Clinical trial NCT03697564
Conditions: Pancreatic Cancer Stage IV
Keywords: Pancreating Cancer Cancer Stage IV gemcitabine nivolumab cabiralizumab BMS-986227 FPA008 GemCaN Stand Up to Cancer
Sponsor: Hitendra Patel
Start date: 2019-10-31; Completion date: 2023-07-13
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see if the combination of nivolumab + cabiralizumab + gemcitabine can give prolonged disease control in patients with advanced pancreatic cancer compared to gemcitabine alone.

Detailed description:
The purpose of this study is to see if the combination of nivolumab + cabiralizumab + gemcitabine can give prolonged disease control in patients with advanced pancreatic cancer compared to gemcitabine alone.

Cabiralizumab is an antibody (a type of protein) that binds to a molecule called CSF-1r. CSF-1r is a molecule present on different types of cells in your immune system that controls parts of your immune system. Blocking CSF-lr could potentially stop the cancer cells which it appears on from escaping the immune system, which could then act to kill the cancer cells.

Nivolumab is an anti-PD-1 antibody that boost the body's immune system. It works by attaching to and blocking a molecule on white blood cells called PD-1. PD-1 is a protein that is present on different types of cells in your immune system and controls parts of your immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus allowing immune cells to recognize and destroy cancer cells.

Gemcitabine is currently used to treat advanced or metastasized (spread) pancreatic cancer. It is used in patients whose disease cannot be removed by surgery and who have already been treated with other chemotherapy

Arms: arm 1: gemcitabine +nivolumab + cabiralizumab
Interventions: intervention 1: Gemcitabine intervention 2: Nivolumab 10 MG/ML Intravenous Solution [OPDIVO] intervention 3: Cabiralizumab
Intervention descriptions: intervention 1: 1000 mg/m2 IV on days 1, 8, and 15 Q4W intervention 2: 480mg IV on Day 1 Q4W intervention 3: 4mg/kg IV on day 1 and 15 Q4W

Protocol documents:
Prot_SAP_000.pdf: 
Open Label Phase II Trial of Nivolumab + Cabiralizumab 
(BMS-986227, FPA008) + Gemcitabine in Patients with 
Stage IV Pancreatic Cancer Achieving Disease Control in 
Response to First-line Chemotherapy (Gem CaN Trial)
NCT03697564
Document Date: 3/20/2019 


UCSD Moores Cancer Center 
HRPP# 181395 
Protocol Version: 4.2 Protocol 
Date: 03/20/2019 
1 
CONFIDENTIAL 
SU2C Dream Team 
Open Label Phase II Trial of Nivolumab + Cabiralizumab (BMS-986227, FPA008) + 
Gemcitabine in Patients with Stage IV Pancreatic Cancer Achieving Disease Control in 
Response to First-line Chemotherapy (Gem CaN Trial). 
Study Chair (Sponsor-Investigator) 
Hitendra Patel, MD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
E-mail: hip003@ucsd.edu
Research Coordinating Center 
UCSD Moores Cancer Center 
3855 Health Sciences Drive #0698 
La Jolla, CA 92093-0698 
HRPP No: 181395 
Protocol Number: CA025-012 
IND No: 141050 
Protocol 
Date 
Original (v 4.2) 
03/20/2019 
CONFIDENTIAL 
This material is the property of the Moores Cancer Center. 
Do not disclose or use except as authorized in writing by the study sponsor. 
The information contained in this document is the property of UCSD (or under its control), and therefore provided 
to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff and an 
applicable Independent Ethics Committee/Institutional Review Board. It is understood that this information will 
not be disclosed to others without written authorization from the Investigator Sponsor except to the extent 
necessary to obtain informed consent from those persons to whom the trial treatment may be administered 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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LIST OF INVESTIGATORS 
 
 
UCSD Investigators: 
Co PI: Andrew Lowy, MD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
alowy@ucsd.edu 
Paul Fanta, MD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
pfanta@ucsd.edu 
Lawrence Leichman, MD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
lleichman@ucsd.edu 
Tony Reid, MD, PhD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
treid@ucsd.edu 
Adam Burgoyne, MD, PhD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
aburgoyne@ucsd.edu 
Aaron Miller, MD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
ammiller@ucsd.edu 
Shumei Kato, MD 
UCSD Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92093 
smkato@ucsd.edu 
Participating Sites: 
PI: Anup Kasi, MD 
University of Kansas Cancer Center 
4000 Cambridge Street 
Kansas City, Kansas 66160 
akasi@kumc.edu 
PI: Peter O’Dwyer 
University of Pennsylvania, 
Philadelphia, PA 
Peter.O'Dwyer@uphs.upenn.edu 
Consulting Investigator: 
David Propper, MD FRCP 
St Bartholomew’s Hospital, London, UK United Kingdom 
david.propper@bartshealth.nhs.uk 
Lead Scientific Investigator: 
Tannishtha Reya, PhD 
Professor, Department of Pharmacology 
University of California San Diego, School of Medicine 
La Jolla, California 92093 
treya@ucsd.edu 
Biostatisticians: 
Karen Messer, PhD 
University of California, San Diego 
Moores UCSD Cancer Center 
3855 Health Sciences Drive #0901 
La Jolla CA, 92093-0901 
E-mail: kmesser@ucsd.edu 
 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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Minya Pu, M.A. 
Principal Statistician 
Division of Biostatistics and Bioinformatics 
UCSD Moores Cancer Center 
3855 Health Sciences Drive #0901 
La Jolla CA, 92093-0901 
mpu@ucsd.edu 
 
 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
HRPP# 181395 
Protocol Version: 4.2 Protocol 
Date: 03/20/2019 
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INVESTIGATOR PROTOCOL AGREEMENT 
Protocol # 181395; CA025-012 
SU2C Dream Team 
 
Title: Open Label Phase II Trial of Nivolumab + Cabiralizumab (BMS-986227, FPA008) + 
Gemcitabine in Patients with Stage IV Pancreatic Cancer Achieving Disease Control in 
Response to First-line Chemotherapy (Gem CaN Trial).  
 
I confirm that my staff and I have carefully read and understand this protocol. I/we agree to 
comply with the procedures and terms of the clinical trial specified herein. In particular, I/we 
have agreed to: 
 
• 
Abide by all obligations stated on the Form FDA 1572 and on other document(s) required by 
local regulatory authority. 
• 
Comply with Good Clinical Practice (GCP) and all applicable regulatory requirements. 
• 
Maintain confidentiality and assure security of the Sponsor (UCSD), SU2C, and BMS 
confidential documents. 
• 
Obtain Institutional Review Board (IRB) approval of the protocol, any amendment to the 
protocol, and periodic re-approval as required, and to keep the IRB informed of any adverse 
events and periodically report the status of the trial to the IRB. 
• 
Not implement any deviations from or changes to the protocol without agreement from the 
Sponsor and prior review and written approval from the IRB, except where necessary to 
eliminate an immediate hazard to the patients or for administrative aspects of the trial (where 
permitted by all applicable regulatory requirements). 
• 
Assure that each patient enrolled into the trial has read, understands, and has signed the 
informed consent. 
• 
Ensure that I and all persons assisting me with the trial are adequately informed and trained 
about the trial treatment and of their trial-related duties and functions as described in the 
protocol. 
• 
Make prompt reports of serious adverse events (SAEs) and deaths within 24 hours (1 business 
day) of becoming aware of the event to the Worldwide.Safety@BMS.com. 
• 
Assure access by the Sponsor, BMS, and/or FDA to original source documents. 
• 
Prepare and maintain adequate and accurate case histories designed to record all observations 
and other data pertinent to the investigation on each individual treated in the investigation. 
• 
Arrange for the transfer of appropriate data from case histories to case report forms for the 
collection and transmission of data to the Sponsor. 
• 
Retain records and documents related to this trial for at least 3 years after the completion of 
the trial as confirmed by the sponsor. 
• 
Cooperate fully with any trial-related GCP audit as performed by the assurance group specified 
by the Sponsor, BMS, or SU2C. 
Abide by the stipulations in the Confidentiality and Financial Disclosure sections and the 
manuscript preparation/authorship guidelines established at the outset of the trial. 
 
 
Investigator’s Printed Name:   
 
 
 
Investigator’ Signature:  
Date:   
 
 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
UCSD Principal Investigator Name: 
 
Hitendra Patel, MD 
 
Printed Name 
 
 
 
Signature 
Date 
 
 
 
 
 
Participating Site Principal Investigator 
 
 
 
Printed Name 
Institution 
 
 
 
Signature 
Date 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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EXPEDITED REPORTING 
REQUIREMENTS 
 
The Study Chair and multi-sites to include: University of Kansas Cancer Center and 
University of Pennsylvania Principal Investigator must be notified within 24 hours of 
learning of any serious adverse events, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study drug. 
The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
 
Multi-sites: 1) University of Kansas Cancer Center and 2) University of Pennsylvania. The 
Institutional Review Board (IRB) of each site must be notified by the site principal 
investigator according to their local policies. 
The FDA must be notified according to the following timelines: 
· 
within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and 
· 
within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, 
and 3) at least possibly related to study participation. 
 
SAEs, whether related or not related to study drug, overdoses, and pregnancies must be 
reported to BMS within 24 hours \ 1 Business Day of becoming aware of the event. 
SAEs must be recorded on either CIOMS, MedWatch, or approved site SAE form. 
Pregnancies must be reported and submitted to BMS on any of the following form(s): 
1. MedWatch or, CIOMS or 
2. BMS Pregnancy Surveillance Form or, 
3. Approved site SAE form 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: +1 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day 
to BMS using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
Refer to protocol section 6.2. Adverse Events for further details. 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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Glossary of Abbreviations 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APC 
Antigen-Presenting Cells 
AST 
Aspartate Aminotransferase 
BMS 
Bristol-Myer Squibb 
BSA 
Body Surface Area 
CA-125 
Cancer antigen 125 
CA19-9 
Carbohydrate antigen 19-9 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
cHL 
Classical Hodgkin’s Lymphoma 
CK 
Creatine Kinase 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CSF1 
Colony Stimulating Factor 1 
CSF-1R 
Colony Stimulating Factor 1 Receptor 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group (CTFG) 
DCR 
Disease Control Rate 
DHHS 
Department of Health and Human Services 
DLT 
Dose-Limiting Toxicities 
DSMP 
Data Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
ER 
Exposure-Response 
ERC 
Ethical Review Committee 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FDAMA 
Food and Drug Administration Modernization Act 
FSH 
Follicle Stimulating Hormone 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GSEA 
Gene Set Enrichment Analysis 
HBsAg 
Hepatitis B Surface Antigen 
HCV RNA 
Hepatitis C Virus RNA 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormonal Replacement Therapy 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
iCPD 
Confirmed Progression 
INR 
International Normalized Ratio 
I-O 
Immuno-Oncology 
irAE 
Immune-Related Adverse Event 
iRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
iUPD 
Unconfirmed Progression 
IUS 
Intrauterine Hormone-Releasing System 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MRI 
Magnetic Resonance Imaging 
MSS 
Microsatellite Stable 
Nab 
Nanoparticle albumin bound 
NCI 
National Cancer Institute 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PDA 
Pancreatic Ductal Adenocarcinoma 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PVNS 
Pigmented Villonodular Synovitis 
RA 
Rheumatoid Arthritis 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SD 
Stable Disease 
SgRNA 
Singe guide RNA 
SOC 
Standard of Care 
SU2C 
Stand Up to Cancer 
SUSAR 
Suspected, Unexpected Serious Adverse Reaction 
TAM 
Tumor-Associated Macrophages 
TB 
Mycobacterium tuberculosis 
TGen 
Translation Genomic Research Institute 
TMB 
Tumor Mutational Burden 
TME 
Tumor Microenvironment 
TKI 
Tyrosine Kinase Inhibitor 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Childbearing Potential 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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N=15 
Patients with stage IV 
pancreatic cancer who 
have achieved disease 
control in response to first 
line chemotherapy, 
defined as : 
 
Must have obtained a 
best response of at least 
stable disease (SD) or 
partial response (PR) for 
a period of at least 2 
months with no further 
shrinkage of ≥ 20% on 
imaging scans. 
TRIAL SCHEMATIC 
 
 
 
Cabira+ nivo+ gem 
 
0 
6 wks 
6 mos 
 
 
 
 
Optional Biopsy
 
Optional Biop 
 
CA 19-9 (or CEA or CA-125 for not expressers of 
CA19-9) q 4 weeks 
CT scan q 8 weeks 
 
 
 
Nivolumab 480 mg IV on day 1 Q4W  
Cabiralizumab 4 mg/kg IV on days 1 and 15 Q4W 
Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 Q4W 
 
 
Treatment commences no less than 2 weeks and no more than 4 
weeks after completing first line chemotherapy 
Patients continue on treatment until disease 
progression. 
 
*Biopsy at C2 D15 (-3 days, +10 days) unless patient 
has clear progression of their disease and then biopsy 
to be obtained at time of progression. 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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Protocol Version: 4.2 
Protocol Date: 3/20/2019  
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CONFIDENTIAL 
 
 
TRIAL SYNOPSIS 
Title and No.: SU2C Dream Team : Open Label Phase II Trial of Nivolumab + Cabiralizumab 
(BMS-986227, FPA008) + Gemcitabine in Patients with Stage IV Pancreatic Cancer 
Achieving Disease Control in Response to First-line Chemotherapy (Gem CaN Trial). 
 
Source of Funding: 
Funding Provided by Stand Up To Cancer (SU2C) Dream Team with drug provided by Bristol-
Myer Squibb (BMS) 
Consulting Investigators: 
David Propper, MD 
St Bartholomew’s Hospital, London, UK 
Lead Scientific Investigator: 
Tannishtha Reya, PhD 
University of California San Diego, School of Medicine 
Trial Sites: 
1. Hitendra Patel, MD , Andrew Lowy, MD: UCSD Moores Cancer Center, San Diego, CA 
2. Peter O’Dwyer, MD University of Pennsylvania, Philadelphia, PA 
3. Anup Kasi, MD University of Kansas Cancer Center, Kansas City, KS 
4. St. Bartholomew’s Hospital, London, UK 
Clinical Phase: Phase II, open-label trial 
Study Duration: Total duration of the trial will be about 18 months. 
Objectives: 
Primary: To estimate Progression Free Survival (PFS rates) at 6 months by RECIST1.1 in 
patients with stage IV pancreatic adenocarcinoma who have achieved disease 
control in response to first line chemotherapy when subsequently maintained on a 
combination regimen of cabiralizumab (FPA008)+ nivolumab + gemcitabine. 
Secondary: 
1. To evaluate safety and tolerability of the combination of nivolumab + cabiralizumab 
(FPA008) + gemcitabine  
 
2. To evaluate  PFS over the course of the study, overall survival (OS), and disease control 
rates at 6 months in patients administered the combination of nivolumab +cabiralizumab 
(FPA008) + gemcitabine. Disease control is defined as being with stable disease (SD) or partial 
response (PR) for a period of at least 2 months.  
Exploratory: 
1. To evaluate differences in disease progression outcomes according to iRECIST vs. RECIST 1.1 
criteria (Appendix 5). 


U C S D M o or e s C a n c er C e nt er   
 
 
 
 
 
 
 
H R P P # 1 8 1 3 9 5  
Pr ot o c ol V er si o n: 4. 2 
Pr ot o c ol D at e: 3/ 2 0/ 2 0 1 9  
1 1  
C O N FI D E N TI A L  
 
 
 
2. T o e x pl or e p ot e nti al bi o m ar k er s t h at m a y h el p pr e di ct r e s p o n s e t o tr e at m e nt i n b ot h t u m or  
a n d bl o o d . 
N o. P ati e nt s: St a g e 1: 8 s u bj e ct s . T h e tri al will b e t er mi n at e d at 
St a g e 1 if n o n e of t h e 8 s u bj e ct s h a v e a d efi n e d r e s p o n s e; 
ot h er wi s e it will c o nti n u e t o St a g e 2.  
St a g e 2: 7 s u bj e ct s. T ot al of 1 5  s u bj e ct s . T h e r e cr uit m e nt p eri o d 
i s a nti ci p at e d t o b e 1 4 - 2 1 m o nt h s . 
T ot al d ur ati o n of st u d y a nti ci p at e d t o b e 2 0 -2 7  m o nt h s.  
N a m e, d o s e of dr u g s:  
 Ni v ol u m a b - 4 8 0 m g I V o n d a y 1  Q 4 W  
 C a bir ali z u m a b ( B M S -9 8 6 2 2 7, F P A 0 0 8) - 4 m g/ k g I V o n d a y s 1 a n d 1 5  Q 4 W  
 G e m cit a bi n e - 1 0 0 0 m g/ m 2 I V o n d a y s 1, 8, a n d 1 5 r e p e at e d  Q 4 W  
Tr e at m e nt Pl a n : 
Ni v ol u m a b + c a bir ali z u m a b + g e m cit a bi n e  
P ati e nt P o p ul ati o n: P ati e nt s wit h st a g e I V p a n cr e ati c c a n c er w h o h a v e a c hi e v e d di s e a s e c o ntr ol, d efi n e d 
a s: m u st h a v e o bt ai n e d st a bl e di s e a s e ( S D) or p arti al r e s p o n s e ( P R) f or a p eri o d of at l e a st 2  m o nt h s wit h 
n o f urt h er s hri n k a g e of ≥ 2 0 % o n i m a gi n g s c a n s o n pri or fir st -li n e c h e m ot h er a p y f or t h eir m et a st ati c 
di s e a s e.  
E n d p oi nt s:  
Pri m ar y: Pr o gr e s si o n fr e e s ur vi v al  at 6 m o nt h s si n c e st art of st u d y tr e at m e nt a s s e s s e d b a s e d o n  R E CI S T 
1. 1 crit eri a.  
 
S e c o n d ar y:  
A d v er s e e v e nt s r at e s, a c c or di n g t o gr a d e a n d b o d y  s y st e m. T h e st u d y will u s e t h e C T C A E v er si o n 5. 0  
(htt p:// ct e p. c a n c er. g o v/r e p orti n g/ ct c. ht ml ) f or r e p orti n g of all gr a d e 3-4 a d v er s e e v e nt s.  
•  
O v er all  s ur vi v a l a n d P F S o v er t h e c o ur s e of t h e st u d y  
•  
Di s e a s e c o ntr ol r at e  
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
HRPP# 181395 
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Inclusion criteria: 
1. Be willing and able to provide written informed consent for the trial. Participants must have signed 
and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved 
written informed consent form in accordance with regulatory and institutional guidelines. This must 
be obtained before the performance of any protocol related procedures that are not part of normal 
participant care. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Histologically or cytologically confirmed pancreatic adenocarcinoma with metastasis, who have 
achieved disease control on prior first-line chemotherapy for their metastatic disease, defined as: 
Must have obtained at least stable disease (SD) or a partial response (PR) for a period of at least 
2 months with no further shrinkage of ≥ 20% on imaging scans. Note: Patients that have had prior 
chemotherapy as adjuvant or neoadjuvant therapy are permitted. 
4. Must have been off their prior cytotoxic regimen a minimum of two weeks but no more than four 
weeks from initiating trial treatment on C1/D1 (May not exceed 5 weeks). 
5. Measurable disease by RECIST 1.1. 
6. ECOG performance status of 0 or 1. 
 
7. Demonstrate adequate organ function as defined in Table 1. 
8. Vitamin D level ≥ 20ng/dL  Note: Vitamin D supplementation is allowed.  Proposed dose: 100,000 
loading dose. Followed by 50,000 units 3 times a week for 2 week. Recheck level.  Final dosing for 
supplementation is deferred to treating physician. Vitamin D supplementation throughout study 
treatment is allowed.  
9. Able to submit an archival tumor specimen (primary or metastatic site). Patients with cytology 
only that do not have adequate archived tumor specimen available, will require a baseline biopsy. 
10. Optional Biopsy: A discussion to be documented with trial investigator at screening regarding the 
purpose of the optional tissue collection from a newly obtained core or excisional biopsy of a tumor 
lesion at baseline and a second biopsy 7 weeks (C2/D15) after starting trial treatment, or at time 
of disease progression (refer to section 6.1.2.8), unless tumor is considered inaccessible or biopsy 
is otherwise considered not in the patients’ best interest. Participation in this trial is not contingent 
on patient consenting to optional tumor biopsies. 
11. Women of childbearing potential (WOCBP) must not be breastfeeding and 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. 
12. WOCBP must agree to follow protocol specified method(s) of contraception (Section 4.3.4) for the 
duration of treatment with study treatment(s) and for a total of 6 months posttreatment completion. 
WOCBP who are continuously not heterosexually active are also exempt from contraceptive 
requirements, but still must undergo pregnancy testing as described in this section 4.3.5. 
13. Males who are sexually active with WOCBP must agree to follow protocol specified method(s) of 
contraception (Section 4.3.4) 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. Azoospermic males are exempt from contraceptive requirements. 


UCSD Moores Cancer Center 
 
 
 
 
 
 
 
 
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Exclusion criteria: 
1. Is currently participating and receiving trial therapy or has participated in a trial of an 
investigational agent and received trial therapy or used an investigational device within 3 weeks of 
the first dose of trial treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of 
physiologic doses of corticosteroids may be approved after consultation with the Sponsor. 
3. Has a known history of active TB (Mycobacterium tuberculosis). 
 
4. Microsatellite unstable patients as assessed by IHC for MMR protein 
 
5. Hypersensitivity to cabiralizumab, nivolumab, or gemcitabine or any of its excipients. 
6. Previous malignancies (except non-melanoma skin cancers, and in situ bladder, gastric, 
colorectal, endometrial, cervical/dysplasia, melanoma, or breast cancers) unless complete 
remission was achieved at least 2 years prior to study entry and no additional therapy is required 
during the study period. 
7. Evidence of central nervous system (CNS) metastasis (negative imaging study, if clinically 
indicated, within 4 weeks of study treatment). 
 
8. 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. 
9. 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. 
10. Current or history of clinically significant muscle disorders (e.g., myositis), recent unresolved 
muscle injury, or any condition known to elevate serum CK levels. 
11. 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 (e.g., 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. 
12. Prior organ allograft or allogeneic bone marrow transplantation. 


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13. Any major surgery within 4 weeks of study treatment. Participants must have recovered from the 
effects of major surgery or significant traumatic injury at least 14 days before the first dose of study 
treatment. 
14. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have 
resolved to Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] v5.0 or baseline before administration of study treatment. Participants with toxicities 
attributed to prior anti-cancer therapy that are not expected to resolve and result in long lasting 
sequelae are permitted to enroll. Patients with ≤ grade 2 neuropathy may qualify for this trial. 
15. Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or anti- 
fungal therapy ≤ 7 days prior to administration of study medication. 
16. Any uncontrolled inflammatory GI disease including Crohn’s Disease and ulcerative colitis. 
17. Transfusion completed within 72 hours prior to first dose of study drug administration. 
 
18. Concomitant use of statins while on study. However, a participant using statins for over 
3 months prior to study drug administration and in stable status without CK rise may be permitted 
to enroll. 
19. Non-oncology vaccine therapies for prevention of infectious diseases (eg, human papilloma virus 
vaccine) within 4 weeks of study drug administration. The inactivated seasonal influenza vaccine 
can be given to participants 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 Sponsor and may 
require a study drug washout period prior to and after administration of vaccine. 
 
20. Participants with abnormal serum chemistry values, which in the opinion of the investigator is 
considered to be clinically significant, will be excluded from the study. This will include participants 
who show clinical signs and symptoms related to their abnormal serum chemistry values, as well as 
participants whose serum chemistry values are asymptomatic but clinically significant (e.g, 
hypokalemia or hyponatremia). 
21. Evidence of coagulopathy or bleeding diathesis. 
22. Treatment with botanical preparations (e.g., herbal supplements, including potential drugs of 
abuse, or traditional Chinese medicines) intended for general health support or to treat the disease 
under study within 2 weeks prior to randomization/treatment. 
23. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the patient’s participation for the full duration of the 
trial, or is not in the best interest of the patient to participate, in the opinion of the treating 
investigator. 
24. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
 


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25. Has received prior therapy with a CSF-1R pathway inhibitors, anti-PD-1, anti-PD-L1, anti PD-L2, 
anti-CTLA-4. 
26. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), Hepatitis B 
(e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Note: Participants 
with positive hepatitis C antibody and negative quantitative hepatitis C by PCR are eligible. 
27. Female who is pregnant or breast-feeding. 
28. Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue as a 
participant. Strict conditions apply and Sponsor approval is required. 
Statistical Methods: The primary endpoint for this clinical trial is progression free survival . The primary 
tumor assessment will be evaluated by RECIST 1.1 at 6 months.  Without maintenance therapy, 96%8 of 
patients are expected to progress by 6 months. A Simon’s two stage optimal design is applied. Accrual 
will be held for interim efficacy analysis when the first 8 patients are accrued. This design will have an 
80% power to reject the null hypothesis that PFS6 is ≤4% and conclude that the true PFS rate at 6 
months is > 4%, if the observed PFS rate is 22%, at 10% significance level. Secondary safety and 
efficacy analyses will also be performed. Please refer to section 8 for more details. 
Study accrual may also be held for safety reasons, please refer to section 4.6 for more details. 


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TABLE OF CONTENTS 
1.0 BACKGROUND AND RATIONALE ................................................................................ 19 
1.1 Overview ................................................................................................................................ 19 
1.2 Rationale For Maintenance Regimens ................................................................................... 20 
1.3 Preclinical Support ................................................................................................................. 21 
1.4 Cabiralizumab (BMS-986227, FPA008) ................................................................................. 23 
1.4.1  Cabiralizumab Clinical Summary..................................................................................... 23 
1.5 Nivolumab (BMS-936558)) ..................................................................................................... 25 
1.5.1  Nivolumab + Cabiralizumab ............................................................................................ 27 
1.6 Justification for Cabiralizumab Dose ...................................................................................... 27 
1.7 Justification for Nivolumab Dose ............................................................................................ 27 
1.8 Justification for Infusion Times for Nivolumab and Cabiralizumab .......................................... 28 
2.0 HYPOTHESIS ................................................................................................................ 30 
3.0 OBJECTIVES ................................................................................................................. 30 
3.1 Primary Objective ................................................................................................................... 30 
3.2 Secondary Objectives ............................................................................................................ 30 
3.3 Exploratory Objectives ........................................................................................................... 30 
3.4 Primary Endpoints .................................................................................................................. 30 
3.5 Secondary Endpoints ............................................................................................................. 30 
4.0 METHODS ...................................................................................................................... 31 
4.1 Eligibility ................................................................................................................................. 31 
4.1.1 Inclusion Criteria ............................................................................................................. 31 
4.1.2 Exclusion Criteria ............................................................................................................ 33 
4.2 Trial Treatments ..................................................................................................................... 35 
4.2.1 Randomization or Treatment Allocation .......................................................................... 37 
4.2.2 Stratification .................................................................................................................... 37 
4.2.3 Dose Selection/Modification ............................................................................................ 37 
4.2.4 Dosing of Cabiralizumab and Nivolumab ........................................................................ 37 
4.2.5 Dose Delay for Cabiralizumab and Nivolumab ................................................................ 37 
4.2.6 Guidelines for Subject  Monitoring After Infusions ........................................................... 38 
Obtain baseline vitals, then every 30 minutes during the infusion and continue to monitor the 
pt for at least 30 minutes after completion ....................................................................... 38 
4.2.7 Management Algorithms for Immuno-oncology Agents ................................................... 38 
4.2.8 Dose Reductions for Cabiralizumab and Nivolumab ....................................................... 39 
4.2.9 Dose Discontinuation Criteria for Cabiralizumab and Nivolumab ..................................... 39 
4.2.10 
Criteria to Resume Treatment with Cabiralizumab and Nivolumab ............................ 41 
4.2.11 
Dose Modification for Gemcitabine ............................................................................ 41 
4.2.12 
Concomitant Medications/Vaccinations (allowed & prohibited) .................................. 42 
4.2.13 
Acceptable Concomitant Medications ........................................................................ 42 
4.2.14 
Prohibited Concomitant Medications ......................................................................... 42 
4.3 Other Restrictions and Precautions ........................................................................................ 43 
4.3.1 Corticosteroids ................................................................................................................ 43 
4.3.2 Vaccines ......................................................................................................................... 43 
4.3.3 Diet ................................................................................................................................. 43 
4.3.4 Contraception ................................................................................................................. 44 
4.3.5 Pregnancy Testing .......................................................................................................... 46 
4.3.6 Use in Pregnancy ............................................................................................................ 46 
4.3.7 Use in Nursing Women ................................................................................................... 46 
4.4 Patient Withdrawal/Discontinuation Criteria ............................................................................ 46 


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4.5 Clinical Criteria for Early Trial Termination by the Sponsor ..................................................... 47 
4.6 Safety Stopping Rule ............................................................................................................. 48 
5.0 Trial Schedule ................................................................................................................. 48 
6.0 TRIAL PROCEDURES ................................................................................................... 52 
6.1 Trial Procedures ..................................................................................................................... 52 
6.1.1 Administrative Procedures .............................................................................................. 52 
6.1.2 Clinical Procedures/Assessments ................................................................................... 53 
6.1.3 Laboratory Procedures/Assessments .............................................................................. 56 
6.1.4 Patient Discontinuation ................................................................................................... 57 
6.1.5 Visit Requirements .......................................................................................................... 57 
6.2 Adverse Events ...................................................................................................................... 62 
6.2.1 Adverse Event Definition ................................................................................................. 62 
6.2.2 Adverse Event Monitoring ............................................................................................... 64 
6.23 Laboratory Test Abnormalities ........................................................................................ 64 
6.24 Reporting Requirements of Adverse Events .................................................................... 65 
6.25 Evaluating Adverse Events ............................................................................................. 70 
6.26 Investigator Responsibility for Reporting Adverse Events ............................................... 72 
7.0 PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ............................. 73 
7.1 Packaging and Labeling Information ...................................................................................... 73 
7.2 Storage and Handling Requirements ...................................................................................... 73 
7.2.1 Nivolumab ....................................................................................................................... 73 
7.2.2 
Cabiralizumab ........................................................................................................... 74 
7.3 Returns and Reconciliation .................................................................................................... 74 
8.0 STATISTICAL CONSIDERATIONS ................................................................................ 74 
8.1 Trial Design ............................................................................................................................ 74 
8.2 Statistical Analysis Plan ......................................................................................................... 74 
8.2.1 Analysis of primary 
endpoint……………………...................................................................................74 
8.2.2 Analysis of the Conduct of the Trial……………………………………………………………..75 
8.2.3 Analysis of Patient Characteristics……………………………………………………….……..75 
8.2.4 Analysis of Study Treatment Administration……………………………………………………75 
8.2.5 Definition of study population for primary efficacy analysis………………………………….76 
8.2.6 Analysis of Secondary Endpoints……………………………………………………………….76 
8.2.7 Analysis of Exploratory 
Endpoints…………………………………………………………………………….76  
9.0 ADMINISTRATIVE AND REGULATORY DETAILS........................................................ 76 
9.1 Institutional Review Board/Ethics Committee Approval .......................................................... 76 
9.2 Investigators protocol agreement ........................................................................................... 77 
9.3 Remaining Samples ............................................................................................................... 77 
9.4 Confidentiality ........................................................................................................................ 77 
9.5 Publication ............................................................................................................................. 77 
9.6 Compliance with Financial Disclosure Requirements ............................................................. 77 
9.7 Compliance with Trial Registration and Results Posting Requirements .................................. 78 
9.8 Required Site Documentation ................................................................................................ 78 
9.8.1 Site Registration Procedures ............................................................................................... 78 
9.8.2 Subject Data Protection ....................................................................................................... 78 
9.9 Quality Management System ................................................................................................. 79 
9.9.1 Data Monitoring Plan ...................................................................................................... 79 


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9.9.2 Data Safety Monitoring .................................................................................................... 79 
9.10 Data Management ................................................................................................................ 80 
9.10.1 
Case Report Forms ................................................................................................... 80 
9.10.2 
Source Documents .................................................................................................... 80 
REFERENCES ...................................................................................................................... 81 
APPENDICES ....................................................................................................................... 85 
Appendix 1 – Nivolumab Package Insert ............................................................................... 85 
Appendix 2 – Gemcitabine Package Insert ............................................................................ 85 
Appendix 3 – NCI CTCAE version 5.0 ................................................................................... 85 
Appendix 4 – ECOG Performance Status ............................................................................. 85 
Appendix 5 – Protocol Criteria for Measurement of Trial Endpoint RECIST 1.1 and 
iRECIST ........................................................................................................... 86 
Appendix 6 – Adverse Event Management for Cabiralizumab and Nivolumab Combination 
Therapy Cohorts .............................................................................................. 94 
Appendix 7 – Laboratory Abnormalities Management Table ............................................... 107 
 
 
TABLES 
Table 1.  Adequate Organ Function Laboratory Values ..................................................... 32 
Table 2. Trial Treatments ................................................................................................. 36 
Table 3. Dose Modification for Gemcitabine ...................................................................... 41 
Table 4. Highly Effective Contraceptive Methods That Have Low User Dependency ........ 45 
Table 5. Table of Assessments (Screen – Treatment Period) ........................................... 49 
Table 6. Table of Asessments (EOT– Follow-Up) .......................................................... 519 
Table 7. Laboratory Tests – performed locally ................................................................ 575 


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1.0 
BACKGROUND AND RATIONALE 
1.1 Overview 
Pancreatic cancer continues to be a very lethal disease. It is estimated that in 2018, 55,440 
Americans will be diagnosed with pancreatic ductal adenocarcinoma (PDA), and 44,330 will 
die from the disease. This makes pancreatic cancer the third leading cause of death from 
cancer in the US.1 
 
Furthermore it is projected that by 2030, PDA will be the second leading cause of death from 
cancer in the US. Worldwide, PDA is the twelfth most common cancer, accounting for an 
estimate of > 300,000 deaths a year. 2 
 
Detection of pancreatic cancer has been notoriously very late in the disease and therefore 
the 5-year survival rate is only 8%. Right now, the only potential cure for pancreatic cancer 
is surgical resection (if the disease is caught early). However only about 20% of PDA 
patients are eligible for potentially curable resection and unfortunately most (> 80%) have 
reoccurrence of their cancer within 2 years of resection, and those recurrences are almost 
universally fatal. 3,4 
 
But there is some hope. Recently there are regimens that actually improve survival for 
patients with advanced stage IV PDA. Conroy and colleagues developed the Folfirinox 
regimen, which in a large randomized trial improved survival over gemcitabine as a single 
agent.5 Von Hoff and colleagues developed the nanoparticle albumin (nab) associated 
paclitaxel plus gemcitabine regimen which improved survival over single agent gemcitabine 
again in a single randomized trial.6 Even more recently Jameson and colleagues have 
presented a combined regimen of nab-paclitaxel + gemcitabine + cisplatin in a small 24 
patient phase Ib/II trial that gave a response rate of 71% with 2 patients having complete 
response and a median survival of 16+ months.7 
 
With the greater chance of patients with advanced pancreatic cancer achieving disease 
control, there is a new challenge – maintaining that control. The challenges of maintaining 
control include: 
 
• Cumulative toxicities of the treatment regimens prevent continuance of the 
chemotherapeutic regimen. 
 
• Patients achieve a maximum amount of tumor shrinkage but that shrinkage often 
stops after a partial response (PR) is reached, so the patient may no longer benefit 
from that regimen or resistance may develop. 
 
• Patients get tired of the treatment regimen and want a rest 


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1.2 Rationale For Maintenance Regimens 
In patients with stage IV pancreatic cancer, 96% of those patients who achieve disease 
control with first line cytotoxic chemotherapy progress within 6 months. Chemotherapy can 
generally not be continued because of cumulative toxicities. Many clinicians however choose 
to continue treatment with gemcitabine or other agents such as capecitabine after disease 
control and withdraw other cytotoxic agents due to cumulative toxicities. The effect of this 
on progression free survival is unknown. 
 
The first randomized trial to address the role of maintenance therapy in metastatic pancreatic 
cancer was completed by Reni and colleagues (Reni M. et al. 2013).8 In this phase II 
randomized maintenance trial, 56 patients who previously had positive optimal response to 
chemotherapeutic regimens (no progression after 6 months of chemotherapy) were 
randomized to either observation or treatment with the tyrosine kinase inhibitor (TKI) 
sunitinib. The results were impressive: 96% of patients had progression after 6 months in 
the observation arm, while only 78% progressed on sunitinib (p = 0.01), 2-year survival was 
23% in sunitinib arm versus 7% in the observation arm (p=0.18). This important trial 
demonstrates that a maintenance approach is promising and should be further explored in 
patients with advanced pancreatic cancer. 
 
Tumor-associated macrophages, TAMs, play an important role not only in tumor progression 
and metastasis but also in resistance to chemotherapy and radiotherapy (De Palma and 
Lewis, 2013; Qian and Pollard, 2010). 9, 10 Pre-clinical models have elucidated the critical 
role of TAMs in cancer development, progression and metastasis (Denardo et al., 2011; 
Mantovani et al., 2017; Nielsen et al., 2016; Xu et al., 2013)11,12, 13, 14 Signaling through the 
cellular receptor for CSF-1, CSF-1R, promotes the differentiation of myeloid progenitors into 
populations of monocytes, macrophages, dendritic cells, and osteoclasts. Several 
therapeutic applications to impair recruitment or to readjust their behavior are currently being 
evaluated (Cannarile et al., 2017; Mantovani et al., 2017). 12, 15 
 
Pancreatic cancer is known to be associated with TAM infiltration and higher TAM infiltration 
is in turn associated with worse prognosis, suggesting that suppressed immune response 
contributes to tumor progression in this patient population. The preclinical studies detailed 
below, evaluated the impact of CSF-1R inhibition in primary KPC tumor cells. 
 
The addition of cabiralizumab as part of a maintenance regimen is based on our preclinical 
data that the stem cell population within pancreatic cancer that are preferentially tumorigenic 
and highly drug resistant to cytotoxic therapy, are in fact, directly dependent on CSF-1R, 
and that its inhibition in these cells leads to significant impairment of pancreatic cancer 
growth. An added benefit of this regimen is that cabiralizumab also targets CSF-1R-
dependent TAMs. 
 
In this proposed trial we wish to evaluate the combination regimen of gemcitabine, CSF- 1R 
and PD-1 blockade on progression free survival in patients with stage IV pancreatic cancer 
who achieved disease control following first line chemotherapy. 


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1.3 Preclinical Support 
Cancer stem cells are capable of unlimited self-renewal, and generate the rest of the cancer 
cells with more limited proliferative capacity. Importantly, pancreatic ductal adenocarcinoma 
(PDA) closely follows a stem cell paradigm, displaying a clear hierarchical organization, with 
stem cells preferentially driving tumor progression, metastasis and chemoresistance. 
Further, pharmacologic or genetic elimination of this population results in increased survival 
in mouse models, demonstrating the functional relevance of this population for pancreatic 
cancer growth in vivo. These data collectively indicate that stem cells within pancreatic 
cancer are critical drivers of disease progression and drug resistance, and suggest that 
development of effective strategies to eradicate these cells could lead to more durable 
treatment responses. Thus, we have focused on defining the dependencies of pancreatic 
cancer stem cells in order to identify their vulnerabilities and identify new targets for therapy. 
 
Mapping stem cell dependencies in pancreatic adenocarcinoma 
 
We have previously reported the development of a novel 
GFP-reporter “knock-in” mouse that visually identifies cells 
expressing the stem cell gene Msi2 (Msi2-GFP). Using this 
reporter strain, we demonstrated that Msi2 reporter+ cells 
possess cancer stem cell features and are responsible for 
tumor initiation, propagation and drug resistance in a 
genetically-engineered mouse model of pancreatic cancer 
(KrasLSL-G12D/+; p53f/f; Ptf1aCre/+, referred to here as “KPC”) 
(Figs. 1 and 2). This work is consistent with that of others. 
This indicated that the Msi2 reporter KPC mice would be a 
particularly unique and powerful tool for tracking and 
understanding of cells that preferentially harbor capacity for 
drug resistance and tumor re-growth. 
 
 
To define the epigenetic and molecular landscape that functionally maintains the aggressive 
and drug-resistant stem cell state, pancreatic cancer stem cells were isolated and analyzed 
from primary Msi reporter KPC tumors. This showed that KPC stem cells are distinct from 
non-stem cells at the global transcriptional level, and driven by the differential expression of 
over 1000 genes. 
 
Figure 1. Msi2+ tumor cells have preferential 
capacity for tumor initiation. Bottom left panel: 
flank transplants; Bottom right panel: orthotopic 
transplants. 
Figure 2. Cancer stem cells from KPC mice are highly resistant to 
gemcitabine in vivo. 


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The landscape that defined the stem cell state was markedly biased towards developmental 
and stem cell signals, and preferentially dormant. Consistent with their ability to survive 
chemotherapy and drive tumor regrowth, the stem cells also shared signatures with multiple 
relapsed cancers including cancer of the breast, liver, and colon. In context of immune 
evasion signature, it is important to note that the RNA Seq analysis also identified PDL1 
expression in both stem and non-stem cells. The fact that the non- stem cell fraction had 10 
fold greater expression may suggest that PDL1 blockade could be particularly useful in 
targeting the bulk of the tumor. In the event that stem cells are  less responsive to PD1/PDL1 
blockade, the work described below focused on identifying stem cell dependencies that 
could be exploited to reduce disease progression (Unpublished data, confidential). 
 
To identify programs that are functionally critical for conferring the stem cell state, we 
complemented the transcriptomic approaches above with a genome-wide CRISPR screen. 
Specifically, we established independent primary cell lines from Msi2-KPC mice, and 
performed CRISPR screens across these replicates with mulitplexed assays to identify 
genes essential for pancreatic cancer stem cell growth. This unbiased approach allowed us 
to effectively screen the entire mouse genome using the GeCKO V2 CRISPR library, which 
contains 6 sgRNA for each gene in the mouse genome, 4 sgRNA targeting each of 
~4000 miRNA, and >2000 control non-targeting sgRNA for a total of 130,000 guides. 
 
An in depth integrated bioinformatics analysis on datasets from the RNA-Seq and CRISPR-
based functional genomics screens unexpectedly identified a network of cytokines and other 
immunoregulatory signals as controlling cancer stem cells. This included the cytokine 
receptor CSF-1R (ligands include CSF-1 and IL-34), which has not previously been 
implicated as a direct regulator of cancer cell or cancer stem cell growth (Unpublished data, 
confidential. Given these findings, we tested whether blocking CSF-1R signaling would 
inhibit tumor cell growth in vitro. Tumor cells with shRNA against CSF-1R or IL-34 led to a 
significant reduction in anchorage independent growth and sphere formation in vitro. 
Further, inhibition of CSF-1R in the tumor cells led to a marked slowing of tumor growth in 
in vivo flank transplants. These data suggest a direct impact of CSF-1R signaling on cancer 
stem cell maintenance specifically, and tumor growth more generally (Unpublished data, 
confidential). 
 
Finally, since signaling through CSF-1R also promotes the differentiation of myeloid 
progenitors, including tumor-associated macrophages (which play a critical role in cancer 
development, progression and metastasis), several therapeutic applications to impair 
recruitment or readjust their behavior are currently being evaluated. Work from other 
members of our team in GEM models indicates that macrophages play an important role in 
maintaining established PDAC, and inhibition of macrophage through CSF-1R blockade 
results in an enhanced T cell immune response. 16 Thus collectively, our findings raise the 
possibility that targeting this pathway could have a compound effect on cancer stem cells to 
improve remissions and on reducing immunosuppression, leading to reduced tumor burden 
and improved survival in pancreatic cancer patients. 


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1.4 Cabiralizumab (BMS-986227, FPA008) 
For more detailed information or background on cabiralizumab, please refer to the 
cabiralizumab IB (BMS, 2018).17 
 
Cabiralizumab is a recombinant, humanized immunoglobulin (Ig) G4 (IgG4) monoclonal 
antibody (mab) that binds to the human CSF-1R. Binding of cabiralizumab to CSFR1 
antagonizes binding of CSF1 and IL34, thereby preventing activation of CSF-1R. 
 
Cabiralizumab inhibits both CSF1 and IL34-induced CSF-1R phosphorylation in a cell line 
engineered to overexpress CSF-1R (CHO-CSF-1R), demonstrating that cabiralizumab 
blocks the activation of ligand-induced CSF-1R signaling pathways. Cabiralizumab also 
inhibits CSF1 and IL34-induced proliferation and survival of peripheral blood monocytes in 
vitro, demonstrating that cabiralizumab inhibits not only the initiation of CSF1 and IL34 
signaling pathways but also the subsequent physiologic responses of primary human 
monocytes to these ligands. 
 
CSF-1R is expressed on cells of the monocyte/macrophage lineage, and signaling through 
CSF-1R via its ligands, CSF1 and IL34, supports differentiation, maintenance, and function 
of monocytes, macrophages, and osteoclasts. TAMs are among the most abundant immune 
cell types in the TME. Substantial evidence suggests that TAMs are polarized toward an 
anti- inflammatory phenotype (M2 TAMs) and through both cell surface inhibitors and soluble 
factors, such as immunosuppressive cytokines, playing a major role in inhibiting anti-tumor 
immune responses.12 CSF1 is a major survival factor for TAMs, and targeting CSF-1R 
through cabiralizumab should reduce TAM-mediated immune suppression, resulting in 
strengthening the anti-tumor response to immunotherapy. Therefore, a drug that inhibits 
CSF-1R should limit the immunosuppressive influence of TAMs on the TME and could be 
complementary and augment current cancer therapies. 
 
1.4.1 Cabiralizumab Clinical Summary 
 
The clinical summary of safety and efficacy is based on five clinical studies. Cabiralizumab 
was evaluated in 1 completed study (Study FPA008-001) and is currently being evaluated 
in 4 ongoing studies (Study FPA008-002, Study FPA008-003, Study CA025001, and Study 
CA025006). A summary of these studies is described below. 
 
Overall, the combination of cabiralizumab and nivolumab appears to be well tolerated, with a 
safety profile similar to that of the individual components, and the frequency and types of 
immune-mediated AEs appear similar across multiple types of tumors. Alteration in liver enzymes 
(eg, AST, ALT, and CK) in the absence of changes in bilirubin and periorbital oedema have been 
observed across multiple trials as a consequence of the depletion of tissue-infiltrating macrophages 
mediated by cabiralizumab.   
 
The combination of cabiralizumab and nivolumab with or without chemotherapy as evaluated in 
the preliminary safety cohort in Study CA025006 is well tolerated. Across all studies, a total of 137 
subjects were treated with cabiralizumab monotherapy, and 302 subjects were treated with 
cabiralizumab in combination with nivolumab, with or without chemotherapy.  
 


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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. Thirty six healthy volunteers and 18 RA subjects received cabiralizumab with no 
dose-limiting toxicities (DLTs) reported and no unexpected treatment-related adverse events 
(AEs) reported from RA subjects treated with three doses up to 6 mg/kg. 
 
Study FPA008-002 is evaluating the safety and efficacy of cabiralizumab monotherapy for 
6 months in approximately 40 subjects with pigmented villonodular synovitis (PVNS). 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 (BMS, 2018).17 
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. 
As of the data cutoff date of 02-Jul-2018, a total of 312 subjects have been treated in Study 
FPA008-003; 24 subjects have been treated in the Phase 1a dose-escalation monotherapy 
cohorts, 16 subjects have been treated in the Phase 1a dose-escalation combination 
cohorts, and 272 subjects have been treated in the Phases 1a and 1b dose-expansion 
combination cohorts. A total of 265 subjects across the study were treated with the 
recommended dose of 4 mg/kg cabiralizumab + 3 mg/kg nivolumab Q2W, and the overall 
safety of these subjects is reported independently. 
 
As of 02-Jul-2018, AEs have been experienced by 264 of 265 (99.6%) subjects treated 
with 4 mg/kg cabiralizumab + 3 mg/kg nivolumab Q2W across multiple cohorts. Treatment-
related AEs were experienced by 245 of 265 (92.5%) subjects. The most commonly 
reported (> 17% of subjects) treatment-related AEs included blood creatine phosphokinase 
increased (122 [46.0%] subjects), periorbital oedema (115 [43.4%] subjects), fatigue (102 
[38.5%] subjects), AST increased (100 [37.7%] subjects), ALT increased and amylase 
increased (51 [19.2%] subjects each), rash (50 [18.9%] subjects), and pruritus (47 [17.7%] 
subjects).  Grade 5 treatment-related AEs were experienced by 3 (1.1%) subjects and 
included acute respiratory failure (2 [0.8%] subjects) and respiratory distress (1 [0.4%] 
subject). Details relating to safety are included in the latest version of the cabiralizumab IB 
(BMS, 2018). 
 
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, pneumonitis, hyponatremia (two subjects each, 1%). Also SAEs included 


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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; refer to Appendix 6 for management 
recommendations in cases of pneumonitis) 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 participants with respiratory failure (unrelated), 1 participant with acute 
respiratory distress (related), and 1 participant with acute respiratory failure  (related). 
 
At a presentation at the Society for Immunotherapy of Cancer, Dr. Zev Wainberg presented 
more details on the activity of cabiralizumab plus nivoloumab. 18 A confirmed objective 
response was observed in 4 of 31 (13%) patients with advanced pancreatic cancer, all 
heavily pretreated. The responses were ongoing (range 168 + to 275+ days). This study 
also evaluated peripheral and tumor biomarkers in pre and post treatment paired biopsies. 
Of note, the four patients with confirmed responses in pancreatic cancer, were microsatellite 
stable (MSS) with low tumor mutation burden (TMB). The pharmacodynamics and genomic 
profiling of these patients treated with the combination of cabiralizumab plus nivolumab 
demonstrated cabira-mediated CSR-1R blockade in 
the periphery and tumor 
microenvironment, this data was presented at ASCO 2018, Abstract 3020. 19 
Study CA025-001 is evaluating the PK, safety, and efficacy of escalaing doses of boh 
cabiralizumab as monotherapy and in combination with nivolumab in Japanese patiets with 
cancer. Thirteen patients have been dosed to date. This study is ongoing  
Study CA025-006  is evaluating the antitumor effects of cabiralizumab in combination with 
nivolumab, with or without chemotherapy in patients with advanced pancreatic cancer. This 
study is ongoing. As of 16-Jul-2018, 11 subjects have been treated with the study drug: 3 
subjects were treated with the Investigator’s choice of chemotherapy (Arm A); 3 subjects 
were treated with 4 mg/kg cabiralizumab on Days 1 and 15 every 4 weeks (Q4W) in 
combination with 480 mg nivolumab Q4W (Arm B); 1 subject was treated with 4 mg/kg 
cabiralizumab on Days 1 and 15 Q4W in combination with 480 mg nivolumab Q4W and 
GEM/nab-paclitaxel on Days 1, 8, and 15 Q4W(Arm C); and 4 subjects were treated with 4 
mg/kg cabiralizumab on Days 1 and 15 Q4W in combination with 480 mg nivolumab Q4W 
and oxaliplatin/5-fluorouracil/leucovorin on Days 1and 15 Q4W (Arm D). 
 
1.5 Nivolumab (BMS-936558)) 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather 
than as self and can be effectively attacked by an activated immune system. An effective 
immune response in this setting is thought to rely on immune surveillance of tumor antigens 
expressed on cancer cells that ultimately results in an adaptive immune response and 
cancer cell death. Meanwhile, tumor progression may depend upon acquisition of traits that 
allow cancer cells to evade immuno-surveillance and escape effective innate and adaptive 
immune responses.20,21,22 Current immunotherapy efforts attempt to break the apparent 


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tolerance of the immune system to tumor cells and antigens by either introducing cancer 
antigens by therapeutic vaccination or by modulating regulatory checkpoints of the immune 
system. T-cell stimulation is a complex process involving the integration of numerous 
positive as well as negative co-stimulatory signals in addition to antigen recognition by the 
T-cell receptor (TCR).23 Collectively, these signals govern the balance between T-cell 
activation and tolerance. 
 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes 
CD28, CTLA 4, ICOS, and BTLA.24 PD-1 signaling has been shown to inhibit CD28- 
mediated upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression 
has also been noted to inhibit T-cell activation and expansion of previously activated cells. 
Evidence for a negative regulatory role of PD-1 comes from studies of PD- 
1 deficient mice, which develop a variety of autoimmune phenotypes.25 These results 
suggest that PD-1 blockade has the potential to activate anti-self T-cell responses, but these 
responses are variable and dependent upon various host genetic factors. Thus, PD- 
1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self- antigens. 
 
PD-1 is a 55 kD type I transmembrane protein primarily expressed on activated T cells, B 
cells, myeloid cells, and antigen-presenting cells (APCs).25 Binding of PD-1 to PD-L1 and 
PD-L2 has been shown to down-regulate T-cell activation in both murine and human 
systems.24, 27,28,29 PD1/PD-L1 interactions may also indirectly modulate the response to 
tumor antigens through T-cell/APC interactions. Therefore, PD-1 engagement may 
represent one means by which tumors evade immuno-surveillance and clearance.30 
Blockade of the PD-1 pathway by nivolumab has been studied in a variety of preclinical in 
vitro assays, and anti-tumor activity using a murine analog of nivolumab has been shown in 
a number of immunocompetent mouse cancer models. Nivolumab has been approved for 
the treatment of patients with unresectable melanoma, unresectable advanced or recurrent 
NSCLC, and RCC in Japan. In the US, nivolumab has been approved for the treatment of 
melanoma, NSCLC, RCC, HCC, and classical Hodgkin  lymphoma. Nivolumab is currently 
being evaluated extensively across a wide range of solid tumors and hematological 
malignancies. These findings provided the rationale for expanding the evaluation PD-1 
pathway blockade in combination with novel immunotherapy agents in clinical studies. 
Nivolumab is a fully human, immunoglobulin G4 (IgG4) [kappa] isotype monoclonal antibody 
that binds to PD-1 with nanomolar affinity (dissociation constant [Kd], 3.06 nM) with a high 
degree of specificity. In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 
nM), and inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC501± nM). 
Nivolumab binds specifically to PD-1 and not to related members of the CD28 family such as 
CD28, ICOS, CTLA-4, and BTLA. Blockade of the PD-1 pathway by nivolumab results in a 
reproducible enhancement of both proliferation and IFN-γ release in the mixed lymphocyte 
reaction (MLR). Using a cytomegalovirus (CMV) re-stimulation assay with human peripheral 
blood mononuclear cells (PBMC), the effect of nivolumab on antigen specific recall response 
indicates that nivolumab augmented IFN-γ secretion from CMV specific memory T cells in a 
dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a 
murine analog of nivolumab enhances the anti-tumor immune response and results in tumor 
rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02). 31 
 
The overall safety experience with nivolumab, as either monotherapy or in combination with 


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other therapeutics, is based on experience in approximately 17,700 participants. Nivolumab 
monotherapy is approved in multiple countries, including the US, European Union (EU), and 
Japan. Nivolumab has been approved by the US FDA for the treatment of patients with 
unresectable/metastatic melanoma (as a single agent and in combination with ipilimumab), 
metastatic NSCLC after disease progression on or after platinum-based chemotherapy, 
advanced RCC previously treated with anti-angiogenic therapy, recurrent or metastatic 
squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or 
after a platinum-based therapy, refractory hepatocellular carcinoma previously treated with 
sofarenib, classical Hodgkin lymphoma that has relapsed or progressed, locally advanced 
or metastatic urothelial cancer after disease progression on or after platinum-based 
chemotherapy, and other cancers. 
 
For nivolumab monotherapy, the safety profile is similar across tumor types. The only 
exception is pulmonary inflammation AEs, which may be numerically greater  in participants 
with NSCLC. In NSCLC patients, it can be difficult to distinguish between nivolumab-related 
and nivolumab-unrelated causes of pulmonary symptoms and radiographic changes. Most 
AEs were low-grade (Grades 1 to 2) with relatively few related high-grade (Grades 3 to 4) 
AEs. There was no pattern in the incidence, severity, or causality of AEs with respect to 
nivolumab dose level. These AEs have included pulmonary toxicity, renal toxicity (including 
acute renal failure), endocrine abnormalities, gastrointestinal (GI) toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. A pattern of immune-related AEs (irAEs) has 
been defined, for which management algorithms have been developed; these are provided 
in Appendix 6. Most high- grade events were manageable with the use of corticosteroids or 
hormone replacement therapy (endocrinopathies) as instructed in these algorithms. There 
is no relationship between the incidence, severity, or causality of AEs and the nivolumab 
dose level. 
 
Nivolumab, alone or in combination with chemotherapy, is currently being tested for the 
treatment of advanced/metastatic PDAC. Preliminary results from Study CA209032 show 
that nivolumab, administered as monotherapy was well tolerated in participants with 
advanced/metastatic PDAC. Despite the lack of objective responses in the 14 participants 
treated in this cohort, 1 participant experienced a prolonged stable disease (48 weeks) 
(Bristol-Myers Squibb) [BMS] internal data). In addition, the combination of nivolumab and 
gemcitabine/abraxane is currently being tested as first line treatment for participants with 
advanced/metastatic PDAC (NCT02309177). The combination appears to be well tolerated 
with a safety profile similar to the individual components. As of February 2017, 20 
participants are evaluable for efficacy. The preliminary ORR is 25% (5 out of 20 participants 
experience PR). In addition, 12 participants experienced prolonged, stable disease (BMS 
internal data). 
 
Taken together, these data suggest that while nivolumab in monotherapy may not be 
sufficient to improve the anti-tumor activity in advanced pancreatic cancer, the combination 
of nivolumab with the appropriate immunotherapy/chemotherapy may indeed improve anti- 
tumor activity in this setting. 
 
 


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1.5.1 Nivolumab + Cabiralizumab 
 
The combination of cabiralizumab and nivolumab as demonstrated in Study FPA008-003 
has a manageable safety profile that is minimally overlapping with that of the 
chemotherapy regimen (gemcitabine) being evaluated in this study. The preliminary data 
suggest that the combination of cabiralizumab and nivolumab mediates favorable 
antitumor effects in subjects with advanced pancreatic cancer. Details relating to efficacy 
are included in the latest version of the cabiralizumab IB (BMS, 2018). Preclinical evidence 
support the potential advantages of combining immunotherapy and chemotherapy, but 
overall, the potential benefit of the proposed combination over standard-of-care 
chemotherapy is not yet known. Nevertheless, the dismal prognosis of patients with 
advanced pancreatic cancer who have a poor prognosis and the lack of curative options 
support the need of novel combinatorial approaches. 
 
1.6 Justification for Cabiralizumab Dose 
A cabiralizumab dose of 4 mg/kg has been tested in combination with nivolumab in 195 
subjects across a number of tumors in Part 1b of Study FPA008-003. The safety profile of 
this dose is described in Section 1.4.1. The cabiralizumab dose of 4 mg/kg Q2W was 
selected in this trial based on the observed reduction of circulating CD16-positive peripheral 
blood monocytes (CD16+ monocytes) and a tolerable safety profile. 
 
Consistent with healthy subjects, rheumatoid arthritis and PVNS trials, a dose-dependent 
reduction in CD16+ monocytes after cabiralizumab administration was observed in subjects 
with cancer in Study FPA008-003. Across trials, cabiralizumab concentrations of 
≥ 10 µg/mL in serum maximize the reduction of non-classical CD16+ monocytes in a majority 
of subjects. In Study FPA008-003, the 4 mg/kg Q2W dose was associated with a Ctrough 
of ≥ 10 µg/mL and consistent suppression of circulating CD16+ monocytes after dosing. 17 
1.7 Justification for Nivolumab Dose 
The nivolumab dose of 480 mg Q4W was selected for this study based on clinical data and 
modeling and simulation approaches using population PK (PPK) and exposure-response 
(ER) analyses examining relationships between nivolumab exposures and efficacy (eg, OS, 
OR) and safety responses, using data from studies in multiple tumor types (melanoma, 
NSCLC, and RCC) with body weight-normalized dosing (mg/kg). The PPK analyses have 
shown that exposure to nivolumab increased dose proportionally over the dose range of 0.1 
to 10 mg/kg administered Q2W, and no clinically meaningful differences in PK across 
ethnicities and tumor types were observed. Nivolumab clearance and volume of distribution 
were found to increase as body weight increases but less than proportionally with increasing 
weight, indicating that milligram-per-kilogram dosing represents an over- adjustment for the 
effect of body weight on nivolumab PK. 
 
Using the PPK and ER models, nivolumab exposures and probabilities of efficacy responses 
and risks of AEs were predicted following nivolumab 480 mg Q4W and compared to those 
following nivolumab 3 mg/kg Q2W. The overall distributions of average nivolumab steady-
state exposures (Cssavg) are comparable following administration with either nivolumab 3 


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mg/kg Q2W or nivolumab 480 mg Q4W. While nivolumab 480 mg Q4W is predicted to result 
in approximately 43% greater steady-state peak concentrations (Cmaxss) compared to 
nivolumab 3 mg/kg Q2W, these exposures are predicted to be lower than the exposure 
ranges observed at doses up to nivolumab 10 mg/kg Q2W used in the nivolumab clinical 
program; the predicted Cmaxss following nivolumab 480 mg Q4W is well below the median 
Cmaxss achieved following administration of nivolumab 10 mg/kg Q2W, a safe and tolerable 
dose level. 
 
Exposure-safety analysis demonstrated that the exposure margins for safety are maintained 
following nivolumab 480 mg Q4W. Safety analyses using available data following nivolumab 
3 mg/kg Q2W and 10 mg/kg Q2W administration indicated that there were no differences in 
A E profiles across body weight groups. 
 
1.8 Justification for Infusion Times for Nivolumab and Cabiralizumab 
Administration of nivolumab using a 30-minute infusion time has been evaluated in subjects 
with cancer. Previous clinical studies of nivolumab monotherapy for the treatment of cancer 
have used a 60-minute infusion duration wherein nivolumab has been safely administered 
up to 10 mg/kg over long treatment periods. Infusion reactions including high-grade 
hypersensitivity reactions have been uncommon across the nivolumab clinical program. In 
Study CA209010, a dose association was observed for infusion site reactions and 
hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg, and 18.5% at 10 mg/kg). All 
the events were Grades 1 to 2 and were manageable. An infusion duration of 30 minutes for 
3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to present any 
safety concerns compared to the prior experience at 10 mg/kg nivolumab dose infused over 
a 60-minute duration. The safety of nivolumab 3 mg/kg administered as a 30-min infusion 
was assessed in Study CA209153 in patients with previously treated advanced NSCLC (see 
Nivolumab IB Section 5.5.1.2)32. Overall, there were no clinically meaningful differences in 
the frequency of hypersensitivity/infusion-related reactions (of any cause or treatment-
related) in cancer patients administered nivolumab over a 30- minute infusion compared with 
that reported for patients treated with the 60-minute infusion. Thus, it was shown that 
nivolumab can be safely infused over 30 minutes in subjects with cancer. 
 
Cabiralizumab has been administered safely  as  a  30-minute  intravenous  infusion  at  up 
to 10 mg/kg in a single dose. Overall, infusion reactions including high-grade 
hypersensitivity reactions have been uncommon across nivolumab and cabiralizumab 
clinical studies. Furthermore, a 30 minute break after the first infusion for the combination 
will ensure appropriate safety monitoring before the start of the second infusion. When 
administering nivolumab in combination with cabiralizumab, the nivolumab infusion should 
be administered first. 


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2.0 
HYPOTHESIS 
The combination regimen of nivolumab + cabiralizumab + gemcitabine can provide  prolonged 
disease control in patients with advanced pancreatic cancer. 
 
 
3.0 
OBJECTIVES 
3.1 Primary Objective 
To estimate progression free survival (PFS) rates at 6 months by RECIST1.1 in patients with 
stage IV pancreatic adenocarcinoma who have achieved disease control in response to first 
line chemotherapy when subsequently maintained on a combination regimen of nivolumab + 
cabiralizumab (FPA008) + gemcitabine. 
 
3.2 Secondary Objectives 
1. To evaluate safety and tolerability of the combination of nivolumab + cabiralizumab 
(FPA008)  
2. + 
gemcitabine. 
The 
study 
will 
use 
the 
CTCAE 
version 
5.0 
(http://ctep.cancer.gov/reporting/ctc.html) for reporting of all adverse events. 
 
3. To evaluate PFS, overall survival (OS) and disease control rates in patients 
administered the combination of nivolumab + cabiralizumab (FPA008) + 
gemcitabine. 
 
3.3 Exploratory Objectives 
1. To evaluate the difference in disease progression outcomes according to iRECIST 
vs. RECIST 1.1 criteria (Appendix 5). 
 
2. To explore potential biomarkers that may help predict response to treatment in both 
tumor and blood. 
 
3.4 Primary Endpoints 
The primary endpoint is Progression Free Survival (PFS) at 6 months. The primary tumor 
assessment will be by RECIST 1.1 criteria at 6 months. An interim analysis will be conducted 
at the end of Stage 1. All available data at the time the final subject has completed the primary 
assessment will be used in the final analysis. 
 
3.5 Secondary Endpoints 
• Adverse events rates, according to grade and body system 
• Overall survival and PFS over the course of the study.  


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4.0 
METHODS 
4.1 Eligibility 
Up to fifteen eligible patients who had achieved disease control, defined as: must have 
obtained stable disease (SD) or partial response (PR) for a period of at least 2 months with no 
further shrinkage of ≥ 20% on imaging scans on prior first-line chemotherapy for their 
metastatic disease. The best response on prior therapy will need to be evaluated and 
documented by the treating investigator at time of determining eligibility for this trial. 
 
4.1.1 Inclusion Criteria 
 
Patients must meet the following criteria in order to be eligible for participation in the trial: 
 
1. Be willing and able to provide written informed consent for the trial. Participants must 
have signed and dated an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) approved written informed consent form in accordance with regulatory 
and institutional guidelines. This must be obtained before the performance of any 
protocol related procedures that are not part of normal participant care. 
 
2. Be ≥ 18 years of age on day of signing informed consent. 
 
3. Histologically or cytologically confirmed pancreatic adenocarcinoma with metastasis, 
who have achieved disease control on prior first-line chemotherapy for their  metastatic 
disease, defined as: Must have obtained at least stable disease (SD) or a partial 
response (PR) for a period of at least 2 months with no further shrinkage of ≥ 20% on 
imaging scan. Note: Patients that have had prior chemotherapy as adjuvant or 
neoadjuvant therapy are permitted. 
 
4. Must have been off their prior cytotoxic regimen a minimum of two weeks but no more 
than five weeks from initiating trial treatment on C1/D1 (May not exceed 5 weeks unless 
discussed with Sponsor). 
 
5. Measurable disease by RECIST 1.1. 
 
6. ECOG performance status of 0 or 1. 
 
7. Demonstrate adequate organ function as defined in Table 1. 
 
8. Vitamin D level ≥ 20ng/dL. Note: Vitamin D supplementation is allowed.  Proposed dose: 
100,000 loading dose. Followed by 50,000 units 3 times a week for 2 week. Recheck level.  
Final dosing for supplementation is deferred to treating physician. Vitamin D supplementation 
throughout study treatment is allowed. 
 
 
9. Able to submit an archival tumor specimen (primary or metastatic site). Patients with 
cytology only that do not have adequate archived tumor specimen available, will 
require a baseline biopsy. 
 


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Optional Biopsy: A discussion to be documented with trial investigator at screening 
regarding the purpose of the optional tissue collection from a newly obtained core or 
excisional biopsy of a tumor lesion at baseline and a second biopsy 7 weeks (C2/D15) 
after starting trial treatment, or at time of disease progression (refer to section 6.1.2.8), 
unless tumor is considered inaccessible or biopsy is otherwise considered not in the 
patients’ best interest. Participation in this trial is not contingent on patient consenting 
to optional tumor biopsies. 
 
10. Women of childbearing potential (WOCBP) must not be breast feeding and have a 
negative serum or urine pregnancy test within 24 hours prior to the start of study 
treatment. 
 
11. WOCBP must agree to follow protocol specified method(s) of contraception (Section 
4.3.4) for the duration of treatment with study treatment(s) and for a total of 6 months 
posttreatment completion. WOCBP who are continuously not heterosexually active are 
also exempt from contraceptive requirements, but still must undergo pregnancy testing 
as described in this section 4.3.5. 
 
12. Males who are sexually active with WOCBP must agree to follow protocol specified 
method(s) of contraception (Section 4.3.4) 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. 
Azoospermic males are exempt from contraceptive requirements. 


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Table 1. Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
Creatinine OR 
Measured or calculatedb creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 
AST (SGOT) or ALT (SGPT) 
≤2.0 × ULN 
Coagulation 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use 
of anticoagulants 
Creatine Kinase 
WNL 
Vitamin D 
≥20ng/dL 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);  
AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
GFR=glomerular filtration rate; 
ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood 
cell (pRBC) transfusion within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for 
treatment; laboratory value requirements should be adapted according to local 
regulations and guidelines for the administration of specific chemotherapies. 
 


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4.1.2 Exclusion Criteria 
 
Patients meeting the following criteria will NOT be eligible to participate in this trial: 
 
1. Is currently participating and receiving trial therapy or has participated in a trial of an 
investigational agent and received trial therapy or used an investigational device within 
3 weeks of the first dose of trial treatment. 
 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor. 
 
3. Has a known history of active TB (Mycobacterium tuberculosis). 
 
4. Microsatellite unstable patients as assessed by IHC for MMR protein 
 
5. Hypersensitivity to cabiralizumab, nivolumab, or gemcitabine or any of its excipients. 
 
6. Previous malignancies (except non-melanoma skin cancers, and in situ bladder, 
gastric, colorectal, endometrial, cervical/dysplasia, melanoma, or breast cancers) 
unless complete remission was achieved at least 2 years prior to study entry and no 
additional therapy is required during the study period. 
 
7. Evidence of central nervous system (CNS) metastasis (negative imaging study, if 
clinically indicated, within 4 weeks of study treatment). 
 
8. 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. 
 
9. 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. 


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10. Current or history of clinically significant muscle disorders (eg, myositis), recent 
unresolved muscle injury, or any condition known to elevate serum CK levels. 
 
11. Uncontrolled or significant cardiovascular disease including, but not limited to, any of 
the following: 
i) Myocardial infarction or stroke/transient ischemic attack within the past 6 
months. 
 
ii) Uncontrolled angina within the past 3 months. 
 
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes). 
 
iv) History of other clinically significant heart disease (e.g., cardiomyopathy, 
congestive heart failure with New York Heart Association functional classification 
III to IV, pericarditis, significant pericardial effusion, or myocarditis). 
 
v) Cardiovascular disease-related requirement for daily supplemental oxygen 
therapy. 
 
12. Prior organ allograft or allogeneic bone marrow transplantation. 
 
13. Any major surgery within 4 weeks of study treatment. Participants must have recovered 
from the effects of major surgery or significant traumatic injury at least 14 days before 
the first dose of study treatment. 
 
14. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] v5.0) or baseline before administration of study 
treatment. Participants with toxicities attributed to prior anti-cancer therapy that are not 
expected to resolve and result in long lasting sequelae after platinum- based therapy, 
are permitted to enroll. Patients with ≤ grade 2 neuropathy may qualify for this trial. 
 
15. Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral 
or anti-fungal therapy ≤ 7 days prior to administration of study medication. 
 
16. Any uncontrolled inflammatory GI disease including Crohn’s Disease and ulcerative 
colitis. 
 
17. Transfusion completed within 72 hours prior to first dose of study drug administration. 
 
 
18. Concomitant use of statins while on study. However, a participant using statins for over 
3 months prior to study drug administration and in stable status without CK rise may be 
permitted to enroll. 


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19. Non-oncology vaccine therapies for prevention of infectious diseases (eg, human 
papilloma virus vaccine) within 4 weeks of study drug administration. The inactivated 
seasonal influenza vaccine can be given to participants 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 Sponsor and may require a study drug 
washout period prior to and after administration of vaccine. 
 
20. Participants with abnormal serum chemistry values, which in the opinion of the 
investigator is considered to be clinically significant, will be excluded from the study. 
This will include participants who show clinical signs and symptoms related to their 
abnormal serum chemistry values, as well as participants whose serum chemistry 
values are asymptomatic but clinically significant (e.g, hypokalemia or hyponatremia). 
 
21. Evidence of coagulopathy or bleeding diathesis. 
 
22. Treatment with botanical preparations (e.g., herbal supplements, including potential 
drugs of abuse, or traditional Chinese medicines) intended for general health support 
or to treat the disease under study within 2 weeks prior to randomization/treatment. 
 
23. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation for 
the full duration of the trial, or is not in the best interest of the patient to participate, in 
the opinion of the treating investigator. 
 
24. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
25. Has received prior therapy with a CSF-1R pathway inhibitors, anti-PD-1, anti-PD-L1, 
anti PD-L2, anti-CTLA-4. 
 
26. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), 
Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). Note: Participants with positive hepatitis C antibody and negative 
quantitative hepatitis C by PCR are eligible. 
 
27. Female who is pregnant or breast-feeding 
 
28. Prisoners or participants who are involuntarily incarcerated. (Note: under certain 
specific circumstances a person who has been imprisoned may be included or 
permitted to continue as a participant. Strict conditions apply and Sponsor approval is 
required. 
 
4.2 Trial Treatments 
The treatments to be used in this trial are outlined below in Table 2. 


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Table 2. Trial Treatments 
 
Study 
Treatment 
Potency 
Dose/ Route 
Dose Frequency 
Route 
IP/Non-IP 
Nivolumab 
100 mg/vial 
and/or 
40 mg/vial 
(10 mg/mL) 
480 mg IV 
Day 1 
Q4W 
IV Infusion 
over 30 
minutes 
IP 
Cabiralizumab 
Solution for 
Injection 
Per available 
vial from 
manufacturer 
(20 mg/mL) 
4 mg/Kg IV 
Days 1 and Day 
15 Q4W 
IV infusion 
over 30 
minutes 
IP 
Gemcitabine 
1000 mg/vial 
and various 
strengths 
1000 mg/m2 IV 
Days 1, 8, and 15 
Q4W 
IV Infusion 
over 30 
minutes 
Non-IP 
 
Nivolumab + cabiralizumab + gemcitabine will be given on Day 1 of each 28-day treatment 
cycle until the progression of disease, discontinuation due to toxicity, withdrawal of consent, 
or study closure. 
 
 
Day 1: 
 
Nivolumab will be administered as a 480 mg IV infusion over 30 minutes and then, after a 30 
minute rest period, cabiralizumab will be administered as a 4mg/kg IV infusion over 30 
minutes. Note: Nivolumab must always be administered first in this combination regimen. 
 
Pre-medication for gemcitabine (based on standard-of-care and local institutional standards) 
will then be administered after a further 30 minute rest period. Efforts should be made to avoid 
use of steroids if at all possible. 
 
Gemcitabine will be then administered as 1000 mg/m2 over 30 to 40 minutes. 
 
Day 8: 
 
Pre-medication for gemcitabine (based on standard-of-care and local institutional standards) 
will then be administered after a further 30 minute rest period. Efforts should be made to avoid 
use of steroids if at all possible. 
 
Gemcitabine will be administered as 1000 mg/m2 over 30 to 40 minutes. 
 
Day 15: 
 
Cabiralizumab will be administered as an IV infusion over 30 minutes. 
 
Pre-medication for gemcitabine (based on standard-of-care and local institutional standards) 
will then be administered after a further 30 minute rest period. Efforts should be made to avoid 
use of steroids if at all possible. 


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Gemcitabine will be then administered as 1000 mg/m2 over 30 to 40 minutes. 
 
 
4.2.1 Dose Selection/Modification 
 
The rationale for selection of doses to be used in this trial is provided in Sections 1.6-1.8. 
 
Details on preparation and administration of trial treatments are provided in the Investigator 
Brochure (cabrilizumab) and Package Inserts (nivolumab and gemcitabine). 
 
4.2.2 Dosing of Cabiralizumab and Nivolumab 
 
For the combination regimen, nivolumab should always be administered first as a 30-minute 
IV infusion followed by a 30-minute IV infusion of cabiralizumab. The time in between infusions 
is expected to be approximately 30 minutes but can be more or less depending on the 
situation. Cabiralizumab will be administered every 2 weeks (± 2days) and nivolumab will be 
administered every 4 weeks (± 2 days). Participants may be dosed with cabiralizumab no less 
than 12 days from the previous dose and with nivolumab no less than 24 days from the 
previous dose. 
 
Dosing calculations should be based on the body weight assessed at Cycle 1 Day 1 prior to 
the first dose of cabiralizumab. If the participant’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 and chemotherapy should be rounded as per SOC 
(usually 10 mg). 
 
Doses of study drugs may be interrupted, delayed, or discontinued depending on how the 
participant tolerates the treatment. 
 
4.2.3 Dose Delay for Cabiralizumab and Nivolumab 
 
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 7). Please discuss with the Sponsor or designee as needed; 
 
• For dose delays or modifications for all other AEs, please refer to the AE 
management table in Appendix 6. 
 
Participants who require a dose delay of cabiralizumab or 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 participant experiences an infusion reaction to cabiralizumab or 


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nivolumab, or both study drugs, the infusion reaction should be treated following the infusion 
reaction treatment guidelines in Appendix 6. 
 
4.2.4 Guidelines for Subject Monitoring After Infusions 
 
Obtain baseline vitals, then every 30 minutes during the infusion and continue to monitor the 
pt for at least 30 minutes after completion. 
 
Notify PI for infusion-related events; blood pressure < 90/60 or > 170/110 mmHg; heart rate 
> 100, or < 60 beats per minute or irregular; shortness of breath. 
 
4.2.5 Management Algorithms for Immuno-oncology Agents 
 
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 6 and are 
applicable to immune-related AEs for all immuno-oncology study treatment combinations. 
 
4.2.6 Dose Reductions for Cabiralizumab and Nivolumab 
 
Dose reduction for cabiralizumab and nivolumab are not permitted. 
 
4.2.7 Dose Discontinuation Criteria for Cabiralizumab and Nivolumab 
 
For comprehensive discontinuation rules, refer to Appendix 6 (AE management) and 
Appendix 7 (Laboratory Abnormalities Management Table). 
 
Treatment of cabiralizumab in combination with nivolumab should be discontinued in the 
following cases unless otherwise specified: 
 


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• 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 Sponsor or designee. 
 
• Any Grade 3 non-skin, drug-related AE lasting > 7 days, or recurrences including drug- 
related uveitis, pneumonitis, hypoxia, bronchospasm, and endocrinopathies with the 
following exceptions: 
 
o Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation. 
 
o Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation. Adrenal 
insufficiency requires discontinuation regardless of control with hormone 
replacement. 
 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 
 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: 
 
o ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5 x ULN (in the 
absence of anticoagulation). If bilirubin raised and Gilberts syndrome suspected 
discuss conjugated bilirubin levels with Sponsor. 
 
 See Appendix 6 and Appendix 7 for guidelines and possibility of 
restarting therapy 
 
o ALT or AST > 20 x ULN (with or without concurrent liver metastases) 
 
o Total bilirubin > 3 x ULN (> 5 x ULN with concurrent liver metastases) 
 
• Any Grade 4 drug-related AE or laboratory abnormality, except for the following 
events which do not require discontinuation: 
 
o Grade 4 neutropenia < 7 days 
 
o Grade 4 lymphopenia or leukopenia < 7 days 
 


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o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis. The Sponsor or designee 
should be consulted for Grade 4 amylase or lipase abnormalities. 
 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
 
o 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 Sponsor or designee. 
 
o 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: 
 
o Dosing delays to manage drug-related AEs are allowed. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 6 weeks from the previous 
dose, the Sponsor or designee 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. 
 
o Dosing delays lasting > 6 weeks from the previous dose that occur for non- drug-
related reasons may be allowed if approved by the Sponsor or designee. Prior 
to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, 
the Sponsor must be consulted. Tumor assessments should continue per- 
protocol every 8 weeks (± 7 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 participant 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 Sponsor. 
 
• Any Grade 3 or higher drug-related diarrhea or colitis, which does not resolve to 
Grade 1 or baseline within 28 days 
 


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• Any Grade 4 skin toxicity 
 
• Any Grade 4 renal toxicity 
 
• Any drug-related Grade 3 or higher pulmonary toxicity 
 
 
If the causality of the AE requiring discontinuation is confirmed to be due to 1 of the study drugs in 
the combination therapy, the other drug(s) 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 participant based on investigator assessment. 
 
 
4.2.8 Criteria to Resume Treatment with Cabiralizumab and Nivolumab 
 
Participants may resume treatment with cabiralizumab and/or nivolumab when the drug- 
related AE resolves as noted in the AE management tables in Appendix 6 or the abnormal 
laboratory management table in Appendix 7. The Sponsor or designee can be contacted at 
any time if further clarification is needed. 
 
4.2.9 Dose Modification for Gemcitabine 
 
Since gemcitabine is standard therapy for pancreatic cancers, sites use the suggested dosing. 
Any laboratory-only abnormalities without clinical manifestations or electrolyte abnormalities 
that may be managed with supplementation also do not automatically need dose modification. 
 
Suggested dose modification will be performed according to the Gemcitabine package insert 
(Refer to Table 3). 
 
Table 3. Dose Modification for Gemcitabine 
 
Absolute granulocyte count 
(x 106/l) 
Platelet count 
(x 106/l) 
Percentage of standard dose 
of gemcitabine (%) 
> 1,000 
and 
> 100,000 
100 
500- < 1,000 
or 
50,000 - < 100,000 
75 
< 500 
or 
< 50,000 
Omit dose 
 
If the causality of the AE requiring drug hold is confirmed to be gemcitabine, the other drugs, 
nivolumab and cabiralizumab may be continued per protocol schedule. 
 
4.2.11.1 Dose Modification on Day 1 of Cycle 
In the event dose modifications are required at the beginning of a cycle or within a cycle due 
to hematologic toxicities, the dose of gemcitabine may be adjusted as detailed in Table 3. 


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Please note that all study drugs will be held at the start of a new cycle if Table 3 criteria are 
not met. 
 
4.2.12 Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial treatment or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Investigator Sponsor. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the patient's primary physician. 
 
4.2.13 Acceptable Concomitant Medications 
 
All concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), multivitamins, nutritional and/or herbal supplements, 
and IV medications and fluids. If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. 
 
All concomitant medications received within 30 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be reported for SAEs 
and ECIs as defined in Section 6.2. 
 
4.2.14 Prohibited Concomitant Medications 
 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial. For specific therapies there is a washout window prior to 
cycle1/day1, indicated below and per eligibility criteria in Section 4.1. 
 
• Immunosuppressive agents; 
 
• Immunosuppressive doses of systemic corticosteroids; 
• Vaccines except as noted in Sections 4.1.2 and 4.3.2; 
 
• Statins for treatment of hypercholesterolemia. Statins will be allowed only if the 
participant is on a stable dose for over 3 months prior to the study and is in a stable 
status without any creatine kinase (CK) elevations; 
 
• Other anti-neoplastic therapies including biologic, immunotherapy, extensive non 
palliative radiation therapy, standard treatments, or investigational agents or devices. 
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Patients 
may receive other medications (not listed here as prohibited) that the investigator deems to be 
medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 


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There are no prohibited therapies during the Post-Treatment Survival Follow-up Phase of the 
trial. 
 
4.3 Other Restrictions and Precautions 
4.3.1 Corticosteroids 
 
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
treatment assignment are excluded. Inhaled or topical steroids, and adrenal replacement 
steroid doses ≤ 10 mg daily prednisone equivalent are permitted in the absence of active 
autoimmune disease. 
 
Participants are permitted to use topical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption) in the absence of active autoimmune 
disease. Adrenal replacement steroid doses ≤ 10 mg daily prednisone are permitted. A brief 
(less than 3 weeks) course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or for 
treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused 
by a contact allergen) and also for the treatment of tumor-related AEs is permitted. 
 
4.3.2 Vaccines 
 
The inactivated seasonal influenza vaccine can be given to participants while on therapy 
without restriction. Influenza vaccines containing live virus or other clinically indicated 
vaccinations for infectious diseases (i.e., pneumovax, varicella, etc.) may be permitted, but 
must be discussed with the Sponsor and may require a study drug washout period prior to and 
after administration of the vaccine. 
 
4.3.3 Diet 
 
Patients should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting. 
 
4.3.4 Contraception 
 
The trial treatments (cabiralizumab, nivolumab, and gemcitabine) may have adverse effects 
on a fetus in utero. Furthermore, it is not known if the trial treatments may have transient 
adverse effects on the composition of sperm. 
 
4.3.4.1 
Woman of Childbearing Potential (WOCBP) 
 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
 
Women in the following categories are not considered WOCBP: 
 


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• Premenarchal 
 
• Premenopausal female with 1 of the following: 
 
o Documented hysterectomy 
 
o Documented bilateral salpingectomy 
 
o Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history 
interview. 
 
• Postmenopausal female 
 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
 
 A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
two FSH measurements in the postmenopausal range is required. 
 
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
4.3.4.2 
Contraception Requirements 
 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol - defined timeframe in section 5.0: 
 
• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
 
• Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 4 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
 
o Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile penetration. 
 
Female Participants: 


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Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 4 during the protocol-defined time frame in Section 5.0. 
 
Table 4. Highly Effective Contraceptive Methods That Have Low User Dependency 
 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly. 
• 
Progestogen- only contraceptive implant a, b 
• 
Intrauterine hormone-releasing system (IUS) b 
• 
Intrauterine device (IUD) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive implants are limited to those which inhibit ovulation. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 6 months  after the last dose of study treatment. 
 


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4.3.5 Pregnancy Testing 
 
WOCBP should only be included after a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24-hours before the first dose of trial 
treatment. 
 
Following initiation of treatment additional pregnancy testing will be performed prior to day 1 
of each cycle during the treatment period, at the end of treatment (EOT) and at 30 days  after 
the last dose of study treatment and as required locally. 
 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
4.3.6 Use in Pregnancy 
 
If a patient inadvertently becomes pregnant while on trial treatment, the patient will immediately 
be removed from the trial. The site will contact the patient at least monthly and document the 
patient’s status until the pregnancy has been completed or terminated. The outcome of the 
pregnancy will be reported to the Sponsor without delay and within 24 hours. The Sponsor will 
report to BMS within 24 hours (working days) if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life- threatening complication 
to the mother or newborn). 
 
The trial investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male patient 
impregnates his female partner, the trial personnel at the site must be informed immediately 
and the pregnancy reported to the Sponsor. The Sponsor will report to BMS and follow the 
pregnancy as described above and in Section 6.2. 
 
4.3.7 Use in Nursing Women 
 
It is unknown whether the trial treatments (nivolumab, cabiralizumab, and gemcitabine) are 
excreted in human milk. Since many drugs are excreted in human milk, and because of the 
potential for serious adverse reactions in the nursing infant, patients who are breast-feeding 
are not eligible for enrollment. 
 
4.4 Patient Withdrawal/Discontinuation Criteria 
 
Patients may withdraw consent at any time for any reason or be withdrawn from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a patient may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. Specific details 


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regarding assessments to be done at an End of Treatment (EOT) visit at time of 
discontinuation or withdrawal are provided in Section 6.1.5.3. 
 
A patient must be discontinued from the trial for any of the following reasons: 
 
• The patient or legal representative (such as a parent or legal guardian) withdraws 
consent 
 
• Confirmed disease progression 
 
• Unacceptable adverse experiences 
 
• Inter-current illness that prevents further administration of treatment 
 
• Investigator’s decision to withdraw the patient 
 
• The patient has a confirmed positive serum pregnancy test 
 
• Noncompliance with trial treatment or procedure requirements 
 
• The patient is lost to follow-up 
 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 5 (Trial Schedule) 
and Section 6.1.5 (Visit Requirements). After the end of treatment, each patient will be followed 
for at least 90 days for adverse event monitoring (serious adverse events will be collected for 
100 days after the end of treatment as described in Section 6.2.3.1). Patients who discontinue 
for reasons other than progressive disease will have post-treatment follow- up every 100 days 
for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up, or the end of the trial, whichever occurs 
first. 
 
4.5 Clinical Criteria for Early Trial Termination by the Sponsor 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
 
2. Poor adherence to protocol and regulatory requirements 
 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to patients 
 
4. Plans to modify or discontinue the development of the trial treatment 


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4.6 
Safety Stopping Rule 
 
For the purposes of the safety stopping rule, a safety event of interest will be defined as 
any drug discontinuation which arises from the adverse event/ laboratory abnormalities 
management algorithms in section 4.2.7 and Appendices 6 and 7, or,  as any grade 3 or 
higher adverse event which is not covered by these management algorithms and which is 
related to GI, pulmonary, hepatic, or neurological toxicity, and is at least possibly related 
to study drug. 
 
For other toxicity and dose modifications please see attached schema/table. 
 
If a subject experiences a safety event of interest, no additional doses of the investigational 
product will be given to that subject. The subject will be counted in the ITT population for 
the efficacy analysis. 
 
As reported in the most recent IB, 43 of 265 (16.2%) subjects experienced discontinuation 
due to a treatment related AE after treatment with cabiralizumab +nivolumab.  Based on 
this experience, we reasonably expect to see an event rate of 16% in this trial.  The safety 
stopping rule will be designed to continue with probability approximately 80% in case the 
event rate is 16% or less: 
 
If at any time 4 subjects experience a safety event of interest, further accrual will be held 
pending safety review, and the study will be restarted only with Principal Investigator 
approval. The safety review will take the form of review of a formal Safety Report, prepared 
following the SOP’s for a DSMC report, by a Safety Review Team which includes the 
Investigators who enrolled subjects in the study, the Principal Investigator, and the UCSD 
DSMC.     
 
This rule has probability 21% of being invoked if the event rate is 16%, and thus 80% 
probability to continue through 15 subjects in this case.  Alternatively, if the event rate is as 
high as 30%, the safety rule has 70% chance of stopping the study for review. 
 
If one or more grade 4 or 5 AE’s are observed (with the exception of a grade 4 AE’s 
covered by the management algorithms of Appendices 6 and 7, which does not lead to 
drug discontinuation) which are at least possibly attributable to study drug, further accrual 
will be held pending safety review as described above, and the study will be restarted only 
with Principal Investigator approval. 
 
FDA will be notified if one of the thresholds to hold a safety review is met. 
 
5.0 
Trial Schedule 
The trial will consist of the following three periods: 
 
Screening (SCN) Period: The screening period will take place only after informed consent is 
obtained and within the 30 days prior to C1/D1. The screening visit may be counted as  the 
baseline visit if completed within 7 days of initial dosing on C1/D1. 
 


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Treatment Period: Patients will be treated at 28 ± 2 day intervals. Patient must begin cycle 1 
within 30 days of signing the IRB approved informed consent document and after the screening 
assessments have been performed and reports have been reviewed to confirm eligibility. The 
patient will continue on maintenance therapy until there is evidence of clear- cut tumor 
progression, has treatment ending toxicities, or withdraws from treatment. Table 5 below 
summarizes the Screen-Treatment Period Schedule of Assessments. 
 
Post Treatment Period: All participants should complete the 3 clinical safety follow-up visits 
( at 30, 60, and 100 days from EOT) regardless of whether new anti-cancer therapy is started, 
except those participants who will withdraw consent for study participation or are unable to 
come to clinic due to disease progression”. Table 6 below summarizes the Post- Treatment 
Period Schedule of Assessments. (6.1.5.4). 


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Table 5. Table of Assessments (Screen – Treatment Period) 
 
 
 
SCN 
CYCLE 1 
CYCLE 2 
CYCLE 3 and 
subsequent cycles 
Trial week 
1 
2 
3 
5 
6 
7 
8 
9 
10 
11 
Cycle day 
- 
1 
8 
15 
1 
8 
15 
21 
1 
8 
15 
Window (Days): 
--30 to - 
1 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Informed Consent 
X a, c 
Inclusion/ Exclusion Criteria 
X 
x 
Medical History 
X b 
Prior and Concomitant Medication Review 
X 
x 
x 
x 
Assess & Report Adverse Events c 
x 
x 
x 
x 
x 
X 
x 
x 
X 
Complete Physical Examination including height and 
Weight 
X 
Weight and BSA calculation 
x 
x 
x 
Symptom Directed Physical Examination 
x 
x 
x 
Vital Signs d 
X 
x 
x 
x 
x 
x 
X 
x 
x 
X 
12- lead ECG 
X 
ECOG (see appendix 4) 
xe 
x 
x 
x 
Serum β HCG Pregnancy Test 
(if applicable) f 
X 
x f 
x 
x 
PT/INR and aPTT 
X 
TSH, T4, T3 
X 
xk 
x 
x 
CBC with Differential, Platelets 
X 
x 
x 
x 
x 
x 
X 
x 
x 
X 
Comprehensive Serum Chemistry Panel g 
X 
x 
x 
x 
x 
x 
X 
x 
x 
X 
Serum Vitamin D 
X 
Creatinine Kinase 
X 
x 
x 
x 
x 
x 
X 
x 
x 
X 
Urinalysis 
X 
x 
x 
x 
HBsAg HCV RNA (qualitative) 
X 
IHC for MMR protein 
X 
Tumor Imaging (CT/MRI) 
& Response Assessment h 
xh 
|------ 
Xh 
------| 
CA19-9 (or CA 125, or CEA if not expressers of CA19-9) 
X 
x 
x 
x 
Archival Tumor Biopsy (refer to 6.1.2.8) 
X 
Optional -Fresh Tumor Biopsy i (refer to 6.1.2.8) 
X 
xh 
Central Lab Blood Sample j (refer to 6.1.2.7) 
X 
x 
x 
X 
X 
Cabiralizumab 
x 
x 
x 
X 
x 
X 
Nivolumab 
x 
x 
x 


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Gemcitabine 
x 
x 
x 
x 
x 
X 
x 
x 
X 
 
 
Footnotes: 
a. Written IRB-approved informed consent must be obtained prior to any screening assessments being performed. 
 
b. Documented medical history to include, demographics, concurrent baseline conditions (using NCI-CTCAE V5.0. Appendix 3), 
prior cancer treatment and surgeries. 
 
c. For the time that the consent form is signed until treatment allocation/randomization, any events of clinical interest (ECI, refer to 
6.2.3.2), serious adverse event, or follow up to a serious adverse event, including death due to any cause that occurs to any patient 
must be reported within 24 hours to the Sponsor. AEs will continue to be assessed and reported throughout the trial treatment 
period, for at least 90 days following the EOT and again at 100 days for serious adverse events (refer to Section 6.2 for complete 
details). 
 
d. Vital signs to include: Blood pressure, pulse, and temperature. 
 
e. ECOG Performance Status must be 0 or 1 to be eligible for entry to the trial. 
 
f. Negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) is required for women of child- 
bearing potential (WOCBP) within 24 hours of start of trial medication. Pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected. Participants must agree to use a contraception as detailed in 
Section 4.3.4 
 
g. Refer to Table 7 for details of required labs to be included. Adequate organ function must be demonstrated in accordance with 
protocol criteria within 10 days of start of trial medication as defined in Table 1. 
 
h. CT/MRI scan to document disease status at baseline to include chest abdomen and pelvis and other regions as clinically 
indicated Brain scan is not required unless to rule out brain metastases if clinically indicated (per PI discretion). The same 
radiographic procedures used to document disease status at baseline must be used throughout the trial. Tumor assessments will 
be conducted using CT or MRI, approximately every 8 ± 1 weeks until trial discontinuation or disease progression, whichever is 
later. All sites of disease must be followed using the same baseline assessment method. The investigator will complete tumor 
measurements and response evaluation per RECIST 1,1 and iRECIST (for nivolumab + cabiralizumab + gemcitabine arm only) . 
 
i. For patients consenting to the optional tumor biopsy, a baseline tumor biopsy and paired blood sample will be taken from each 
patient and used for profiling (collected within the 4 weeks prior to cycle 1/day1). If possible (patient condition permitting) this will 
be repeated at C2/D15 (-3 days, + 10 days) or at the time of disease progression. If a biopsy is proposed outside these times, it 
should be discussed with trial monitor, If the biopsy cannot be collected within this timeframe this is to be discussed with the 
sponsor. 
 
j. Each patient will have 30 ml of blood collected at the following timepoints: Pre-treatment (0-14 days prior to C1/D1), and during 
the trial prior to treatment on days 1 of cycles 1, 2, 4, 6, and every 2 cycles thereafter. For those patient consenting to the optional 
tumor biopsy, an additional 30 ml blood sample will also be collected at the time of biopsy refer to section 6.1.2.8. 
 
k. Thyroid panel: TSH, T4, T3 test if screening labs is done within two weeks of cycle 1 day1 then no need to repeat. 


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Table 6. Table of Assessments (EOT– Follow-Up) 
 
 
Post-Treatment Period 
EOT 
Safety 
Follow-Up 
Survival 
Follow-up 
Scheduling Window (Days) 
At time of 
discontinuation 
(+7 days of last 
dose or date of 
discontinuation) 
30, 60, 100 
days(± 7 days) 
from EOT 
Every 100 days 
post Safety FU 
Post-trial anticancer treatment status 
X 
X 
X 
Disease/Survival Status a 
X 
X 
X 
Concomitant Medication Review 
X 
X 
Assess & Report Adverse Events b 
X 
X 
Symptom Directed Physical Examination 
X 
Vital Signs and Weight c 
X 
ECG 
X 
ECOG (see appendix 4) 
X 
Serumβ HCG Pregnancy Test for WOCBP 
X 
X 
CBC with Differential 
X 
Comprehensive Serum Chemistry Panel 
X 
Urinalysis 
X 
Tumor Imaging & Response Assessments d 
X 
CA19-9 e 
X 
Central Lab Blood Samples 
X 
Xf 
Review contraception use as required by 
protocol Section 4.3.4 (where applicable) 
X 
X 
Contact Information Review f 
X 
X 
X 
Footnotes for Table 6. Post –Treatment Period 
a. Post-treatment follow-up for disease status until documented disease progression, initiating a non- 
trial cancer treatment, withdrawing consent or becoming lost to follow-up. After documented disease 
progression each pt will be followed by telephone for survival status. 
b. Assess and record any new or ongoing AEs at time of EOT. Following the EOT, each patient will be 
followed for 30 days, for adverse event monitoring. Serious adverse events and Events of Clinical 
Interest (ECI) will be collected for 100 days after the end of treatment as described in Section 6.2 
c. Vital signs to include: Blood pressure, pulse, respiratory rate, and temperature. 
d. Tumor assessments will be conducted using CT or MRI at trial discontinuation or disease 
progression, whichever is later. All sites of disease must be followed using the same baseline 
assessment method. 
e. CA19-9 assessments will be taken at baseline and approximately every 4 weeks during the trial 
treatment period and at the end of treatment visit. All CA19-9 assessments are to be assayed by the 
same laboratory for each patient. The Investigator is encouraged to obtain radiological assessments 
and CA19-9 values earlier if there is a strong clinical suspicion of disease progression, in order to 
confirm or refute the clinical impression. 
f. Site to confirm contact information for patient and a designated family member and remind patient of 
FU telephone contact that will be conducted every 90 days for survival status 


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6.0 
TRIAL PROCEDURES 
6.1 Trial Procedures 
Individual trial procedures (Administrative, Clinical, and Laboratory) are described in detail 
below. The specific visit requirements are detailed in Section 6.1.5. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
 
Furthermore, additional evaluations/ testing may be deemed necessary by the Sponsor for 
reasons related to patient safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the patient. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
6.1.1 Administrative Procedures 
 
6.1.1.1 
Informed Consent 
The Investigator or qualified designee must obtain documented consent from each potential 
patient prior to participating in a clinical trial. 
 
Consent must be documented by the patient’s dated signature. A copy of the signed and dated 
consent form should be given to the patient before participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the patient must receive the IRB/ERC’s approval/favorable 
opinion in advance of use. The patient or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
patient’s willingness to continue participation in the trial. The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the patient’s dated signature or by the patient’s legally acceptable 
representative’s dated signature. 
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
6.1.1.2 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed and documented by the investigator or 
qualified designee to ensure that the patient qualifies for the trial. 
 
6.1.1.3 
Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator. Details regarding the disease for 
which the patient has enrolled in this trial will be recorded separately and not listed as medical 
history. 


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6.1.1.4 
Prior and Concomitant Medications Review 
6.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the patient within the 30 
days before starting the trial. Treatment for the disease for which the patient has enrolled in 
this trial will be recorded separately and not listed as a prior medication. 
 
6.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medications including prescription, over- the-
counter (OTC), multivitamins, nutritional and/or herbal supplements, IV medications and fluids, 
if any, taken by the patient during the trial. All medications related to reportable SAEs and 
Events of Clinical Interest (ECIs) should be recorded as defined in Section 6.2. 
 
6.1.1.5 
Disease Details and Treatments 
6.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
 
6.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. The investigator will assess and provide as part of the 
baseline eCRF data, the Best Response on the last treatment prior to enrollment in this trial. 
Patients must have been off their prior cytotoxic regimen a minimum of two weeks but no more 
than five weeks from initiating trial treatment on C1/D1. 
 
6.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment. If a patient initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the EOT visit must occur before the first dose of the new 
therapy. 
 
 
 
6.1.2 Clinical Procedures/Assessments 
 
6.1.2.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each patient to evaluate for potential new 
or worsening AEs as specified in the Trial Schedule Section 5.0 (during the trial treatment 
period, for 100 ( (±7 days) following last dose of trial treatment, or date of discontinuation. 
This will be contingent on patients clinical status. Adverse experiences will be graded and 
recorded throughout the trial and during the 30 day follow-up period according to NCI 
CTCAE Version 5.0 Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to trial treatment. 
 


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Please refer to section 6.2 for detailed information regarding the assessment and recording of 
AEs. 
 
6.1.2.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. 
 
6.1.2.3 
Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration on day 1, 8, and 15 of each cycle. 
 
6.1.2.4 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Schedule (Section 5.0). Vital signs should include temperature, pulse, respiratory 
rate, and blood pressure. Weight will be measured at the start of each treatment cycle. Height 
will be measured at screening only. 
 
6.1.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (Appendix 4) at screening, 
prior to the administration of trial treatment on day 1 of each cycle and at discontinuation of 
trial treatment as specified in the Trial Schedule. 
 
6.1.2.6 
Tumor Imaging and Assessment of Disease (Refer to Appendix 5) 
The patient’s pancreatic cancer will be evaluated by the investigator based on tumor 
assessments using RECIST 1.1 criteria. In additional, iRECIST criteria will be assessed. 
 
Tumor assessments for evaluation of response will be conducted using CT or MRI, with IV 
contrast if not medically contraindicated, approximately every 8 ± 1 weeks until trial 
discontinuation or disease progression, whichever is later. All sites of disease must be followed 
using the same baseline assessment method. 
 
All target lesions will be measured by consistent imaging techniques for each patient 
throughout the trial. Suitable imaging techniques include CT-scan, or MRI. The same 
technique should be used for each evaluation in an individual patient. Copies of the scans 
must be available for review. 
 
In the event that PD by RECIST 1.1 or iUPD is determined for a patient, a repeat scan must 
be performed within 4 - 6 weeks to confirm PD. Trial treatment may be continued during this 
time (past the initial PD assessment) but only if patient is clinically stable as defined by: 
 
• No worsening of performance status 
 


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• No clinically relevant increase in disease related symptoms 
 
• No requirement for intensified management of disease related symptoms (analgesics, 
radiation, palliative care) 
 
CA19-9 assessments (or CEA or CA-125 for not expressers of CA19-9) will be taken at 
baseline and approximately every 28 days during the trial treatment period. All CA19-9 
assessments must be assayed by the same laboratory for each patient. Disease  progression 
will not be determined by CA19-9, however increases in CA19-9 may warrant the investigator 
to obtain radiographic assessments. 
 
Note: In order to more precisely determine time to progression, the investigator is encouraged 
to obtain radiological assessments and CA19-9 values earlier if there is a strong clinical 
suspicion of disease progression. In order to either confirm or refute the clinical impression. 
 
Note: Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases) 
 
6.1.2.7 
Blood Collection 
Each patient will have 30 ml of blood collected at the following timepoints: Pre-treatment (0- 
14 days prior to cycle1/day1), and during the trial prior to treatment on days 1 of cycles 1, 2, 
4, 6, and every 2 cycles thereafter. 
 
For those patient consenting to the optional tumor biopsy, an additional 30 ml blood sample 
will also be collected at the time of biopsy refer to section 6.1.2.8. 
 
Blood samples will be sent and analyzed by Dr. Reya’s Laboratory at University of California 
San Diego. 
 
Specific details for blood sample collection and processing will be provided to the investigative 
sites in the Trial Laboratory Manual. 
 
6.1.2.8 
Tumor Tissue Collection 
All patients will be required to provide an archival tissue block from either primary or metastatic 
site. 
 
Patients with cytology only that do not have adequate archived tumor specimen available, 
will require a baseline biopsy. 
 
For patients consenting to the optional tumor biopsy, a baseline tumor biopsy will be taken 
from each patient and used for profiling (collected within the 4 weeks prior to cycle 1/day1).  If 
possible (patient condition permitting) this will be repeated on Week 7, C2 Day 15 (-3 days, 
+ 10 days) or at the time of clear disease progression. If the biopsy cannot be collected within 
this timeframe this is to be discussed with the sponsor. Tissue samples will be sent and 
analyzed by Dr. Reya’s Laboratory at University of California San Diego. 
 


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Specific details for tumor tissue collection and handling will be provided to the investigative 
sites in the Trial Laboratory Manual. 
 
6.1.3 Laboratory Procedures/Assessments 
 
Safety laboratory tests for hematology, chemistry, and urinalysis (as detailed in Table 7) will 
be performed by the local laboratory for each investigational site at screening, baseline and 
throughout the trial treatment period. HBsAg and HCV RNA (qualitative) will be performed at 
screening if not performed within the last 3 months. 
Table 7. Laboratory Tests – performed locally 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin- WOCBP only 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR) 
Platelet count 
Alanine 
aminotransferase (ALT) 
or Aspartate 
aminotransferase (AST) 
Protein 
aPTT 
WBC (total and 
differential) 
Microscopic exam (If 
abnormal results are 
noted) 
HBsAG 
Red Blood Cell 
Count 
Lactate dehydrogenase 
(LDH) 
HCV RNA qualitative 
Absolute Neutrophil 
Count 
Calcium 
Creatine Kinase 
Absolute 
Lymphocyte Count 
Potassium 
Vitamin D 
Sodium 
Total Bilirubin 
Direct Bilirubin (If total 
bilirubin is elevated 
above the upper limit of 
normal) 
Total protein 
Blood Urea Nitrogen 
Creatinine 
TSH with T3, free T4 
 
6.1.4 Patient Discontinuation 
 
When a patient discontinues prior to trial completion, all applicable activities scheduled for the 
EOT visit should be performed at the time of discontinuation. Any adverse events which are 
present at the time of discontinuation/withdrawal should be followed in accordance with the 
safety requirements outlined in Section 6.2 - Adverse Events. 
 
6.1.5 Visit Requirements 


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Visit requirements are outlined in Section 5.0 - Trial Schedule. 
Specific procedure-related 
details are provided above in Section 6.1 - Trial Procedures. 
 
6.1.5.1 
Screening Period 
Screening of potential patients will be performed only after informed consent is obtained and 
within 30 days prior to first dose of trial medication (unless otherwise noted below). All 
necessary laboratory values and assessment reports must be available and reviewed prior to 
cycle1/ day 1. 
 
The following will be completed as part of the screening visit: 
 
1. Written informed consent 
 
2. Medical history including concurrent baseline conditions (using NCI CTCAE version 
5.0; Appendix 3), prior cancer therapy (including documentation of prior surgery, 
adjuvant or neoadjuvant chemotherapy and radiotherapy) 
 
3. Complete physical examination including height (cm) and weight (kg) 
 
4. ECOG Performance Status (see Appendix 4) 
 
5. Vital signs (blood pressure, pulse, and temperature) 
 
6. Computed tomography (CT) / magnetic resonance imaging (MRI) scan to document 
disease status (including chest, abdomen, pelvis, and other regions as clinically 
indicated. In addition, brain scan is not required but will be done to exclude brain 
metastases if clinically indicated only. This decision will at PI discretion. If a CT scan 
was taken within 28 days prior to first dose, a new scan is not necessary. However, if a 
new scan is to be done, it should be performed within 10 ± 2 days prior to starting trial 
medication. 
 
7. Electrocardiogram (ECG) 
 
8. PT/INR and aPTT 
 
9. Complete blood count (CBC) with differential and platelet count 
 
10. Comprehensive serum chemistries (refer to Table 7) 
 
11. Serum Vitamin D 
 
12. Creatine kinase (CK) 
 
13. TSH with T3, free T4  
 
14. IHC for MMR protein 
 


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15. CA19-9 (or CEA or CA-125 if not expressers of CA19-9) 
 
16. HBsAg and HCV RNA (qualitative) if not performed in the last 3 months 
 
17. Urinalysis (refer to Table 7) 
 
18. Serum or urine β-HCG pregnancy test for women of child-bearing potential (refer to 
Section 4.3.4 for more details) 
19. Concomitant medication notation (to include all medications taken within 30 days prior 
to enrollment) 
 
20. Optional baseline biopsy is to be obtained up to 4 weeks (28 days) prior to first dose 
of trial medication (C1/D1). Refer to Section 6.1.2.8 
 
21. Central Lab Blood Sample 3 X 10 mL vials 
 
6.1.5.2 
Treatment Period 
Patients will be treated at 28 ± 2 day intervals. Patient must begin cycle 1 within 30 days of 
signing the IRB approved informed consent document and after the screening assessments 
have been performed and reports have been reviewed to confirm eligibility. Screening clinical 
evaluations and laboratory assessments may be used as the Cycle 1/ Day 1 evaluations if 
they are completed within 7 days prior to trial treatment administration. 
 
Treatment will be administered by qualified and trained site personnel in a hospital, clinic, or 
other outpatient setting appropriate for chemotherapeutic infusions. 
 
For subsequent cycles, all assessments must be conducted prior to treatment administration 
and within 72 hours (except those noted), or if medical or scheduling conditions require a 
delay. 
 
Day 1 of each cycle 
 
• Inclusion/exclusion review (Cycle 1 only) 
 
• Directed physical exam 
 
• Vital signs 
 
• BSA only needs to be changed if there has been a change > 10% in body weight from 
Cycle 1 /Day 1 
 
• ECOG Performance Status (Appendix 4) 
 
• Hematology: CBC with differential and platelet count. Results must be reviewed prior 
to treatment initiation to ensure patient still meets inclusion criteria. 
 
• Serum chemistries (refer to Table 7). Results must be reviewed prior to treatment 


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initiation to ensure patient still meets inclusion criteria. 
 
• Creatinine kinase (CK) 
 
• TSH, T3 and T4 free 
 
• CA19-9 (C1/D1) (or CEA or CA-125 for non-expressers of CA19-9) 
• Urinalysis 
 
• Serum or urine β-HCG pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
of HCG). Results must be reviewed prior to treatment initiation confirming a negative 
serum β-HCG for women of child-bearing potential and documentation of the patients 
confirmation of preferred acceptable method of contraception per Section 4.3.4 starting 
from the day of trial treatment initiation (refer to Section 4.3.4 for more details). 
 
• AEs using the NCI CTCAE V5.0 (Appendix 3) 
 
• Concomitant medication notation of all medications taken within the 30 days prior to 
C1/D1 
 
• Nivolumab + cabiralizumab + gemcitabine administration 
 
• Day 8, and 15 (± 2 day) of each cycle 
• Vital signs 
 
• AEs using the NCI CTCAE 5.0 (Appendix 3) 
 
• Concomitant medication notation 
 
• Hematology: CBC with differential and platelet count - results must be reviewed prior 
to trial treatment administration 
 
• Serum chemistries (refer to Table 7) - results must be reviewed prior to trial treatment 
administration 
 
• Gemcitabine administration - Days 8 and 15 
 
• Cabiralizumab administration - Day 15 only Week 7 C2/D15 (-3 days, +10 days) 
• Optional repeat biopsy refer to Section 6.1.2.8 
 
• Central Lab Blood Sample to be collected at time of biopsy, 3 X 10 mL vials 
 
End of 2 treatment cycles (every 8 ± 7 days) until disease progression or end of trial, 
whichever comes first 


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Note: In order to more precisely determine time to progression, the investigator is encouraged 
to obtain radiological assessments and CA19-9 values earlier if there is a strong clinical 
suspicion of disease progression. In order to either confirm or refute the clinical impression. 
 
Duration of Treatment Period: The patient will continue on study and have the assessments 
performed as detailed above and per Table 5 beyond 3 cycles until there is evidence of clear-
cut tumor progression, has treatment ending toxicities, or withdraws from treatment. At which 
time the patient will be scheduled for the End of Treatment (EOT) visit. 
 
6.1.5.3 
End of Treatment (EOT) 
The patient will return to the clinic for the EOT visit and have the following performed within 7 
days after completing the last dose of study treatment or date of discontinuation. 
 
• Directed physical exam 
 
• ECOG Performance Status (see Appendix 4) 
 
• Vital signs 
 
• ECG 
 
• Hematology: CBC with differential and platelet count 
 
• Serum chemistries 
 
• CA19-9 (or CEA or CA-125 if not expressers of CA19-9) 
 
• Urinalysis 
 
• Serum β-HCG pregnancy test (for WOCBP) 
 
• Central lab blood sample, 3 X10 mL vials 
 
• Concomitant medication 
 
• CT/MRI scan to evaluate disease status (using same imaging method as Baseline, 14 
day window) . 
 
• AEs using the NCI CTCAE Version 5.0 (see Appendix 3) 
 
• Review contraception use as required by protocol Section 4.3.4 (where applicable) 
 
• Confirm contact information for patient and a designated family member and remind 
patient of FU telephone contact that will be conducted every 100 days for survival status 
after the last safety follow-up visit. 


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6.1.5.4 
Follow-up Period 
Three Safety Follow-up visits should be conducted approximately 30, 60, and 100 (±7 days) 
after the last dose of trial treatment, or date of discontinuation. All participants should complete 
the three clinical safety follow-up visits regardless of whether new anti-cancer therapy is 
started, except those participants who will withdraw consent for study participation or are 
unable to come to clinic due to disease progression. The following assessments will be 
performed: 
 
• Serum β-HCG pregnancy test (for WOCBP) 
 
• AEs using the NCI CTCAE Version 5.0 (see Appendix 3) 
 
• Review contraception use as required by protocol Section 4.3.4 (where applicable) 
 
• Confirm contact information for patient and a designated family member and remind 
patient of FU telephone contact that will be conducted every 100 days for survival 
status. 
 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Patients with an AE 
of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning 
of a new anti-cancer therapy, whichever occurs first. 
 
SAEs that occur within 100 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety, whether related or not related to study drug. 
 
6.1.5.5 
Survival Follow-up Phase 
Following the 100 days safety follow up, the patients are to be contacted via telephone every 
100 days for survival information until death, withdrawal of consent, or the end of the trial, 
whichever occurs first. 
 
6.2 Adverse Events 
6.2.1 Adverse Event Definition 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a preexisting medical condition in a clinical investigation participant administered study drug 
and that does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of investigational product, whether or 
not considered related to the investigational product. 
Progression of the cancer under study or events which are unequivocally due to disease 
progression should not be reported as an AE during the study (unless it is considered to be 
drug related by the investigator). 


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A non-serious adverse event is an AE not classified as serious. 
 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
• results in death 
 
• is life-threatening (defined as an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
 
• requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below) 
 
• results in persistent or significant disability/incapacity 
 
• is a congenital anomaly/birth defect 
 
• is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed 
in the definition above.) Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization.) 
 
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via 
the study drug is an SAE. 
 
 
Although pregnancy and potential drug-induced liver injury (DILI), are not always serious by 
regulatory definition, however, these events must be reported within the SAEs timeline. 
 
Any component of a study endpoint that is considered related to study therapy should be 
reported as an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, 
anaphylaxis must be reported). 
 
NOTE: The following hospitalizations are not considered SAEs: 
 
• A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
 
• Elective surgery, planned prior to signing consent 
 
• Admissions as per protocol for a planned medical/surgical procedure 


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• Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
 
• Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 
 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 
• Admission for administration of anticancer therapy in the absence of any other SAEs. 
 
6.2.2 Adverse Event Monitoring 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care. 
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins after initiation of study treatment and ends 3 days 
following the last administration of study treatment or start of new anti-cancer therapy, 
whichever is earlier. 
 
All patients experiencing an adverse event, regardless of its relationship to study drug [or at 
least possibly related to the drug], will be monitored until: 
• the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 
• any clinically significant abnormal laboratory values have returned to baseline; 
• there is a satisfactory explanation other than the study drug for the changes 
observed; or 
• death. 
 
6.23 
Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and reported 
to BMS as such. 


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The following laboratory abnormalities should be documented and reported appropriately: 
 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
 
• Any laboratory abnormality that required the participant to have study drug 
discontinued or interrupted 
 
• Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used 
by the reporting investigator (e.g., anemia versus low hemoglobin value). 
 
6.24 
Reporting Requirements of Adverse Events 
 
6.24.1.1 Expedited Reporting 
 
The Study Chair and multi-sites: University of Kansas Cancer Center and University of 
Pennsylvania Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or within 30 
days of the last administration of the study drug. 
SAEs, whether related or not related to study drug, overdoses and pregnancies must be 
reported to BMS within 24 hours \ 1 Business Day of becoming aware of the event. SAEs 
must be recorded on either CIOMS, MedWatch, or approved site SAE form. 
Pregnancies must be reported and submitted to BMS on any of the following form(s): 
1. MedWatch or, CIOMS or 
2. BMS Pregnancy Surveillance Form or, 
3. Approved site SAE form 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Facsimile Number: +1 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day 
to BMS using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization. 
The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 


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Any serious event (injuries, side effects, deaths or other problems), which in the opinion of 
the Principal Investigator was unanticipated, involved risk to subjects or others, and was 
possibly related to the research procedures. 
Any serious accidental or unintentional change to the IRB-approved protocol that alters the 
level of risk. 
Any deviation from the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research subject. 
Any new information (e.g., publication, safety monitoring report, updated sponsor safety 
report), interim result or other finding that indicates an unexpected change to the risk/benefit 
ratio for the research. 
Any breach in confidentiality that may involve risk to the subject or others. 
Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by 
the Principal Investigator. 
 
Multi-sites: The Institutional Review Board (IRB) of each site must be notified by the site 
principal investigator according to their local policies. 
The FDA must be notified according to the following timelines: 
        within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and 
        within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, 
and 3) at least possibly related to study participation. 
6.24.1.2 Routine Reporting Requirements 
The UCSD HRPP must be notified of any adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual Continuing 
Review. 
The IRB of each site must be notified by the site principal investigator according to their local 
policies. 
The FDA must be notified of all non-serious adverse events annually at the time of the 
annual report. 
6.24.1.3 Serious Adverse Events 
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 (e.g., a follow-up skin biopsy). 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these 
aforementioned time periods, which is believed to be related to study drug or protocol- 
specified procedure. 


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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. 
 
An appropriate SAE form (e.g. ex-US = CIOMS form or USA = Medwatch form) should be 
used to report SAEs to BMS. If you prefer to use your own Institutional form, it must be 
reviewed by BMS prior to study initiation. Note:  Please include the BMS Protocol number  on 
the SAE form or on the cover sheet with the SAE form transmission. 
 
• The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i 
 
• The MedWatch form is available at: MedWatch 3500 Form 
 
The Sponsor will reconcile the clinical database AE cases (case level only) transmitted to 
BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). 
 
• The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com the 
SAE reconciliation report and include the BMS protocol number every 3 months and 
prior to data base lock or final data summary 
 
• GPV&E will send the investigator the report to verify and confirm all SAEs have been 
transmitted to BMS GPV&E. 
 
• 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 
(Worldwide.Safety@bms.com). 
 
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). 
 
In accordance with local regulations, BMS will notify sponsor 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). Sponsor investigator notification of these events will be 
in the form of either a SUSAR Report or a Semi-Annual SUSAR Report. 
 
• 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 (e.g., animal) study, important safety 


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recommendations from a study data monitoring committee, or Sponsor Investigator, 
or BMS decision to end or temporarily halt a clinical study for safety reasons. 
 
• 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 Investigator 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. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on 
either CIOMS, MedWatch, or approved site SAE form. 
 
Pregnancies must be reported and submitted to BMS. BMS will perform due diligence follow-
up using the BMS Pregnancy Form which the investigator must complete. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
SAE Facsimile Number: +1 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day 
to BMS using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
Non-Serious Adverse Event 
 
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 [eg, IND US trial] 
as part of an annual reporting requirement. 
 
Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects. 
 
Non-serious Adverse Event Collection and Reporting 
 
The collection of non-serious AE information should begin at initiation of study drug. 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. 
 
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.   


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The Adverse Event information required to be sent to BMS is noted in the ‘Bristol-Myers 
Squibb Early Asset Investigator Sponsored Research (ISR) Import Plan’ which describes 
the method of collection and submission to BMS via the mailbox:  
MG-RD-GPVE-PHARMACOVIGILANCE@bms.com 
 
When the file is submitted to BMS, it must be noted the file contains All Non Serious 
Adverse Events (only adverse events not previously submitted to BMS within the 3 months) 
should be reported. 
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. 
 
6.24.1.4 Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor Investigator and the Sponsor 
Investigator will report within 24 hours (working days) to BMS Worldwide Safety. 
 
Events of clinical interest for this trial include: 
 
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. 
 
Potential drug-induced liver injury (DILI) is defined as: 
 
ALT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
 
AND 
 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
 
AND 
 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
Whenever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs meeting 
the defined criteria above must be reported as serious adverse events (SAEs). See Section 
6.24.1.3 and Appendix 3 for reporting details.   
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 


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exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant). 
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 
reporting procedures. 
 
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 CIOMS, 
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 Investigator 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. 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any patient must be 
reported within 24 hours to the Sponsor Investigator and the Sponsor Investigator will report 
within 24 hours (working days) to BMS Global Safety if it causes the patient to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 100 days following 
cessation of treatment, or 30 days following cessation of treatment if the patient initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to study drug, must be reported within 24 hours to the BMS Global Safety. 
 
6.25 
Evaluating Adverse Events 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 
 
AE Severity Grade 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 5.0. A copy of the CTCAE 
Version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick 
_Reference_8.5x11.pdf 
 
Any adverse event which changes CTCAE grade over the course of a given episode will have 


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each change of grade recorded on the adverse event case report forms/worksheets. 
 
When specific adverse events are not listed in the CTCAE they will be graded by the 
investigator according to the following grades and definitions, consistent with the CTCAE 
Version 5.0. 
 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age- 
appropriate instrumental activities of daily living (ADL). Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden 
 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
• Grade 5: Death related to AE. 
 
Duration 
 
The investigator will record the start and stop dates of the adverse event. If less than1 day, 
this will be indicated in the appropriate length of time in units. 
 
Action Taken 
 
Did the adverse event cause the trial treatment to be discontinued? 
Relationship 
All adverse events regardless of CTCAE grade must also be evaluated for causal relationship 
to trial treatment/ trial interventions. 
 
The determination of the likelihood that trial treatment caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials 
on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document 
must be retained for the required regulatory time frame. 
 
The criteria below are intended as reference guidelines to assist the investigator in assessing 
the likelihood of a relationship between the trial treatment and the adverse event based upon 
the available information. 
 
The following components are to be used to assess the relationship between trial treatment 
and the AE; the greater the correlation with the components and their respective elements (in 


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number and/or intensity), the more likely the trial treatment caused the adverse event (AE): 
 
Exposure: Is there evidence that the patient was actually exposed to trial treatment such as: 
reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
trial treatment? Is the time of onset of the AE compatible with a drug-induced effect? 
 
Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors? 
 
Dechallenge: Was trial treatment discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. 
If no, this is a negative dechallenge. 
 
Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the trial treatment; or (3) the trial is a 
single-dose drug trial); or (4) trial treatment is/are only used one time. 
 
Rechallenge: Was the patient re-exposed to trial treatment in this trial? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. 
If no, this is a negative rechallenge. 
Note: If a rechallenge is planned for an adverse event which was serious and which may have 
been caused by either of the trial treatments, or if re-exposure to trial treatment poses 
additional potential significant risk to the patient, then the rechallenge must be approved in 
advance by the Sponsor Investigator as per dose modification guidelines in the protocol. 
 
Consistency with Trial Treatment Profile: Is the clinical/pathological presentation of the AE 
consistent with previous knowledge regarding trial treatment or drug class pharmacology or 
toxicology? 
 
Relationship 
Attribution 
Description 
Unrelated to the trial 
treatment/intervention 
Unrelated 
The AE is clearly NOT related to the trial 
treatment/intervention 
Unlikely 
The AE is doubtfully related to the trial 
treatment/intervention 
Related to the trial 
treatment/intervention 
Possible 
The AE may be related to trial 
treatment/intervention 
Probable 
The AE is clearly related to trial 
treatment/intervention 
 


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6.26 
Investigator Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to the Sponsor, the regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations. 
 
 
7.0 
PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
For the purposes of this trial the term Investigational Products refer to both nivolumab and 
cabiralizumab. 
 
Gemcitabine will not be provided to the site as part of this trial but will be obtained directly 
from the treating investigator’s designated pharmacy supply. Therefore the packaging, 
storage, and handling of gemcitabine will follow the dispensing pharmacy’s own standard 
operation procedures. 
 
7.1 Packaging and Labeling Information 
Investigational Product will be provided by BMS. For further instructions regarding the 
investigation product for this trial please refer to the current version of the Investigator’s 
Brochures for complete storage, handling, dispensing, and infusion information. 
 
7.2 Storage and Handling Requirements 
Investigational Products must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
 
The investigator or authorized person at the trial site must maintain records of receipt and 
ongoing inventory of clinical trial supply of Investigational Products at the site including the 
dispensing and administration of the Investigational product vials used for each patient. 
 
Clinical trial supplies of Investigational Products may not be used for any purpose other than 
that stated in the protocol. 
 
7.2.1 Nivolumab 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) or 40 mg/4 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 (Tween 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. 


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Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected from 
light and freezing. 
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container 
The administration of nivolumab infusion must be completed within 24 hours of preparation. 
If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C 
to 8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can 
be at room temperature (20°C to 25°C, 68°F to 77°F) and room light. The maximum of 8 hours 
under room temperature and room light conditions includes the product administration period. 
 
7.2.2 Cabiralizumab 
Cabiralizumab drug product is supplied for IV administration as a sterile, aqueous, colorless 
to pale yellow, clear to slightly opalescent, pyrogen-free solution in glass vials stoppered with 
coated stoppers, and equipped with aluminum seals. Light (few) particulates may be present. 
Cabiralizumab drug product is shipped refrigerated at 2 - 8°C and stored refrigerated 2- 8°C 
until time of use. Vials are for single-use only. Drug product should be protected from light 
and freezing. 
 
7.3 Returns and Reconciliation 
Upon completion or termination of the trial, all unused and/or partially used Investigational 
Product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept. 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 Trial Design 
This is an open label single arm clinical trial compared against historical response rates.   
 
A Simon’s optimal two-stage design will be used for this study. Up to 15 subjects will be 
accrued and treated with Nivolumab + cabiralizumab + gemcitabine. The primary endpoint is 
the proportion who are progression free at 6 months (PFS6) according to RECIST 1.1 criteria. 
33 Based on no maintenance after best response to prior chemotherapy 8, historical controls 
treated with gemcitabine alone had only 4% of patients with no progression at 6 months. If the 
PFS6 rate in this study is ≤4%, we will consider the treatment as not meeting the threshold of 
further consideration. We will test the null hypothesis H0: p≤ 4% against the alternative 
hypothesis H1: p>22%, where p is the progression free response rate after six months of study 
treatment. The two-stage design proposed below will have 80% power to reject the null 
hypothesis at 10% significance level and conclude that the true PFS rate at 6 months is above 
4%, if the observed PFS6 rate is ≥22%. The study design is described in detail is as follows: 
 
Stage 1: 8 subjects will be treated; if needed, accrual will be held until the progression results 
for these subjects are known for the first six months. The trial will be terminated at Stage 1 if 
none of the 8 subjects are progression free at 6 months; otherwise it will continue to Stage 2. 
 


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Stage 2: 7 more patients will be accrued. We will reject the therapy if, among all the 15 (8+7) 
subjects, the number of patients who have a PFS6 response is ≤1; if ≥2 patients are 
progression free at 6 months by RECIST 1.1, the treatment will be claimed to be successful. 
We will conclude that the study treatment is associated with a progression free response in 
more than 4% of patients at 6 months.  
 
Note that if a patient is not evaluable at 6 months (e.g., if there is an early dropout), as specified 
in section 8.2.5, it will be treated as disease progression for the primary efficacy outcome.   
 
Early stopping probability: Under this design, if the null hypothesis is true, the probability of 
stopping the trial early will be 72.1%. The sample size calculation was done using PASS 
version 14.0.3 (released September 22, 2015). Sample size calculation did not incorporate the 
safety endpoint. Statistics for safety outcomes will be presented descriptively.   
 
We expect to accrue 1-2 patients every month. All patients will be accrued within  14-21 
months. Patients will be followed for 6 months. The total duration of this study will be about 
20-27 months. 
 
8.2 Statistical Analysis Plan 
 
8.2.1 Analysis of primary endpoint 
 
Primary efficacy analysis includes interim efficacy analysis and final efficacy analysis for the primary 
endpoint.  
  
The interim efficacy analysis will be conducted at the end of Stage 1. The study enrollment will be put on 
hold for interim analysis until tumor response results for Stage 1 patients are known. 
 
The final efficacy analysis will calculate the UMVUE estimate of PFS at 6 months, p-value and 95% CI 
for progression free response rates.39, 40 The calculation will be performed using R clinfun package 
(www.r-project.org).  
 
 
8.2.2 Analysis of the Conduct of the Trial 
 
Enrollment, major protocol violations, and discontinuations for the trial will be summarized 
using a CONSORT diagram. 
 
8.2.3 Analysis of Patient Characteristics 
 
Demographic and baseline characteristics, such as age, race, BSA, duration of pancreatic 
cancer, site(s) of metastatic disease, prior cancer treatment, and baseline ECOG performance 
status will be summarized using medians (range) for continuous variables and proportions for 
categorical variables. 
 
8.2.4 Analysis of Study Treatment Administration 
 
Study treatments dose administration will be listed and dose modifications will be flagged.  


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8.2.5 Definition of study population for primary efficacy analysis 
 
All subjects who undergo at least one dose of the study treatment will be included in the 
analysis. For the primary endpoint, “Intention-to-treat” analyses will be performed for an 
endpoint. To be specific, if the endpoints for a subject cannot be assessed (for example, a 
subject drops out early prior to the 6 months assessments due to any reason), it will be 
considered to be an event that does not favour the study therapy (e.g., disease progression 
for the primary outcome).  
 
 
8.2.6 Analysis of Secondary Endpoints 
 
 
 
8.2.6.1 
Safety Analyses 
 
This study can also be stopped early due to safety reasons, please refer to section 4.6 for more details. 
 
Safety analyses will be performed for all patients having received at least one dose of study 
treatment. The proportion of subjects experiencing adverse events, serious adverse events, 
and treatment delays will be summarized. Tolerability will be assessed based on dosage 
delays and discontinuation due to adverse events.   
 
All AEs will be listed, documenting the course, outcome, severity, and relationship to the study 
treatment. Incidence rates of AEs and the proportion of subjects prematurely withdrawn from 
the study due to AEs will be shown. 
 
 
8.2.6.2 
 Secondary Efficacy Analyses 
Secondary efficacy analysis will be performed for outcomes including progression free survival 
over the course of the study, duration of response, disease control rate and overall survival. 
For survival outcomes including overall survival, median survival times together with their 95% 
confidence intervals will be estimated with the Kaplan-Meier method, and report number of 
events. For proportions, a 95% confidence interval will be calculated using the exact method. 
 
 
8.2.7 Analysis of Exploratory Endpoints 
8.2.7.1 
Comparison of RECIST 1.1 and iRECIST criteria 
Given that both nivolumab and cabiralizumab are immunotherapy agents, disease progression 
will be defined by RECIST and iRECIST criteria (Appendix 5). Proportion of progression-free 
patients at 6 months using iRECIST will be performed using the same method as for the 
primary endpoint of RECIST 1.1. Cross tables of response categories from the two criteria will 
be presented. Number and proportion of patients who are considered to be PFS based on 
RECIST but a non-response based on iRECIST (and vice versa) will be described.  
 
Tumour and blood samples will be collected pre-treatment and during treatment. These 
biomarker assessments will potentially aid in understanding treatment efficacy. All samples 
will be linked anonymised and only identified by the trial ID and unique sample number 


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allocated by the trial coordinating team. The results of any exploratory analysis will not be 
included in the clinical study report and may be reported separately from the main study 
results. Association between a biomarker and a response outcome will be assessed using 
Cox models. The stage (1 vs 2) variable will be included as a covariate.  
 
 
9.0 
ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 Institutional Review Board/Ethics Committee Approval 
Before trial initiation, this protocol and informed consent form will be submitted for review and 
approval to the IRBs charged with oversight for the clinical sites. In addition, any form of 
proposed advertising and advertising text for patient recruitment must be reviewed and 
approved by the IRB. The Investigator will forward to the Sponsor Investigator a copy of the 
IRB’s approval of this protocol, any amendments, informed consent form, and any 
modifications to the informed consent, based on the FDA regulations set forth in 21 CRF 56 
of the Code of Federal Regulations. 
 
In addition, the Investigator will be responsible for forwarding to the Sponsor Investigator a 
description of the IRB members (including profession and affiliation) or a United States (US) 
Department of Health and Human Services (DHHS) General Assurance number and 
expiration date. If neither of these is available, the chairperson must submit a statement 
indicating that the members of the board responsible for the review meet the FDA and other 
appropriate regulatory requirements. In addition, the labeling for all approved trial medications 
should be submitted to the IRB for information purposes. 
 
Clinical supplies will not be shipped to the clinical site until IRB approval is obtained for the 
protocol. Any existing amendments, informed consent, and photocopies of the approved 
documents must be received by the Sponsor Investigator prior to drug shipment. 
 
9.2 Investigators protocol agreement 
The Investigator must sign the Investigator’s Protocol Agreement. The original must be kept 
on file by the Sponsor Investigator and the Investigator must retain a copy. The completed 
Investigator’s Protocol Agreement signifies agreement to comply with all procedures outlined 
by this protocol by the Investigator. An Investigator’s Protocol Agreement must be signed if 
and when a protocol amendment is issued. 
 
9.3 Remaining Samples 
Any samples remaining after the trial specified analyses is completed will be stored by the 
Sponsor Investigator at UCSD if the patient consented for use of their remaining samples for 
future research purposes. This includes the original specimen collected from the patient 
[blood, tumor tissue]) as well as derivatives created from the original specimen (DNA, RNA, 
blocks or slides). 
 
If a patient has not consented for their remaining samples to be used for future research 
purposes, remaining samples and derivatives will be destroyed and documented on the 
Sample Destruction/Return Request Form- refer to Trial Laboratory Manual. 
 


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9.4 Confidentiality 
The Investigator and any other personnel involved in this trial shall not disclose, or use for any 
purposes (other than for the performance of this trial any data, records, or other information 
(hereinafter collectively “information”) disclosed to the Investigator or other trial personnel. 
Such information shall remain the confidential and proprietary property of the Sponsor 
Investigator, BMS and SU2C, and shall be disclosed only to the Investigator or other 
designated trial personnel. 
 
Patient confidentiality will be ensured by using assigned site-specific Screening and 
Randomization numbers (refer to Section 6.1) throughout the trial. 
 
9.5 Publication 
As a general rule, no trial results should be published without prior approval of the Sponsor 
Investigator. The rights of the investigator and the Sponsor Investigator with regard to 
publication of the results of this trial are described in the investigator contract. 
 
9.6 Compliance with Financial Disclosure Requirements 
All Investigators will be required to submit written financial disclosures to the Sponsor 
Investigator prior to participating in this clinical trial and any changes in disclosures during the 
course of the trial as per 21 CFR part 54. 
 
9.7 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Investigator Sponsor of the trial 
is solely responsible for determining whether the trial and its results are patient to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 
Information posted will allow patients to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information. 
 
9.8 Required Site Documentation 
Before the study can be initiated at any site, the following documentation must be provided 
to the UCSD Moores Cancer Center Clinical Trials Office. 
• A copy of the official IRB approval letter for the protocol and informed consent. 
• A copy of the IRB-approved consent form. 
• CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation. 
• CAP and CLIA Laboratory certification numbers and institution lab normal values. 
• Executed clinical research contract. 
9.8.1 Site Registration Procedures 
 
All patients must be registered with the UCSD Moores Cancer Center Clinical Trials Office 


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before enrollment to study. Prior to registration, eligibility criteria must be confirmed with the 
UCSD Study Coordinator. To register a patient, call Monday through Friday, 
8:00AM-4:30PM. Study sites other than UCSD must fax informed consent documentation, 
completed eligibility checklist, and all source documentation for eligibility confirmation to the 
UCSD Clinical Trials Office (Fax: 858-822-5360). Once eligibility is confirmed, patient will be 
given a unique sequential study number. 
 
Patients will be given a unique sequential study number and will be randomized at the time 
of enrollment. UCSD will fax the outside study site for confirmation of patient registration and 
ability to start study treatment, the patient’s study number, and the Arm the patient is 
randomized to. 
 
9.8.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
subjects who have provided written informed consent must also sign a subject authorization 
to release medical information to the study Sponsor and allow a regulatory authority, or 
Institutional Review Board access to subject’s medical information relevant to the study. 
 
 
9.9 Quality Management System 
All aspects of the study will be carefully monitored by the Sponsor Investigator and/or its 
authorized representative for compliance with applicable government regulations with respect 
to current ICH GCP guidelines as well as other applicable regulations and guidelines. 
 
9.9.1 Data Monitoring Plan 
 
Data monitoring procedures will be carried out by the Sponsor Investigator for all participating 
sites, and will be performed on a regular basis to comply with Good Clinical Practice 
guidelines. 
 
Review of the case report forms, cross-reference with source documents (including radiology 
review), review of trial related regulatory documents and logs (e.g. enrollment, trial site staff), 
would be monitored on an ongoing basis during monitoring sessions. The monitor will ensure 
that the investigation is conducted according to protocol design and regulatory requirements. 
 
The monitor will complete a written monitoring report and provide to the Sponsor Investigator. 
The report will include a summary of what the site monitor reviewed and the site monitor’s 
statements concerning the significant findings/facts, deviations and deficiencies, conclusions, 
actions taken or to be taken, and/or actions recommended to ensure compliance. The site 
Principal Investigator will be expected to submit any Corrective Action Plans, in writing, to the 
Sponsor Investigator. A copy of the monitoring forms, final monitoring reports, and Corrective 
Action Plan will be kept in the site monitor’s trial file follow up at the next monitoring session. 
 
9.9.2 Data Safety Monitoring 
 
Data and Safety Monitoring/Auditing 
 
Data and Safety reporting will be supported by the study statisticians according to the 
monitoring plan. Briefly, comprehensive safety and data monitoring reports will be generated 


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every six months for review by the study team before being sent to the UCSD DSMC, 
described below. The study will used the VELOS electronic data capture system at UCSD. 
 
In addition to adverse event monitoring and clinical oversight by the principal investigator 
and co-investigators, this study will also use the UCSD Moores Cancer Center Data Safety 
and Monitoring Committee (DSMC) to provide oversight in the event that this treatment 
approach leads to unforeseen toxicities. Data from this study will be reported semi-annually 
and will include: 
1) the protocol title, IRB protocol number, and the activation date of the study. 
2) the number of patients enrolled to date 
3) the dates of patient enrollment 
4) demographic summary of patients 
5) a summary of safety including all death, and adverse events regardless of grade and 
attribution 
6) a response evaluation for evaluable patients when available 
7) a summary of any recent literature that may affect the ethics of the study. 
 
9.10 Data Management 
9.10.1 Case Report Forms 
 
All the clinical data will be captured by the site on electronic case report forms (eCRFs).   The 
eCRFs will be used for all consented patients. The investigator and trained trial personnel will 
enter and edit the data via a secure network, with secure identification and password 
requirement. A complete electronic audit trial will be maintained. The investigator will be 
required to provide approval of all data to confirm accuracy.  Copies of the eCRFs  will be 
provided to the investigator at the conclusion of the trial. 
 
9.10.2 Source Documents 
 
Source documents serve as the evidence of the existence of the patient and the data collected 
for this trial. Source documents will be the responsibility of the Investigator and will be filed at 
the site and available as needed by the Sponsor Investigator or assigned clinical monitor. 
 
Data captured on the eCRF is to be transcribed from source document and must be consistent 
with any discrepancies explained and documented. 


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APPENDICES 
 
 
Appendix 1 – Nivolumab Package Insert 
 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf 
 
 
 
 
Appendix 2 – Gemcitabine Package Insert 
 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf 
 
 
 
 
 
Appendix 3 – NCI CTCAE version 5.0 
 
The CTCAE Version 5.0 can be accessed and downloaded from the CTEP website at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
 
 
Appendix 4 – ECOG Performance Status 
 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin 
Oncol. 1982;5:649-655. 


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Appendix 5 – Protocol Criteria for Measurement of Trial Endpoint RECIST 
1.1 and iRECIST 
 
1. 
Definitions 
 
1.1. Evaluable for adverse events. All patients will be evaluable for adverse event evaluation 
from the time of their first treatment. 
 
1.2. Evaluable for response. All patients who have received at least one cycle of therapy and 
have their disease re-evaluated will be considered evaluable for response (exceptions 
will be those who exhibit objective disease progression prior to the end of cycle 1 who 
will also be considered evaluable). Patients on therapy for at least this period and who 
meet the other listed criteria will have their response classified according to the definitions 
set out below. 
 
Response and progression will be evaluated in this study using the revised international 
criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) 
committee as well as the modified iRECIST guidelines. Investigators should note the 
different requirements for confirmatory scans as well as follow up for the two criteria. 
 
See section 6.1.2.6 for criteria for continuing treatment past RECIST 1.1 disease 
progression. 
 
2. 
RECIST 1.1 Response and Evaluation Endpoints 
 
2.1. Measurable Disease. Measurable tumour lesions (nodal, subcutaneous, lung 
parenchyma, solid organ metastases) are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm with 
chest x-ray and as ≥10 mm with CT scan or clinical examination. Bone lesions are 
considered measurable only if assessed by CT scan and have an identifiable soft tissue 
component that meets these requirements (soft tissue component ≥10 mm by CT scan). 
Malignant lymph nodes must be ≥15 mm in the short axis to be considered measurable; 
only the short axis will be measured and followed. All tumour measurements must be 
recorded in millimetres (or decimal fractions of centimetres). Previously irradiated lesions 
are not considered measurable unless progression has been documented in the lesion. 
 
2.2. Non-measurable Disease. All other lesions (or sites of disease), including small lesions 
are considered non- measurable disease. Bone lesions without a measurable soft tissue 
component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin 
and abdominal masses followed by clinical examination are all non- measurable. Lesions 
in previously irradiated areas are non-measurable, unless progression has been 
demonstrated. 
 
2.3. Target Lesions. When more than one measurable tumour lesion is present at baseline 
all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) 
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recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis of 
≥15 mm by CT scan and only the short axis of these nodes will contribute to the baseline 
sum. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should be 
considered non-target lesions. Nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed (see 8.2.4). At baseline, the sum of 
the target lesions (longest diameter of tumour lesions plus short axis of lymph nodes: 
overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for 
each assessment, even if very small. If extremely small and faint lesions cannot be 
accurately measured but are deemed to be present, a default value of 5 mm may be 
used. If lesions are too small to measure and indeed are believed to be absent, a default 
value of 0 mm may be used. 
 
2.4. Non-target Lesions. All non-measurable lesions (or sites of disease) plus any measurable 
lesions over and above those listed as target lesions are considered non- target lesions. 
Measurements are not required but these lesions should be noted at baseline and should 
be followed as “present” or “absent”. 
 
2.5. Response. 
 
All patients will have their BEST RESPONSE from the start of study treatment until the 
end of treatment classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and 
normalization of tumour markers. Pathological lymph nodes must have short axis 
measures <10 mm (Note: continue to record the measurement even if <10 mm and 
considered CR). Residual lesions (other than nodes <10 mm) thought to be non- 
malignant should be further investigated (by cytology specialized imaging or other 
techniques as appropriate for individual cases4 before CR can be accepted. Confirmation 
of response is only required in non-randomised studies. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter 
for tumour lesions and short axis measure for nodes) of target lesions, taking as reference 
the baseline sum of diameters. Non target lesions must be non-PD. Confirmation of 
response is only required in non-randomised studies. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of ≥5 mm. Appearance of new lesions will also 
constitute progressive disease (including lesions in previously unassessed areas). In 
exceptional circumstances, unequivocal progression of non- 


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target disease may be accepted as evidence of disease progression, where the overall 
tumour burden has increased sufficiently to merit discontinuation of treatment or where 
the tumour burden appears to have increased by at least 73% in volume. Modest 
increases in the size of one or more non-target lesions are NOT considered unequivocal 
progression. If the evidence of PD is equivocal (target or non-target), treatment may 
continue until the next assessment, but if confirmed, the earlier date must be used. 
 
Table S1: Integration of target, non-target and new lesions into response 
assessment 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best 
Requires 
Response 
this Category 
for 
also 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes <10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ 
evaluated 
not 
all 
No 
PR 
SD 
Non-PD/ 
evaluated 
not 
all No 
SD 
Documented at least once ≥4 wks. 
from baseline 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumour markers, 
tumour nodes <10 mm 
No Target 
Non-CR/non-PD 
No 
Non- 
CR/non- 
PD 
No Target 
Not all evaluated 
No 
NE 
No Target 
Unequivocal PD 
Any 
PD 
No Target 
Any 
Yes* 
PD 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. This is a reason for stopping therapy, but is NOT objective PD. 
Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
*Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may 
be continued pending further assessments – see table S2. 
 
3. 
iRECIST Response Assessment 
 
Overall response will also be assessed using iRECIST. Immunotherapeutics may result 
in infiltration of immune cells leading to transient increase in the size in malignant lesions, 
or undetectable lesions becoming detectable. The criteria are identical to those of 
RECIST 1.1 in many respects but have been adapted to account for instances where an 
increase in tumour burden, or the appearance of new lesions, does not reflect true 


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tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are 
designated with a prefix. iRECIST time-point and best overall responses will be recorded 
separately. 
 
3.1. Confirming Progression 
 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
iCPD is confirmed if further increase in tumour burden, compared to the last assessment, 
is seen as evidenced by one or more of the following: 
 
• Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
 
o Continued unequivocal progression in non-target disease with an increase in 
tumour burden 
 
o Increase in size of previously identified new lesion (s) (an increase of at least 5 
mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions. 
 
• RECIST 1.1 criteria are met in lesions types (target  or  non-target  or  new lesions) 
where progression was not previously identified, including  the appearance of 
additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those 
criteria are met compared to baseline). As can be seen in table 2, the prior documentation 
of iUPD does not preclude assigning iCR, iPR, or iSD in subsequent time-point 
assessments or as best overall response (BOR) providing that iCPD is not documented 
at the next assessment after iUPD. 
 
3.2. New lesions 
 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in 
short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and New 
Lesion-Non-Target (NLNT) to allow clear differentiation from baseline target and non-
target lesions. 


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New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of target lesions should NOT be included in the sum of 
measures of original target lesions identified at baseline. Rather, these measurements 
will be collected on a separate table in the case record form. 
 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted 
at least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression 
from iUPD with either an increase of at least 5 mm in the absolute value of the sum of 
NLT OR an increase (but not necessarily unequivocal increase) in the size of NLNT 
lesions OR the appearance of additional new lesions. 
Table S2: Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD 
with 
no 
change 
OR 
decrease 
from last 
TP 
iUPD 
with 
no 
change 
O 
R decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously identified and 
increase in size (≥5 mm in SOM for NLT or any increase for 
NLNT) or number. If no change in NLs (size or number) from 
last TP, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in further 
increase in size of NT disease (need not meet RECIST 1.1 
criteria for unequivocal PD) 
iUPD 
Non-iCR/Non- 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
o further increase in SOM of at least 5 mm, otherwise 
remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
o previously identified T lesion iUPD SOM ≥5 mm and / or 
o NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
o previously identified T lesion iUPD ≥5 mm and / or 
o previously identified NT lesion iUPD (need not be 
unequivocal) and /or 
o size or number of new lesions previously identified 


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Non- 
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
o increase in size or number of new lesions previously 
identified 
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD 
would be the same. ** in any lesion category. *** previously identified in assessment immediately prior to this 
TP. 
 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
Table S3: iRECIST Best Overall Response (iBOR) 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, 
iPR 
, iUPD, NE 
iCR, iPR, iUPD, NE iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, NE iCR 
iCR, iPR, iSD, iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, NE, iCPD iPR, iSD, iUPD, NE, iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
1. Table assumes a randomised study where confirmation of CR or PR is not required. 
2. NE = not evaluable that cycle. 
3. Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
4. For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each 
TPR but is not shown in the table for ease of presentation. 
 
5. 
Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR or 
iCR/iPR (whichever is first recorded) are first met until the first date that recurrent or 
progressive disease is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline). 
 
Stable disease duration will be measured from the time of start of treatment until the 
criteria for progression are met, taking as reference the smallest sum on study (including 
baseline). 
 
6. Methods of Measurement 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Assessments should 
be identified on a calendar schedule and should not be affected  by delays in therapy. 
While on study, all lesions recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small 


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(e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned. For 
lesions which fragment/split add together the longest diameters of the fragmented 
portions; for lesions which coalesce, measure the maximal longest  diameter for the 
“merged lesion”. 
 
6.1. Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by colour photography including a ruler to estimate the size 
of the lesion is recommended. If feasible, imaging is preferred. 
 
6.2. Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions ≥20 mm on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
 
6.3. CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for 
body scans). Other specialized imaging or other techniques may also be appropriate for 
individual case.4 For example, while PET scans are not considered adequate to measure 
lesions, PET-CT scans may be used providing that the measures are obtained from the 
CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast). PET scans per PI discretion. 
 
6.4. Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT is advised. 
 
6.5. Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
 
6.6. Tumour Markers. Tumour markers alone cannot be used to assess objective tumour 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. 
 
6.7. Cytology, Histology. These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumour types such 
as germ cell tumours, where known residual benign tumours can remain). When effusions 
are known to be a potential adverse effect of treatment (e.g. with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic 
origin of any effusion that appears or worsens during treatment when the 


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measurable tumour has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease. 


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Appendix 6 – Adverse Event Management for Cabiralizumab and Nivolumab Combination Therapy 
Cohorts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 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. 
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 3/4 
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 
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: 
 
stools per day over baseline; 
incontinence; IV fluids ≥24 
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 
– nivolumab therapy per protocol 
1 to 2 mg/kg/day methylprednisolone IV or 
IV equivalenta 
– 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 


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a 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 
therapy per protocol 
– Monitor creatinine every 2 to 3 days 
– 0.5 to 1 mg/kg/day methylprednisolone 
IV or oral equivalenta 
– Consider renal biopsy if clinicallyindicated 
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 
therapy per protocol 
– Monitor creatinine every 2 to 3 days 
– 0.5 to 1 mg/kg/day methylprednisolone 
IV or oral equivalenta 
– Consider renal biopsy if clinicallyindicated 
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 andnivolumab 
– therapy per protocol 
1 to 2 mg/kg/day methylprednisolone IV 
or IV equivalenta 
– Consult nephrologist 
– Consider renal biopsy if clinicallyindicated 
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 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. 
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 
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 
– Discontinue cabiralizumab and nivolumab therapy 
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 
symptoms; New/worsening 
per protocol 
hypoxia; 
Life-threatening 
– Hospitalization 
– Pulmonary and infectious disease consults 
– 2 to 4 mg/kg/day methylprednisolone IV or IV 
equivalentb 
– Add prophylactic antibiotics for opportunistic 
infections 
– Consider bronchoscopy, lung biopsy if 
clinically indicated 


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Hepatic Adverse Event Management Without Liver Metastasis 
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 
– Contact the Sponsor 
– Evaluate for non-drug related causes of the laboratoryabnormalities 
(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 Sponsor/MM and the investigator 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 Sponsor if there are clinical signs of muscle or hepatic 
injury or other clinical symptoms 
– Contact the Sponsor if there is a concurrent increase of bilirubin, AST, 
ALT, or alkaline phosphatase 
– Notify the Sponsor 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 
protocol 
– Increase frequency of monitoring of (including but 
not limited to) AST, ALT, bilirubin, alkaline 
phosphatase, and INR (every48-72 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 
phosphatase along with ALT, start steroids 
immediately 
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 therapyper 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 
– Consider prophylactic antibiotics for opportunistic infections 
– Discuss with Sponsor 


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a 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. 
Hepatic Adverse Event Management Without Liver Metastasis 
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 
– Monitor for other clinical symptoms (fatigue, nausea, 
vomiting, abdominal pain, fever, rash, 
and/or eosinophilia) 
AST or ALT > 20 xULN 
or 
Total bilirubin >3 
xULN 
– Discontinue cabiralizumab and nivolumab therapy 
– Increase frequency of monitoring to every 1 to 2 
days 
– Consider 1 to 2 mg/kg/day methylprednisolone IV or 
IV equivalenta 
– 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 


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Hepatic Adverse Event Management with Liver Metastasis 
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 therapy per 
protocol 
–  
– Continue LFT monitoring per protocol until resolution. 
– Continue monitoring for and other associated clinical 
signs or symptoms 
– Contact the Sponsor 
– Evaluate for non-drug-related causes of the laboratory 
abnormalities (e.g. obstruction, viral infection, Gilbert’s 
disease, etc) 
– Under selected circumstances (e.g alternative etiology is 
identified), the patient may receive additional therapyonly 
after consultation and agreement between the Sponsor/MM 
and the investigator if receiving additional treatment with 
cabiralizumab and nivolumab is in the best interest of the 
patient (e.g if the subject has demonstrated a response to 
therapy) 
AST or ALT > 5 to ≤ 12 xULN 
and 
Total bilirubin ≤ 2 xULN 
– 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 Sponsor if there are clinical signs of muscle 
or hepatic injury or other clinical symptoms 
– Contact the Sponsorif there is a concurrent increase 
of bilirubin, AST, ALT, or alkaline phosphatase 
– Notify the Spnsor if there is an AST or ALT increase 
> 5 xULN 
– Frequency of retesting can decrease to once a week or less if 
abnormalities stabilize or the study drug has been 
discontinued and the subject is asymptomatic. 
– Consider gastroenterology or hepatology referral 
AST or ALT > 12 to ≤ 20xULN 
and 
Total bilirubin ≤ 2 xULN 
or 
Isolated total bilirubin > 3.0 to 
≤ 5 xULN 
– Delay cabiralizumab and nivolumab therapy per 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 AST/ALT return to ≤ 12 xULN 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: 


Protocol Version 4.2 Protocol Date: 
12/11/2018 
CONFIDENTIAL 
100 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 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. 
Hepatic Adverse Event Management with Liver Metastasis 
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 
– If there is a concurrent increase of alkaline phosphatase 
along with ALT, start steroids immediately 
– Monitor for other clinical symptoms (fatigue, nausea, 
vomiting, abdominal pain, fever, rash, and/or 
eosinophilia) 
– Discontinue cabiralizumab and nivolumab therapy per 
protocol 
– 0.5–1 mg/kg/daymethylprednisolone or oral equivalent 
and when LFT returns to Grade 1 or baseline, taper 
steroids over at least 1 month 
– Consider prophylactic antibiotics for opportunistic infections 
– Discuss with Sponsor 
AST or ALT > 20 xULN 
or 
Total Bilirubin > 5 xULN 
– Discontinue cabiralizumab and nivolumab therapy 
– Increase frequency of monitoring to every 1–2 days 
– Consider 1 to 2 mg/kg/day methylprednisolone IV 
or IV equivalenta 
– Consider adding prophylactic antibiotics for 
opportunistic infections 
– Consult gastroenterologist and hepatologist, if clinically 
indicated 
If returns to Grade 2 or baseline: 
– 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 


Protocol Version 4.2 Protocol Date: 
12/11/2018 
CONFIDENTIAL 
101 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 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. 
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 cabiralizumab and nivolumab therapy per protocol a 
– 1 to 2 mg/kg/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 therapyper 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 Sponsor 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, 
–  Delay or discontinueac,cabiralizumab and nivolumab 
therapy per protocol 
hypotension, shock out of 
proportion to current illness) 
– 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 


Protocol Version 4.2 Protocol Date: 
12/11/2018 
CONFIDENTIAL 
102 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Refer to NCI CTCAE v 5.0 for term-specific grading criteria. 
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. 
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, topicalsteroids) 
– Continue cabiralizumab and nivolumab 
therapy per protocol 
If persists >1-2 weeks or recurs: 
– Consider skin biopsy 
– Delay cabiralizumab and nivolumab therapyper 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 protocol 
– Consider skin biopsy and dermatology 
consult 
– 1 to 2 mg/kg/day IVbmethylprednisolone 
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 


Protocol Version 4.2 Protocol Date: 
12/11/2018 
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103 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 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. 
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; 
limiting instrumental ADL 
– Delay cabiralizumab and nivolumab 
therapy per protocol 
– Treat symptoms per local guidelines 
– Consider 0.5 to 1 mg/kg/daya 
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 
nivolumab therapy 
– Obtain neurology consult 
– Treat symptoms per local guidelines 1 
to 2 mg/kg/dayIV 
a 
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 


Protocol Version 4.2 Protocol Date: 
12/11/2018 
CONFIDENTIAL 
104 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 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. 
Periorbital Edema Adverse Event Management 
Grade of Periorbital Edema 
(NCI CTCAE v 5.0) 
Management 
Follow-Up 
Periorbital Edema > baseline but 
– Continue cabiralizumab and nivolumab therapy 
If worsens: 
< Grade 2 
per protocol 
– Monitor edema weekly 
– Follow as stated below 
Grade 2 
– Delay cabiralizumab and nivolumab therapy per 
– protocol 
Start systemic treatment including steroids, eye 
drops, or analgesics as neededa 
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 andnivolumab 
– therapy per protocol 
Systemic treatment including steroids, eye 
drops, or analgesics as neededa 
– 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 


Protocol Version 4.2 Protocol 
Date: 11/02/2018 
CONFIDENTIAL 
105 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 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 5.0) 
Management 
Follow-Up 
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 infusion per protocol 
Systemic treatment including NSAIDs, corticosteroids 
and antihistaminesa 
– 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: 
– Discontinuetreatment at the visit 
– Discuss with Sponsor as needed 
Grade ≥3 
– Discontinue cabiralizumab and nivolumab therapy per 
– protocol 
Systemic treatment including NSAID , corticosteroids, and 
antihistaminesa 
– 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, ifindicated 


Protocol Version 4.2 Protocol 
Date: 11/02/2018 
CONFIDENTIAL 
106 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 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. 
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 protocol 
– Start antibiotics and inflammatory 
medications including steroidsa 
– Ophthalmologicconsult, 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 asinfliximab, as 
clinically indicated 
Grade ≥3 
– Discontinue cabiralizumab and 
– nivolumab therapy per protocol 
Start antibiotics and inflammatory 
medications including steroidsa 
– Ophthalmologicconsult, 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 asinfliximab, as 
clinically indicated 
– Follow up until resolution 


Protocol Version 4.2 Protocol 
Date: 12/11/2018 
CONFIDENTIAL 
107 
 
 
 
Appendix 7 – Laboratory Abnormalities Management Table 
 
Laboratory Abnormalities Management (CK and LDH) 
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 protocol 
Measure CK isoenzyme panel to 
identify source of elevation 
Increase frequency of monitoring 
(every 48-72 hours or more, as 
clinically indicated) 
Notify the Sponsor 
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 Sponsor 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 
Discuss with Sponsor 
CK or LDH > 
20 xULN 
Discontinue cabiralizumab and 
nivolumab therapy per protocol 
Follow up until resolution 


Protocol Version 3.0 
Protocol Date: 09/24/2018 
CONFIDENTIAL 
108 
 
 
 
 
 


Protocol Version 4.2 
Protocol Date: 12/11/2018 
CONFIDENTIAL 
109 
 
 
 


Protocol Version 4.2 
Protocol Date: 12/11/2018 
CONFIDENTIAL 
110 
 
 
 


Protocol Version 4.2 
Protocol Date: 12/11/2018 
CONFIDENTIAL 
111 
 
 
 


Protocol Version 4.2 Protocol 
Date: 12/11/2018 
CONFIDENTIAL 
112 
 
 
 


Protocol Version 4.2 Protocol 
Date: 12/11/2018 
CONFIDENTIAL 
113 
 
 
 


Protocol Version 4.2 
Protocol Date: 12/11/2018 
CONFIDENTIAL 
114