immune system are needed for this to occur. It seems likely that both memory 
helper and effector cells would be needed to sustain long-term responses. Increasing emphasis has been 
placed on understanding the relationships of the tumor, cellular infiltrate, and immunologic milieu 
surrounding each tumor. 
 
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family of T-cell co-stimulatory 
receptors that include Ig super family member CD28, CTLA-4, inducible co-stimulator (ICOS), and B and T 
lymphocyte attenuator (BTLA) (Investigator Brochure, 2014). PD-1 is transiently but highly expressed on 
activated T cells functioning to limit immune effectors at the site of activation. Chronic stimulation may 
prevent the re-methylation of the PD-1 gene leading to continuous expression and characterizes a state   
of “exhausted” T cells that lose function and proliferative capacity while enhancing a suppressive tumor 
microenvironment. PD-1 may act together with other T-cell modulating molecules, including CTLA-4, TIM- 
3, lymphocyte-activation gene 3 (LAG-3) as well as indoleamine-pyrrole 2, 3-dioxygenase 1 (IDO-1), 
cytokines, and transforming growth factor beta (TGF-beta). 
 
Two ligands specific for PD-1 have been identified: PD-ligand 1 (PD-L1, also known as B7-H1 or CD274,   
expressed on tumor, antigen-presenting cells [APCs], and dendritic cells [DCs]) and PD-L2 (also known 
as B7-DC or CD273, expressed on endothelial cells). The interaction of PD-1 with PD-L1 and PD-L2 
results in negative regulatory stimuli that down-modulate the activated T-cell immune response through 
SHP-1 phosphatase. 
  
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis (C57BL/6) and cardiomyopathy 
(BALB/c). In transplantable tumor models that expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and 
CD8+ T cells dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that 
were largely resistant to single antibody treatment.[29] Despite minimal immunopathologic sequelae in 
PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant 
autoimmune infiltrates in multiple organs, leading to eventual lethality. 
 
PD-L1 expression is found on a number of tumors, and is associated with poor prognoses based on OS 
in many tumors, including melanoma,[30] renal,[31] esophageal,[32] gastric,[33] ovarian,[34] 
pancreatic,[35] lung [36] and other cancers (Investigator Brochure, 2014). 
 
The PD-1/PD-L1 axis plays a role in human infections, particularly in hepatitis C virus (HCV) and human 
immunodeficiency virus (HIV). In these cases, high expression levels of PD-1 were found in viral-specific 
CD8+ T cells that also display a non-responsive or exhausted phenotype. Non-responsive PD-1-high T 
cells were observed in simian immunodeficiency virus (SIV) infection in rhesus macaques. Treatment of 
SIV-infected macaques with an anti-PD-1 mAb (3 mg/kg x4) resulted in decreased viral loads and 
increased survival along with expanded T cells with increased T-cell functionality. 
 
Nivolumab is approved for the treatment of several types of cancer in multipleregions including the United 
States (US, Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-2014). Nivolumab is also 
being investigated in various other types of cancer as monotherapy or in combination with other therapies, 
and as single-dose monotherapy for the treatment of sepsis. 


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2.3.1 
Preclinical Data 
 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related    
members of the CD28 family. Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 and PD- 
L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in vitro[37] Nivolumab 
binds with high affinity to activated human T-cells expressing cell surface PD-1 and to cynomolgus 
monkey PD-1.2 In a mixed lymphocyte reaction (MLR), nivolumab promoted a reproducible concentration-
dependent enhancement of IFN- release.[38] In intravenous (IV) repeat-dose toxicology studies in 
cynomolgus monkeys, nivolumab was well tolerated at doses up to 50 mg/kg, administered weekly for 5 
weeks, and at doses up to 50 mg/kg, administered twice weekly for 27 doses. While nivolumab alone was 
well tolerated in cynomolgus monkeys, combination studies have highlighted the potential for enhanced 
toxicity when combined with other immunostimulatory agents. In addition, an enhanced pre- and postnatal 
development (ePPND) study in pregnant cynomolgus monkeys with nivolumab was conducted. 
Administration of nivolumab at up to 50 mg/kg 2QW was well tolerated by pregnant monkeys; however, 
nivolumab was determined to be a selective developmental toxicant when administered from the period of 
organogenesis to parturition at > 10 mg/kg (area under the concentration- time curve [AUC] from time zero 
to 168 hours [AUC(0-168 h)] 117,000 g*h/mL). Specifically, increased developmental mortality (including 
late gestational fetal losses and extreme prematurity with associated neonatal mortality) was noted in the 
absence of overt maternal toxicity. There were no nivolumab-related changes in surviving infants tested 
throughout the 6-month postnatal period. Although the cause of these pregnancy failures was 
undetermined, nivolumab-related effects on pregnancy maintenance are consistent with the established 
role of PD-L1 in maintaining fetomaternal tolerance in mice.[39] 
 
 
2.3.2 
Clinical Data to Date 
 
2.3.2.1 
Pharmacokinetics 
The PK of nivolumab was studied in subjects with cancer 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 (CL) 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) was 6.8 L (27.3%), and geometric mean 
elimination half-life (t1/2) was 25 days (77.5%). Steady-state concentrations of nivolumab were reached  
by 12 weeks when administered at 3 mg/kg Q2W, and systemic accumulation was approximately 3.7-fold. 
The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered every 2 weeks. Additionally, nivolumab has a low potential for drug-drug interactions. The 
clearance of nivolumab increased with increasing body weight. The PPK analysis suggested that the 
following factors had no clinically important effect on the CL of nivolumab: age (29 to 87 years), gender, 
race, baseline LDH, PD-L1 status, solid tumor type, baseline tumor size, and hepatic impairment. 
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, and body weight had an effect 
on nivolumab CL, the effect was not clinically meaningful. PPK analysis suggest that nivolumab CL in 
subjects with cHL was approximately 32% lower relative to subjects with NSCLC; however, the lower CL 
in cHL subjects was not considered to be clinically relevant as nivolumab exposure was not a significant 
predictor for safety risks for these patients. When nivolumab is administered in combination with 
ipilimumab, the CL of nivolumab was increased by 29%, whereas there was no effect on the clearance of 
ipilimumab. 
 
PPK and exposure response analyses have been performed to support use of nivolumab 240 mg 
Q2W, 360 mg Q3W, and 480 mg Q4W dosing regimens in subjects with cancer in addition to the 
3 mg/kg Q2W regimen. A flat dose of nivolumab 240 mg Q2W was selected since it is identical to a dose 
of 3 mg/kg for subjects weighing 80 kg, the observed median body weight in nivolumab treated cancer 
patients, while the nivolumab 360 mg Q3W and 480 mg Q4W regimens allow flexibility of dosing with less 
frequent visits and in combination with other agents using alternative dosing schedules to Q2W. Using a 


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PPK model, the overall distributions of nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are 
comparable after treatment with either nivolumab 3mg/kg or 240 mg Q2W. Following nivolumab 360 mg 
Q3W and 480 mg Q4W, Cavgss are expected to be similar to those following nivolumab 3 mg/kg or 240 
mg Q2W, while Cminss are predicted to be 6% and ~16% lower, respectively, and are not considered to 
be clinically relevant. Following nivolumab 360 mg Q3W and 480 mg Q4W, Cmaxss are predicted to be 
approximately ~23% and ~43% greater, respectively, relative to that following nivolumab 3 mg/kg Q2W 
dosing. However, the range of nivolumab exposures (median and 90% prediction intervals) following 
administration of 240 mg flat Q2W, 360 mg Q3W, and 480 mg Q4W regimens across the 35 to 160 kg 
weight range are predicted to be maintained well below the corresponding exposures observed with the 
well tolerated 10 mg/kg nivolumab Q2W dosing regimen. 
 
The PK of single-dose nivolumab monotherapy in subjects with sepsis is under evaluation; however, no 
data are currently available. 
 
2.3.2.2 
Clinical Efficacy 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and in 
combination with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, cHL, SCLC, 
gastric cancer, SCCHN, urothelial cancer, HCC, and CRC. In confirmatory trials, nivolumab as 
monotherapy demonstrated a statistically significant improvement in OS as compared with the current 
standard of care in subjects with advanced or metastatic NSCLC, unresectable or metastatic melanoma, 
advanced RCC, or SCCHN. Nivolumab in combination with ipilimumab improved PFS and ORR over 
ipilimumab alone in subjects with unresectable or metastatic melanoma. No efficacy data are currently 
available for nivolumab treatment in subjects with sepsis. 
 
 
2.3.2.3 
Clinical Safety 
 
The  overall  safety  experience  with  nivolumab,  as  a  monotherapy  or  in  combination  with  other 
therapeutics, is based on experience in approximately 16,900 subjects treated to date. 
 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the incidence, 
severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, the safety profile of 
nivolumab monotherapy is acceptable in the context of the observed clinical efficacy, and manageable 
using established safety guidelines. Clinically relevant AEs typical of stimulation of the immune system 
were   infrequent   and   manageable   by   delaying   or   stopping   nivolumab   treatment   and   timely 
immunosuppressive therapy or other supportive care. Based on preliminary data from an ongoing Phase 
1 study, there have been no unexpected safety findings to date in patients with sepsis who received a 
single dose of nivolumab monotherapy. In several ongoing clinical trials, the safety of nivolumab in 
combination with other therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and 
targeted therapies is being explored. Most studies are ongoing and, as such, the safety profile of 
nivolumab combinations continues to evolve. The most advanced combination under development is 
nivolumab + ipilimumab, which is approved in subjects with unresectable or metastatic melanoma 
and being studied in multiple tumor types. Results to date suggest that the safety profile of 
nivolumab+ipilimumab combination therapy is consistent with the mechanisms of action of nivolumab and 
ipilimumab. The nature of the AEs is similar to that observed with either agent used as monotherapy; 
however, both frequency and severity of most AEs are increased with the combination.


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2.3.3 
Dose Rationale 
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to the3 mg/kg Q2W 
dosing regimen in subjects with cancer. A flat dose of nivolumab 240 mg Q2W was selected since it is 
identical to a dose of 3 mg/kg for subjects weighing 80 kg, the observed median body weight in nivolumab 
treated cancer patients. Using a PPK model, the overall distributions of nivolumab exposures (Cavgss, 
Cminss, Cmaxss, and Cmin1) are comparable after treatment with either 3 mg/kg or 240 mg nivolumab. The 
predicted range of nivolumab exposures (median and 90% prediction intervals) resulting from a 240 mg flat 
dose across the 35 to 160 kg weight range is maintained well below the corresponding exposures observed 
with the well tolerated 10 mg/kg nivolumab Q2W dosage. Across the various tumor types in the clinical 
program, nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and the 
relationship between nivolumab exposure produced by 3 mg/kg and efficacy and safety has been found to 
be relatively flat. Given the similarity of nivolumab PK across tumor types and the similar exposures 
predicted following administration of 240 mg flat dose compared to 3 mg/kg Q2W regimen, it is expected 
that the safety and efficacy profile of 240 mg Q2W nivolumab will be similar to that of 3 mg/kg nivolumab. 
Hence, a flat dose of 240 mg nivolumab has been incorporated into the oncology clinical studies. 
 
 
2.4 Sterotactic Body Radiation Therapy (SBRT) 
 
SBRT is an important recent advance in the treatment of localized pancreatic cancer. While studies using 
conventional chemoradiation for non-metastatic pancreatic cancer have had conflicting results, SBRT is a 
contemporary form of RT that involves a short course of radiation delivered at a higher dose than 
conventional RT. Studies of SBRT have been encouraging and suggest that it can cause tumor regression 
away from involved vasculature, thereby improving the chances of negative surgical margins. Importantly, 
because the radiation course is short, the potential for delay of definitive surgery is reduced. 
 
Additionally, shorter courses of radiation may be immunologically preferential, resulting in acute rather 
than chronic antigen exposure and thereby reducing T cell anergy, exhaustion, and senescence. 
 
2.4.1 
Clinical Data to Date 
Results of SBRT in patients with LAPC are encouraging. Early phase I/II studies using single-fraction 
SBRT (25 Gy in 1 fraction) demonstrated excellent freedom from local progression (FFLP) at 1 year 
(>90%) and minimal acute toxicity in patients with locally advanced disease, but resulted in high late 
grade 2-4 gastrointestinal (GI) toxicity[40-42] [43, 44]. A single-arm phase II multi-institutional study to 
determine whether gemcitabine with fractionated SBRT (in 5 fractions of 6.6 Gy, total 33.0 Gy) would 
achieve reduced late grade 2-4 GI toxicity compared with a historical cohort of patients treated with 
gemcitabine and a single 25 Gy-fraction of SBRT was subsequently conducted.[45] Forty-nine LAPC 
patients received up to 3 doses of gemcitabine (1,000 mg/m2) followed by a one-week break and SBRT 
(33.0 Gy in 5 fractions). Following SBRT, patients continued gemcitabine until progression or toxicity. 
Rates of acute and late (primary endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% 
and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT 
(67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant 
improvement in pancreatic pain (P<.001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. Median 
plasma CA19-9 was reduced following SBRT (median time post-SBRT 4.2 weeks, 220 vs. 62 U/mL, 
p<0.001). Median overall survival was 13.9 months (95% CI, 10.2-16.7). FFLP at 1 year was 78%. Four 
patients with LAPC at diagnosis (8%) underwent margin- and node-negative resections. 


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2.4.2 
Dose Rationale 
At this time, there is no clear consensus regarding an optimal fractionation schedule for patients with 
locally advanced pancreas cancer.[40, 46] To date, Stanford has treated more than 150 patients with 
SBRT, and this treatment has resulted in local control rates of >90% with acceptable acute GI toxicity. A 
single fraction of Linac-based SBRT (25 Gy x 1) has resulted in excellent tumor control. However, close to 
50% of these patients developed late grade 2-5 duodenal toxicity within one year, primarily because of   
the proximity of the duodenum to the pancreas. Delivering hypofractionated radiation (5 or 6.6 Gy over 5 
days) instead of single fraction treatment appears to result in similar tumor control with less late toxicity 
(≤20%) [45, 47-49] 
 
Using the linear-quadratic formulation, the biologically equivalent dose (BED) of the proposed 
fractionation schedules are given in comparison to other commonly used schemes (Table 3). The 
proposed 6.6 Gy x 5 schedule (BED early/late 54.8/105.6) closely approximates that of standard 
chemoradiation (BED early/late 60/83.3), but without concurrent chemotherapy and treating a smaller 
tumor margin (0.3 cm vs. ~2 cm). Furthermore, the proposed 6.6 Gy x 5 fractionation schedule has a 
much lower late BED (105.6 vs. 146.7) with a similar early BED (54.8 vs. 70) as the previous 40 Gy x 5 
regimen. In this study, we will refine our current understanding of radiation tolerance of the pancreas and 
adjacent organs. 
 
Table 3: Estimated biological equivalent dose (BED) of Fractionation Schedules 
 
 
The dose 6.6 Gy x 5fx has been shown to be safe and effective in the treatment of LAPC and is a 
commonly used regimen for the delivery of SBRT. Furthermore, it approximates the pre-clinical model 
we have used which employed 3 doses of 6 Gy at 48-hour intervals. 


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2.5 
Rationale 
 
2.5.1 
Rationale for Study Population and Interventional Treatment 
Pancreatic cancer remains a deadly malignancy despite incremental gains made with the increased use 
of multi-agent chemotherapy in the metastatic setting. Disease in the localized setting remains the optimal 
opportunity to improve the number of patients cured of this deadly disease. Surgery continues to provide 
the best opportunity for cure, but only 15-20% of patients with pancreatic cancer present with upfront, 
resectable disease.[2] However, even with the integration of multi-agent chemotherapy, gains have 
remained modest. In resectable disease, the addition of capecitabine to gemcitabine in the postoperative 
setting has improved median survival from 25.5 months to 28 months.[50] Given the majority of patients 
present with advanced disease, with 30-40% having locally advanced unresectable disease and median 
overall survival of 15-16 months, there is certainly need for improved therapy[2]. Treatment for LAPC 
most commonly involves either chemotherapy alone or combined with radiation therapy(RT). What has 
been demonstrated is that patients with LAPC who can be downstaged and undergo R0 resection have a 
significant improvement in overall survival. However, conventional chemoradiation converts less than 
10% of patients with locally advanced disease to resectable.[10] If the tumoricidal effects of radiation can 
be augmented then higher R0 resection rates may be achieved and in turn, improved survival rates. We 
hypothesize that the clinical efficacy of RT in pancreatic cancer is limited by its promotion of 
innate and adaptive immune suppression and CSF1R blockade with cabiralizumab combined with 
PD-1 blockade with nivolumab will enhance the efficacy of SBRT by reprogramming the TAM 
compartment in tumors, thereby preventing an immune suppressive phenotype and augmenting 
T-cell mediated anti-tumor response. 
 
Immunosuppressive effect of radiation in pancreatic cancer: 
In preclinical model systems with an intact tumor microenvironment, we have shown that RT in pancreatic 
cancer leads to marked immune suppression within the tumor microenvironment (TME) via expansion of 
immune suppressive tumor associated macrophages (TAMs)[51]. Phenotypic analysis of TAMs from a 
pre-invasive pancreatic model (p48Cre;LSL-KrasG12D, KC mice) treated with12Gy RT, demonstrated a 
reduction in iNos, Irf5, and H2eb1 expression but upregulation in Arg1, consistent with M2-like 
macrophage differentiation. Further, RT increased STAT3 phosphorylation, diminished MHCII expression 
in TAMs, and increased TAM expression of CD206, PD-L1, and CSFR1, but modestly diminished CD40 
expression (Figure 9). 
 
 
 
 Figure9:RTincreasesTAMinfiltrationandinducesM2-polarizationinpre-invasivePDA.
 
 
(a) KC mice underwent pancreas-directed RT or sham treatment at 6 weeks of life and pancr 
were assayed 3 days later (n=10/group). IHC on paraffin-embedded pancreatic sections 
performed using mAbs directed against CD45+-pan leukocytes, F480+ cells, and Arg1+ c 
Cellular infiltrates were quantified by examining 10 HPFs per slide. (b) mRNA levels of iNos,
H2Eb1, and Arg1 were tested in RT- or sham-treated pancreata by nanostring assay. (c) ST
phosphorylation was evaluated by western blotting. (d) Gr1–F4/80+ cells in sham- and RT-tre 
pancreata from KC mice were gated and tested for co-expression of CD11b and MHCII.
fraction of Gr1– F4/80+CD11b+ TAMs expressing MHCII was quantified. (e) Gr1–F4/80+CD1 
TAMs from sham or RT-treated KC pancreata were gated by flow cytometry and tested 
expression of CD206, PD-L1, CSFR1, and CD40. Representative histogram overlays are sho 
MFIs are indicated for each respective treatment group. 


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A similar increase in M2 polarized TAMs following RT was also seen in an invasive model of pancreatic 
cancer with KPC-derived orthotopic pancreatic tumors (p48Cre;LSL-KrasG12D;LSL-Trp53R172H , KPC 
mice).(Figure 10) 
 
Figure 10: RT increases infiltration of 
TAMs and induces M2-like polarization 
in invasive PDA. 
The fraction of Gr1–F4/80+CD11b+ TAMs among CD45+ leukocytes in 
the TME was determined by flow cytometry. TAMs were then gated and 
tested for expression of MHC II, CD204, and CD206. Representative 
contour plots and summary data are shown. 
 
This M2 reprogramming was also 
observed when invasive tumors 
were treated with fractionated RT given as 3 doses of 6 Gy at 48 hour intervals. It was then shown that 
this change in TAM infiltration and M2-phenotype was modulated by RT-induced expression (about 5 
fold) of M-CSF from pancreatic tumor cells (Figure 11). 
 
Figure 11: RT-induced M-CSF expression from pancreatic tumor cells. 
 
 
 
 
 
Furthermore, blockade of M-CSF reduced TAM infiltration in RT treated pancreatic tumors and reversed 
their M2 reprogramming (Figure 12). 
 
Figure 12: M-CSF blockade mitigates the M2 macrophage reprogramming associated with RT. 
 
 
 
Next, we demonstrated that blockade of M-CSF enhanced the anti-tumor efficacy of RT in invasive 
pancreatic cancer (Figure 13). 
 
 
 
 
a) qPCR for CSF1 was performed on RT- 
and sham-treated orthotopic PDA tumors on 
day 3 after RT (n=3/group). (b) IHC for M- 
CSF was performed on day 3 in pancreata of
irradiated 
and 
sham-treated 
KC 
mice 
(n=3/group). 
 
 
WT mice were orthotopically implanted with KPC- 
derived tumors and cohorts were treated with tumor- 
focused RT or sham-treated at 18 days. Select cohorts
were additionally treated with a neutralizing α-M-CSF
mAb. Mice were sacrificed on day 21 and tested for the 
fraction of tumor infiltrating Gr1–F480+CD11b+ TAMs.
Further, TAMs were then gated and tested for MHCII,
CD204, and CD206 expression. 


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Figure 13: M-CSF blockade enhances the effect associated with RT 
 
 
 
Finally, we showed that RT induced M2-polarized macrophages induce T cell anergy and ineffectual 
adaptive immunity, thereby limiting the efficacy of RT treatment. This was able to be reversed using 
concurrent blockade of M-CSF with RT to prevent the generation of tumor promoting T cell populations and 
increase the therapeutic effect of RT (Figure 14). 
 
Figure 14: RT programs tumor-infiltrating T cells in invasive PDA into tumor promoting entities in an 
M-CSF dependent manner 
 
 
 
 
These observations highlight the necessity to reprogram macrophages toward an M1- like phenotype to 
overcome the immunosuppression and resultant tumor regrowth after RT. The early infiltration of M2- 
polarized TAMs following RT, leads to a T-cell suppressive response. Besides directing CD4+ T-cell 
differentiation toward a Th2 or Treg phenotype, tumor-infiltrating myeloid cells can also induce apoptosis or 
exhaustion in tumor-specific cytotoxic T lymphocytes via PD-L1– PD1 ligation. We found that RT induces 
up-regulation of PD-L1 in PDA-infiltrating TAMs, which is potentially another mode of immune suppression 
that can account for radioresistance in PDA. A similar finding has been demonstrated by Twyman-Saint 
Victor et al. in which they show that RT alone has only modest efficacy in PDA cell lines implanted in the 
flank, but combination therapy with PD-1 and CTLA4 inhibition offers impressive tumor protection.[11] 
Similarly, in models of colorectal and breast cancer, RT has been shown to up-regulate 
 
WT mice were orthotopically implanted with KPC- 
derived tumors and cohorts were treated with tumor- 
focused RT or sham-treated at 18 days. Select cohorts
were additionally treated with (D) a neutralizing α-M- 
CSF mAb or (E) a 
neutralizing α-F4/80 mAb.
Representative photographs of PDA tumors, average 
tumor weights, and tumor volumes 
are shown 
(n=12/group). 
(a) Sham- or RT-treated orthotopic KPC-derived tumors were assayed on day 3 after 
treatment for the fraction of tumor-infiltrating CD3+ T cells the CD4:CD8 T cell ratio,
and the fraction of tumor-infiltrating Tregs. (b) Select cohorts of sham- or RT-treated 
orthotopic KPC-derived tumors were additionally treated with a neutralizing α-M-CSF
mAb and tested for the fraction of tumor-infiltrating CD3+ T cells and (c) 
CD4+CD25+FoxP3+ Tregs on day 3 after treatment (n=10/group; *p<0.05, **p<0.01). 
(d) WT mice were administered a subcutaneous injection of Pan02-derived tumor +
PBS, Pan02 cells + T cells harvested from day 21 sham-treated orthotopic KPC- 
derived PDA (10:1 ratio), or Pan02 cells + T cells harvested from RT-treated PDA.
Animals were sacrificed on day 35 and subcutaneous tumors harvested.
Representative images of tumors from each treatment cohort, average tumor weight,
and tumor volume are shown (n=5/cohort). (e) WT mice were administered a 
subcutaneous injection of KPC-derived tumor cells + PBS,  KPC cells + T cells 
harvested from sham-treated KPC-derived PDA (10:1 ratio), KPC cells + T cells 
harvested from αM-CSF-treated PDA, KPC cells + T cells harvested from RT-treated 
PDA, or KPC cells + T cells harvested from αM-CSF + RT-treated PDA. Animals were 
sacrificed at day 17 & subcutaneous tumors were weighed (n=5/cohort; *p<0.05). 


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PD-L1 on myeloid cells, whereas the efficacy of radiation is synergistically enhanced when combined with 
blockade of the PD-L1– PD1 axis.[12] These reports highlight a fundamental and seemingly paradoxical 
principal of immunotherapy: accentuating immune suppression by RT-induced up-regulation of PD-L1 can 
enhance the therapeutic efficacy of immunotherapeutics targeting PD-L1 or PD1. Similarly, our data imply 
that although αMCSF immunotherapies have only modest efficacy in absence of RT, it can impressively 
diminish tumor growth when combined with RT. Hence, RT may enhance the therapeutic efficacy of 
immunotherapy not only via the mechanisms discussed here, but also through modulation of the immune 
contexture of the TME, which provides targets for immunotherapeutic manipulation. Therefore, in order to 
improve the effect of radiation therapy by preventing an immune suppressive phenotype and augmenting 
T-cell mediated anti-tumor response, we propose to investigate the combination of cabiralizumab, 
nivolumab and radiotherapy in the treatment of locally advanced pancreatic cancer 
 
 
 
2.5.2 
Rationale for Correlative Science 
 
2.5.2.1 
Determination of Pharmacodynamic Biomarkers 
 
Plasma levels of CSF1 are a measure of cabiralizumab target engagement. CSF1 is cleared from 
circulation under normal physiological conditions by macrophages (primarily liver Kupffer cells) via 
CSF1R-mediated endocytosis and intracellular degradation.[52] Cabiralizumab binds to and blocks 
CSF1R, resulting in a large, rapid increase in circulating CSF1 concentration, after which CSF1 levels 
reach a new steady state. Prior studies measuring both CSF1 and IL34 in the serum from all subjects 
receiving cabiralizumab demonstrated results comparable to what was observed in nonclinical studies: 
marked by a rapid and sustained elevation of serum CSF1R ligands that was restored to baseline upon 
clearance of cabiralizumab. The data show that a minimum biological effect occurred at 5 μg/mL, and a 
half-maximal response (EC50) was 8 μg/mL cabiralizumab. In this study plasma levels of CSF1 will be 
measured at multiple timepoints to determine target engagement by carbiralizumab at administered dose. 
 
Another measure of target engagement by cabiralizumab are noncalssical CD16+ monocytes. 
Nonclassical CD16+ monocytes are dependent on CSF1R signaling for survival and/or differentiation and 
are reduced upon CSF1R inhibition. Nonclassical CD16+ monocyte levels in peripheral blood have been 
or are being assessed in all three clinical studies with cabiralizumab as pharmacodynamic markers of 
CSF1R inhibition. In general across all three studies, cabiralizumab treatment results in a transient 
increase in nonclassical CD16+ monocytes at four hours followed by complete reduction, to the limits of 
the assay, by 72 hours. The duration of nonclassical CD16+ monocyte reduction is dose and 
concentration dependent and levels return to normal once drug has decreased below approximately 10 
μg/mL. Cabiralizumab does not reduce classical CD16- monocyte levels. In this study blood will be 
serially collected for flow cytometry analysis to monitor monocyte subsets over time. 
 
 
2.5.2.2 
Treatment effect on innate and adaptive immunity 
 
We and others have shown that the volume of CD8+ T cells in the pancreatic tumor microenvironment 
(TME) correlates with a favorable outcome as does a high CD8+/CD4+ratio.[53-55] Furthermore, CD8+ T 
cells and Th1-polarized CD4+ T cells have anti-tumor properties, whereas the Th2, Treg, and Th17 CD4+ 
T cell subsets are pro-tumorigenic in human and murine pancreatic cancer. T cell cytotoxic potential can 
be inferred from their expression of activating receptors. Our experiments will measure the effects of 
CSF1R and PD-1 blockade in combination with SBRT on T cell subset infiltration, differentiation, and 
activation by comparing pre- and on- treatment biopsies. We will measure pathologic response, 
characterized by degree of tumor necrosis as previously described.[56] Changes in immune infiltrate will 
be assessed by IHC against the following markers including, but not limited to, CD3, CD4, CD8, Foxp3, 
PD-1, PD-L1, Granzyme B, CD68, CD163, ARG1 and iNOS. 


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The relative composition and function of the tumor and its immune infiltrate before and on treatment will 
be further elucidated using a novel 3-D microfluidic system (patient-derived organotypic tumor spheroids 
(PDOTS), pioneered by the Wong lab, that allows for ex vivo culture of organotypic spheroids freshly 
isolated from patient or murine tumors, which contain autologous tumor-infiltrating myeloid and lymphoid 
immune cells.[57] They have recently shown that this system can predict therapeutic responses to 
checkpoint blockade by observing tumor cell killing. Additionally, the microfluidic nature of the device 
allows for the accurate quantification of cytokine release, providing a quantitative assessment of early 
immune activation. By using this 3D microfluidic culturing system, the Wong lab has performed proof-of- 
principle studies in a large collection of human tumors to successfully create PDOTS (including primary 
human PDAC) as well as have shown that murine-derived organotypic tumor spheroids (MDOTS) derived 
from various models can respond to checkpoint blockade. After culturing, we can quantify total immune 
cells (CD45+), viable cells (Calcein) among total cells (Hoechst 32242). This data serves as proof-of- 
principle that the MDOTS/PDOTS system is a viable method for assessing the anti-tumor immune 
response ex vivo. We will utilize the PDOTS system to evaluate both before and after treatment, the 
immune responses using various readouts, including viability, and cytokine/chemokine secretion changes 
to determine changes in the tumor cells as well as infiltrating immune cells in the tumor 
microenvironment. PDOTS will be derived from the pre- and on-treatment biopsies as well as from those 
tumors which undergo surgical resection. This will allow us to understand the biology and therapeutic 
implications of remaining viable tumor cells as well as the effects of the changes in the TME such as 
alterations in the populations of immune cells. Freshly collected biopsy specimens from patients will be 
partially digested into organoids and loaded into 3D microfluidic devices and treated with the therapeutic 
combinations in the accompanying clinical trial. These biopsy samples will be also evaluated for immune 
composition profiles by flow cytometry prior to the ex vivo treatment (immune profiling – above). After the 
treatment, spheroids will be stained for AO/PI live/dead staining, to quantify cell death. Furthermore, we 
will quantitatively profile the secreted chemokines/cytokines production in these same conditions using 
the multiplex Luminex platform at different time points after treatments. Changes in various types of 
immune cells, including T cell activation/expansion, such as Th1 cytokines responding to type I interferon 
(IFNγ, CXCL9, CXCL10, IL-12, etc.), and those related to effector T cells function versus T regulator cells 
expansion (IFNγ, IL-2, TGF-β, IL-10, etc.) will be evaluated. For myeloid cells, we will focus on those 
involved in inflammation and myeloid activation (IL6, IL-1β, Flt-3L, G-CSF, GM-CSF etc.) versus 
immunosuppression (CCL2, CXCL1, CCL22, PDGF, IL-10 etc.). Based on the generated data, we will 
further evaluate detailed changes of different immune cell populations using high-throughput single cell 
RNA transcriptomic quantification platform 10x genomics, which will be run at the NYU Genome 
Technology Center. Different immune populations will be identified based on the transcriptional 
signatures using unsupervised density based clustering on t-Distributed Stochastic Neighbor Embedding 
(t-SNE) analysis. This will be used to further evaluate key immune populations and signaling pathways 
that respond to the treatment. 
 
Despite the recent success of checkpoint blockade-based monotherapy in human melanoma and 
non-small cell lung cancer (NSCLC), many patients do not experience durable clinical benefit.[58] 
Nevertheless, recent evidence suggests that even in the absence of clinical response, most melanoma 
and NSCLC patients receiving anti-PD-1 do mount a biologic response that is detectable in the 
periphery.[59, 60] Furthermore, we have previously shown that changes in immunogenicity in the 
pancreatic tumor microenvironment is reflected to a lower extent in the systemic immune circulation.[61] 
Patients who fail treatment despite this response often have substantial tumor burden requiring a 
reinvigoration beyond that provided by nivolumab alone. It is conceivable then that in this study of 
patients with LAPC, some patients may mount an inflammatory immune response to cabiralizumab, 
nivolumab and SBRT detectable in the periphery without evidence of tumor response. These patients 
might benefit from agonistic or alternative checkpoint immunotherapies. Moreover, it may be possible to 
identify early biomarkers of response to be utilized in patients who might benefit from combination 
therapy. Given this possibility, we will collect blood specimens from enrolled subjects at multiple pre- 
specified time points. Flow cytometry will be performed on isolated leukocytes for a panel of established 
markers including, but not limited to, CD45, CD56, CD3, CD8, CD4, CD45RA, CD45RO, CCR7, CD27, 
PD-1, CTLA-4, PD-1, TIM3, LAG3, 2B4, CTLA-4, Tbet, Eomes, Foxp3, Gata-3, Rort, CD38, Ki-67, 
CD33, CD14, CD15, HLA-DR, CD11b, CD11c, CD80, CD86, CD36 and CD206. Serum cytokines IFN-, 
TNF,  IL-17,  IL-10,  IL-4,  IL-1,  and  IL-6  will  be  measured  by  cytometric  bead  array  (CBA).  The 


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characteristics of various immune subsets present in blood corresponding to baseline, treatment with dual 
immunotherapy and SBRT plus dual immunotherapy can be compared to distinguish the contribution of 
each treatment modality in the peripheral immune response. Moreover, we will correlate the degree of 
response in the periphery measured by fold change in inflammatory and differentiation markers to 
baseline tumor characteristics including size and nodal status as well as the degree of pathologic and 
radiographic response. 
 
 
 
2.6 Potential Risks & Benefits 
 
2.6.1 
Known Potential Risks 
 
2.6.1.1 
Cabiralizumab 
The following paragraphs explain the side effects that have been observed when cabiralizumab was 
given alone. 
 
The most common side effects of cabiralizumab (occurring in 10% or more of the patients): 
 
• 
Increased blood level of an enzyme (creatine phosphokinase) from muscle damage 
• 
Increased blood level of liver enzymes (asparate aminotransferase, alanine aminotransferase, 
and gamma-glutamyltransferase) associated with liver function 
• 
Swelling (also called edema) including swelling of eye/eyelid, face, arms, legs and/or localized to 
some part of the body 
• 
Skin problems including itching and/or rash (discolored area and/or raised bumps) 
• 
Fatigue and tiredness 
• 
Increased blood level of fat-digesting enzyme (lipase) 
• 
Nausea or the urge to vomit 
• 
Vomiting 
• 
Increased blood level of creatinine (a substance normally eliminated by the kidneys into the urine) 
• 
Decreased appetite 
 
Less common side effects of cabiralizumab in this study (occurred in more than 5% to less than 10% of 
patients): 
 
• 
Increased blood level of an enzyme (lactate dehydrogenase) that helps turn sugar into energy 
• 
Increased blood level of a digestive enzyme (amylase) 
• 
Joint pain 
• 
Increased blood level of a liver or bone enzyme (alkaline phosphatase) 
• 
Lack of enough red blood cells (anemia) 
• 
Increased blood level of a liver pigment (bilirubin) often a sign of liver problems 
• 
Inflammation of the lungs that may cause difficulty breathing and can be life-threatening 
• 
Decreased blood level of magnesium 
 
Most of the above less common reported events were mild, and resolved on their own without treatment. 
 
There may be side effects that we cannot predict and in some cases they may be serious, long-lasting, or 
fatal. 


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2.6.1.2 
Nivolumab 
Frequently reported categories of adverse events in clinical studies of nivolumab are listed below: 
 
Likely 
• 
Fatigue 
 
Less Likely 
• 
Anemia 
• 
Adrenal insufficiency 
• 
Endocrine disorders (hypophysitis) 
• 
Hyperthyroidism 
• 
Hypothyroidism 
• 
Uveitis 
• 
Abdominal Pain 
• 
Colitis 
• 
Diarrhea 
• 
Dry mouth 
• 
Nausea 
• 
Pancreatitis 
• 
Fever 
• 
Infusion-related  reaction 
• 
Injection site reaction 
• 
Increased alanine aminotransferase 
• 
Increased aspartate aminotransferase 
• 
Increased blood bilirubin 
• 
Increased creatinine 
• 
Increased lipase 
• 
Decreased lymphocyte count 
• 
Decreased neutrophil count 
• 
Decreased platelet count 
• 
Increased serum amylase 
• 
Anorexia 
• 
Arthralgia 
• 
Pleural effusion 
• 
Pneumonitis 
• 
Pruritis 
• 
Rash (maculo-papular) 
• 
Skin hypopigmentation 
• 
Sweet’s syndrome 
 
Rare but serious 
• 
Cardiomyopathy 
• 
Myocarditis 
• 
Pericardial tamponade 
• 
Pericarditis 
• 
Diplopia 
• 
Graves  ophthalmopathy 
• 
Optic neuritis retrobulbar 
• 
Colonic perforation 
• 
Gastritis 
• 
Allergic reaction 
• 
Autoimmune disorder 
• 
Cytokine release syndrome 


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• 
Sarcoid granuloma 
• 
Hyperglycemia 
• 
Diabetes mellitus with ketoacidosis 
• 
Polymyositis 
• 
Rhabdomyolysis 
• 
Myositis 
• 
Encephalopathy 
• 
Facial nerve disorder 
• 
Demyelination myasthenic syndrome 
• 
Encephalitis 
• 
Guillain-Barre  syndrome 
• 
Meningoencephalitis 
• 
Meningoradiculitis 
• 
Myasthenia gravis 
• 
Myasthenic syndrome 
• 
Peripheral motor neuropathy 
• 
Peripheral sensory neuropathy 
• 
Acute kidney injury 
• 
Bronchiolitis obliterans with organizing pneumonia 
• 
Erythema multiforme 
 
 
 
2.6.1.3 
SBRT 
Because of the short duration of treatment, acute side effects of SBRT typically occur after 
completion of treatment, but not during the course of radiation. 
 
• 
Fatigue, acute and mild 
• 
Dermatitis (skin irritation, redness, itchiness, discomfort), acute and mild 
• 
Asymptomatic, temporary changes in blood work (decrease in blood counts, increase in 
liver enzymes) 
• 
Nausea 
• 
Vomiting 
• 
Diarrhea 
• 
Weight loss 
• 
Anorexia 
• 
Abdominal pain 
• 
Gastric, esophagus, small bowel or large bowel irritation/ulceration, bleeding, fistula, 
obstruction or changes in motility following therapy 
• 
Chest wall pain 
• 
Indigestion 
• 
Radiation fibrosis 
• 
Liver damage 
• 
Kidney damage 
• 
Late second malignancy 
• 
Delayed wound healing 
 
 
 
2.6.2 
Other Risks of Study Participation 
 
Additional risks associated with participation in this study, include the risk of phlebotomy and breach of 
confidentiality. Risks associated with phlebotomy include weaknesses, redness, pain, bruising, bleeding, 


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or infection at the needle site. Privacy protection procedures are in place and good clinical practice 
guidelines are followed for the study to minimize risks associated with research procedures and 
participation. 
 
2.6.3 
Known Potential Benefits 
Blockade of CSFR-1 with cabiralizumab and PD-1 with nivolumab may enhance the efficacy of SBRT in 
LAPC by preventing an immune suppressive phenotype and augmenting T-cell mediated anti-tumor 
response. As a result, a more effective local therapeutic modality may improve R0 resection rates and 
therefore improve survival rates. In addition, some subjects may develop memory T cells that can exert 
long-term anti-tumor effects even after patients are off treatment, which may lead to possible long term 
survival of the participants. 
 
It is possible that some study subjects who receive the study therapies may experience an improvement   
in their pancreatic cancer during the study. However, if the patient receives such benefit, because the 
study therapy is not FDA-approved for pancreatic cancer, the study doctor cannot prescribe it after he/she 
finishes the study. Also, patients may not get any benefit from being in this research study. Others with 
pancreatic cancer may benefit in the future from what is learned in this study. 
 
 
3 Objectives and Purpose 
3.1 Primary Objectives 
1) 
To determine the safety and tolerability of combined cabiralizumab, nivolumab and radiotherapy in 
the treatment of locally advanced pancreatic cancer. 
 
2) 
To estimate the R0 surgical resection rate following treatment with combined cabiralizumab, 
nivolumab and radiotherapy in subjects with locally advanced unresectable pancreatic cancer. 
 
 
3.2 Secondary Objectives 
1) 
To evaluate preliminary anti-tumor activity of combined cabiralizumab, nivolumab and radiotherapy 
in subjects with locally advanced unresectable pancreatic cancer. 
 
 
 
3.3 Exploratory Objectives 
1) 
To  evaluate  the  pharmacodynamic  (PD)  effect  of  the  combination  regimen  on  biomarkers  in 
peripheral blood samples and tumor biopsy specimens. 
 
2) 
To evaluate the effect of cabiralizumab, nivolumab and radiotherapy on innate and adaptive 
immunity in peripheral blood samples and tumor biopsy specimens. 
 
 
 
4 Study Design and Endpoints 
4.1 Description of Study Design 


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This is a multi-center, single arm, open label Phase II interventional study of cabiralizumab, nivolumab and 
SBRT in subjects with locally advanced unresectable pancreatic cancer. The study will consist of 3 
periods: Screening (up to 4 weeks), Treatment (up to 2 years), and Survival Follow-up (up to 60 months 
after final subject completes treatment). Subjects will be enrolled into the study following completion of 2- 6 
months of multi-agent chemotherapy (gemcitabine/nab-paclitaxel or FOLFIRINOX) with documentation of 
stable or responsive disease. Subjects will undergo baseline imaging to confirm locally advanced 
unresectable disease as defined by NCCN Guidelines 3.2017. Core baseline tissue biopsies will be 
obtained at time of endoscopic fiducial placement. Cabiralizumab and nivolumab will be administered on 
D1 of a 14 day cycle. SBRT will commence on D8 and be administered as 6.6 Gy x 5 consecutive 
fractions. Patients will have a biopsy, then restaging imaging will be performed 4 weeks after initiation of 
treatment Subjects will continue on treatment with cabiralizumab and nivolumab every 2 weeks and 
subsequent imaging will then be conducted every 8 weeks at which time participants will be evaluated 
with CT chest, abdomen and pelvis for response based on RECIST 1.1 criteria and potential for surgical 
resection. If at any response assessment, tumor is deemed resectable, subject may discontinue 
cabiralizumab and nivolumab and proceed to definitive surgical resection. A total of 6  subjects will be 
included in the preliminary safety cohort. The 6 subjects will be monitored for up to 6 weeks before 
additional subjects may be treated. Unacceptable toxicities will be assessed during this time.(see section 
7.3) If there are fewer than three unacceptable toxicities in the first 6 subjects enrolled,   then study will 
proceed to the expansion phase with an additional 14 subjects. If more than 2 of the first 6 subjects 
experience an unacceptable toxicity, enrollment will be paused and different doses/schedules considered 
in collaboration with study sponsor and BMS. 
 
Subjects who withdraw from the study during the initial 42 days for reasons other than an unacceptable 
toxicity  will be replaced. No dose escalations or de-escalations are permitted within each subject’s 
treatment. Cabiralizumab dose adjustments are allowed if there has been +/- 10% weight change since 
the previous treatment. 
 
 
 
4.2 Study Endpoints 
 
4.2.1 
Primary Study Endpoints 
1) Adverse events will be graded according to the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE v. 5.0). Unacceptable toxicity will be assessed during the first 42 days of 
treatment. (see section 7.3) 
 
2) R0 resection rate, determined by blinded pathologic assessment. 
 
 
4.2.2 
Secondary Study Endpoints 
1) Overall response rate 
2) Progression free survival rate 
3) Overall survival rate 
4) Distant metastasis free survival rate 
 
RECIST 1.1 assessments will be used to determine overall response rate, distant metastasis free survival 
rate, and progression free survival. 
 
5) Plasma  and  tissue  levels  of  CSF1  measured  at  multiple  time  points  to  determine  target 
engagement by carbiralizumab 
6) Nonclassical CD16+ monocyte levels in peripheral blood and tissue measured at multiple time 
points to determine target engagement by carbiralizumab 


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4.2.3 
Exploratory Endpoints 
 
Immune changes within blood and tissue following treatment and correlation with clinical endpoints 
 
5 Study Enrollment and Withdrawal 
5.1 Inclusion Criteria 
Participants must meet the following criteria on screening examination in order to be eligible to participate 
in the study: 
 
5.1.1 
Histologically confirmed locally advanced, unresectable pancreatic cancer as defined by 
NCCN Guidelines 3.2017 
 
 
Locally advanced unresectable disease is defined by the NCCN as: 
• 
Tumors of the head that have greater than 180 degrees of SMA encasement or any 
celiac abutment, unreconstructable SMV or portal occlusion, or aortic invasion or 
encasement. 
• 
Tumors of the body with SMA or celiac encasement of greater than 180 degrees, 
unreconstructable SMV or portal occlusion, or aortic invasion. 
• 
Tumors of the tail with SMA or celiac encasement of greater than 180 degrees. 
Irrespective of location, all tumors with evidence of nodal metastasis outside of the 
resection field are deemed unresectable. 
 
 
5.1.2 
Age > 18 years 
 
5.1.3 
Patients must agree to pretreatment and on treatment tumor biopsy 
 
5.1.4 
ECOG performance status of 0 or 1 
 
5.1.5 
Completion of at least 2 months, but no more than 6 months of standard induction 
chemotherapy for LAPC, which must include either FOLFIRINOX or gemcitabine and nab- 
paclitaxel, preferably within 2-4 weeks but no longer than 8 weeks. 
 
 
5.1.6 
Normal organ and marrow function as defined below: 
 
• 
absolute neutrophil count ≥ 1,500/mm3 
• 
platelets ≥ 100,000/mm3 
• 
total bilirubin ≤ 1.5 x institutional upper limit of normal (except participants with Gilbert’s 
syndrome who must have normal direct bilirubin) 
• 
AST(SGOT) and ALT(SGPT) ≤ 2 × institutional upper limit of normal 
• 
creatinine 
≤ 1.5 mg/ dL 
OR 
• 
creatinine clearance≥ 30 mL/min (as estimated by Cockcroft Gault Equation) 
 
(140 - age [yrs]) (body wt [kg]) 
Creatinine clearance for males = ———————————— 
(72) (serum creatinine [mg/dL]) 
Creatinine clearance for females = 0.85 x male value 


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5.1.7 
Ability to understand and sign a written informed consent document. Participant must have 
willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and 
other study procedures. 
 
 
5.1.8 
 Women of childbrearing potential (WOCBP) must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the 
start of study treatment. 
 
5.1.9 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study treatment(s) and for a total of 5 months post-treatment completion. 
 
5.1.10 
Males who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception (see appendix 1) for the duration of treatment with study treatment(s) and 
for a total of 7 months posttreatment completion. In addition, male participants must be 
willing to refrain from sperm donation during this time. 
 
 
 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
5.2.1 
Resectable, borderline resectable or metastatic disease 
5.2.2 
Medical history and concurrent disease as below: 
 
 
• 
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14  
days of study treatment administration except for adrenal replacement steroid doses > 10 
mg daily prednisone equivalent in the absence of active autoimmune disease. 
Note: Treatment with a short course of steroids (< 5 days) up to 7 days prior to initiating 
study treatment is permitted. 
• 
Interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected treatment-related pulmonary toxicity. 
• 
Current or history of clinically significant muscle disorders (eg, myositis), recent 
unresolved muscle injury, or any condition known to elevate serum CK levels 
• 
Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following: 
-Myocardial infarction or stroke/transient ischemic attack within the past 6 months 
-Uncontrolled angina within the past 3 months 
-Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes) 
-History of other clinically significant heart disease (eg, cardiomyopathy, 
congestive heart failure with New York Heart Association functional classification 
III to IV, pericarditis, significant pericardial effusion, or myocarditis) 
-Cardiovascular disease-related requirement for daily supplemental oxygen 
therapy. 
• 
Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or 
anti-fungal therapy ≤ 7 days prior to administration of study medication. 
• 
Any uncontrolled inflammatory GI disease including Crohn’s Disease and ulcerative 
colitis. 


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5.2.3 
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. 
 
5.2.4 
Restricted Concomitant Therapies: 
 
a. Concomitant use of statins while on study. However, a patient using statins for over 3 
months prior to study drug administration and in stable status without CK rise may be 
permitted to enroll. 
 
b. Non-oncology vaccine therapies for prevention of infectious diseases (eg, human 
papillomay virus vaccine) within 4 weeks of study drug administration. The  
inactivated seasonal influenza vaccine can be given to patients before treatment and 
while on therapy without restriction. Influenza vaccines containing live virus or other 
clinically indicated vaccinations for infectious diseases (ie, pneumovax, varicella, etc) 
may be permitted, but must be discussed with the principal investigator and may 
require a study drug washout period prior to and after administration of vaccine. 
 
5.2.5 
Known human immunodeficiency virus (HIV), known active hepatitis A, or known hepatitis B or C 
infection. 
 
5.2.6 
History of acute diverticulitis within the last 6 months, or current chronic diarrhea 
 
5.2.7 
Pregnant or lactating women. 
 
5.2.8 
Women of childbearing potential (WOCBP) with either a positive or no pregnancy test (serum 
or urine) at baseline. (Postmenopausal women must have been amenorrheic for at least 
12 months to be considered of non-childbearing potential.) 
 
5.2.9 
WOCBP who are unwilling or unable to use an acceptable method to minimize the risk of 
pregnancy (see appendix 1) for the entire study period and for at least 5 months after the last 
dose of investigational product. WOCBP who are continuously not heterosexually active are 
also exempt from contraceptive requirements, but still must undergo pregnancy testing as 
described in section 5.1.8. 
 
5.2.10 
Sexually active fertile men not using effective birth control if their partners are WOCBP 
 
5.2.11 
History of primary immunodeficiency. 
 
5.2.12 
History of organ allograft or allogeneic bone marrow transplant. 
 
5.2.13 
Any prior radiation therapy, immunotherapy, or biologic (‘targeted’) therapy for treatment of 
the patient’s pancreatic tumor. Patient should have received either FOLFIRINOX or 
gemcitabine and nab-paclitaxel prior to enrollment. 
 
5.2.14 
Treatment for other invasive carcinomas within the last five years who are at greater than 5% 
risk of recurrence at time of eligibility screening. Carcinoma in-situ and basal cell carcinoma/ 
squamous cell carcinoma of the skin are allowed. 


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5.2.15 
Participation in any investigational drug study within 4 weeks preceding the start of study 
treatment. 
 
5.2.16 
Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without 
complete recovery. 
 
5.2.17 
History of allergy to study treatments or any of its components 
 
5.2.18 
Known history of sensitivity to infusions containing Tween 20 (polysorbate 20) and Tween 80 
(polysorbate 80) 
 
 
 
 
 
5.3 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
5.4 Vulnerable Subjects 
 
Vulnerable subjects will not be eligible for enrollment into the study. Locally advanced pancreatic cancer 
does not occur in children, therefore they are excluded. Pregnant women are not included in the study 
given the unknown safety effects of radiation therapy and study drugs to the developing fetus. Prisoners 
or subjects who are involuntarily incarcerated are not eligible. Subjects who are compulsorily detained for 
treatment of either a psychiatric or physical (eg, infectious disease) illness are not eligible as they will be 
unable to adhere to the study timeline. 
 
 
5.5 Strategies for Recruitment and Retention 
The study will be posted on the NYU Perlmutter Cancer Center website and on clinicaltrials.gov. Any 
language that will be used to advertise this study on the NYU Perlmutter Cancer Center Website will first be 
submitted for IRB review and approval prior to posting. The patients who are eligible for this research study 
come directly from the study investigators’ clinical patient population. Thus, the investigators are very 
familiar with their patients’ disease status and potential eligibility given the protocol’s inclusion and 
exclusion criteria. The investigator will approach eligible potential subjects and explain the study in a 
private room, including the reasons why subjects will be eligible, risks, benefits, and the regimes to be 
evaluated. Consent will be obtained in a private room by   the PI, Co-I, or research coordinator/research 
nurse at the time of the subject’s visit prior to any study assessments/procedures. The subjects will be 
given a chance to ask questions to the person consenting him/her and will be able to take the consent 
home to discuss it with family/friends prior to signing. If the subject agrees s/he will sign the consent form 
either at the first contact (if the investigator/delegate is convinced that the subject understands) or at the 
time of a return visit after having had time to study the consent in more depth. Study procedures will not 
begin until after the consent form has been properly obtained. The subject is entitled to decide not to 
participate in the trial, without affecting their right to other medical care, and may discontinue participation 
in the trial at any time without penalty or loss of benefits to which they are entitled. 
 
All efforts will be made to actively recruit and retain women and members of minority groups in this study. 
The inclusion and exclusion criteria in this study should not have a negative effect on the enrollment of the 
desired populations. 
 
Target enrollment for this study is 10-12 patients over 2 years. The target accrual goal is 5-6 patients per 
year at NYU Langone Health. Patients will be recruited from physicians participating in this study. 
Consenting, screening, and treatment will take place at the NYU Langone Health PCC or participating 
sub-sites under the supervision of the Site PI.


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The Principal Investigator will: 
 
1. Obtain signed and dated informed consent from the potential subject before any study specific 
procedures are performed. 
 
2. Determine patient eligibility; see Section 5.1 and 5.2 
 
3. Submit registration to NYU Langone Health Perlmutter Cancer Center CTO 
 
4. Receive registration confirmation from the NYU Langone Health Perlmutter Cancer Center 
CTO, including a unique study identification number assigned to the patient that will be distributed 
to the study team upon registration of the patient. 
 
The informed consent process and documentation follows, established procedures of the NYU Langone 
Health Perlmutter Cancer Center Clinical Trials Office. 
 
 
5.6 Registration Procedures 
 
5.6.1 
General Guidelines 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedure unless a procedure is being performed as part of the patient’s standard of care. 
Enrollment in the study requires that all inclusion and exclusion criteria have been met. Enrollment 
occurs upon confirmation of registration from the NYULH PCC Clinical Trials Office. The following 
materials must be submitted to the CTO for subject registration: 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 
3. All supporting documentation verifying each eligibility criterion has been met 
 
Registration will occur within 48 hours of research coordinator receipt of all of the above documents. A 
written confirmation of enrollment including a unique study identification number assigned by the research 
coordinator will be disbursed to the study team upon registration. 
 
Once eligibility is verified, a unique patient study number will be issued within 24 hours of receiving all 
required registration material. The patient will not be identified by name. This is the point, at which, the 
patient is considered accrued on study. 
 
 
 
5.6.2 
Multi-Site Surveillance 
As the lead investigator in a multi-site trial, the Principal Investigator is responsible for organizing and 
conducting monthly teleconferences with all participating sites. The PI will also be responsible for 
including data from all of the participating sites within the overall trial’s quarterly Data and Safety 
Monitoring report to the DSMC to include minutes from monthly PI teleconferences. Each participating 
site will be responsible for submitting the results and recommendations from the DSMC’s quarterly 


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reviews to their IRB of record at the time of continuing review. Additionally, the NYU Langone Health 
PCC Clinical Trial Office, Quality Assurance Unit will provide remote extensive monitoring including real-
time review of all eCRFs to ensure completeness and compliance with the protocol (100% source 
documentation verification).  Additionally, a first subject audit is to be completed within four weeks of 
enrollment. 
 
5.6.3 
Patient Registrations at Additional Sites 
Enrollment at addition sites can begin once each site’s IRB has approved this protocol, a copy of each 
site’s IRB approval, Citi training certificates, Medical Licenses and signed CVs are provided to NYU 
Langone Health Perlmutter Cancer Center (PCC) Clinical Trials Office. Once, all required documents are 
provided to NYU Clinical Trials Office an activation notification will be sent to the PI and research 
coordinator of that site. Central registration for this study will take place at NYU Langone Health PCC 
Quality Assurance Unit (PCC-QAU@nyumc.org). 
 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedures unless a procedure is being performed as part of the patient’s standard of care. Once a 
patient has signed consent, each site must notify the NYU Langone Health PCC Quality Assurance Unit 
and forward a copy of the signed consent to NYU Langone Health PCC Clinical Trials Office within 24 
hours. 
 
Enrollment in the study requires that all inclusion and exclusion criteria have been met. Enrollment 
occurs upon confirmation of registration from the NYU Langone Health PCC Clinical Trials Office. The 
following materials must be submitted to the Quality Assurance Unit at NYU Langone Health via email 
(PCC-QAU@nyumc.org): 
 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met. 
 
Registration will occur once the Senior Research Nurse for Quality Assurance conducts a central review 
of the submitted materials. Once eligibility is verified, a unique subject study number will be issued within 
48 hours of receiving all required registration material. This number is unique to the participant and must 
be written on all data and correspondence for the participant. The NYU Langone Health PCC CTO will 
return a signed eligibility confirmation worksheet email with the subject’s unique study number. 
 
The subject will not be identified by name. This is the point, at which, the patient is considered accrued 
on study. Protocol treatment should  begin within  designated timeframe; issues  that would cause 
treatment delays should be discussed with the overall PI, Dr. Cohen. All screen failures/ineligible 
subjects, as well as subject’s who withdraw consent prior to initiation of protocol therapy must be 
submitted to the CTO in a manner analogous to the procedures noted above. Applicable source 
documentation will be required within the corresponding submissions. 
 
Subjects must not start any protocol procedures prior to registration; each participating institution will 
order the study agent directly from the supplier, Bristol-Myers Squibb (Nivolumab and Carbiralizumab). 
 
Each site is responsible for reporting all unexpected problems involving risks to participants or others to 
NYU Langone PCC Clinical Trials Office and to their IRB as per site institutional policy. 
 
Please email all SAEs to NYUPCCsafetyreports@nyumc.org, Dr. Cohen, PCC Assigned Medical Monitor, 
and the NYU Langone Health CTO regulatory specialist. 
 
 
5.7 Duration of Study Participation 
 


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Subjects may remain on study therapy for a maximum of 2 years, or until progressive disease (occurring within 
2 years) as 


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determined by RECIST criteria, withdrawal due to toxicity, withdrawal of consent, or at the discretion of 
the investigator. 
 
Subjects tolerating therapy may continue on study until disease progression(when occurring within 2 
years) or eligible for surgical resection. It is well known that patients who receive immunotherapy can 
experience pseudoprogression, which is initial progression of disease based on RECIST 1.1 criteria, but 
later achievement of tumor regression based on RECIST 1.1 criteria. Any patients with no clinical 
deterioration and progression of disease based on RECIST 1.1 criteria are allowed to continue 
treatment until a second scan is done within 6 weeks of the prior scan. If the second scan confirms 
progression of disease by RECIST 1.1, then the patient will be taken off study. 
 
5.8 Total Number of Participants and Sites 
 
There will be 3 sites participating in the study, including NYUMC. A total of 6-22 patients will be enrolled. 
 
 
5.9 Participant Withdrawal or Termination 
 
5.9.1 
Reasons for Withdrawal or Termination 
 
Subjects will be treated until progression, intolerable toxicities or definitive surgical resection; however, if 
the patient does not experience any of the below (listed) reasons, they can be treated for 2 years, and then 
be considered for continuation of treatment beyond 2 years if no excessive toxicities occur and      
following discussion with and approval by the sponsor. If approval is granted, subjects will continue treatment 
and follow-up, all procedural assessments will continue as previously outlined in the study calendar.  A subject has 
the right to voluntarily discontinue study treatment or withdraw from the study at any time, for any reason, 
and without repercussion. The investigator and sponsor have the right to discontinue a patient from study 
treatment or withdraw a patient from the study at any time. 
 
Reasons for subject withdrawal from the study may include, but are not limited to: 
 
• 
Significant noncompliance on the part of the patient 
• 
Refusal of the patient to continue treatment or observations 
• 
Concurrent illness that prevents further administration of treatment 
• 
Disease progression 
• 
Unacceptable adverse events regardless of grade 
• 
Termination of study 
• 
Patient consent withdrawal 
• 
Decision by the investigator that termination is in the participant’s best medical interest 
• 
Unrelated medical illness or complication 
• 
Patient is deceased 
• 
Pregnancy or intent to become pregnant 
 
 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
Participants will be removed from study when any of the following criteria apply: 
• 
Lost to follow-up 


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• 
Withdrawal of consent for data submission 
• 
Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). All patients who withdraw from study drug prematurely will 
undergo end-of-treatment assessments within 30 days after the last dose, if possible. Regardless of the 
reason for withdrawal, effort shall be made to follow safety events from the time of withdrawal through 
resolution or until the event stabilizes. Subjects who discontinue study drugs will continue to be followed 
for adverse events for up to 100 days and for survival every 12 weeks (+/- 1 week) from the date of last 
dose of study drug(s), either in person or by telephone contact, up to 18 months, then every 6 months 
thereafter until the participant’s death or until the participant is lost to follow-up or until study 
closure 
(approximately 60 months after last subject terminates treatment). 
 
 
 
 
 
5.9.2     Handling of Participant Withdrawals or Termination 
Withdrawal from the study can be made in writing to the Principal Investigator, Dr. Deirdre Cohen. Any 
samples/specimens remaining after formal withdrawal, will be destroyed/discarded per Institutional 
guidelines. 
 
 
5.10 Premature Termination or Suspension of Study 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to Dr. Deirdre Cohen, BMS, the IND/IDE sponsor and any 
regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly inform the 
IRB and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the sponsor, IRB and/or FDA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6 Study Agents 
 
Table 4 
Study treatments  
Product 
Description / 
Class and Dosage 
Form 
Potency/Route of 
Administration 
Blinded or 
Open Label 
Packaging / 
Appearance 
Storage 
Conditions 
(Per Label) 
Nivolumab 
(BMS-936558-01) 
Solution for 
Injection 
100 mg 
(10 mg/mL) 
Open label 
Vial 
Refer to the label 
on container 
and/or 
Investigator 
Brochure 
Nivolumab  
(BMS-936558-01) 
Solution for 
Injection 
40 mg 
(10 mg/mL) 
Open label 
Vial 
Refer to the label 
on container 
and/or 
Investigator 
Brochure 
Cabiralizumab 
(BMS-986227) 
Solution for 
Injection 
100 mg 
(20 mg/mL) 
Open label 
Vial 
Refer to the label 
on container 
and/or 
Investigator 
Brochure 
 
6.1 Cabiralizumab 
 
6.1.1 
Acquisition 
Cabiralizumab will be supplied by BMS directly and shipped to the investigational pharmacy at the 
respective ordering participating institution. 
 
6.1.2 
Formulation, Appearance, Packaging, and Labeling 
 
For details on shipping, storage, and maintenance, please refer to the Investigator Brochure.  
Cabiralizumab drug product is supplied for IV administration as a sterile, aqueous, colorless to pale 
yellow, clear to slightly opalescent, pyrogen-free solution in 5 mL glass vials stoppered with coated 
stoppers, and equipped with aluminum seals. Light (few) particulates (consistent in appearance to 
proteinaceous particles) may be present. Each vial contains a minimum of 5 mL of a 20 mg/mL 
solution of cabiralizumab (approximately 100 mg per vial). 


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6.1.3 
Product Storage and Stability 
 
Cabiralizumab drug product is shipped refrigerated at 2–8°C and stored refrigerated at 2–8°C until time of 
use. The contents of the vials supplied are sterile, pyrogen-free, and contain no preservatives. Vials are for 
single-use only. Drug product should be protected from light. The investigational product should be stored 
in a secure area according to local regulations. It is the responsibility of the investigator to ensure that    
the investigational product must only be dispensed to study participants. The investigational product    
must be dispensed only from official study sites by authorized personnel according to local regulations. 
 
The product storage manager should ensure that the study treatment is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns regarding 
the quality or appearance of the study treatment arise, the study treatment should not be dispensed, and 
BMS should be contacted immediately 
 
6.1.4 
Preparation 
 
Solutions of cabiralizumab for IV infusion are prepared by dilution of the drug product in 0.9% sodium 
chloride or 5% dextrose injection. Since cabiralizumab solution contains no preservatives, diluted  
solutions for infusion should be administered or discarded within four hours after preparation. The IV 
administration set for cabiralizumab infusion must contain a 0.2 or 0.22 μm in-line filter or a 0.2 or 0.22   
μm syringe filter. Please refer to the current version of the Investigator Brochure and/or pharmacy manual 
for complete preparation, storage, and handling information. 
 
6.1.5 
Route of Administration 
Injection,for intravenous use. Investigational product documentation must be maintained that includes all 
processes required to ensure drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents and administration sets). 
 
 
6.2 Nivolumab 
 
6.2.1 
Acquisition 
Nivolumab will be supplied by BMS directly and shipped to the investigational pharmacy at the respective 
ordering participating institution 
 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is a clear to opalescent, colorless to pale yellow liquid, 
which may contain light (few) particulates. The drug product is a sterile, non-pyrogenic, single-use, 
isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 (TweenTM 80), at pH 6.0 and 
includes an overfill to account for vial, needle, and syringe holdup. It is supplied in 10-cc Type I flint glass 
vials, stoppered with butyl rubber stoppers and sealed with aluminum seals. The only difference between 
the two drug product presentations is the vial fill volume. 
 
6.2.3 
Product Storage and Stability 
Nivolumab should be stored between 2 and 8oC and should be protected from light, freezing, and 
shaking. If stored in a glass front refrigerator, vials should be stored in the carton. 
 


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6.2.4 
Preparation 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding (polyethersulfone membrane) in-line filter at the protocol-specified doses and infusion 
times. It is not to be administered as an IV push or bolus injection. When the dose is based on patient 
weight (ie, mg/kg), nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. 
When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection can be infused 
undiluted or diluted so as not to exceed a total infusion volume of 120 mL. 
 
During drug product preparation and handling, vigorous mixing or shaking is to be avoided. Instructions for 
dilution and infusion of nivolumab injection may be provided in the clinical protocol, pharmacy binder, 
pharmacy manual, or pharmacy reference sheet. Care must be taken to assure sterility of the prepared 
solution as the product does not contain any antimicrobial preservative or bacteriostatic agent. Nivolumab 
infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and infusion sets, and  
glass bottles. 
 
Please refer to the current version of the Investigator Brochure and/or pharmacy manual for complete 
preparation, storage, and handling information. 
 
6.2.5 
Route of Administration 
 
Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, 
low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). 
 
Do not co-administer other drugs through the same intravenous line. 
Flush the intravenous line at end of infusion. 
6.3 Study Agent Accountability Procedures 
 
Drug should be destroyed at the site, after the investigator approves the drug destruction policy at 
the site. Drug will not be returned. Destruction will be documented in the Drug Accountability Record 
Form.   
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. 
 
7 Treatment Plan 
7.1 Cabiralizumab and Nivolumab Administration 
 
Cabiralizumab and Nivolumab will be initiated on Cycle 1 Day 1 prior to the initiation of SBRT on Day 8. 
Subjects will receive nivolumab flat dose of 240mg IV over 30 minutes followed by cabiralizumab 4mg/kg 
IV over 30 minutes. The time in between infusions is expected to be approximately 30 minutes but can be 
more or less depending on the situation. Dosing calculations should be based on the body weight 
assessed at Cycle 1 Day 1 prior to the first dose of cabiralizumab. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the prior dose, the dose must be recalculated. 
All doses should be rounded to the nearest milligram. Treatment with combined immunotherapies will 
continue every 14 days (+/- 2 days) unless a further delay is mandated by toxicity criteria. 1 cycle is 
considered to be 14 days. Treatment will continue until unacceptable toxicity, disease progression, 
conversion to and eligible for surgical resection or completion of two years of treatment. The first six 
subjects enrolled will be evaluated for unacceptable toxicity in the first 42 days on study. 


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7.2 SBRT 
 
7.2.1 
Fiducial Placement 
 
Treatment on this protocol requires placement of 1-5 gold (99.9% pure, 1-5 mm length, visicoils, or other) 
fiducials for targeting purposes. The fiducials will be used as surrogates for targeting the daily tumor 
position during treatment. The fiducials will be placed directly into the tumor and/or periphery under 
endoscopic ultrasound or CT guidance. Fiducials may be implanted prior to enrollment as this is an 
acceptable standard of care procedure for any patient receiving radiotherapy for pancreatic cancer. Also, 
if a patient had an attempted surgical resection that was aborted, fiducials may have been implanted 
intraoperatively, which is also allowable prior to study enrollment. 
 
If fiducials are not placed intraoperatively and/or prior to enrollment, placement will be done and is 
expected to be done on an outpatient basis. In rare occurrences when fiducials/clips cannot be placed, 
patients may be treated at the discretion of the PI. 
 
Fiducials must be placed prior to Cycle 1 Day 1 of study treatment. 
 
7.2.2 
Simulation 
 
Patients will be simulated supine with the addition of a 4D CT if appropriate. A stereotactic 
immobilization device with abdominal compression will be used. Oral contrast will be delivered 
approximately one hour prior to simulation to allow opacification of small bowel unless 
contraindicated. Intravenous (IV) contrast may be delivered for the simulation if deemed necessary 
by the treating radiation oncologist. 
 
As long as the specified dosimetric parameters for SBRT are reached, patients may be treated on any 
IGRT-enabled machine. 
 
7.2.3 
Treatment  Planning 
 
Volume definitions 
GTV: The gross tumor volume (GTV) will be defined as all gross disease evident on imaging and 
examination at the site of treatment (pancreas). 
 
PTV: The planning target volume (PTV) will be a 3-5 mm concentric expansion on the GTV. An 
additional margin of up to 3 mm may be added as needed if 4D CT reveals extensive respiratory 
motion of the target. 
 
Dose specification 
The PTV doses should meet the following criteria: 
 
1) 93% of the PTV should receive at least 93% of the prescribed dose 
2) < 5% of the PTV should receive more than 110% of the prescribed dose. Efforts will be made to 
reduce heterogeneity if possible. 
 
Normal Structures The following dose goals will apply for normal tissues: 
• 
Kidney: mean dose < 10 Gy (total kidney volume) 
• 
Small bowel: maximum 35 Gy, mean <25Gy, V30< 5cc, V35Gy <1cc 
• 
Duodenum: maximum 35Gy, mean <25Gy, V30< 5cc, V35Gy <1cc 
• 
Stomach: 35 Gy, mean <25Gy, V30< 5cc, V35Gy <1cc 
• 
Large bowel: maximum 35Gy, mean <25Gy, V30< 5cc, V35Gy <1cc 
• 
Liver: V30<10% 


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 Cabiralizumab+nivolumab
 Allsolidtumors(n=205)
 Cabiralizumab+nivolumab
 Pancreaticcancer(n=33)
 
 
• 
Spinal cord: maximum 20Gy 
 
 
7.2.4 
Treatment 
 
Treatment will be delivered on 5 consecutive days (Day 8 cycle 1 to Day 12 cycle 1) except during 
holidays or inclement weather conditions. SBRT will be dose at 6.6 Gy for 5 days. In the event that a 
treatment is postponed due to machine malfunction, holiday, or inclement weather condition, the missed 
treatment will be delivered the following business day. Localization will be verified with pretreatment 
imaging prior to every fraction. Ideally, this will include Tomotherapy localization or cone beam CT, 
although kV/kV imaging may be used if necessary. 
 
7.3   Definition of Unacceptable Toxicity 
 
Adverse events (AE) will be graded according to the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE v. 5.0). During the initial safety lead in, unacceptable toxicity will be assessed for the 
first six subjects enrolled into the study for the initial 42 days of treatment. This observation interval is 
based upon inclusion of the known median times to onset of common immune-related adverse events 
attributed to nivolumab and allows for an adequate amount of time for unexpected toxicities with the 
combined administration of cabiralizumab, nivolumab, and SBRT to emerge. Subjects who do not 
complete the safety lead in observation period for reasons other than drug-related toxicity will be 
replaced. Replacement subjects will receive the same treatment but will be assigned a new subject 
number. During the safety observation (within 42 days of initiation of study therapy), subjects, who for 
reasons other than study-drug related toxicity, either miss 1 or more of their scheduled doses of 
nivolumab or cabiralizumab, or do not complete planned SBRT, will not be considered evaluable for 
safety for the purposes of the safety lead in and will be replaced. The safety observation period includes 
Day 1 Cycle 1 to Day 14 of Cycle 3 (6 weeks). 
 
The combination of nivolumab and cabiralizumab has demonstrated a tolerable safety profile, with 
elevations in creatine kinase and serum liver enzymes (without elevation in bilirubin) being the most 
common treatment related adverse events seen (see Table 5)[26]. 
 
Table 5: Safety profile for cabiralizumab and nivolumab 
 
 
Any grade, n (%) 
Grade 3–4, n (%) 
Any grade, n (%) 
Grade 3–4, n (%) 
Any TRAE 
184 (90) 
100 (49) 
31 (94) 
20 (61) 
AEs leading to discontinuation 
15 (7) 
10 (5) 
3 (9) 
3 (9) 
Clinical TRAEs (≥ 15% of pts treated with combination) 
84 (41) 
1 (<1) 
10 (30) 
0 
Periorbital edema 
Fatigue 
74 (36) 
11 (5) 
14 (42) 
1(3) 
Rash 
38 (19) 
8 (4) 
7(21) 
0 
Pruritus 
34 (17) 
2 (1) 
n/a 
n/a 
Nausea 
30 (15) 
0 
n/a 
n/a 
Treatment-related laboratory abnormalities of interest 
Serum enzyme elevationsa 
103 (50) 
40 (20) 
17 (52) 
11 (33) 
Pancreatic enzyme elevationsb 
42 (20) 
24 (12) 
2 (6) 
1 (3) 
Treatment-related deaths 
3 (1.5)c 
0 
 
 a
 
Includes AE terms indicative of elevated CPK, AST, ALT, and LDH. Includes AE terms indicative of elevated amylase and lipase. c
 
Includes pneumonitis in a patient with thyroid cancer (cabiralizumab 1 mg/kg + nivolumab 3 mg/kg), and respiratory distress (n = 1, 
cabiralizumab 4 mg/kg + nivolumab) and acute respiratory distress (n = 1, cabiralizumab 4 mg/kg + nivolumab) in 2 patients with lung
cancer. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; LDH = lactate dehydrogenase;
TRAE, treatment-related adverse event 


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The addition of SBRT to cabiralizumab and nivolumab is hypothesized not to significantly increase the 
rate of adverse events. Toxicity of SBRT alone includes anorexia, fatigue, abdominal pain, diarrhea, 
ulceration, hemorrhage, fistula, perforation, stenosis, nausea, vomiting and dermatitis. As a result, 
unacceptable toxicity of the combination of SBRT, nivolumab and cabiralizumab will be defined as the 
following: 
 
Unacceptable  Toxicity 
• 
Grade 3 fatigue lasting >2 weeks 
• 
Grade 3 nausea lasting >7 days despite maximal medical management 
• 
Grade > 3 anorexia 
• 
Grade > 3 vomiting 
• 
Grade > 3 diarrhea 
• 
Grade > 3 pancreatitis 
• 
Grade 3 abdominal pain 
• 
Grade > 3 radiation dermatitis 
• 
Grade > 3 GI hemorrhage 
• 
Grade > 3 GI fistula 
• 
Grade > 3 GI stenosis 
• 
Any Grade GI perforation 
 
 
8 Dosing Delays/Dose Modifications 
Dose delays and modifications will be made using the following recommendations. The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP website  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical 
treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and until the final study visit. Participants continuing to experience toxicity at 
the off-study visit may be contacted for additional assessments until the toxicity has resolved or is 
deemed irreversible. 
 
 
8.1 Cabiralizumab and Nivolumab Dose Adjustments 
There are no dose reductions for cabiralizumab or nivolumab. Subjects will receive nivolumab 240mg IV 
followed by cabiralizumab 4mg/kg IV every two weeks. Unacceptable toxicity as defined in Section 7.3 
will be assessed for the first 42 days on study in the initial 6 patients. During and following the safety lead 
in assessment period, administration of cabiralizumab and/or nivolumab in combination therapy should be 
delayed for the following: 
• 
Any Grade 3 fatigue which does not resolve to Grade 1 or baseline before the next treatment 
visit; 
• 
Any drug-related laboratory abnormalities would not require a dose delay unless clinically 
indicated or specified in the protocol or abnormal laboratory management table (Appendix 2). 
Please discuss with the PI as needed; 
• 
For dose delays or modifications for all other AEs, please refer to the AE management table in 
Appendix 3. 
 
Patients who require a dose delay of cabiralizumab/nivolumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume study drug dosing when re-treatment criteria are met. If a 
patient experiences an infusion reaction to cabiralizumab or nivolumab, or both study drugs, the infusion 


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reaction should be treated following the infusion reaction treatment guidelines in Section 8.5  and Appendix 
3. If the causality of the AE requiring a dose delay is confirmed to be due to one of the study drugs of 
the combination therapy, the non-offending drug may be continued per protocol taking into account 
the safety and clinical benefit to the patient. 
 
 
8.2 Management Algorithms for Cabiralizumab and Nivolumab 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration from AEs 
caused by other therapeutic classes. Nivolumab and cabiralizumab are considered I-O agents in this 
protocol. Early recognition and management of AEs associated with I-O agents may mitigate severe 
toxicity. Management algorithms have been developed from extensive experience with nivolumab to 
assist investigators in assessing and managing the following groups of AEs: 
• 
GI 
• 
Renal 
• 
Pulmonary 
• 
Hepatic 
• 
Endocrinopathies 
• 
Skin 
• 
Neurological 
 
Specific algorithms for the management of irAEs are provided in Appendix 3 and are applicable to 
immune-related AEs for all immuno-oncology study treatment combinations. 
 
For subjects who require more than 4 weeks of corticosteroids or other immunosuppressants to manage 
an adverse event, consider the following recommendations: 
 
• 
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic infections 
such as Pneumocystis jiroveci and fungal infections. 
 
• 
Early consultation with an infectious disease specialist should be considered. Depending on the 
presentation, consultation with a pulmonologist for bronchoscopy or a gastroenterologist for 
endoscopy may also be appropriate. 
 
• 
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the differential 
diagnosis. 
 
 
 
 
8.3 Dose Discontinuation Criteria for Cabiralizumab and Nivolumab 
For comprehensive discontinuation rules, refer to Appendix 3 (AE management) and Appendix 2 
(laboratory  abnormalities). 
 
Treatment with cabiralizumab in combination with nivolumab should be discontinued in the following 
cases unless otherwise specified: 
 
• 
Any Grade 3 or higher uveitis or 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 within the second re 
treatment period or that requires systemic treatment 
• 
Any Grade 3 or higher infusion-related reactions and hypersensitivity requiring discontinuation. 
Any re-initiation of therapy in this circumstance would require consultation with the PI. 
• 
Any  Grade  3  non-skin,  drug-related  AE  lasting  >  7  days,  including  drug-related  uveitis, 
pneumonitis, hypoxia, bronchospasm, and endocrinopathies with the following exceptions: 


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➢ 
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement do not require discontinuation 
➢ 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except: 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with Grade ≥ 2 
bleeding requires discontinuation 
• 
Any drug-related liver function test abnormality that meets any one of the following criteria 
requires  discontinuation: 
➢ 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 x ULN (in the absence of 
anticoagulation). See Appendix 2 and Appendix 3 for guidelines and possibility of restarting 
therapy 
➢ 
ALT or AST > 20 x ULN 
➢ 
Total bilirubin > 3 x ULN 
• 
Any Grade 4 drug-related AE or laboratory abnormality, except for the following events which do 
not require discontinuation: 
➢ 
Grade 4 neutropenia < 7 days 
➢ 
Grade 4 lymphopenia or leukopenia < 7 days 
➢ 
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. The PI should be consulted for Grade 4 amylase or 
lipase abnormalities. 
➢ 
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 AEs, such as adrenal insufficiency, adrenocorticotropic 
hormone deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose-controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the PI. 
➢ 
Grade 4 CK up to 20 x ULN (in the absence of clinical sequelae) 
• 
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
➢ 
Dosing delays to manage drug-related AEs are allowed. Prior to re-initiating treatment in a 
patient with a dosing delay lasting > 6 weeks from the previous dose, the PI 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  per protocol, 
or more frequently if clinically indicated during such dosing delays or per the Investigator’s  
discretion. 
➢ 
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug related 
reasons may be allowed if approved by the PI. Prior to re-initiating treatment in a patient with 
a dosing delay lasting > 6 weeks, the PI must be consulted. Tumor assessments should 
continue per-protocol every 8 weeks (± 3 days) even if dosing is delayed. Periodic study visits 
to assess safety and laboratory studies should also continue per-protocol or more frequently 
if clinically indicated during such dosing delays or per the investigator’s discretion. 
• 
Any AE, laboratory abnormality, or intercurrent illness which, in the opinion of the investigator, 
presents a substantial clinical risk to the patient with continued cabiralizumab and/or nivolumab 
dosing 
• 
Any drug-related Grade 3 or higher neurological toxicity 
• 
Any Grade 3 or higher periorbital edema and persistent Grade 2 periorbital edema requiring 2 
missed doses unless approved by PI. 
• 
Any Grade 3 or higher drug-related diarrhea or colitis, which does not resolve to Grade 1 or 
baseline within 28 days 
• 
Any Grade 4 skin toxicity 
• 
Any Grade 4 renal toxicity 
• 
Any drug-related Grade 3 or higher pulmonary toxicity 


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If the causality of the AE requiring discontinuation is confirmed to be due to one of the study drugs in the 
combination therapy, the other drug may be continued per protocol schedule under the following scenarios: 
Timely resolution of the AE based on the treatment modification table 
Clinical benefit is shown by the patient based on investigator assessment. 
 
 
 
8.4 Criteria to Resume Treatment with Cabiralizumab and Nivolumab 
Patients may resume treatment with cabiralizumab and/or nivolumab when the drug-related AE resolves 
as noted in the AE management tables in Appendix 3 or the abnormal laboratory management table in 
Appendix 2. 
 
 
8.5 Treatment of Cabiralizumab and Nivolumab Infusion Reactions 
 
Cabiralizumab and nivolumab may induce infusion or hypersensitivity reactions. If such reactions occur, 
they may manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension or 
hypertension, bronchospasm, or other symptoms. 
 
Infusion reactions should be graded according to CTCAE v5.0 guidelines. It may be unclear if an 
infusion reaction is due to cabiralizumab, nivolumab, or to both study drugs. Therefore, one set of 
treatment recommendations (based on the most conservative treatments for infusion reactions due to 
either study drug) is provided below and may be modified based on clinical judgment, local treatment 
standards and guidelines, and/or specific symptoms, as appropriate: 
 
For Grade 1 symptoms: Mild reaction (eg, localized cutaneous reactions including mild pruritus, flushing, 
and rash), requires infusion rate to be decreased; intervention may be indicated. 
 
• 
Decrease the rate of the study drug infusion until recovery from symptoms. 
• 
Remain at bedside and monitor the patient’s vital signs until resolution of symptoms. 
 
Diphenhydramine 50 mg may be administered at the discretion of the treating 
 
physician. 
• 
When symptoms resolve, restart the infusion at the original infusion rate. 
• 
If a patient has an infusion reaction with nivolumab, cabiralizumab can be given (without 
 
prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling 
 
purposes, the 
cabiralizumab infusion may be given the next day. Prophylactic pre-infusion 
 
medications should be given prior to all subsequent nivolumab infusions. 
• 
If a patient has an infusion reaction with cabiralizumab, prophylactic pre-infusion medications 
 
should be given prior to all subsequent cabiralizumab and nivolumab infusions. 
• 
The following prophylactic pre-infusion medications are recommended prior to future infusions of 
 
cabiralizumab and nivolumab: diphenhydramine 50 mg (or equivalent) and/or paracetamol 
 
(acetaminophen) 325 mg to 1000 mg at least 30 minutes before additional study drug 
 
administrations. 
 
For Grade 2 symptoms: Moderate reaction (ie, any symptom not listed above [mild symptoms] or below 
[severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, and hypotension with systolic 
blood pressure >80 mmHg), requires infusion interruption but responds promptly to symptomatic 
treatment (eg, antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, corticosteroids, and IV 
fluids); prophylactic pre-infusion medications indicated for< 24 hours. 
 
• 
Interrupt the study drug infusion. 
• 
Begin an IV infusion of normal saline and treat the patient with diphenhydramine 50 mg IV (or 
 
equivalent) and/or paracetamol (acetaminophen) 325 mg to 1000 mg. 
• 
Remain at bedside and monitor the patient’s vital signs until resolution of symptoms. 
 
Corticosteroid therapy may be administered at the discretion of the treating physician. 


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• 
When symptoms resolve, restart the infusion at 50% of the original infusion rate; if no further 
 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
 
rate. 
• 
Monitor the patient closely. If symptoms recur, immediately discontinue the infusion; no further 
 
study drug will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain at 
 
bedside and monitor the patient until resolution of symptoms. 
• 
If a patient has an infusion reaction with nivolumab infusion, cabiralizumab infusion can be given 
 
(without prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling 
 
purposes, the cabiralizumab infusion may be given the next day. Prophylactic pre infusion 
 
medications should be given prior to all subsequent nivolumab infusions. 
• 
If a patient has an infusion reaction with cabiralizumab, prophylactic pre-infusion medications 
 
should be given prior to all subsequent cabiralizumab and nivolumab infusions. 
• 
The following prophylactic pre-infusion medications are recommended prior to future infusions of 
cabiralizumab and nivolumab: diphenhydramine 50 mg (or equivalent) and/or paracetamol 
(acetaminophen) 325 mg to 1000 mg should be administered at least 30 minutes before additional 
 
study 
drug administrations. If necessary, corticosteroids (up to 25 mg of SoluCortef or 
equivalent)  
may be used. 
• 
The amount of study drug infused must be recorded. 
 
For Grade 3 or Grade 4 symptoms: Severe reaction such as bronchospasm, generalized urticaria, 
systolic blood pressure <80 mmHg, or angioedema; Grade 3 symptoms including prolonged symptoms, 
which require 6 or more hours to respond to symptomatic medication and/or discontinuation of infusion; 
recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae, 
such as renal impairment, pulmonary infiltrates; Grade 4: life-threatening; pressor or ventilation support 
indicated. 
 
• 
Immediately discontinue the study drug infusion. No further study drug will be administered. The 
 
amount of study drug infused must be recorded on the CRF. 
• 
Begin an IV infusion of normal saline and treat the patient as follows: Recommend 
 
bronchodilators, epinephrine 0.2 mg to 1.0 mg of a 1:1,000 solution for subcutaneous 
 
administration or 0.1 mg to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, 
 
and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. 
• 
Remain at bedside and monitor the patient’s vital signs until recovery from symptoms. 
• 
The patient should be monitored until the investigator is comfortable that the symptoms will not 
 
recur. 
• 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine or 
corticosteroids). 
 
 
 
8.6   Radiation Dose Adjustments 
 
Radiation therapy will be stopped for any ≥ grade 4 toxicities with exception of laboratory abnormalities. 
Radiation therapy will be held for Grade 3 nausea that is not well controlled with anti- emetic support, until 
nausea resolves to Grade 2 or less. It will then be resumed at same dose. 


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9 Study Procedures and Schedule 
9.1 Laboratory Procedures/Evaluations 
 
9.1.1 
Clinical Laboratory Evaluations 
 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet 
count. 
• 
Comprehensive Metabolic Panel: creatinine, total bilirubin, alanine aminotransferase (ALT), 
aspartate 
• 
aminotransferase (AST), alkaline phosphatase (ALP), albumin, blood urea nitrogen (BUN), 
Calcium, Carbon Dioxide (Bicarbonate), chloride, glucose, potassium, sodium, total protein 
• 
Biochemistry: CPK and LDH, amylase and lipase, Free T4, TSH, CA 19-9, PT/PTT 
• 
Urinalysis: dipstick urinalysis, including protein, hemoglobin and glucose; if dipstick is abnormal, 
complete urinalysis with microscopic evaluation is required. 
• 
Pregnancy test, usually to be done within 24 hours prior to study intervention and results must 
be available prior to administration of study product. 
 
 
9.1.2 
Other Assays or Procedures 
 
Three to four core biopsy samples will be taken at the pre-treatment time point using sterile technique. Each 
core will provide material for histologic analysis and PDOT creation and analysis. Post-treatment core 
biopsy samples and/or surgically resected specimens will be sectioned for the same analyses. Pathologic 
response will be characterized by degree of tumor necrosis. Tissue will be evaluated for expression of 
CSF1 using IHC. Changes in immune infiltrate will be assessed by IHC against, including but not limited to, 
CD3, CD4, CD8, Foxp3, PD-1, PD-L1, Granzyme B, CD68, CD163, ARG1 and iNOS. PDOT’s will be 
used to evaluate tumor cell viability, the relative composition and function of the tumor immune infiltrate, 
cytokine/chemokine profiles and single cell RNA sequencing. 
 
 
9.1.2.1 
Specimen Preparation, Handling, and Storage 
 
9.1.2.2 
Tissue 
 
Tumor tissue for pathology analysis will be processed by the appropriate department at each participating 
institution. All tumor tissue for research will be processed by the NYU Center for Biospecimen Research 
and Development (CBRD) and then sent to the lab of either Dr. George Miller or Dr. Kwok Wong for 
analysis. 
 
Please note: Dr. Kwok Wong will not have access to PHI, and will only be handling samples per 
professional service. 
 
Please see laboratory manual for full details on tissue collection, handling and storage. Pre-treatment 
biopsies and post-treatment biopsies and/or surgically resected specimens from each subject will be 
obtained for a total of two to three tissue samples per patient. For fixed tissue, paraffin embedding, 
sectioning, immunohistochemistry and scanning will be performed by the NYU Experimental Pathology 
Research Laboratory. Staining will be manually quantified after analysis on a digital image database. 
Fresh tissue will be used to establish PDOT’s in the laboratory of Dr. Wong. 
 
 
9.1.2.3 
Research Blood Sample Collection 
 
Four green-top tubes, one-red top tube, and one lavender top tube will be collected from each patient per 


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week. Peripheral blood 
leukocytes will be isolated with the assistance of the George Miller Lab in 
accordance with established lab practice and stored at -80C until the end of the study period for a 
maximum of 4 cycles per subject. 


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Serum will be harvested and stored at -80C for a total of a maximum of 4 cycles per subject. Flow 
cytometry and cytometric bead array will be performed for all participant samples at the end of the study 
period. Staining will be performed using an established panel and protocol in the George Miller Lab. Data 
will be acquired on an LSR II and analyzed in FlowJo software. 
 
9.1.3    Specimen Shipment 
 
See laboratory manual for full details on specimen shipment. 
 
9.2 Study Schedule 
 
9.2.1    Screening 
 
Screening Visit (Day -28 to -1) 
• 
Obtain informed consent of potential participant verified by signature on informed consent form. 
• 
Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• 
Perform  medical  examinations  needed  to  determine  eligibility  based  on  inclusion/exclusion 
criteria. 
• 
Complete history and physical examination, including weight and height, and ECOG performance 
status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase, TSH and free T4, PT/PTT, urinalysis, CA 19-9) 
• 
Baseline imaging study with CT chest, abdomen and pelvis 
• 
Pregnancy test (serum or urine) for women of childbearing potential 
• 
12 lead ECG 
• 
AE assessment 
• 
Fiducial placement and pre-treatment tissue biopsy 
• 
Research blood draw for pharmacodynamics markers and immune monitoring 
• 
Schedule study visits for participants who are eligible and available for the duration of the study. 
 
 
9.2.2 
Enrollment/Baseline 
 
Enrollment/Baseline Visit (Cycle 1, Day 1) Pre-Treatment Evaluations 
 
Results of clinical and laboratory evaluations must be reviewed to confirm that the subject continues to 
meet eligibility criteria before drug administration. The pre-treatment evaluations consist of the following: 
 
• 
Physical examination, including weight 
• 
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) within 24 hours prior to the start of study treatment. 
• 
Record vital signs, ECOG performance status 
• 
Review of concomitant medications 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase, TSH and free T4, CA 19-9) 
• 
Scientific correlate blood samples (to be collected within 30 minutes, pre-dose) 


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• 
AE assessment 
• 
Administer the study treatment with cabiralizumab and nivolumab. 
 
 
 
9.2.3 
Intermediate  Visits 
 
9.2.3.1 
Cycle 1, Day 8 (+/- 1 day) 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase) 
• 
Scientific correlate blood samples 
• 
AE assessment 
• 
SBRT administration (Day 8-12) 
 
 
9.2.3.2 
Cycle 2, Day 1 (+/- 1 day) 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase, TSH and free T4) 
• 
Scientific correlate blood samples 
• 
AE assessment 
• 
Administer the study treatment with cabiralizumab and nivolumab. 
 
9.2.3.3 
Cycle 2, Day 8 (+/- 1 day) 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase) 
• 
Scientific correlate blood samples 
• 
AE assessment 
• 
Tumor Biopsy (+/- 3 days) 
 
9.2.3.4 
Cycle 2, Day 12 (+/- 2 days) 
 
• 
CT chest, abdomen and pelvis 
 
9.2.3.5 
Cycle 3, Day 1 (+/- 1 day) 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase, TSH and free T4, CA 19-9) 
• 
Scientific correlate blood samples 
• 
AE assessment 
• 
Administer the study treatment with cabiralizumab and nivolumab. 


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9.2.3.6 
Cycle 3, Day 8 (+/- 1 day) 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase) 
• 
Scientific correlate blood samples 
• 
AE assessment 
 
 
 
9.2.3.7 
Cycle 4, Day 1 (+/- 1 day) and all subsequent 14 day cycles 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, CPK, 
amylase, lipase, TSH and free T4) 
• 
Scientific correlate blood samples (maxiumum 4 cycles) 
• 
AE assessment 
• 
Administer the study treatment with cabiralizumab and nivolumab. 
• 
CT chest, abdomen, and pelvis (prior to cycle 6 (+/- 3 days and then every 8 weeks thereafter (+/- 
7 days) 
 
 
9.2.4 
Final Study Visit 
 
On the last day of treatment, or on the day when treatment is discontinued, subjects are to return to the 
study site to complete all end of treatment assessments as follows: 
 
Final Study Visit 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, 
CPK, amylase, lipase, TSH and free T4, CA 19-9) 
• 
Scientific correlate blood samples 
• 
12 lead ECG 
• 
Review of concomitant medications 
• 
AE assessment 
 
 
9.2.5 
Unscheduled Visit 
If additional visits are needed (e.g., for resolution of an adverse event), the following procedures and 
evaluations may be performed as needed at the discretion of the treatment physician: 
 
• 
physical examination, including weight 
• 
Record vital signs, ECOG performance status 
• 
Clinical laboratory tests (hematology, complete serum chemistry panel, hepatic panel, LDH, 
CPK, amylase, lipase, TSH and free T4, CA 19-9) 
• 
Urinalysis 


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• 
Urine pregnancy test 
• 
12 lead ECG 
• 
AE assessment 
• 
Concomitant  medications 
• 
CT Scans 
 
 
 
 
9.3 Concomitant Medications, Treatments, and Procedures 
 
All concomitant prescription medications taken during study participation will be recorded on the case 
report forms (CRFs). For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in the CRF are 
concomitant prescription medications, over-the-counter medications and non-prescription medications. 
 
No investigational or commercial agents or therapies other than cabiralizumab and/or nivolumab may be 
administered with the intent to treat the participant’s malignancy. Myeloid growth factors will NOT be used 
throughout study. Live attenuated vaccines while on study or 30 days following completion of study are 
NOT permitted. 
 
After confirmation and documentation that a subject has met all the inclusion criteria and note of the 
exclusion criteria, supportive care treatments (transfusions etc.) can be prescribed as medically 
appropriate. The following treatments are permitted during study: 
• 
The use of erythropoietin or other specific red blood cell growth factors and red blood cell 
transfusion will be permitted as clinically indicated during the study after documentation of anemia 
secondary to study treatment. These agents cannot be used prior to this occurrence. 
• 
Other concomitant medications, including premedication may be given as clinically indicated 
 
9.4 Participant Access to Study Agent at Study Closure 
Study agents will be supplied for the study period only. 
 
 
10 Assessment of Safety 
10.1 Specification of Safety Parameters 
 
10.1.1 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
 
 
10.1.2 Definition of Serious Adverse Events (SAE) 


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Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious. 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug is an 
SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be reported as an SAE 
(eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported). 
 
 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events. 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final study reports as 
specified in the agreement or, if a regulatory requirement i.e IND US trial, reporting will be provided as part of an 
annual reporting requirement.  
 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is considered 
both excessive and medically important. All occurrences of overdose must be reported as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-rays, and any 
other potential safety assessments, whether or not these procedures are required by the protocol, should also be 
recorded as a non-serious or serious AE, as appropriate, and reported accordingly.


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10.1.3 Definition of Unanticipated Problems (UP) 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
 
10.2 Classification of an Adverse Event 
 
10.2.1 Severity of Event 
 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity. 
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
 
10.2.2 Relationship to Study Agent 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the drug, is unlikely to be attributed to concurrent disease  
or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 


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• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
 
 
10.2.3 Non-serious Adverse Event Collection and Reporting 
 
 
The collection of non-serious AE information should begin from the time of consent. All non-serious adverse 
events (not only those deemed to be treatment-related) should be collected continuously during the treatment 
period and for a minimum of 100 days following the last dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. 
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study drug and for 
those present at the end of study treatment as appropriate. 
 
10.2.4 Expectedness 
 
The principal investigator and/or sub-investigator(s) will be responsible for determining whether an AE is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study agent. 
 
10.3 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the  
appropriate RF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system 
throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 100 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 


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All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study. The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study. 
The sponsor should also be notified if the investigator should become aware of the development of   
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study. 
 
 
10.4 Reporting Procedures – Notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others. The following describes the NYULMC IRB reporting requirements, 
though Investigators at participating sites are responsible for meeting the specific requirements of their 
IRB of record. 
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts. 
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be 
caused by the research procedures. 
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations: 
– one or more participants were placed at increased risk of harm 
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a 
more severe or frequent side effect; Other research finds arm of study has no therapeutic value; 
FDA labeling change or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or 


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as a written report of the event (including a description of the event with information regarding its fulfillment 
of the above criteria, follow-up/resolution and need for revision to consent form and/or other study 
documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
10.4.1 Adverse Event Reporting 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up. For this study, the study 
treatment follow-up is defined as 100 days following the last administration of study treatment. 
 
 
 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
 
All adverse events occurring during the study period must be recorded. The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause. Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
 
Potential Drug Induced Liver Injury (DILI)  
 
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard medical practice 
in identifying and monitoring hepatic issues should be followed. 
 
10.4.2 Serious Adverse Event and Unanticipated Problem Reporting 
 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats 
and requirements of the various entities to which they are responsible, but at a minimum those events 
that must be reported within 5 days of PI notification are those that are: 
• related to study participation, 
• unexpected, and 
• Harmful or have the potential to cause harm (see definitions, section 10.1) 
      
 
Events should be reported using the NYU CTO Medical Events Form. 
Adverse events that do not fit the above immediately reportable criteria must still be reported to the IRB at 
each annual review, either in a summary or tabular format. 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the site investigator’s responsibility to report UPs to their IRB and to the overall principal 
investigator. The UP report will include the following information: 


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• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the DSMC/study sponsor within 24 hours of 
the investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the DSMC/study sponsor within 24 hours of the 
investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and OHRP within 5 days 
of the IR’s receipt of the report of the problem from the investigator. 
 
Serious adverse event reporting will begin in conjunction with the date of treatment administration. Any 
SAEs occurring prior to study drug administration that the investigator believes may have been caused 
by a protocol procedure must be reported immediately to the principal investigator, with a notification 
email sent to NYUPCCsafetyreports@nyumc.org and recorded on the case report form. 
 
All fatal or life-threatening adverse events must be immediately reported to the Principal Investigator, via 
appropriate reporting mechanism and the NYU Langone Health IRB by telephone or e-mail. Within 24 
hours 
of 
the 
event, 
the 
Serious 
Adverse 
Event 
Form 
must 
be 
emailed 
to  
NYUPCCsafetyreports@nyumc.org  and PCC Assigned Medical Monitor whether full information regarding 
the event is known or not.  
 
Additional follow-up by the investigator will be required if complete information is not known. De-identified 
source documentation of all examinations, diagnostic procedures, etc. which were completed with 
respect to the event should be included with the SAE form. Care should be taken to ensure that the 
patient’s identity is protected and the patient’s identifiers (as assigned at the time of study enrollment) are 
properly mentioned on any copy of source document provided to the Sponsor. For laboratory results, 
include the laboratory normal ranges. 


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All other serious adverse events must be reported to the sponsor and DSMC’s appointed medical monitor 
within 24 hours by e-mail (NYUPCCsafetyreports@nyumc.org) or fax (212-263-0715). The Serious 
Adverse Event Form must also be emailed to the 
principal investigator and Clinical Trials Office 
(NYUPCCsafetyreports@nyumc.org) or it can be faxed (212-263-0715), this documentation will be 
forwarded to the DSMC’s appointed medical monitor 
within 24 hours of the event whether full 
information regarding the event is known or not. Additional follow-up by the investigator will be required 
if complete information is not known. 
 
Current contact information shall be maintained at the site within the regulatory binder. 
 
All serious adverse events (SAEs) will be evaluated by the DSMC if meeting the requirements for 
expedited reporting, the study Sponsor will report the adverse event to all regulatory authorities with 
jurisdiction over ongoing trials with the study drug and to all other investigators involved in clinical trials 
with the study drug. The investigator is responsible for reporting all SAEs to the appropriate IRB, DSMC, 
and FDA. 
 
 
 
 
10.4.3 Reporting of Pregnancy 
If, following initiation of the investigational product(s), it is subsequently discovered that a study participant 
is pregnant or may have been pregnant at the time of investigational product exposure, including 
during at least 5 half-lives after product administration, the investigational product will be permanently 
discontinued in an appropriate manner. The pregnancy must be reported immediately to the 
principal 
investigator, and the Clinical Trials Office, by emailing: NYUPCCsafetyreports@nyumc.org, PCC Assigned 
Medical Monitor, and the s t u d y sponsor (NYU Langone Health PCC) will report to BMS in accordance 
with the procedures described below. Pregnancy in itself is not regarded as an adverse event unless 
there is a suspicion that the investigational product may have interfered with the effectiveness of a 
contraceptive medication. This will be reported to the IRB if necessary. Each pregnancy case will be 
followed until pregnancy resolution. 
 
The  investigator must immediately notify Worldwide.Safety@bms.com of this event via MedWatch or 
appropriate Pregnancy Surveillance Form in accordance with SAE reporting procedures. The pregnancy, 
AEs associated with maternal exposure and pregnancy outcomes must be reported and submitted to 
BMS on a BMS Pregnancy Surveillance Form or the MedWatch, or approved site SAE form, and reported 
to BMS within 24 hours/1 business day by confirmed fax or reported via electronic mail to:  
Worldwide.Safety@BMS.com. If only limited information is initially available, follow-up reports may be 
required. Your original forms are to remain on site. Follow-up information should be obtained on pregnancy 
outcomes for one year following the birth of the offspring. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported on the MedWatch, BMS Pregnancy 
Surveillance Form, or approved site SAE form. A BMS Pregnancy Surveillance Form may be provided 
upon request. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In order for Sponsor 
or designee to collect any pregnancy surveillance information from the female partner, the female partner 
must sign an informed consent form for disclosure of this information. 
 


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10.5 Reporting Procedures – Notifying the Study Sponsor 
Since multiple sites will be participating, the following describes events that must be reported to the study 
sponsor (NYU Langone Health PCC) and the study sponsor reports to BMS in an expedited fashion. 
 
Initial Report: within 24 hours: 
The following events must be reported to the study sponsor (NYULMC PCC) by email within 24 hours of 
awareness of the event using the NYU CTO Medical Events Form: 
 
• Unanticipated problems related to study participation, 
• 
Serious adverse events, regardless of whether they are unexpected. 
 
 
The investigator shall maintain a copy of the Medical Events Form on file at the study site. All report forms 
must be signed and dated by the Principal Investigator. If the Principal Investigator is not available at the 
time of the initial report, then the form can be submitted by a Sub-Investigator. This form should be 
reviewed by the Principal Investigator, whom sign/date initial report upon return. 
 
Report to: 
 
NYUPCCsafetyreports@nyumc.org 
(212) 273-2748 
 
 
AND 
 
Deirdre Cohen, MD 
160 E. 34th Street, 
New York, NY 10016 
Phone: 212-731-5656 
deirdre.cohen@nyumc.org 
 
AND 
 
PCC Assigned Medical Monitor 
 
Events of Clinical Interest (any medical event that is deemed significant via Principal Investigator’s 
expertise, but does not apply to SAE categories) will be reported within 2-5 days, or as per study Sponsor 
specifications. 
 
 
Follow-up report:  
As a follow-up to the initial report, the investigator shall provide further information, as applicable, on the 
unanticipated event or the unanticipated problem in the form of a written narrative. This should include a 
copy of the completed Unanticipated Problem form, and any other diagnostic information that will assist 
the understanding of the event. 
 
Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval 
before they are initiated. Any protocol deviations initiated without Sponsor and the investigator’s 
IRB approval that may affect the scientific soundness of the study, or affect the rights, safety, or 
welfare of study subjects, must be reported to the Sponsor and to the investigator’s IRB as soon 
as a possible, but no later than 5 working days of the protocol deviation. 


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• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB notification of withdrawal 
of approval. 
 
• 
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. 
• 
An SAE report should be completed for any event where doubt exists regarding its seriousness;  
• 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), the 
relationship should be specified in the narrative section of the SAE Report Form. 
• 
If the BMS safety address is not included in the protocol document (eg, multicenter studies where events 
are reported centrally), the procedure for safety reporting must be reviewed/approved by the BMS Protocol 
Manager. Procedures for such reporting must be reviewed and approved by BMS prior to study activation. 
• 
For studies with long-term follow-up periods in which safety data are being reported, include the timing of 
SAE collection.  
 
 
Reporting to BMS 
 
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. 
• 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are suspected 
(related to the investigational product) and unexpected (ie, not previously described in the IB). An event 
meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of a SUSAR Report.  
o 
Other important findings which may be reported by BMS as an Expedited Safety Report (ESR) 
include: increased frequency of a clinically significant expected SAE, an SAE considered associated 
with study procedures that could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety finding from a nonclinical (eg, animal) 
study, important safety recommendations from a study data monitoring committee, or sponsor 
decision to end or temporarily halt a clinical study for safety reasons. 
o 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the IB. 
Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will 
submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the 
informed consent requires revision. The investigator should also comply with the IRB/IEC procedures 
for reporting any other safety information.  
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, suspected serious 
adverse reactions (whether expected or unexpected) shall be reported by BMS to the relevant competent health 
authorities in all concerned countries according to local regulations (either as expedited and/or in aggregate 
reports). 


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Adverse Event 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 that the file contains: 
both non-serious Adverse Events and previously submitted Serious Adverse Events (which were 
submitted to BMS within 24 hours / 1 business day of event awareness within the 3 months). 
 
 
Serious Adverse Event Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether or not related to the 
BMS product associated with this study, must be collected, including those thought to be associated with 
protocol-specified procedures. CIOMS, MedWatch, or site approved form and reported to BMS within 24 
hours \ 1 business day to comply with regulatory requirements. 
Either the CIOMS, MedWatch, or approved site SAEform should be completed for any event where doubt 
exists regarding its status of seriousness. Note: Please include the BMS Protocol number on the SAE 
form or on the cover sheet with the SAE form transmission. 
The study clinician will complete a SAE Form within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted to the DCC/study sponsor within 24 hours of site awareness. See 
Section 1, Key Roles for contact information. 
• Other SAEs regardless of relationship will be submitted to the DCC/study sponsor within 72 hours 
of site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
the DCC/study sponsor and should be provided as soon as possible. 
 
 
Investigators should report to the responsible regulatory authority as appropriate. 
 
All SAEs must be reported by confirmed facsimile (fax) transmission or reported via electronic mail to: 
 
BMS Protocol number must be included on the SAE form or on the cover sheet with the SAE form 
transmission 


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SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: +1-609-818-3804 
 
If only limited information is initially available, follow-up reports may be required. 
 
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the required 
method for reporting. The paper forms should be used and submitted immediately, only in the event the 
electronic system is unavailable for transmission. When paper forms are used, the original paper forms 
are to remain on site. 
 
 
 
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin at initiation of the study. Non-serious AE 
information should also be collected from the start of the observational period intended to establish a 
baseline status for the subjects. 
 
Non-serious adverse events must be recorded on the Non-interventional Research AE/SAE Form and 
individually reported to BMS within 7 business days to comply with regulatory requirements. 
 
All non-serious AEs must be reported by confirmed fax transmission or reported via electronic mail to: 
 
Non-serious AE Email Address: Worldwide.Safety@BMS.com 
 
Non-serious AE Facsimile Number: +1-609-818-3804 
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of the 
BMS product associated with this study and for those present at the end of the study, as appropriate. 
 
The study Sponsor will reconcile the clinical database AE 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. 
 
 
 
 
 
 
 
10.6 Reporting Procedures – Notifying the FDA 
 
The study sponsor is required to report certain study events in an expedited fashion to the FDA. These 
written notifications of adverse events are referred to as IND/IDE safety reports. 
 
The following describes the IND safety reporting requirements by timeline for reporting and associated 
type of event: 


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• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected, 
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form; see Attachment 1), or in a 
narrative format. If supplied as in a narrative format, the minimum information to be supplied is noted 
above at the beginning of section 8.3. The contact information for submitting IND safety reports is noted 
below: 
NYU Langone Health Contacts:  
NYUPCCsafetyreports@nyumc.org 
AND 
Deirdre Cohen, MD 
160 E. 34th Street, 
New York, NY 10016 
Phone: 212-731-5656 
deirdre.cohen@nyumc.org 
 
 AND 
 PCC Assigned Medical Monitor 
 
10.7 Reporting Procedures – Participating Investigators 
It is the responsibility of the study sponsor to notify all participating investigators of any adverse event that 
meets the FDA 15-day reporting requirement criteria as note above. The same materials and timeline 
used to report to the FDA are used for notifying participating investigators. 
 
10.8 Safety Oversight 
 
All Internal SAEs reported by the CTO, occurring to patients on clinical trials that are not monitored by 
any other institution or agency, are reported via email: NYUPCCsafetyreports@nyumc.org and reviewed 
within 48 hours by the medical monitor. Based on the review, one of three determinations will be made: 
 
• 
SAE report is considered to be adequate 
• 
Queries for clarification to PI regarding treatment attribution and/or resolution of SAE or 
completeness of other information. The committee may request a cumulative review of 


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all SAEs on the study to date. 
• 
Request for full DSMC committee review of protocol at the next scheduled meeting. 
 
The DSMC Coordinator will record the committee’s decision and incorporate it into the study summary for 
the next scheduled study review. 
 
 
11 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory  requirement(s). 
 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan detailed 
below. Serious adverse events are evaluated regularly by the principal investigator in conjugation with 
the research team, the DSMC is notified of serious adverse events via email initially, reviewed offline by 
the designated medical monitor, and presented at the next DSMC monthly meeting. The Data Safety 
and Monitoring Committee (DSMC) will review the study at least quarterly. Medical monitoring will 
include a regular assessment of the number and type of serious adverse events. 
 
 
11.1 Data and Safety Monitoring Committee 
 
 
This investigator-initiated study will be monitored by the Data Safety Monitoring Committee (DSMC) of the 
New York University (NYU) Perlmutter Cancer Center (PCC). The DSMC operates based on the National 
Cancer Institute approved Charter. It is an existing and multidisciplinary committee (consisting of clinical 
investigators/oncologists, biostatisticians, nurses, and research administration staff knowledgeable of 
research methodology and design and in proper conduct of clinical trials) that is responsible for monitoring 
safety, conduct and compliance in accordance with protocol data monitoring plans for interventional clinical 
trials conducted in the NYULMC Perlmutter Cancer Center that are not monitored by another institution or 
agency. The DSMC reports to the Director of the NYULMC PCC. 
 
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this phase II trial will be monitored by 
DSMC quarterly (from the date the first patient is enrolled), at protocol-specified interim time points, and 
at the completion of the study prior to study closure. This review includes accrual data, subject 
demographics and adverse events. Principal Investigators are required to attend the review of their 
studies. Additional reviews can be scheduled based on SAE reports, investigator identified issues, 
external information, etc. The DSMC will review safety data every 3 months.  DSMC summary reports are 
available to facilitate the review and monitoring of this study.    These reports include the following:  patient 
listings and summary reports that describe study enrollment and accrual, eligibility, demographic 
characteristics, dose modifications, adverse experiences, subject’s death and additional external published 
data if applicable to the study.  Cumulative toxicities, SAEs, and AEs are reviewed, to identify possible 
adverse events with elevated frequency that is unexpected.  Once a recommendation is made if further 
action is required, the Investigator’s must respond within 10 business days of receipt of DSMC letter.   
 
 
 
12 Statistical Considerations 
12.1 Statistical and Analytical Plans (SAP) 
 


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All variables will be summarized with tabular and graphical descriptive statistics. Assessment of variable 
distributions will be conducted, and potential transformations sought if data do not approximate normality.


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12.2 Statistical Hypotheses 
The co-primary outcomes are safety and efficacy, assessed using the R0 resection rate. Adverse events 
will be tabulated. The current expected R0 resection rate is 5%. We will consider this regimen promising 
if we can achieve an R0 resection rate of 20% or higher. With 20 patients, the lower bound of a 95% 
confidence interval around the R0 resection rate will exceed 5% when the true R0 resection rate is 20%  
or higher. 
 
The secondary outcomes are the overall response rate, progression free survival, overall survival, and 
distant metastasis free survival rate. 
 
 
12.3 Analysis Datasets 
 
The Safety Analysis Dataset will include all participants who receive any dose of the proposed 
investigational therapy. The Efficacy Analysis Dataset will include all participants who receive at least 
75% of the first three planned cycles of cabiralizumab and nivolumab and 75% of planned SBRT dose. 
 
 
12.4 Description of Statistical Methods 
 
12.4.1 General Approach 
 
All variables will be summarized with tabular and graphical descriptive statistics. Assessment of variable 
distributions will be conducted, and potential transformations sought if data do not approximate normality. 
 
 
12.4.2 Analysis of the Primary Efficacy Endpoint(s) 
 
Safety will be evaluated by tabulating the type and severity of all dose-limiting toxicities and adverse 
events. If more than two of the first six patients experience an unacceptable toxicity, accrual will be 
temporarily halted   while the study team investigates potential dose modifications. The rate of R0 
resection will be calculated as the proportion of enrolled patients who achieve R0 resection. The rate of 
R0 resection will be estimated with its associated exact 95% confidence interval. If the lower bound of the 
confidence interval exceeds the null rate of 5%, the therapy will be deemed worthy of further investigation. 
 
 
12.4.3 Analysis of the Secondary Endpoint(s) 
Overall response will be tabulated according to RECIST criteria. Progression-free survival will be 
measured as the time from enrollment until the occurrence of the earlier of progression or death. Overall 
survival will be measured as the time from enrollment until death from any cause. Distant metastasis-free 
survival will be as the time from enrollment until the occurrence of the earlier of distant metastasis or 
death. PFS, OS, and DMFS will be estimated using the Kaplan-Meier method. 
 
 
12.4.4 Safety Analyses 
 
The rate of unacceptable toxicity will be estimated, both within the safety run-in cohort of six patients and 
continuously in the entire cohort of 20 patients. A Bayesian monitoring rule will be applied, such that 
accrual will be temporarily suspended if the posterior probability that the unacceptable toxicity rate 
exceeds 0.33 goes above a pre- specified threshold of 75%. We will assume a Beta(1,2) prior, which is 
prior information equivalent to one unacceptable toxicity observed in three treated patients. This 
minimally informative prior is justified as there is some clinical experience with the combination therapy. 
Early termination for toxicity will be considered based on a posterior probability above 75% (in 


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parentheses), that the toxicity rate exceeds 33%. Toxicity will be carefully monitored in the 20 patients. 
Termination will be considered if unacceptable toxicity is observed in: 2 of 3 patients (0.84), 3 of 6 patients 
(0.81), 4 of 9 patients (0.79), 5 of 12 patients (0.58), 6 of 15 patients (0.78), 7 of 18 
patients (0.77), or 8 of 20 patients (0.77). 
 
 
12.4.5 Adherence and Retention Analyses 
 
All patients will be followed from enrollment until withdrawal, completion, or death, whichever occurs 
earlier. 
 
 
12.4.6 Baseline Descriptive Statistics 
 
Baseline characteristics will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of subjects screened, the 
primary reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age, gender), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment using descriptive statistics and 
tabular formats. 
 
 
12.4.7 Planned Interim Analysis 
 
A single interim analysis is planned after the first six patients have been treated. If there are fewer than 
two unacceptable toxicities in the first six patient enrolled (as defined in section 7.3), an additional 14 
patients will be accrued. 
 
12.4.7.1 Safety Review 
 
A Bayesian monitoring rule will be applied, such that accrual will be temporarily suspended if the posterior 
probability that the unacceptable toxicity rate exceeds 0.33 goes above a pre-specified threshold of 75%. 
We will assume a Beta(1,2) prior, which is prior information equivalent to one unacceptable toxicity observed 
in three treated patients. This 
minimally informative prior is justified as there is some clinical experience 
with the combination therapy. Early termination for toxicity will be considered based on a posterior probability 
above 75% (in parentheses), that the toxicity rate exceeds 33%. Toxicity will be carefully monitored in the 20 
patients. Termination will be considered if unacceptable toxicity is observed in: 2 of 3 patients (0.84), 3 of 
6 patients (0.81), 4 of 9 patients (0.79), 5 of 12 patients (0.58), 6 of 15 patients (0.78), 7 of 18 patients (0.77), 
or 8 of 20 patients (0.77). 
 
 
12.4.7.2 Efficacy Review 
 
There will be no interim analyses for efficacy. 
 
 
12.4.8  Exploratory Analyses 
 
Immune response parameters will be assessed. These analyses will be purely descriptive and 
hypothesis-generating; no formal hypothesis testing will be conducted. 
 
 
12.5 Sample Size 


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We will initially enroll six patients. Should the threshold for continuation be reached (two or fewer patients 
with unacceptable toxicity in the first six), we will accrue an additional 14 patients for a total of 20 patients. 
An exact 95% confidence interval around the R0 resection rate will exclude the null rate of 5% if the true 
rate is 20% or higher. 
 
 
 
13 Source Documents and Access to Source Data/Documents 
 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source 
documents. If this is the case, it should be stated in this section what data will be collected on CRFs and 
what data will be collected from other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”. If the item is 
not applicable to the individual case, write “N/A”. All entries should be printed legibly in black ink. If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it. All such changes must be initialed and dated. DO NOT ERASE OR 
WHITE OUT ERRORS. For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
 
TrialMaster, an electronic database capture system will be created to record the data for this trial. 
Research coordinators will input clinical trial data into the database. This database is password protected 
and only the PI, assigned study team members, and CTO staff will have access to the database. 
DataCore, a core resource of the institution, will provide the primary data collection instrument for the 
study. All data requested in the system must be reported. All missing data must be explained. The 
quality assurance specialists will monitor this trial every 4-6 weeks for data entry accuracy. 
 
Source documentation should be consistent with data entered into any electronic medical record or Trial 
master.  Relevant source documentation to be reviewed by the DSMC throughout the study includes: 
 
1. Baseline measures to assess pre-protocol disease status 
2. Concurrent  medications 
3. Treatment records 
4. Adverse events 
 
 
 
 
14 Quality Assurance and Quality Control 
This study will be monitored according to the monitoring plan detailed below, subsite monitoring follows 
parameters detailed in Section 14.1. The Investigator will also ensure that the monitor or other 
compliance or quality assurance reviewer is given access to all the above noted study-related documents 
and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.),   and has adequate space to 
conduct the monitoring visit. A risk-based, data-driven monitoring approach will be used to verify data for 
this trial which will also include a centralized review of data for quality, trends, consistency and general 
safety review. A quality assurance specialist will make regularly


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scheduled trips to the investigational site to review the progress of the trial, study data and site    
processes. At each visit, the monitor will review various aspects of the trial including, but not limited to: 
screening and enrollment logs; compliance with the protocol and study manual and with the principles of 
Good Clinical Practice; completion of case report forms; source data verification; study drug accountability 
and storage; facilities and staff. 
 
During scheduled monitoring visits, the investigator and the investigational site staff must be available to 
meet with the quality assurance specialist in order to discuss the progress of the trial, make necessary 
corrections to case report form entries, respond to data clarification requests and respond to any other 
trial-related inquiries of the monitor. In addition to on-site monitoring visits, the Sponsor and/or 
representatives will also be routinely reviewing data. Any queries identified through this review will be 
managed within the systems established for query resolution and tracking. Inquiries related to study 
conduct, which require further information or action will be discussed within the study team for appropriate 
and documented escalation plans. It is expected that response to data clarification requests and other 
trial-related inquiries will occur throughout the course of the study through regular communication with the 
site monitor, the Sponsor or representatives, and review/entry of data into the electronic study database. 
 
At any time during the course of the study, representatives of the FDA and/or local regulatory agencies 
may review the conduct or results of the study at the investigational site. The investigator must promptly 
inform NYU PCC CTO and BMS of any audit requests by health authorities, and will provide BMS with the 
results of any such audits and with copies of any regulatory documents related to such audits. 
 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use personal 
identifiable health information may be required from each patient before commencement of research 
activities. This authorization document must clearly specify what parties will have access to a patient’s 
personal health information, for what purpose and for what duration. 
 
 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a standardized   
data and safety monitoring, which includes scientific peer review, IRB review and DSMC review as well as 
internal auditing. 
 
The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal investigator in 
conjunction with the research nurses, data manager and research team. 
 
(2) DSMC, quarterly 
 
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by the trial PI for 
continuation of the protocol. It includes a summary of all AEs, total enrollment with demographics, 
protocol violations, and current status of subjects as well as available research data. 
 
In addition, the quality assurance unit will monitor this trial every 4-6 weeks, this includes real- time 
review of all eCRFs to ensure completeness and to verify adherence to the protocol; the 
completeness, accuracy and consistency of the data; and adherence to ICH Good Clinical Practice 
guidelines. Additionally, a first subject audit is to be conducted within four weeks of enrollment. 
14.1 Subsite QC monitoring 
 
Monitoring visits are done remotely unless otherwise specified, via remote EMR access. If not possible, 
secure email exchange will be utilized. The quality assurance specialist will confirm an upcoming 


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monitoring visit with a Subsite Investigator and staff. If remote EMR access is not available, then the 
Subsite Coordinator will ensure that all source documents for subjects are de-identified and labeled only 
with the subject ID number(s), and emails all requested documents to the quality assurance specialist by 
the specified visit date. All documents are reviewed and a monitoring report is submitted within 5  
business days from the date of the visit. Any outstanding documents will be listed in the report as a high- 
priority request for the next monitoring visit. It is expected that response to data clarification requests and 
other trial-related inquiries will occur throughout the course of the study through regular communication 
with the site monitor, the Sponsor or representatives, and review/entry of data into the electronic study 
database. Continued non-compliance and failure to submit documentation will result in the suspension of 
subject enrollment at the site, until the documents have been received. 
 
 
 
15 Ethics/Protection of Human Subjects 
15.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
 
15.2 Institutional Review Board 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form  
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
 
 
15.3 Informed Consent Process 
 
15.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The following consent materials are submitted with this protocol 
Informed Consent. 
 
 
15.3.2 Consent Procedures and Documentation 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB- 
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants should have 
the opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. 
The participant will sign the informed consent document prior to any procedures being done specifically 


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for the study. The participants may withdraw consent at any time throughout the course of the trial. A 
copy of the signed informed consent document will be given to the participants for their records. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The 
consent process, including the name of the individual obtaining consent, will be thoroughly documented in 
the subject’s research record. Any alteration to the standard consent process (e.g. use of a translator, 
consent from a legally authorized representative, consent document presented orally, etc.) and the 
justification for such alteration will likewise be documented. 
 
The consenting process and documentation will follow Standard Operating Procedures (Obtaining 
Informed Consent for Clinical Trials) of the NYULMC PCC CTO. 
 
 
15.3.3 Informed Consent 
Consent will be obtained only by a participating investigator who has completed requisite training for 
human subject research and has been instructed by the Principal Investigator about the research study 
and consent process. Investigators will review the informed consent form with patients and address any 
questions or concerns prior to obtaining written informed consent for participation and HIPAA 
authorization. 
 
Patients will be given adequate time to read the consent form. They will be given time to ask questions 
about the study in private exam rooms. Questions will be answered by a participating physician, or 
qualified research study team member all of whom have completed requisite training for human subject 
research. Investigators will review the informed consent form with patients and address any questions or 
concerns prior to obtaining written informed consent for participation. Investigators will stress that 
participation in the study is completely voluntary and will not affect the care patients receive or result in 
any loss of benefits to which patients are otherwise entitled. 
 
For non-English speaking patients, institutional translation services will be utilized. All procedures for 
consenting non-English speaking patients will be in accordance with NYU Langone Health PCC CTO 
guidelines and policies. 
 
For patients who cannot read; a witness, not related to the research study will be present. The consent 
will be read to the patient. The patient will also be allowed to ask any questions s/he may have. The 
investigator will ask the patient questions to ensure s/he understands the study. If the investigator 
determines the subject understands the study, the patient will mark an X where his/her name would go 
and the witness will sign the consent form. 
 
 
15.3.4 Documentation of Consent 
The Principal Investigator or IRB approved sub-investigator will be responsible for documentation in the 
medical record that consent has been obtained from all participants. A signed copy of the consent form 
will be given to each participant. Original consent forms will be stored in the subject’s medical chart. 
 
 
15.4 Participant and Data Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 


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• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization. For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will   
be transmitted to and stored at NYU Langone Medical Center. This will not include the participant’s  
contact or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used by 
clinical sites and by NYU Langone Medical Center research staff will be secured and password protected. 
At the end of the study, all study databases will be de-identified and archived at the NYU Langone  
Medical Center. 
 
 
 
15.4.1 Research Use of Stored Human Samples, Specimens, or Data 
• Intended Use: Samples and data collected under this protocol may be used to provide a tertiary 
treatment option for patients with locally advanced unresectable pancreatic cancer. No genetic 
testing will be performed. 
• Storage: Access to stored samples will be limited to the study team. Samples and data will be 
stored using codes assigned by the investigators. Data will be kept in password-protected 
computers. Only investigators will have access to the samples and data. 
• Tracking: Data will be tracked using Trialmaster. 
o Disposition at the completion of the study: All stored samples will be sent to CBRD . 
Study participants who request destruction of samples will be notified of compliance with 
such request and all supporting details will be maintained for tracking. However, 
withdrawal of consent with regard to biosample storage will not be possible after the 
study is completed 
 
 
 
15.5 Future Use of Stored Specimens 
 


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Data collected for this study will be analyzed and stored at NYU Langone Health. After the study is 
completed, the de-identified, archived data will be transmitted to and stored via an electronic database 


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system, under the supervision of Dr. Deirdre Cohen, with the potential for use by other researchers 
including those outside of the study. Permission of storage of samples, specimens, and data are optional 
to participate in this future use study and will be included in the informed consent. Subjects have the option 
to permit/decline the banking of their samples and data for future research (beyond the scope of the 
study) and will be asked to indicate their decision on the informed consent form. They can choose to/not 
to allow this long-term storage for future research and still be in the study. 
 
With the participant’s approval and as approved by local IRBs, de-identified biological samples will be 
stored at the NYU Center for Biospecimen Research & Development. These samples could be used for 
research into the causes of pancreatic cancer, its complications and other conditions for which individuals 
with pancreatic cancer are at increased risk, and to improve treatment. True genetic testing will not be 
performed on the samples, however data from the research could potentially predict patterns within the 
samples. The CBRD will also be provided with a code-link that will allow linking the biological specimens 
with the phenotypic data from each participant, maintaining the masking of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research.. 
 
When the study is completed, access to study data and/or samples will be provided through the 
supervision of the principal investigator, Dr. Deirdre Cohen, these samples will be stored indefinitely. 
 
 
 
16 Data Handling and Record Keeping 
16.1 Data Collection and Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained 
and captured in a progress note and maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into Trialmaster, a 21 CFR Part 11-compliant data capture system 
provided by DataCore. The data system includes password protection and internal quality checks, such 
as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered directly from the source documents. 
 
16.2 Study Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a longer 
period if required by an agreement with the sponsor. In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained. 


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16.3 Protocol Deviations 


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A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements.  All protocol deviations must be 
addressed in study source documents and reported to IRB Program Official at the time of annual 
continuing review.  If a protocol deviation is determined to be reportable new information, the IRB will be 
notified immediately. 
 
 
16.4 Publication and Data Sharing Policy 
 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s responsibility 
to register the trial in an acceptable registry, so the research results may be considered for publication in 
ICMJE member journals. The ICMJE does not review specific studies to determine whether registration is 
necessary; instead, the committee recommends that researchers who have questions about the need to 
register err on the side of registration or consult the editorial office of the journal in which they wish to 
publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register 
and report results of certain "applicable clinical trials": 
 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations 
of a product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 
• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 


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17 Study Finances 
17.1 Funding Source 
 
17.2 Participant Reimbursements or Payments 
No subjects will receive payments or stipends for participation in this research study. BMS may provide 
coverage for tests and/or procedures that are a part of the research study, if it is not covered by the 
subject’s insurance. 
 
 
18 Study Administration 
18.1 Study Leadership 
 
The Steering Committee will govern the conduct of the study. The Steering Committee will be composed 
of the Study Chairman, the PI of the Coordinating Center, the PI of the clinical sites, and designated 
members of the study team The Steering Committee will meet monthly to discuss the trial’s progress, 
these meetings are facilitated by CTO’s quality assurance specialists. 
 
 
19 Conflict of Interest Policy 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that   
has been reviewed and approved by the study sponsor prior to participation in this study. All NYULH 
investigators will follow the applicable University conflict of interest policies. 


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20 Schedule of Events 
 
 
Activity 
 
Screening/ 
Baseline  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
 
Subsequent Cycles 
(cycle = 14 days) 
 
End of Study 
Visit 
Day -28 to -1 
 
Day 1 
 
Day 
8 
Day 1 
(Day 15) 
Day 8 
(Day 
22) 
Day 10- 
14 
(Day 24- 
28) 
Day 1 
(Day 
29) 
Day 8 
(Day 
36) 
Day 1 
(Day 
43) 
Day 8 
(Day 
50) 
Day 1  
Day 8  
 
Study team 
procedures 
Informed Consent 
X 
Eligibility 
Assessment 
X 
Medical History 
X 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fiducial Placement 
X 
 
 
Carbiralizumab 
X 
X 
X 
X 
X 
 
Nivolumab 
X 
X 
X 
X 
X 
 
SBRT 
X 
 
 
Cardiology 
assessments 
 
 
Electrocardiogram 
X 
 
X 
Laboratory 
Assessments 
 
 
Comprehensive 
metabolic profile1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with 
differential1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LDH1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CPK1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Amylase & Lipase1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free T4, TSH2 
X 
X 
X 
X 
X 
X 
X 
CA 19-93 
X 
X 
X 
X 
PT/PTT4 
X 
 
Pregnancy Test 
X 
X 
 
Urinalysis4 
X 
 
Imaging 
Assessments 
 
CT chest, abdomen 
and pelvis5 
X 
X 
X5 
 
 
Correlative 
Studies6 
 
Research 
Blood for 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Tumor 
Biopsy 
X 
 
 
 
X 
 
 
 
 
Follow up 
Patient 
Contact7 


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1. To be collected at weekly intervals for the first 42 days (ie cycles 1-3) and then Day 1 of every subsequent cycle (ie every 14 days) 
2. To be collected on Day 1 of every cycle, ie every 14 days 
3. To be collected on Day 1 of every other cycle, ie Cycle 1 day, Cycle 3 Day 1, Cycle 5 Day 1 etc 
4. To be collected at screening and then as clinically indicated 
5. Baseline imaging with CT chest, abdomen and pelvis with IV contrast to be done within 28 days of Cycle 1 Day 1. Post SBRT 
imaging to be done Cycle 2 Day 12 (+/- 2 days). CT chest, abdomen, and pelvis (prior to cycle 6 (+/- 3 days and then every 8 weeks 
thereafter (+/-7 days). 
6. Research blood will be collected prior to initiation of treatment on Cycle 1 Day1 and then every week thereafter for the first 6 weeks 
on study through Cycle 4 Day 1. 
7. Patients will be followed for survival every 12 weeks (± 1 week) from the date of last dose of investigational drug(s), either in person or 
by telephone contact, up to 18 months, then every 6 months thereafter until death or lost to follow-up (for a maximum of 5 years after final 
patient completes treatment).. Information will be obtained on subsequent cancer treatments, SAE’s and AE’s possibly or probably 
related to investigational drug(s) for up to 100 days, date and cause of death (if subject deceased). 


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21 References 
 
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2. 
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Winter, J.M., et al., 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution 
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Fatima, J., et al., Pancreatoduodenectomy for ductal adenocarcinoma: implications of positive 
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Crane, C.H., Hypofractionated ablative radiotherapy for locally advanced pancreatic cancer. J 
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Hamilton, J.A. and A. Achuthan, Colony stimulating factors and myeloid cell biology in health and 
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Masteller, E.L. and B.R. Wong, Targeting IL-34 in chronic inflammation. Drug Discov Today, 
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human malignant tumors. Cancer Sci, 2014. 105(1): p. 1-8. 
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Wainberg, Z., et al. First-in-Human Phase 1 Dose Escalation and Expansion of a Novel 
Combination, Anti–CSF-1 Receptor (cabiralizumab) Plus Anti–PD-1 (nivolumab), in Patients With 
Advanced 
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Sharpe, A.H., et al., The function of programmed cell death 1 and its ligands in regulating 
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1 ligand-2 expression in human esophageal cancer. Clin Cancer Res, 2005. 11(8): p. 2947-53. 
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34. 
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(Berl), 2003. 81(5): p. 281-7. 
35. 
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ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res, 2007. 13(7): p. 2151- 
7. 
36. 
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and immunosubversion. Nat Rev Immunol, 2006. 6(10): p. 715-27. 
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458(7235): p. 206-10. 
38. 
Wang, C., et al., In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and 
in vivo toxicology in non-human primates. Cancer Immunol Res, 2014. 2(9): p. 846-56. 
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41. 
Koong, A.C., et al., Phase I study of stereotactic radiosurgery in patients with locally advanced 
pancreatic cancer. Int J Radiat Oncol Biol Phys, 2004. 58(4): p. 1017-21. 
42. 
Koong, A.C., et al., Phase II study to assess the efficacy of conventionally fractionated 
radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic 
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43. 
Schellenberg, D., et al., Gemcitabine chemotherapy and single-fraction stereotactic body 
radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys, 2008. 72(3): p. 678-86. 
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Schellenberg, D., et al., Single-fraction stereotactic body radiation therapy and sequential 
gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys, 2011. 
81(1): p. 181-8. 
45. 
Herman, J.M., et al., Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body 
radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer, 2015. 
121(7): p. 1128-37. 


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46. 
Chang, B.K. and R.D. Timmerman, Stereotactic body radiation therapy: a comprehensive review. 
Am J Clin Oncol, 2007. 30(6): p. 637-44. 
47. 
Timmerman, R., et al., Optimizing dose and fractionation for stereotactic body radiation therapy. 
Normal tissue and tumor control effects with large dose per fraction. Front Radiat Ther Oncol, 2007. 40: 
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Moningi, S., et al., The Role of Stereotactic Body Radiation Therapy for Pancreatic Cancer: A 
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Pollom, E.L., et al., Single- versus multifraction stereotactic body radiation therapy for pancreatic 
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Neoptolemos, J.P., et al., Comparison of adjuvant gemcitabine and capecitabine with 
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Seifert, L., et al., Radiation Therapy Induces Macrophages to Suppress T-Cell Responses 
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Fukunaga, A., et al., CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating 
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De Monte, L., et al., Intratumor T helper type 2 cell infiltrate correlates with cancer-associated 
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Hiraoka, N., et al., Prevalence of FOXP3+ regulatory T cells increases during the progression of 
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Lee, S.M., et al., Validation of a Proposed Tumor Regression Grading Scheme for Pancreatic 
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Huang, A.C., et al., T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. 
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60. 
Kamphorst, A.O., et al., Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted 
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61. 
Daley, D., et al., gammadelta T Cells Support Pancreatic Oncogenesis by Restraining alphabeta 
T Cell Activation. Cell, 2016. 166(6): p. 1485-1499 e15. 


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Appendix 1: 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
 
Highly effective methods of contraception have a failure rate of < 1% when used 
consistently and correctly. WOCBP and female partners of male subjects, who are 
WOCBP, are expected to use one of the highly effective methods of contraception listed 
below. Male subjects must inform their female partners who are WOCBP of the 
contraceptive requirements of the protocol and are expected to adhere to using 
contraception with their partner. Acceptable contraception methods of include: 
• 
Progestogen: hormonal contraception associated with inhibition of ovulation 
 
• 
Hormonal methods of contraception including oral contraceptive pills  containing 
combined estrogen + progesterone 
 
• 
Vaginal Ring 
 
• 
Injectables 
 
• 
Implants 
 
• 
Intrauterine Devices (IUDs) such as Mirena® 
 
• 
Non-hormonal IUDs, such as ParaGard ® 
 
• 
Bilateral Tubal Occlusion 
 
• 
Vasectomised partner with documented azoospermia 90 days after procedure. 
A Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success. 
 
 
• 
Intrauterine Hormone-Releasing System (IUS). 
• 
Complete Abstinence 
Complete Abstinence is defined as the complete avoidance of heterosexual 
intercourse. Complete abstinence is an acceptable form 


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Appendix 2: 
 
LABORATORY ABNORMALITIES MANAGEMENT TABLE 
 
 
 
 
 
Grade of Liver Test 
Elevation 
Management 
Follow-Up 
CK > 10x ULN 
– Consider measuring CK isoenzymes 
as clinically indicated 
If CK isoenzymes are abnormal 
Consider checking troponin levels 
Consider other assessments (including uromyoglobin) 
as clinically indicated 
If CK isoenzymes are normal 
Continue dosing, per protocol 
Monitor CK level as clinically indicated 
CK or LDH > 15 to 
 20x ULN 
Delay cabiralizumab and nivolumab 
therapy per protocola 
Measure CK isoenzyme panel to identify 
source of elevation 
Increase frequency of monitoring (every 
48-72 hours or more, as clinically 
indicated) 
If CK or LDH returns to  15 xULN within  
28 days: 
Resume routine monitoring, resume cabiralizumab 
and nivolumab therapy at same dose level as per 
protocol 
If CK isoenzyme panel is normal continue monitoring 
the subject. 
If CK isoenzyme panel is abnormal then consider 
measuring troponins. 
If troponins are abnormal, contact BMS Medical 
Monitor to determine if the subject can be retreated. 
If CK or LDH elevations persist at the same level 
> 28 days or worsen: 
Discontinue further dosing 
CK or LDH > 20 
xULN 
– Discontinue cabiralizumab and 
nivolumab therapy per protocol 
– Follow up until resolution 
a. If the AE requiring a dose delay was due to one of the study drugs, the non-offending drug may be continued, 
taking into account the safety and clinical benefit to the patient. 
Laboratory Abnormalities Management (CK and LDH) 


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Appendix 3: 
ADVERSE EVENT MANAGEMENT FOR CABIRALIZUMAB AND NIVOLUMAB 
 
Gastrointestinal Adverse Event Management 
Rule  out  noninflammatory  causes.  If  a  noninflammatory  cause  is  identified,  treat  accordingly  and  continue  nivolumab  therapy. 
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis. 
Grade of Diarrhea/Colitis 
(NCI CTCAE v5.0) 
Management 
Treatment and Follow-Up 
Grade 
1: 
Diarrhea:<4 
stools/day 
over 
baseline; 
Colitis: asymptomatic 
– Continue cabiralizumab and 
nivolumab therapy per protocol 
– Symptomatic  treatment 
– Close monitoring for worsening symptoms 
– Educate patient to report worsening immediately 
If worsens: 
– Treat as Grade 2 or ¾ 
Grade 
2: 
Diarrhea: 
4-6 
stools/day over baseline; IV 
fluids indicated 
<24 hours; not interfering with 
ADL; Colitis: abdominal pain; 
blood in stool 
– Delay cabiralizumab and nivolumab per 
a 
protocol 
– Symptomatic  treatment 
If improves to Grade 1 in ≤4 days: 
– Resume cabiralizumab and nivolumab therapy per protocol 
If persists in 5–7 days or recurs: 
– 0.5–1 mg/kg/day methylprednisolone or oral equivalent 
– When symptoms improve to Grade 1, taper steroids over at least 1 
month, consider prophylactic antibiotics for opportunistic infections, 
and resume cabiralizumab and nivolumab therapy per protocol 
If worsens or persists after >3-5 days with oral steroids: 
– Treat as Grade 3 or 4 
Grade 3–4: Diarrhea (G3): 
7 stools 
per 
day 
over  
baseline; 
incontinence; 
IV  
fluids 224 hours; interfering  
with  
ADL; Colitis  (G3):  
Severe 
abdominal 
pain,  
medical 
 
intervention  
indicated,   and peritoneal 
signs 
Grade 
4: 
Life-threatening 
perforation 
– Delay or discontinue cabiralizumab and 
b 
nivolumab therapy per protocol 
– 1 to 2 mg/kg/day methylprednisolone IV 
c 
or IV equivalent 
– Add prophylactic antibiotics for 
opportunistic  infections 
– Consider lower endoscopy if clinically 
indicated 
If Grade 3 AE improves to Grade 1 or baseline within 28 days: 
– Taper steroids over at least 1 month 
– Resume dosing of cabiralizumab and nivolumab 
If Grade 4: 
– Permanently discontinue cabiralizumab and nivolumab 
– Continue steroids until Grade 1, then taper steroids over at least 1 
month 
If persists for >3-5 days or recurs after improvement: 
– Add infliximab 5 mg/kg (if no contraindications) 
– Follow up until resolution 
– Note: Infliximab should not be used in cases of perforation or sepsis 
a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient 


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b 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient 
c 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
Renal Adverse Event Management 
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue nivolumab therapy. 
Grade 
of 
Creatinine 
Elevation 
(NCI CTCAE v 5.0) 
Management 
Follow-Up 
Grade 1: Creatinine >1.0x 
to 1.5x baseline; >1 x ULN 
to 1.5x ULN 
– Continue cabiralizumab and nivolumab 
therapy at the same dose level per 
protocol 
– Monitor creatinine weekly 
If returns to baseline : 
– Resume routine creatinine monitoring per protocol 
If worsens: 
– Follow as stated below 
Grade 2: Creatinine >1.5x to 
3.0x baseline; >1.5 x ULN 
to 3.0x ULN 
– Delay cabiralizumab and nivolumab 
a 
therapy per protocol 
– Monitor creatinine every 2 to 3 days 
– 0.5 to 1 mg/kg/day 
methylprednisolone IV or oral 
b 
equivalent 
– Consider renal biopsy if clinically 
indicated 
If returns to Grade 1 or baseline before the next dosing visit: 
– Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume cabiralizumab 
and nivolumab therapy at the same dose level 
– Routine creatinine monitoring per protocol 
If elevations persist for >14 days or worsen: 
– Treat as Grade 4 
Grade  3:  Creatinine  >3.0  x 
baseline; 
>3.0x ULN to 6.0x ULN 
– Delay cabiralizumab and nivolumab 
a 
therapy per protocol 
– Monitor creatinine every 2 to 3 days 
– 0.5 to 1 mg/kg/day 
methylprednisolone IV or oral 
b 
equivalent 
– Consider renal biopsy if clinically 
indicated 
If returns to Grade 1 or baseline before the next dosing visit: 
– Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume cabiralizumab 
and nivolumab therapy at the same dose level 
– Routine creatinine monitoring per protocol 
If elevations persist for >14 days or worsens: 
– Treat as Grade 4 
Grade   4: 
Creatinine 
>6.0x 
ULN 
– Discontinue cabiralizumab and c 
nivolumab therapy per protocol 
– 1 to 2 mg/kg/day methylprednisolone 
b 
IV or IV equivalent 
– Consult nephrologist 
– Consider renal biopsy if clinically 
indicated 
If returns to baseline or Grade 1: 
– Taper steroids over at least 1 month and add prophylactic 
antibiotics for opportunistic infections 
If worsens: 
– Follow up until resolution 
– Clinical referrals as needed 


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a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient. 
b 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
c 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient. 
Pulmonary Adverse Event Management 
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue nivolumab therapy. Evaluate with 
imaging and pulmonary consultation. 
Grade of Pneumonitis 
(NCI CTCAE v 5.0) 
Management 
Follow-Up 
Grade 
1: 
Radiographic 
changes only 
– Consider delay of cabiralizumab and nivolumab 
therapy 
– Monitor for symptoms every 2 to 3 days 
– Consider pulmonary and infectious disease 
consults 
– Re-image at least every 3 weeks 
If worsens: 
– Treat as Grade 2 or 3–4 
Grade 2: Mild to moderate 
new symptoms 
– Delay cabiralizumab and nivolumab therapy per 
a 
protocol 
– Pulmonary and infectious disease consults 
– Monitor symptoms daily, consider 
hospitalization 
– 1 mg/kg/day methylprednisolone IV or oral 
equivalent 
– Consider bronchoscopy and lung biopsy, 
if clinically indicated 
– Re-image every 1–3 days 
If improves <14 days: 
– When symptoms return to near baseline, taper steroids 
over at least 1 month, consider prophylactic antibiotics for 
opportunistic infections and resume cabiralizumab and 
nivolumab therapy per protocol 
If does not improve after 2 weeks or worsens: 
– Treat as Grade 3–4 
Grade 
3–4: 
Severe 
new 
symptoms; 
New/worsening 
hypoxia; 
Life-threatening 
– Discontinue cabiralizumab and nivolumab 
b 
therapy per protocol 
– Hospitalization 
– Pulmonary and infectious disease consults 
– 2 to 4 mg/kg/day methylprednisolone IV or IV 
c 
equivalent 
– Add prophylactic antibiotics for opportunistic 
infections 
– Consider bronchoscopy, lung biopsy if 
clinically indicated 
If improves to baseline: 
– Taper steroids over at least 6 weeks 
If does not improve after 48 hours or worsens: 
– Add additional immunosuppression (eg, 
cyclophosphamide, IVIG, or mycophenolate mofetil) 
– Follow up until resolution 


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a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient. 
b 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by patient. 
c 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


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Page 102 
 
 
 
 
 
 
Hepatic Adverse Event Management 
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue nivolumab therapy. Consider imaging for obstruction. 
Grade of Liver 
Test Elevation 
Management 
Follow-Up 
AST or ALT >3.0x ULN 
and 
Total bilirubin >2x ULN 
or 
INR > 1.5 
– Discontinue cabiralizumab and nivolumab per 
protocol 
– Start steroids 
– Continue LFT monitoring per protocol until resolution. 
– Continue monitoring for and other associated clinical signs or symptoms 
– Evaluate for non-drug related causes of the laboratory abnormalities 
(eg, obstruction, viral infection, Gilbert’s disease, etc.) 
– Under selected circumstances (eg, alternative etiology is identified), 
patient may receive additional therapy only after consultation and 
agreement between the the investigator and Sponsor if receiving 
additional treatment with cabiralizumab and nivolumab is in the best 
interest of the patient (eg, if the subject has demonstrated a response to 
therapy) 
AST or ALT >5 to ≤12 
xULN 
and 
Total bilirubin 2x ULN 
– Continue cabiralizumab and nivolumab therapy if 
there are no clinical signs of significant muscle  
or hepatic damage 
– Increase frequency of monitoring of AST, ALT, 
bilirubin, alkaline phosphatase, and INR (every 
48-72 hours or more frequently, as clinically 
indicated) 
– Monitor for other clinical symptoms (fatigue, 
nausea, vomiting, abdominal pain, fever, rash, 
and/or eosinophilia) 
– Contact the PI if there are clinical signs of muscle or hepatic  injury or 
other clinical symptoms 
– Contact the PI if there is a concurrent increase of bilirubin, AST, ALT, or 
alkaline phosphatase 
– Notify the PI if there is an AST or ALT increase >5x ULN 
– Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or the trial drug has been discontinued and the subject is 
asymptomatic 
– Consider gastroenterology or hepatology referral 
AST or ALT > 12 to 
 20 xULN 
and 
Total bilirubin  2 xULN 
or 
Isolated total bilirubin > 
2 to  3 xULN 
– Delay cabiralizumab and nivolumab therapy per 
a 
protocol 
– Increase frequency of monitoring of (including but 
not limited to) AST, ALT, bilirubin, alkaline 
phosphatase, and INR (every 48-72 hours or more 
frequently, as clinically indicated) 
– If there is a 2-fold ALT increase compared to the 
previous measurement, start steroids immediately 
– Consider steroid treatment on any total bilirubin 
increase of over 2.0x ULN 
– If there is a concurrent increase of alkaline 
If AST/ALT return to 12x ULN within 7 days: 
– Resume routine monitoring 
– Resume cabiralizumab and nivolumab therapy at same dose level per 
protocol 
If elevations persist and remain at the same level >7 days but 28 days: 
– Start steroids immediately and discontinue further dosing 
– Continue monitoring and consider dosing the subject with nivolumab 
therapy at the same dose level 
– Consider tapering steroids over at least 1 month 
If elevations persist at the same level >28 days or worsen: 
– Discontinue cabiralizumab and nivolumab therapy per protocol 
– 0.5-1 mg/kg/day methylprednisolone or oral equivalent, and when LFT 
returns to Grade 1 or baseline, taper steroids over at least 1 month 


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Hepatic Adverse Event Management 
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue nivolumab therapy. Consider imaging for obstruction. 
Grade of Liver 
Test Elevation 
Management 
Follow-Up 
phosphatase along with ALT, start steroids 
immediately 
– Monitor for other clinical symptoms (fatigue, 
nausea, vomiting, abdominal pain, fever, rash, 
and/or eosinophilia) 
– Consider prophylactic antibiotics for opportunistic infections 
– Discuss with PI 
AST or ALT > 20 
xULN 
or 
Total bilirubin >3 
xULN 
– Discontinue cabiralizumab and nivolumab therapyb 
– Increase frequency of monitoring to every 1 to 2 
days 
– Consider 1 to 2 mg/kg/day methylprednisolone IV 
or IV equivalentc 
– Consider adding prophylactic antibiotics for 
opportunistic  infections 
– Consult gastroenterologist and hepatologist, if 
clinically indicated 
If returns to Grade 2: 
– Consider steroid taper over at least 1 month if they have been started 
If does not improve in >3–5 days, worsens, or rebounds: 
– Consider adding mycophenolate mofetil 1 g BID 
– If no response within an additional 3–5 days, consider other 
immunosuppressants per local guidelines 
– Follow up until resolution 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit to 
the patient. 
b 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient. 
c 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


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Page 104 
 
 
 
Endocrinopathy Adverse Event Management 
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue nivolumab therapy. Consider 
visual field testing, endocrinology 
consultation, and imaging. 
Description 
Management 
Follow-Up 
Asymptomatic TSH elevation 
–  Continue cabiralizumab and nivolumab therapy per 
protocol 
If TSH <0.5x LLN or TSH >2x ULN, or consistently 
out of range in 2 subsequent measurements: 
–  Include free T4 at subsequent cycles as clinically 
indicated; consider endocrinology consult 
Symptomatic  endocrinopathy 
– Evaluate endocrine function 
– Consider pituitary scan 
Symptomatic with abnormal lab/pituitary scan: 
– Delay caabiralizumab and nivolumab therapy per 
protocol 
– 1 to 2 mg/kbg/day methylprednisolone IV or PO 
equivalent 
– Initiate appropriate hormone therapy 
No abnormal lab/pituitary MRI scan but symptoms 
persist: 
– Repeat labs in 1–3 weeks and MRI in 1 month 
If improves within 28 days (with or without 
hormone replacement): 
– Taper steroids over at least 1 month and consider 
prophylactic antibiotics for opportunistic infections 
– Resume cabiralizumab and nivolumab therapy per 
protocol 
– Patients with adrenal insufficiency may need to 
continue steroids with mineralocorticoid component 
If persists for over 28 days: 
– Delay cabiralizumab and nivolumab therapy 
– Continue steroids as needed 
– Upon resolution, discuss with PI if patients are 
clinically stable on further dose delay and 
discontinuation 
– Follow up until resolution or return to baseline 
Suspicion of adrenal crisis 
(e.g. 
severe 
dehydration, 
hypotension, shock out of 
proportion 
to 
 
current 
illness) 
– Delay or discontinue cabiralizuma,acb and 
nivolumab therapy per protocol 
– Rule out sepsis 
– Stress dose of IV steroids with mineralocorticoid 
activity 
– IV fluids 
– Consult  endocrinologist 
– If crisis is ruled out, treat as above for 
symptomatic endocrinopathy 
a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient. 
b 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


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Page 105 
 
 
 
c 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient. 
 
Skin Adverse Event Management 
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue nivolumab therapy. 
Grade of Rash 
(NCI CTCAE v 5.0) 
Management 
Follow-Up 
Grade 1–2: Covering  30% BSAa 
– Symptomatic therapy (e.g. 
antihistamines, topical steroids) 
– Continue cabiralizumab and 
nivolumab therapy per protocol 
If persists >1-2 weeks or recurs: 
– Consider skin biopsy 
– Delay cabiralizumab and nivolumab therapy per protocol 
– Consider 0.5–1 mg/kg/day methylprednisolone IV or oral 
equivalent. 
– Once improving ,taper steroids over at least 1 month, 
consider prophylactic antibiotics for opportunistic infections, 
and resume cabiralizumab and nivolumab therapy per 
protocol 
If worsens: 
– Treat as Grade 3–4 
Grade 3–4: Covering > 30% 
BSA; 
life-threatening 
consequencesd 
– Delay or discontinue cabiralizumab 
and nivolumab therapy per 
b,c 
protocol 
– Consider skin biopsy and dermatology 
consult 
– 1 to 2 mg/kg/day IV 
methylpreddnisolone IV or IV 
equivalent 
If improves to Grade 1 within 28 days: 
– Taper steroids over at least 1 month and add prophylactic 
antibiotics for opportunistic infections 
– Resume cabiralizumab and nivolumab therapy per protocol 
If persists > 28 days or worsens: 
–Consider to discontinue cabiralizumab and nivolumab therapy 
per protocol 
a 
Refer to NCI CTCAE v 5.0 for term-specific grading criteria. 
b 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient 
c 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient 
d 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


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Neurological Adverse Event Management 
Grade of Neurological 
Toxicity (NCI CTCAE v 
5.0) 
Management 
Follow-Up 
Grade 1: Asymptomatic or mild 
symptoms; Intervention not indicated 
– Continue cabiralizumab and nivolumab 
therapy per protocol 
If worsens: 
– Treat as Grade 2, 3, or 4 
Grade 2: Moderate symptoms; 
l imiting instrumental ADL 
– Delay cabiralizumab and 
a 
nivolumab therapy per protocol 
– Treat symptoms per local guidelines 
b 
– Consider 0.5 to 1 mg/kg/day 
methylprednisolone IV or PO 
If improves to baseline within 28 days: 
– Resume cabiralizumab and nivolumab therapy at same 
dose level per protocol when improved to baseline 
If worsens or persists after 28 days: 
– Treat as Grade 3-4 
Grade 3–4: Severe symptoms; 
limiting self-care ADL; life- 
threatening 
– Discontinue cabiralizumab and 
c 
nivolumab therapy 
– Obtain neurology consult 
– Treat symptoms per local 
guidelines 1 to 2 mg/kg/daby IV 
methylprednisolone or PO 
– Add prophylactic antibiotics for 
opportunistic infections 
If improves to Grade 2: 
– Taper steroids over at least 1 month 
If worsens or atypical presentation: 
– Consider IVIG or other immunosuppressive therapies per 
local guidelines 
– Continue follow-up until resolution 
a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient. 
b 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
c 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient. 


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Page 107 
 
 
 
 
 
 
 
 
Periorbital Edema Adverse Event Management 
Grade of Periorbital Edema 
(NCI CTCAE v 5.0) 
Management 
Follow-Up 
Periorbital Edema > baseline but 
< Grade 2 
Grade 2 
– Continue cabiralizumab and nivolumab 
therapy per protocol 
– Monitor edema weekly 
– Delay cabiraalizumab and nivolumab therapy 
per protocol 
– Start systemic treatment including stebroids, 
eye drops, or analgesics as needed 
If worsens: 
– Follow as stated below 
If returns to Grade 1 or baseline before the next dosing visit: 
– Continue systemic treatment 
– Resume cabiralizumab and nivolumab therapy at same dose 
level without delay 
– Routine eye monitoring per protocol, if clinically stable 
If swelling persists >14 days but returns back to baseline or 
normal within 28 days: 
– Continue nivolumab and cabiralizumab dosing at same level 
– If recurs at Grade 2 or above, discontinue cabiralizumab and 
nivolumab therapy 
Grade ≥3 
– Discontinue cabiralizumab and c 
nivolumab therapy per protocol 
– Systemic treatment including stebroids, eye 
drops, or analgesics as needed 
– Consult an ophthalmologist if needed 
If returns to Grade 1 after discontinuation: 
– Systemic treatment including tapering steroids as needed 
– Any follow-up and ophthalmology consults, if clinically 
indicated 
– Monitor and follow up until resolution 
a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient. 
b 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
c 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient. 


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Infusion Reaction Adverse Event Management 
Grade of Infusion 
Reactions 
(NCI CTCAE v 5.0) 
Management 
Follow-Up 
Grade 1 
– Decrease infusion rate of cabiralizumab and 
nivolumab therapy per protocol and restart at normal 
infusion rate once symptoms subside 
– Monitor patient and use symptomatic treatment as 
clinically indicated (which includes antihistamines 
and NSAIDs) 
If infusion reaction symptoms subside within 3 hours of 
nivolumab 
– cabiralizumab therapy can be given without any prophylactic 
medications if the reaction is nivolumab related 
– Subsequent dosing should include prophylactic 
pre-infusion medications for nivolumab 
– If the infusion reaction is related to cabiralizumab therapy, 
prophylactic medication should be given prior to dosing of 
cabiralizumab and nivolumab 
– Continue cabiralizumab and nivolumab dosing at same level 
Grade 2 
– Interrupt cabiralizumab and/or nivolumab 
a,b 
infusion per protocol 
– Systemic treatment including NSAIDs, 
c 
corticosteroids and antihistamines 
– Normal saline infusion and constant monitoring of 
vitals and other parameters 
– If symptoms resolve within 3 hours, continue 
infusion at 50% rate for 30 minutes and then 
increase to 100% if clinically stable 
– Resume cabiralizumab and nivolumab therapy at same 
dose level and monitor per protocol 
– Pre-infusion prophylactic medications are recommended for 
future 
dosing, including antihistamines, NSAID, and 
corticosteroids up to  25 mg as needed. 
If symptoms recur: 
– Discontinue treatment at the visit 
– Discuss with PI as needed 
Grade ≥3 
– Discontinue cabiralizumab and nivolumab therapy per 
b 
protocol 
– Systemic treatment including NSAID , corticosteroids, 
c 
and antihistamines 
– Normal saline infusion and constant monitoring of 
vitals and other parameters 
– Follow institutional guidelines for anaphylaxis 
– Bronchodilators as clinically indicated with or 
without hospitalization 
If returns to Grade 1 after discontinuation: 
– Systemic treatment including tapering steroids, 
NSAIDs, and antihistamines until resolution, as 
needed 
– Follow up until resolution 
– Any other clinical referrals, if indicated 
a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient 
b 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient 


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c 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
 
 
Uveitis Adverse Event Management 
Grade of Uveitis 
(NCI CTCAE v5.0) 
Management 
Follow-Up 
Grade 1 
– Observe symptoms 
– Continue cabiralizumab and nivolumab 
therapy 
– Watch for worsening of symptoms including visual disturbances, light 
sensitivity, decrease vision 
– Monitor weekly 
If worsens: 
– Follow as stated below 
Grade 2 
– Delay or discontinue cabiralizumab 
and nivolumab therapy per 
a,b 
protocol 
– Start antibiotics and inflammatory 
c 
medications including steroids 
– Ophthalmologic consult, if clinically 
indicated 
– Immunosuppressive agents (e.g, 
anti-TNF agents such as 
Infliximab) 
If symptoms resolve within 14 days: 
– Continue cabiralizumab and nivolumab therapy at same dose level and 
start tapering of steroid doses 
If symptoms resolve between 14 -28 days: 
– Consider continuing dosing at same dose level for nivolumab and a 
dose level lower for cabiralizumab on resolution to baseline or Grade 1 
and start tapering of steroid doses. 
– If it is Grade 2 drug-related uveitis that does not resolve within 14 
days, consider to discontinue study drug(s) 
If  symptoms  persist  or  worsen  in  28  days  regardless  of  systemic 
treatment: 
– Discontinue both cabiralizumab and nivolumab therapy 
– Continue monitoring of symptoms including visual disturbances, eye pain, 
and dimness of vision and follow up until resolution or return to baseline 
– Continue steroids, antibiotics, and other medications such as 
infliximab, as clinically indicated 
Grade 3 
– Discontinue cabiralizumab and b 
nivolumab therapy per protocol 
– Start antibiotics and inflammatory 
c 
medications including steroids 
– Ophthalmologic consult, if clinically 
indicated 
– Immunosuppressive agents (e.g, 
anti-TNF agents such as 
Infliximab) 
– Discontinue both cabiralizumab and nivolumab therapy 
– Continue monitoring of symptoms including visual disturbances, eye pain, 
and dimness of vision, and follow up until resolution or return to baseline 
– Continue steroids, antibiotics, and other medications such as 
infliximab, as clinically indicated 
– Follow up until resolution 
a 
If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient 


 
b 
If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and 
clinical benefit is shown by the patient 
c 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
 
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