A Phase 2 Study of Cabiralizumab (BMS-986227, FPA008) Administered in Combination With Nivolumab (BMS-936558) With and Without Chemotherapy in Patients With Advanced Pancreatic Cancer
Phase: PHASE2
Conditions: Advanced Pancreatic Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 2 Study of Cabiralizumab (BMS-986227, FPA008) Administered in Combination with 
Nivolumab (BMS-936558) with and without Chemotherapy in Patients with Advanced 
Pancreatic Cancer) 
 
PROTOCOL(S) CA025-006 
 
NCT Number: NCT03336216 
  
Document Date (Date in which document was last revised): June 17, 2019 

Page:
1
Protocol Number:
CA025006
IND Number:
134,940
EUDRACT Number:
2018-000339-28
Date:
13-Oct-2017
Revised Date:
17-Jun-2019
Clinical Protocol CA025006
A Phase 2 Study of Cabiralizumab (BMS-986227, FPA008) Administered in Combination with 
Nivolumab (BMS-936558) with and without Chemotherapy in Patients with Advanced 
Pancreatic Cancer 
Short Title: A Study of Cabiralizumab Given With Nivolumab With and Without Chemotherapy 
in Participants With Advanced Pancreatic Cancer
Revised Protocol 04
Study Director/Medical Monitor
3401 Princeton Pike 
Lawrenceville, NJ 08648
Telephone (office): 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Revised Protocol No.: 04
Date: 17-Jun-2019
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promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Revised Protocol No.: 04
Date: 17-Jun-2019
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
04
17-Jun-2019
The following are major changes to the protocol:

Clarified that BICR will be used to assess the primary endpoint of PFS 
per RECIST v1.1.

Clarified the assessment (Investigator/BICR) used for each efficacy 
evaluation included as a secondary endpoint.

Time of on-treatment biopsy was changed to an earlier time point on 
Cycle 2 Day 8.
Revised Protocol 
03
24-Apr-2018
The following are major changes to the protocol:

Removal the cross over post disease progression for participants 
treated with chemotherapy only.
 

Additional data added to support the combination of cabiralizumab 
and nivolumab. 
Revised Protocol 
02
09-Mar-2018
The following are major changes to the protocol:

Eligible participants include those that have progressed after only 
1 line of chemotherapy

All participants must have fresh tumor biopsy taken during screening. 
Up to approximately 8 participants/cohort (~20%) will be allowed on 
treatment with pretreatment biopsies that do not yield adequate tumor 
tissue

If ONIVYDE-based regimen is not available per institution/country 
guidelines, FOLFIRI can be used in Arm A.

Adequate organ function is defined as ALT and AST < 2 x ULN
Revised Protocol 
01
28-Nov-2017
, the following section have been revised:

Expanded rationale for combining immunotherapy and chemotherapy 
agents 

Removed criteria excluding participants who had any GI surgery and 
an inability to tolerate oral medication

Added criteria for permanent dose discontinuation and exceptions
 
Original Protocol
13-Oct-2017
Not applicable
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CA025006
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cabiralizumab
OVERALL RATIONALE FOR THE REVISED PROTOCOL 04
This protocol has been revised to clarify that blinded independent central review (BICR) will be 
used to assess the primary endpoint of progression-free survival (PFS) per RECIST v1.1. In 
addition, this revision clarifies the assessment (Investigator/BICR) used for each efficacy 
evaluation included as part of the secondary endpoints.
On-treatment tumor biopsy samples will now be collected at an earlier time point on Cycle 2 Day 8 
to increase the number of biopsies collected.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Synopsis was updated.
Synopsis was updated to reflect the 
changes in the body of the protocol 
as summarized below.
Table 2-1 Screening 
Procedural Outline; 
 
 
Included that fresh pretreatment tumor 
biopsies must be obtained from a 
metastatic tumor lesion or from an 
unresectable primary tumor lesion.
Included for clarity.
Table 2-1 Screening 
Procedural Outline; Section 
9.1.1 Imaging Assessment 
for the Study
Timing of body imaging/baseline tumor 
assessments at screening was changed –
now must be performed 30 days prior to 
first dose of study treatment.
Changed to align with BMS 
protocol standards.
Table 2-2 On-Treatment 
Procedural Outline; Table 
2-3 Follow-up Procedural 
Outline 
Brain Imaging row was removed. Brain 
Scan was added to “Others” row.
Brain metastases are an exclusion 
criteria in this study; therefore, 
Procedural Outline is not required 
for participants with a history of 
brain metastases.
Table 2-2 On-Treatment 
Procedural Outline; Section 
5.1.2 Treatment Period
Updated text:
Randomization should occur no more 
than 3 business days prior to the first day 
of treatment on Cycle 1 Day 1, unless 
otherwise agreed upon with the Medical 
Monitor. Previously, randomization 
occurred on Cycle 1 Day 1.
Changed to allow sufficient time for 
sites to prepare for study treatments.
Section 3.1.1.1 Rationale for 
the 2L Cohort; Section 5.4.1 
Rationale for Chemotherapy-
only Regimens; 
Revised text for rationale for the 2L 
Cohort.
Updated rationale for the 2L Cohort 
for improved readability. 
Revised Protocol No.: 04
Date: 17-Jun-2019
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CA025006
BMS-986227
cabiralizumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Section 3.2.1.3 Clinical 
Summary; Section 5.4.2 
Rationale for Cabiralizumab 
and Nivolumab Combination 
Therapy
Study CA025001 was added to the list of 
studies evaluating cabiralizumab in 
Section 3.2.1.2.
Safety and efficacy summaries for Study 
FPA008-003 were updated with data from 
the latest Investigator Brochure for 
cabiralizumab (IB version 6, October 
2018). 
Updated to provide latest 
information on the safety profile of 
cabiralizumab.
Section 3.1.5 Rationale for 
Combining Immunotherapy 
and Chemotherapy 
Regimens; Section 3.3 
Benefit Risk Assessment; 
Section 5.1.2 Treatment 
Period; Section 5.2 Number 
of Participants
Updated text for the preliminary safety 
cohort in participants receiving 
cabiralizumab in combination with 
nivolumab and chemotherapy (2L Cohort 
Treatment Arms C and D).
Updated to clarify treatment arms 
included in the safety cohort and to 
indicate that the predefined 4-week 
observation period for the safety 
cohort has been completed. Review 
of the preliminary data from the 
safety cohort indicated that the 
combination of cabiralizumab with 
nivolumab and chemotherapy is 
well tolerated.
Table 4-1 Objective and 
Endpoints 
Clarified that BICR will be used to assess 
the Primary Endpoint of PFS per 
RECIST v1.1.
Clarified that investigator assessment will 
be used to assess the Secondary Endpoint 
of PFS per RECIST v1.1 and that BICR 
and investigator assessment will be used 
to evaluate the Secondary Endpoints of 
ORR, DOR, and PFSR per RECIST v1.1.
Updated to clarify assessments used 
for efficacy endpoints.
 
 
 
Section 5.1.3 Treatment 
Beyond Progression
Section was moved from 7.4.7 to 5.1.3 
and language was updated.
Moved and updated as part of an 
update to BMS protocol standards.
Section 5.2 Number of 
Participants
Changed randomized to treated. 
Sentence now reads: “Approximately 160 
participants will be treated 
(approximately 40 participants in each 
treatment arm).”
Updated to clarify the number of 
participants determined based on the 
statistical justification highlighted in 
Section 10.1.
Section 6.1 Inclusion Criteria
Updated criterion 4) f) to: Azoospermic 
males are required to use a condom for 
the duration of the study.
Male contraceptive requirements 
modified to require condom use for 
all males, including azoospermic 
males, who are sexually active with 
WOCBP to align with BMS 
protocol standards.
Revised Protocol No.: 04
Date: 17-Jun-2019
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CA025006
BMS-986227
cabiralizumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Section 6.1 Inclusion 
Criteria; Appendix 4 Women 
of Childbearing Potential 
Definitions and Methods of 
Contraception
Inclusion Criterion 4) d) and Appendix 4 
were revised to extend the duration of 
posttreatment contraception in WOCBP 
to 6 months for participants receiving 
ABRAXANE. Participants receiving any 
other study treatment must use 
contraception for 5 months posttreatment.
Duration of posttreatment contraception 
required for male participants was 
changed to 7 months.
The duration of posttreatment 
contraception in WOCBP who 
received ABRAXANE was 
extended to 6 months to align with 
the US prescribing information for 
ABRAXANE.
Aligned with Inclusion 
Criterion 4) e)
Section 6.2 Exclusion 
Criteria; Section 7.6.1 
Prohibited and/or Restricted 
Treatments
Exclusion criterion 4) b) was updated to 
indicate that receipt of a live/attenuated 
vaccine within 30 days of first treatment 
is not permitted.
Updated per BMS protocol 
standards.
Section 6.3 Lifestyle
Restrictions
The following sentence was added:
Male participants receiving gemcitabine,
ABRAXANE, and fluorouracil should 
seek advice regarding cryoconservation 
of sperm prior to treatment because of the 
possibility of infertility.
Statement added to alert potential 
male participants of infertility 
following treatment with 
gemcitabine, ABRAXANE, and
fluorouracil.
Table 7-1 Study Treatments 
for CA025006
Added new dosage strength of 
cabiralizumab (140 mg/vial).
The dosage strength of 140 mg/vial 
was introduced to accommodate a 
larger quantity of drug per vial, to 
minimize waste during preparation 
in the clinic.
Section 7.1 Treatments 
Administered
Provided additional details for 
ONIVYDE dosing, as follows:
The recommended starting dose of 
ONIVYDE in participants known to be 
homozygous for the UGT1A1*28 allele is 
50 mg/m2 administered by intravenous 
infusion over 90 minutes. Increase the 
dose of ONIVYDE to 70 mg/m2 as 
tolerated in subsequent cycles.
Updated 
 
to clarify
irinotecan dosing in patients known 
to be homozygous for the 
UGT1A1*28 allele.
Section 7.4.1 Dose Delay for 
Cabiralizumab and 
Nivolumab
The following criterion was added:
If symptoms or signs of Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) appear, nivolumab 
should be withheld and the patient 
referred for specialized care for 
assessment and treatment.
Dose Delay criterion was added to 
align with the nivolumab 
Investigator Brochure v17.
Revised Protocol No.: 04
Date: 17-Jun-2019
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CA025006
BMS-986227
cabiralizumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Section 7.4.4 Dose 
Discontinuation Criteria for 
Cabiralizumab and 
Nivolumab
The following two discontinuation 
criteria were removed: 
Adrenal insufficiency requires 
discontinuation regardless of control with 
hormone replacement.
Any Grade 3 or higher drug-related 
diarrhea or colitis, which does not resolve 
to Grade 1 or baseline within 28 days.
Removed for consistency 
 
Section 7.4.4 Dose 
Discontinuation Criteria for 
Cabiralizumab and 
Nivolumab
The following criteria were added: 
Confirmed Stevens-Johnson syndrome 
(SJS) or toxic epidermal necrolysis (TEN) 
will result in permanent discontinuation 
of nivolumab.
Any Grade 3 or higher myocarditis will 
result in permanent discontinuation of 
nivolumab.
Discontinuation criteria were added 
to align with the nivolumab 
Investigator Brochure v17.
Section 7.4.6 Dose 
Modification for 
Chemotherapy
The following criterion was added:
In addition, if participants experience 
tolerability issues for 5-FU / leucovorin 
and ONIVYDE, and FOLFIRI, dose 
modifications for these 2 regimens should 
be performed according to their 
respective SmPCs and institutional 
guidelines.
Dose modification guidelines were 
clarified for 5-fluorouracil / 
leucovorin and ONIVYDE, and 
FOLFIRI 
 
Section 8.1 Discontinuation
from Study Treatment
Modified text related to pregnancy cases 
to include that BMS/Medical Monitor 
must be notified within 24 hours of a 
pregnancy event.
Modified in-the-case-of-pregnancy 
instructions to clarify expectations 
for reporting pregnancy.
Section 9.2 Adverse Events
Added the following paragraph on 
IMAEs: “IMAEs are AEs consistent with 
an immune-mediated mechanism or 
immune-mediated component for which 
non-inflammatory etiologies (eg, 
infection or tumor progression) have been 
ruled out. IMAEs can include events with 
an alternate etiology which were 
exacerbated by the induction of 
autoimmunity. Information supporting the 
assessment will be collected on the 
participant’s CRF.”
Updated per BMS protocol 
standards.
Section 9.2.1 Time Period 
and Frequency for Collecting 
AE and SAE Information
Provided additional details on SAE 
collection and safety references for all 
study drugs
Updated to include appropriate 
references to the Reference Safety 
Information for all investigational 
products administered in
CA025006.
Revised Protocol No.: 04
Date: 17-Jun-2019
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CA025006
BMS-986227
cabiralizumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Section 9.2.5 Pregnancy
Modified second paragraph related to 
treatment continuation and pregnancy to:
Remove redundant text related to 
timing of notifying BMS Medical 
Monitor/designee of pregnancy. 
Add text for circumstances in which 
continuation of study treatment may 
be discussed.
Updated text related to treatment 
continuation and pregnancy to 
clarify the circumstances for 
continuation of study treatment in 
the case of pregnancy.
Table 9.4.4-1 Clinical 
Laboratory Tests
Included that pregnancy tests should also 
be performed monthly during treatment 
and safety follow-up periods in WOCBP.
Updated 
 
Table 2-1 Screening 
Procedural Outline; Table 
2-2 On-treatment Procedural 
Outline; Table 2-3 Follow-up 
Procedural Outline; Table 
9.4.4-1 Clinical Laboratory 
Tests
Thyroid panel (TSH, free T3, and free 
T4) was added.
Included as part of BMS protocol 
standards. 
Revised Protocol No.: 04
Date: 17-Jun-2019
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CA025006
BMS-986227
cabiralizumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Table 10.3.1-1 Efficacy -
Statistical Analyses
Updated the Statistical Analysis Method 
text.
Added row for OS.
Updated/added for clarity.
Appendix 2 Study 
Governance Considerations
Updated language around reporting 
potential serious breaches and added 
section on Scientific Publications.
Updated per BMS protocol 
standards.
Appendix 3 Adverse Events 
and Serious Adverse Events 
Definitions and Procedures 
for Recording, Evaluating, 
and Follow-up and Reporting
Added the following new sections:
Events Meeting the AE Definition.
Events Not Meeting the AE 
Definition.
Definition of Serious Adverse Event 
(SAE).
Modified the following sections:
SAEs (text related to pregnancy and 
drug-induced liver injury).
Evaluating AEs and SAEs (updated 
and rearranged bulleted information).
Reporting of SAEs to Sponsor or 
Designee (updated and rearranged 
bulleted information related to pregnancy 
and paper report forms).
Modifications made to information 
related to AEs and SAEs to align 
with the 
 Common 
Protocol Template, regulatory 
definition EMA GVP Module VI 
(EMA/873138/2011) and ICH E2A, 
and clarify the instructions for 
reporting pregnancy.
Appendix 7 Adverse Event 
Management for 
Cabiralizumab and 
Nivolumab Combination 
Therapy Cohorts
Gastrointestinal Adverse Event 
Management: option to delay treatment 
with Grade 3-4 event was 
removed - discontinue cabiralizumab and 
nivolumab per protocol.
Renal Adverse Event Management: 
updated range for Grade 1 and combined 
row for Grades 2 and 3. For Grade 4, 
added monitor creatinine daily
Hepatic Adverse Event Management 
Algorithm: Footnote stating I-O therapy 
may be delayed rather than discontinued 
if AST/ALT ≤ 8 x ULN or T.bili ≤ 5 x 
ULN was removed.
Updated to better align with 
nivolumab protocol standards.
Language was modified to align 
protocol with current Nivolumab 
Investigator Brochure and 
nivolumab program safety 
parameters.
All sections
Minor typographical errors were 
corrected and edits were made for 
consistency and clarity.
Minor changes, therefore they have 
not been summarized.
Revised Protocol No.: 04
Date: 17-Jun-2019
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE REVISED PROTOCOL 04 ............................. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04............................ 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Rationale for Selection of Patients with Advanced Pancreatic Cancer .. 
3.1.1.1 Rationale for the 2L Cohort ............................................................ 
3.1.2 Rationale for Inhibiting CSF1R in Cancer .............................................. 
3.1.3 Rationale for Immunotherapy .................................................................. 
3.1.4 Rationale for Combining Cabiralizumab and Nivolumab ....................... 
3.1.5 Rationale for Combining Immunotherapy and Chemotherapy Regimens
.....................................................................................................................
3.2 Background ....................................................................................................... 
3.2.1 Cabiralizumab.......................................................................................... 
3.2.1.1 Mechanism of Action....................................................................... 
3.2.1.2 Preclinical Summary ....................................................................... 
3.2.1.3 Clinical Summary............................................................................ 
3.2.2 Nivolumab ................................................................................................ 
3.2.3 Clinical Experience Involving Serum Enzyme Elevations ....................... 
3.2.3.1 Serum Enzyme Elevations with Cabiralizumab .............................. 
3.2.3.2 Management of Isolated Laboratory Abnormalities ....................... 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Screening Period ...................................................................................... 
5.1.2 Treatment Period ..................................................................................... 
5.1.3 Treatment Beyond Disease Progression .................................................. 
5.1.4 Follow-up Period ..................................................................................... 
5.1.4.1 Safety Follow-up Period ................................................................. 
5.1.4.2 Imaging Follow-up Period .............................................................. 
5.1.4.3 Survival Follow-up Period .............................................................. 
5.1.5 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for Chemotherapy-only Regimens ........................................... 
5.4.1.1 Treatment Arm A ............................................................................. 
5.4.2 Rationale for Cabiralizumab and Nivolumab Combination Therapy...... 
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CA025006
cabiralizumab
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5.4.3 Rationale for Cabiralizumab in Combination with Nivolumab and 
Gemicitabine + Nab-paclitaxel or FOLFOX .............................................. 
5.5 Justification for Cabiralizumab Dose ................................................................ 
5.6 Justification for Nivolumab Dose ..................................................................... 
5.6.1 Rationale for Infusion Times for Cabiralizumab and Nivolumab ........... 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening ..................................................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Dose Delay for Cabiralizumab and Nivolumab ....................................... 
7.4.2 Management Algorithms for Immuno-oncology Agents .......................... 
7.4.3 Dose Reduction for Cabiralizumab and Nivolumab ................................ 
7.4.4 Dose Discontinuation Criteria for Cabiralizumab and Nivolumab ........ 
7.4.5 Criteria to Resume Treatment with Cabiralizumab and Nivolumab ....... 
7.4.6 Dose Modification for Chemotherapy ..................................................... 
7.4.6.1 Dose Modification for Gemcitabine + Nab-paclitaxel ................... 
7.4.6.2 Dose Modification for FOLFOX ..................................................... 
7.4.7 Treatment of Cabiralizumab and Nivolumab-Related Infusion Reactions
.....................................................................................................................
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Dosing of Cabiralizumab and Nivolumab ............................................... 
7.5.2 Retained Samples for Bioavailability/Bioequivalence/Biocomparability 
7.6 Concomitant Therapy........................................................................................ 
7.6.1 Prohibited and/or Restricted Treatments................................................. 
7.6.2 Other Restrictions and Precautions ......................................................... 
7.6.2.1 Imaging Restrictions and Precautions ............................................ 
7.7 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Follow-up after Conclusion of Study Treatment ...................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.1.2 Methods of Measurement ......................................................................... 
 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
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CA025006
cabiralizumab
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9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug-Induced Liver Injury ....................................................... 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
9.4.5 Imaging Safety Assessment ...................................................................... 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
 
 
 
 
10.3.7 Interim Analyses ..................................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
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CA025006
cabiralizumab
Revised Protocol No.: 04
Date: 17-Jun-2019
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APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING ....................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
APPENDIX 6 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 7 ADVERSE EVENT MANAGEMENT FOR CABIRALIZUMAB AND 
NIVOLUMAB COMBINATION THERAPY ARMS ........................................... 
APPENDIX 8 LABORATORY ABNORMALITIES MANAGEMENT TABLE ...... 
APPENDIX 9 TNM STAGING ................................................................................... 
APPENDIX 10 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
122
126
130
138
139
152
153
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Clinical Protocol
BMS-986227
CA025006
cabiralizumab
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Date: 17-Jun-2019
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
1
SYNOPSIS
Protocol Title: A Phase 2 Study of Cabiralizumab (BMS-986227, FPA008) Administered in 
Combination with Nivolumab (BMS-936558) with and without Chemotherapy in Patients with 
Advanced Pancreatic Cancer
Short Title: A Study of Cabiralizumab Given With Nivolumab With and Without Chemotherapy 
in Patients With Advanced Pancreatic Cancer
Study Phase: 2
Rationale:
Pancreatic ductal adenocarcinoma (PDAC) remains a dreadful diagnosis due to its often advanced 
stage at diagnosis and poor sensitivity to chemotherapy. Treatment options for patients with 
metastatic pancreatic cancer are limited. Currently FOLFIRINOX (combined regimen of 
oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine combined with 
nab-paclitaxel (ABRAXANE) are globally recognized as the standard of care for patients with 
advanced pancreatic cancers. In newly diagnosed patients, gemcitabine + nab-paclitaxel is 
currently considered the treatment option of choice, with a reported median progression-free 
survival (PFS) of 5.5 months and a median overall survival (OS) of 8.5 months, as well as a more 
tolerable safety profile and the potential to be administered in patients with advanced age and 
comorbidities. However, progression after 1L chemotherapy is inevitable in patients with 
advanced pancreatic cancers, and treatment options for patients who progress after 1L 
chemotherapy are limited and associated with significant toxicity. Development of novel therapies 
is therefore needed to treat this chemotherapy-refractory disease.
Immunotherapy has emerged as a therapeutic approach that offers effective and durable treatment 
options for subsets of patients with various types of cancer. However, perhaps due to a lack of 
pre-existing T-cell immunity and/or a highly immunosuppressive tumor microenvironment 
(TME), patients with PDAC have not experienced similar benefits with immunotherapy.
 
For example, in heavily 
pretreated participants with advanced/metastatic PDAC, preliminary data from Study FPA008-003 
showed that cabiralizumab (BMS 986227; a monoclonal antibody [mAB] targeting 
colony-stimulating factor 1 receptor [CSF1R]) in combination with nivolumab (a checkpoint 
blocking antibody [anti-programmed death-1 [PD-1] mAb) provided durable clinical benefit 
(partial response or stable disease), including prolonged, sustained partial responses in a 
population that has not benefited from anti-PD-1 therapy alone. Furthermore, the addition of 
standard-of-care (SOC) chemotherapy could further potentiate the anti-tumor effects of 
immunotherapy approaches by reducing the tumor burden, exposing antigens, and directly 
affecting the immunosuppressive TME compartment.
To explore the synergy of the proposed combinatorial approach, participants with locally 
advanced/metastatic pancreatic tumors who have progressed during or after no more than 1 line of 
Revised Protocol No.: 04
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
systemic chemotherapy in the metastatic setting will receive cabiralizumab administered in 
combination with nivolumab, nivolumab and gemcitabine + nab-paclitaxel, or nivolumab and 
oxaliplatin/5-fluorouracil (5-FU)/leucovorin (calcium folinate; FOLFOX), or investigator’s choice 
of reference SOC chemotherapy alone.
Study Population:
Participants must be at least 18 years old and have histological or cytological confirmed diagnosis 
of locally advanced or metastatic adenocarcinoma of the pancreas, which has progressed during or 
after no more than 1 prior line of systemic chemotherapy in the metastatic setting (gemcitabine or 
FU-based regimens).
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the PFS of cabiralizumab administered in 
combination with nivolumab with and without chemotherapy 
relative to investigator’s choice of chemotherapy in participants 
with advanced/metastatic pancreatic cancer who progressed on or 
after the first line of chemotherapy (either gemcitabine-based or 
5-FU-based chemotherapy).

PFS per RECIST v1.1 by BICR
Secondary

To evaluate the anti-tumor activity of cabiralizumab administered 
in combination with nivolumab with or without chemotherapy 
relative to investigator’s choice of chemotherapy in participants 
with advanced/metastatic pancreatic cancer who progressed on or 
after the first line of chemotherapy (either gemcitabine-based or 
5-FU-based chemotherapy) using RECIST v1.1.

PFS per RECIST v1.1 by investigator 
assessment; ORR, DOR, and PFSR at 
6, 9, and 12 months per RECIST v1.1 
by BICR and investigator assessment

To assess OS.

OS and OSR at 6 months, 1 year, and 
2 years

To assess the safety of cabiralizumab administered in 
combination with nivolumab with or without chemotherapy in 
participants with advanced/metastatic pancreatic cancer who 
progressed on or after the first line of chemotherapy (either 
gemcitabine-based or 5-FU-based chemotherapy).

Incidence of AEs, SAEs, AEs leading 
to 
discontinuation, 
death, 
and 
laboratory abnormalities
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Objectives
Endpoints
Abbreviations: 5-FU = 5-fluorouracil; 
 AE = adverse event; BICR = blinded independent 
central review; 
 
ORR = objective response rate; OS = overall survival; OSR = overall survival rate; PFS = progression-free survival; 
PFSR = progression-free survival rate; 
 
RECIST = Response Evaluation Criteria In Solid 
Tumors; SAE = serious adverse event; 
Overall Design:
This is a Phase 2, open-label, randomized study to evaluate the efficacy, safety, tolerability, 
 of cabiralizumab in combination with nivolumab with 
or without gemcitabine + nab-paclitaxel or oxaliplatin, 5-FU, and leucovorin (calcium folinate; 
FOLFOX), or an alternative choice of chemotherapy,
in participants with locally 
advanced/metastatic pancreatic tumors who have progressed during or after no more than 1 line of 
systemic chemotherapy (either gemcitabine-based or 5-FU-based) in the metastatic setting.
The study design schematic is presented below.
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CA025006
BMS-986227
cabiralizumab
Study Design Schematic
Note: ONIVYDE-based regimen can be substituted with FOLFIRI.
Abbreviations: ECOG = Eastern Cooperative Oncology Group; Q2W = every 2 weeks; Q4W = every 4 weeks; 
R = randomized.
Six participants per arm in both Treatment Arms C and D were treated and monitored for 4 weeks
as part of a preliminary safety cohort. 
 
 
 
 Enrollment was allowed to proceed after completion of the safety lead-in period.
Number of Participants:
Approximately 160 participants will be treated (approximately 40 participants in each treatment 
arm). The false positive rate (FPR) is set at approximately 20%, and the false negative rate (FNR) 
is set at approximately 10%. The median PFS is assumed as 3.1 months in Treatment Arm A based 
on the NAPOLI-1 study and 5.4 months in Treatment Arms C and D by combining cabiralizumab 
and nivolumab with chemotherapy. In this setting, it will be required to observe at least 59 PFS 
events in each of Treatment Arms A and C and Treatment Arms A and D. If assuming a fixed 
accrual rate of 16 participants per month with equal distribution across 4 treatment arms, a total of 
approximately 80 participants are needed to be treated for Treatment Arms A and C (or D) in order 
to achieve the 59 PFS events required. In case a lower FPR is desired, a longer follow-up or 
additional participants may be treated in order to observe additional PFS events.
Treatment Arms and Duration:

Treatment Arm A: Investigator choice of chemotherapy (gemcitabine + /nab-paclitaxel 
[ABRAXANE] 
or 
5-FU/leucovorin 
[calcium 
folinate]/irinotecan 
liposome 
[ONIVYDE]*).
*ONIVYDE-based regimen can be substituted with FOLFIRI.

Treatment Arm B: Cabiralizumab administered in combination with nivolumab.
Treatment Arm
R (A:B:D) 1:1:2
Stratified by ECOG 
Status (0 or 1)
R (A:B:C) 1:1:2
Stratified by ECOG 
Status (0 or 1)
Prior 5-fluorouracil-
based chemotherapy
B. Cabiralizumab Q2W + Nivolumab Q4W
D. Cabiralizumab Q2W + Nivolumab Q4W and
Oxaliplatin/5-Fluorouracil/Leucovorin (FOLFOX) Q2W
C. Cabiralizumab Q2W + Nivolumab Q4W and
Gemcitabine + Nab-paclitaxel (Abraxane®) D1, 8, and 15 Q4W
A. Investigator choice of chemotherapy: 
-
Gemcitabine + Nab-paclitaxel (ABRAXANE®)
-
5-Fluorouracil/Leucovorin/Irinotecan Liposome (ONIVYDE®)
Prior gemcitabine-
based chemotherapy
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CA025006
BMS-986227
cabiralizumab

Treatment Arm C: Cabiralizumab administered in combination with nivolumab and 
gemcitabine + nab-paclitaxel (ABRAXANE).

Treatment Arm D: Cabiralizumab administered in combination with nivolumab and 
oxaliplatin/5-FU/leucovorin (calcium folinate; FOLFOX).
Participants will be allowed to continue study treatment until the first occurrence of any of the 
following situations:
Progressive disease defined per RECIST v1.1, unless participants meet criteria for treatment 
beyond progression.
Clinical deterioration suggesting that no further benefit from treatment is likely.
Intolerability to therapy.
Participant meets criteria for discontinuation of study treatment.
Withdrawal of consent.
Study treatment: 
Treatment 
Arm(s)
Study Treatment
Unit Dose 
Strength(s)/Dosage 
Level(s)
Dosage Formulation
Frequency of 
Administration
(28-day Cycle)
Route of 
Administration
A
Investigator choice of 
chemotherapy
As appropriate
As appropriate
As appropriate
B, C, and D
Cabiralizumab
4 mg/kg IV
Days 1 and 15
IV Infusion
B, C, and D
Nivolumab
480 mg IV
Day 1
IV Infusion
C
Gemcitabine
1000 mg/m2 IV
Days 1, 8, and 15
IV Infusion
C
Nab-paclitaxel
(ABRAXANE)
125 mg/m2 IV
Days 1, 8, and 15
IV Infusion
D
Oxaliplatin
85 mg/m2 IV
Days 1 and 15
IV Infusion
D
5-FU
400 mg/m2 Bolus
AND
2400 mg/m2 IV
Days 1 and 15
Bolus and IV 
Infusion
D
Leucovorin
(calcium folinate)
400 mg/m2 IV
Days 1 and 15
IV Infusion
Abbreviations: 5-FU = 5-fluorouracil; IV = intravenous; Q2W = every 2 weeks; Q4W = every 4 weeks
Data Monitoring Committee: No
 
 
 
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised Protocol No.: 04
Date: 17-Jun-2019
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are presented in Table 2-1 (Screening Procedural Outline), 
Table 2-2 (On-treatment Procedural Outline), and Table 2-3 (Follow-up Procedural Outline). 
In limited circumstances, assessments and procedures may occur outside the indicated timeframes 
due to scheduling issues, but the Sponsor should be notified accordingly.
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CA025006
BMS-986227
cabiralizumab
Table 2-1:
Screening Procedural Outline
Procedure
Screening
Visit (Day -30
to Day-1)
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol specific informed consent 
is signed.
IRT Participant Assignment/Treatment Assignment
X
After the participant consents, the site will use the IRT to have the participant 
number assigned. After the participant has completed all screening procedures, IRT 
will be used for treatment assignment or discontinuing the participant. Subsequent 
visits will need to be registered into the IRT system for drug supply.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior 
to first dose.
Medical History
X
Include any toxicities or allergy related to previous treatments, irAEs, cardiac 
signs/symptoms/disease, and immunization (eg, influenza vaccine).
Prior Systemic Therapies
X
Including radiotherapy, surgery, and systemic therapy.
ECOG Status Assessment
X
See Appendix 6
Archived Tumor Tissue Sample
X
Archival tumor tissue samples, if available, may be provided for participants in all 
arms as 1 paraffin block or 20 FFPE unstained slides. Samples must be shipped to 
the central laboratory.
Fresh Pretreatment Tumor Biopsy
X
All participants require a mandatory pretreatment biopsya during screening
Biopsy samples must be documented to have adequate tumor content for 
molecular analyses prior to participant treatment

Tumor samples must be obtained from a metastatic tumor lesion or from an 
unresectable primary tumor lesion.

Tumor content may be evaluated either by local pathology H&E or submission 
to the central laboratory for central assessment of tumor content.

Up to approximately 20% of the cohort will be allowed on treatment with a 
pretreatment biopsy that does not yield adequate tumor tissue, beyond that, 
re-biopsy may be performed if the sample has been inadequately prepared or 
contains insufficient tumor content
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Table 2-1:
Screening Procedural Outline
Procedure
Screening
Visit (Day -30
to Day-1)
Notes

If adequate tumor tissue is confirmed from a biopsy done in the preceding 90 days 
with no intervening therapy and at least 20 unstained slides are available, the 
sample may replace the mandatory pretreatment biopsy. Residual sample(s) may 
be retained for additional research.
Safety Assessments
PE
X
If the screening PE is performed within 24 hours prior to dosing on Day 1, then a 
single exam may count as both the screening and predose evaluation.
Physical Measurements
X
Includes height and weight.
Vital Signs
X
Includes body temperature, respiratory rate, and seated blood pressure and heart rate. 
Blood pressure and heart rate should be measured after the participant has been 
resting quietly for at least 5 minutes.
Concomitant Medication Use
X
Medications taken within 4 weeks prior to study treatment administration must be 
recorded on the CRF.
12-lead ECG
X
12-lead ECGs should be recorded after the participant has been supine for at least 
5 minutes. 
Clinical Complaints
X
Clinical complaints related to the disease under study present 14 days prior to the 
first dose of study treatment must be collected.
Laboratory Tests
Includes blood and urine samples.
Serology, Hematology, Serum Chemistry,
Urinalysis, and Thyroid Panel
X
See Section 9.4.4.
Pregnancy Test (Serum or Urine)
X
For WOCBP only; serum will be collected at screening and within 24 hours prior 
to dosing. The serum pregnancy test may be completed on the first day of treatment 
provided that the results are available before the start of study treatment. If 
performed within 24 hours of dosing on Cycle 1 Day 1, then Cycle 1 Day 1 
pregnancy test is not required.
Follicle Stimulating Hormone
X
Women only if needed to confirm post-menopausal status. Refer to Appendix 4.
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CA025006
BMS-986227
cabiralizumab
Table 2-1:
Screening Procedural Outline
Procedure
Screening
Visit (Day -30
to Day-1)
Notes
Adverse Event Reporting
Monitor for Serious Adverse Events
X
All SAEs must be collected from the date of the participant’s written consent until 
100 days after discontinuation of dosing or the participant’s participation in the 
study if the last scheduled visit occurs at a later time.
eSAEs should be approved in the electronic capture system within 5 business days 
of entry.
Efficacy Assessments
Disease Assessment
X
Please see inclusion criteria (Section 6.1) for details.
Body Imaging/Baseline Tumor Assessment
X
See Section 9.1.1. Assessed by RECIST v1.1 criteria (see Appendix 5). Must be 
performed within 30 days prior to first dose
Brain Imaging
X
See Section 9.1.2. MRI of the brain without and with contrast is required for 
participants with suspected brain metastases.
Other: Bone scan
X
See Section 9.1.2. As clinically indicated per local standards.
Abbreviations: AE = adverse event; BMI = body mass index; CRF = Case Report Form; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
eSAE = electronic serious adverse event; FFPE = formalin-fixed paraffin-embedded; HIV = human immunodeficiency virus; irAE = immune-related adverse 
event; IRT = Interactive Response Technology; MRI = magnetic resonance imaging; PE = physical examination; RECIST v1.1 = Response Evaluation Criteria 
in Solid Tumors version 1.1; SAE = serious adverse event; WOCBP = women of childbearing potential
a Samples collected after the last cancer treatment (either systemic or local) will be considered as fresh biopsies.
Revised Protocol No.: 04
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CA025006
BMS-986227
cabiralizumab
Table 2-2:
On-Treatment Procedural Outline
Procedure
Cycle 1 and Cycle 2
Subsequent Cycles
EOT
Notes
D1 
2 
days
D2
2 
days 
D8
2 
days
D15
2 
days
D21
2 
days
D1
2 
days
D8a
2 
days
D15
2 
days
Safety Assessments
PE
X
X
X
X
X
Predose.
Symptom-directed PE
X
X
X
As needed, if clinically indicated.
ECOG Performance Status
X
X
X
X
X
ECOG score (Appendix 6).
Vital Signs
X
X
X
X
X
See note in screening procedures. 
Vital Signs to be collected for every treatment 
arm before infusion of the first drug on Day 1 
and Day 15. Approximately the same time as 
ECG
Cycle 1 and Cycle 5 Only.

For cabiralizumab (BMS-986227), vital signs 
will be obtained before the infusion and then 
every 15 minutes (5 minutes) until 60 
minutes after completion of the infusion.

For nivolumab, vital signs will be obtained
before 
the 
infusion 
and
10 minutes 
(5 minutes) 
after 
completion 
of 
the 
infusion.
If any vital sign is abnormal (based on clinician’s 
assessment) at the final check, the participant 
must be observed for a further period of time, as 
clinically indicated.
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BMS-986227
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Table 2-2:
On-Treatment Procedural Outline
Procedure
Cycle 1 and Cycle 2
Subsequent Cycles
EOT
Notes
D1 
2 
days
D2
2 
days 
D8
2 
days
D15
2 
days
D21
2 
days
D1
2 
days
D8a
2 
days
D15
2 
days
ECG
X
X
X
See note in screening procedures.
Single Lead ECG tests will be conducted for all 
participants prior to the start of the infusion of 
the first drug 
Initial 6 participants enrolled in Treatment Arms 
C and D only:
12-lead ECG to be performed at both predose 
and 4 hours postdose on Cycle 1Day 1 only
Laboratory Tests
See note in screening procedures and 
Section 9.4.4. Predose on Day 1.
Chemistry, Hematology,
Thyroid Panel, and 
Urinalysis
X
X
X
X
X
Xa
X
X
Pregnancy Test
X
X
X
WOCBP: Serum or urine pregnancy test must be 
performed within 24 hours prior to
administration of study treatment and on Day 1 
of each cycle.
AE Reporting and Concomitant Medication Assessments
Concomitant Medication 
Assessments
X
Review prior to dosing.
Monitor for Non-serious 
Adverse Events
X
Non-serious AEs will be collected starting with 
the first dose of study treatment and through 
100 days after last dose of study drug.
Monitor for Serious 
Adverse Events
X
See note in screening procedures.
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Table 2-2:
On-Treatment Procedural Outline
Procedure
Cycle 1 and Cycle 2
Subsequent Cycles
EOT
Notes
D1 
2 
days
D2
2 
days 
D8
2 
days
D15
2 
days
D21
2 
days
D1
2 
days
D8a
2 
days
D15
2 
days
Sample Collections
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Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Table 2-2:
On-Treatment Procedural Outline
Procedure
Cycle 1 and Cycle 2
Subsequent Cycles
EOT
Notes
D1 
2 
days
D2
2 
days 
D8
2 
days
D15
2 
days
D21
2 
days
D1
2 
days
D8a
2 
days
D15
2 
days
Efficacy Assessments
Body 
Imaging/Radiographic 
Tumor Assessments
See Section 9.1.1
Tumor assessments should occur every 8 weeks 
(starting from first dose 7 days) for the first 
48 weeks, then every 12 weeks (7 days) until 
withdrawal of consent, death, or initiation of 
another anti-cancer treatment, whichever occurs 
first.
Other: Brain Scan / Bone 
Scan
See Section 9.1.2
As clinically indicated per local standards.
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CA025006
BMS-986227
cabiralizumab
Table 2-2:
On-Treatment Procedural Outline
Procedure
Cycle 1 and Cycle 2
Subsequent Cycles
EOT
Notes
D1 
2 
days
D2
2 
days 
D8
2 
days
D15
2 
days
D21
2 
days
D1
2 
days
D8a
2 
days
D15
2 
days
Clinical Drug Supplies
Randomize
Randomization should occur no more than 
3 business days prior to the first day of treatment 
on Cycle 1 Day 1, unless otherwise agreed upon 
with the Medical Monitor.
Study Drug 
Administration
See Table 7.1-1
Dosing calculations for cabiralizumab are based 
on the body weight assessed at Cycle 1 Day 1. 
Weight measurements should be repeated prior 
to each dosing of cabiralizumab.
Abbreviations: 
 D = day; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; 
PE = physical examination; 
RECIST v1.1=Response Evaluation Criteria in Solid Tumors version 1.1; WOCBP = women of childbearing 
potential
a Only for participants treated with gemcitabine and nab-paclitaxel (ABRAXANE).
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CA025006
BMS-986227
cabiralizumab
Table 2-3:
Follow-up Procedural Outline
Procedure
Safety Follow-upa
Survival/Response Long-term 
Follow-up
Notes
FU 1
30 days
(7 days) 
FU 2
60 days
(7 days)
FU 3
100 days
(7 days)
Begins After Completion of 
Safety Follow-up Q12W
(2 weeks) Until 2 Years After 
Last Dose of Study Treatment
Safety Assessments
System-directed PE
X
X
X
Targeted, system-directed PE 
only.
Physical Measurements 
X
X
X
Weight only
Vital Signs
X
X
X
See note in screening procedures.
ECGs
X
X
X
See note in screening procedures.
ECOG Performance Status
X
X
X
ECOG score (Appendix 6)
Laboratory Tests
See note in screening procedures.
Serum Chemistry, Thyroid 
Panel, and Hematology
X
X
X
Urinalysis
As clinically indicated
Pregnancy Test
X
X
X
Adverse Event Reporting
Concomitant Medication 
Assessments
X
X
X
Monitor for Non-serious 
Adverse Events
X
X
X
See note in screening procedures.
Monitor for Serious Adverse 
Events
X
X
X
See note in screening procedures.
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CA025006
BMS-986227
cabiralizumab
Table 2-3:
Follow-up Procedural Outline
Procedure
Safety Follow-upa
Survival/Response Long-term 
Follow-up
Notes
FU 1
30 days
(7 days) 
FU 2
60 days
(7 days)
FU 3
100 days
(7 days)
Begins After Completion of 
Safety Follow-up Q12W
(2 weeks) Until 2 Years After 
Last Dose of Study Treatment
Efficacy Assessments
Body Imaging/Radiographic 
Tumor Assessment 
See Section 9.1.1
Tumor assessments should occur 
every 12 weeks (7 days) until 
withdrawal of consent, death, or 
initiation of another anti-cancer 
treatment, whichever occurs first.
Other: Brain Scan / Bone Scans
See Section 9.1.2
As clinically indicated per local 
standards.
Abbreviations: ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FU = Follow-up; PE = physical examination; MRI = Magnetic 
Resonance Imaging; Q12W = every 12 weeks.
a Follow-up visits at Days 30, 60, and 100 (7 days each) should occur after the last dose or on the date of discontinuation (7 days)
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In the event that multiple procedures are required at a single time point, the following is a list of 
procedures from highest to lowest priority:
2) Safety (electrocardiogram [ECG])
3) Clinical laboratory assessments
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3
INTRODUCTION
CA025006 is a Phase 2 study of cabiralizumab (a recombinant, humanized immunoglobulin G4 
[IgG4] monoclonal antibody [mAb] that binds to human colony-stimulating factor 1 receptor 
[CSF1R]; BMS-986227 or FPA008) in combination with nivolumab (a programmed cell death-1 
[PD-1] receptor blocking mAb)
with or without
chemotherapy in participants with 
advanced/metastatic pancreatic cancer who have progressed on or after 1 line of chemotherapy 
(Second-line [2L] Cohort).
In this study, the efficacy, safety profile, tolerability
of cabiralizumab 
administered in combination with nivolumab, with or without chemotherapy, will be evaluated 
versus standard-of-care chemotherapy.
In the 2L Cohort, cabiralizumab will be administered in combination with nivolumab (Treatment 
Arm B), nivolumab and gemcitabine + nab-paclitaxel (ABRAXANE®; Treatment Arm C), or 
nivolumab and
oxaliplatin/5-fluorouracil (5-FU)/leucovorin (calcium folinate; FOLFOX; 
Treatment Arm D), or participants will receive investigator’s choice of reference standard-of-care 
chemotherapy alone (Treatment Arm A).
3.1
Study Rationale
Pancreatic ductal adenocarcinoma (PDAC) remains a dreadful diagnosis due to its often advanced 
stage at diagnosis and poor sensitivity to chemotherapy. Treatment options for patients with 
metastatic pancreatic cancer are limited. Gemcitabine combined with nab-paclitaxel 
(ABRAXANE) is a United States (US) Food and Drug Administration (FDA) approved 1L 
treatment for patients with advanced pancreatic cancers. This regimen showed a median 
progression-free survival (PFS) of 5.5 months and a median overall survival (OS) of 8.5 months 
and is the predominantly used regimen in metastatic pancreatic cancer.
Immunotherapy has emerged as a therapeutic approach that offers effective and durable treatment 
options for subsets of patients with various types of cancer. However, these successes have not 
manifested similar benefits for PDAC patients mostly due to a lack of pre-existing T-cell immunity 
and/or a highly immunosuppressive tumor microenvironment (TME). 
 
 
 
The addition of chemotherapy could further potentiate 
the anti-tumor effects of immunotherapy approaches by reducing the tumor burden, exposing 
antigens and directly affecting the immunosuppressive TME compartment.
To explore the synergy of the proposed combinatorial approach, cabiralizumab in combination 
with nivolumab with or without chemotherapy will be administered to participants who have 
progressed on or after 1 line of systemic chemotherapy in the metastatic setting.
3.1.1
Rationale for Selection of Patients with Advanced Pancreatic Cancer
Despite a relatively low incidence projected for 2017 (53,670 new cases), PDAC is expected to be 
the third leading cause of cancer-related deaths (mortality 43,090) in the US in 2017. In Europe, 
PDAC was the fourth most fatal cancer in 2014, accounting for 82,300 deaths with a life 
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expectancy of 5% at 5 years. A similar trend is observed in Japan, where 40,000 new cases of 
PDAC were expected for 2016 with 33,700 deaths.1
The high mortality observed worldwide can be explained by the often advanced stage at diagnosis 
and the poor responses to conventional chemotherapy treatments.
3.1.1.1
Rationale for the 2L Cohort
In 2015, the FDA granted its first approval for a chemotherapy combination to treat patients with 
advanced pancreatic cancer that has progressed after gemcitabine-based chemotherapy. 
Unfortunately, even these new agents can only provide minor improvements in outcomes. The 
combination of ONIVYDE® (irinotecan liposome injection) with fluorouracil and leucovorin 
(calcium folinate) resulted in an increase in median OS to 6.1 months compared with 4.2 months 
with fluorouracil/leucovorin (calcium folinate). In addition, these regimens also have significant 
toxicity and additional options are clearly needed in advanced pancreatic cancer.
Thus, development of newer and novel agents in the treatment of diseases resistant to 
chemotherapy such as PDAC is an area of unmet need.
Taken together, these data highlight the refractory nature of the disease to conventional treatment 
approaches and the need for alternative therapeutic options for patients diagnosed with 
advanced/metastatic pancreatic cancer that progress after the 1L of chemotherapy.
3.1.2
Rationale for Inhibiting CSF1R in Cancer
Macrophages are myeloid-derived cells that carry out a variety of functions in the human body. 
They can colonize tissues and tumors through two distinct mechanisms: hematogenous seeding 
from circulating monocytes or local self-renewal in the form of tissue-resident macrophages.2
Recent studies have shown that macrophages exert their physiological effect within, and play roles 
unique to, the tissues in which they are active.3 Macrophage regulation is complex as these cells 
actively secrete and respond to multiple cytokine and chemokine gradients within their local 
environment. Macrophages are among the most abundant immune cell types in the TME. Based 
on their opposing functions, macrophages can be classified into 2 major phenotypes, M1 and M2. 
M1 macrophages are immunostimulatory and tumor suppressive, while M2 macrophages are 
immunosuppressive and tumor promoting. Substantial evidence suggests that TAMs are polarized 
towards an anti-inflammatory M2 phenotype.4 Consistent with this, increased levels of TAMs are 
associated with a poor prognosis in the majority of cancers.5 Based on their tumor-promoting 
phenotype, TAMs have become an attractive therapeutic target. 
CSF1R signaling plays a fundamental role in the differentiation, maintenance, and function of 
macrophages.6 There are 2 ligands for CSF1R: CSF1 and IL34. These agonists bind to overlapping 
regions of CSF1R with similar affinity.7 Mice lacking CSF1R, CSF1, or IL34 have deficiencies in 
macrophages, underscoring the essential role of the CSF1R pathway in the biology of this cell 
type.7,8 Pharmacologic treatments that block CSF1R in cancer settings are expected to reduce or 
reprogram M2 TAMs and reduce immune suppression. Following treatment with anti-CSF1R 
agents, the remaining macrophage compartment may be repolarized from an M2 
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immunosuppressive state to an M1 anti-tumor state, which would support T-cell responses. This 
conversion associated with concurrent treatment modalities, such as anti-PD-1 treatment, could 
have an increased effect on reduction of tumor growth.9 Support for targeting CSF1R in cancer 
comes from animal studies in which antibody or small molecule inhibition of CSF1R decreases 
M2 TAMs resulting in decreased immune suppression and a more robust cytotoxic T-cell 
response.10,11,12 Cabiralizumab is a recombinant, humanized IgG4 mAb that binds to human 
CSF1R. The interaction of cabiralizumab and CSF1R antagonizes the binding of both CSF1 and 
IL34 to CSF1R, thereby preventing receptor activation. In vitro, cabiralizumab inhibits CSF1 and 
IL34-induced proliferation and survival of peripheral blood monocytes. In vivo, cabiralizumab 
inhibits the survival of subsets of monocytes and macrophages.
Taken together, these and other emerging data suggest that blocking CSF1R with cabiralizumab 
treatment may reduce immunosuppression in the tumor environment generated by TAMs and 
enhance the efficacy of immune-based anti-cancer therapies including nivolumab.
3.1.3
Rationale for Immunotherapy
Antibody-based therapy for cancer has become established in recent years and is now one of the 
most successful and important strategies for treating patients with hematological malignancies and 
advanced solid tumors.13 Aside from targeting antigens that are involved in cancer-cell 
proliferation and survival, antibodies can also function to either activate or inactivate 
immunological pathways that are important in cancer immune surveillance.14 It is now clear that 
an antigen-specific anti-cancer immune response is the result of a complex dynamic interplay 
between the T lymphocyte cells (T cells), the TME, and the target cancer cells. The critical balance 
of T-cell activity that dictates whether endogenous anti-tumor immune responses will be effective 
are largely understood to be controlled by antigen-specific stimuli sensed by the T-cell receptor 
and by the combined activity of both positive (co-stimulatory) and negative (co-inhibitory) T-cell 
surface molecules.15 Within the past decade, antibodies against these key receptors have been 
designed and evaluated in the clinic with impressive results, heralding the onset of immunotherapy 
as a key pillar of anti-cancer therapy.16
The most extensively studied immunotherapies in cancer target the negative regulatory receptors 
cytotoxic T-lymphocyte antigen-4 (CTLA-4) or PD-1.17 Inhibition of these negative regulatory 
receptors, referred to as immune checkpoint blockade, results in the enhanced activation of T-cell 
responses and potent anti-tumor activity in nonclinical models. Studies with CTLA-4 blockade 
provided the first clinical evidence of improvement in OS with immune modulatory anti-cancer 
therapy in patients with metastatic melanoma.18,19 Following that, Topalian et al showed that anti-
PD-1 antibody therapy resulted in objective responses in patients with melanoma, non-squamous 
cell lung cancer (NSCLC), and renal cell carcinoma (RCC).20
The TME plays a central role in determining the pro-inflammatory or immunosuppressive nature 
of the anti-tumor responses. Emerging data on the role of the TAMs and their impact on tumor 
progression and prognosis supported the development of antibodies that specifically target TAMs,
and currently, several antibodies targeting TAMs are being tested in multiple clinical trials.
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With recent emerging clinical evidence of significant anti-tumor activity of single-agent 
immunotherapies, combination therapies are now being explored because they could lead to 
greater depth of response and OS. 
3.1.4
Rationale for Combining Cabiralizumab and Nivolumab
Given the complex nature of an anti-tumor immune response, effective cancer therapy may require 
combining multiple immunotherapy agents. 
In 
an 
orthotopic 
PDAC 
model, 
CSF1R 
pathway 
blockade 
selectively 
decreased 
immunosuppressive TAMs, reduced immunosuppression, and skewed the remaining macrophage 
population to a pro-inflammatory state, which increased the anti-tumor CD8+ T-cell response.11
This, in turn, produced an increased interferon response that upregulated T-cell checkpoint 
inhibitors, including programmed death-ligand 1 (PD-L1), on tumor cells. This counter-regulation 
served to limit the anti-tumor T-cell response through engagement of the T-cell inhibitor PD-1. 
Anti-PD-1 treatment was able to overcome the PD-L1-mediated inhibition. Anti-PD-1 or CSF1R
pathway inhibitors as single agents showed limited efficacy in restraining PDAC tumor growth in 
this model, but combining anti-PD-1 with CSF1R blockade potently elicited tumor regression even 
in large established tumors.21
In a recent clinical study, RG7155 (a CSF1R-targeting antibody) was tested in subjects with solid 
tumors and was shown to substantially reduce CSF1R+ and CD163+ macrophages in tumors.11 This 
reduction in macrophages was associated with a shift toward cytotoxic CD8+ T cells, similar to 
what was observed in the mouse tumor models. These data suggest that TAMs behave similarly in 
humans and mice to suppress the anti-tumor immune response. 
Preliminary data from FPA008-003 clinical trial showed how the combination of cabiralizumab 
and nivolumab was able to induce durable partial responses (PR) in a cohort of patients with 
advanced, metastatic pancreatic cancer (see Section 5.4.2 for details)
The totality of the data suggests that reprogramming the TAM compartment in tumors via 
cabiralizumab-mediated CSF1R blockade could reduce immunosuppressive TAMs in the TME
and increase CD8+ T-cell anti-tumor responses. However, PD-L1 expression in the TME could 
still be acting to restrain the anti-tumor CD8 response. The addition of an anti-PD-1 agent, such 
as nivolumab, could remove the negative effect of the PD-L1 upregulation.
3.1.5
Rationale for Combining Immunotherapy and Chemotherapy Regimens
Until recently, chemotherapy was thought to have negative effects on the immune system by 
reducing the lymphocyte numbers and inhibiting the expansion of activated lymphocytes. In 
reality, chemotherapy can promote the anti-tumor effects of the immune system by decreasing 
tumor burden, promoting immunogenic cell death, and interfering with the immunosuppressive 
TME.22 The effects of paclitaxel on the microtubule dynamics and the induction of apoptosis are 
well known. In addition to the cytotoxic effects, paclitaxel can modulate the TME in a variety of 
ways.22 Paclitaxel can induce macrophage activation and release of inflammatory cytokines in 
mouse models23 and can induce apoptosis on regulatory T cells, thus reducing their 
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immunosuppressive abilities.24 Gemcitabine, in addition to the antimetabolite effects on cancer 
cells, can also promote an immune inflammatory environment by selectively decreasing the 
infiltration of myeloid suppressor cells in the TME, and cisplatin can stimulate immune responses 
by activating antigen-presentation capacities of macrophages.25,26
On the other hand, immunotherapy can, in addition to the direct effects on the immune system, 
affect the metabolism and the effects of chemotherapy. TAMs are directly implicated in increasing 
the resistance to gemcitabine and cisplatin by upregulating cytidine deaminase (CDA) in tumor 
cells. The CDA is an enzyme that metabolizes gemcitabine and cisplatin into their inactive forms,
thus reducing the apoptotic effects of these drugs on cancer cells.27
A proof of principle of synergy between chemotherapy and checkpoint inhibitors has been 
provided by the approval in May 2017 of pembrolizumab in combination with pemetrexed and 
carboplatin for the treatment of subjects with previously untreated metastatic NSCLC. In this 
setting, the combination of immunotherapy and chemotherapy showed improvement over 
chemotherapy in ORR (55% versus 29%, respectively) and PFS (13 months versus 8.9 months, 
respectively).28
Considering the central role of TAMs and T cells in influencing the anti-tumor responses in 
pancreatic cancer and the role of chemotherapy to target the tumor cells and support the responses 
of the immune system, the combination of chemotherapy and immunotherapy represents a 
promising approach to improve the response rate of this otherwise deadly disease. 
Despite the increased experience with approaches that combine chemotherapy and 
immunotherapy, the potential for overlapping toxicities in the setting of combination therapies 
cannot be excluded. As a consequence, the seriousness, relatedness, frequency, severity and 
causality of the adverse events (AEs) can be different from what is usually observed after 
administration of chemotherapy or immunotherapy alone. 
 
 
In addition, all agents that will be used in 
the proposed combinations have shown well-defined toxicity profiles based on a safety database 
comprised of participants treated with either monotherapy or combinations across multiple tumor 
types. The combination of nivolumab with gemcitabine + nab-paclitaxel in 1L pancreatic cancer 
was shown to be safe in a Phase 1/2 study.29 Among participants with previously untreated 
pancreatic cancer treated with nivolumab and gemcitabine + nab-paclitaxel, 1 dose-limiting 
toxicity (DLT) of Grade 3 non-immune hepatitis was reported and attributed to gemcitabine. The 
participant with this DLT was able to continue on treatment with nivolumab and nab-paclitaxel 
without any further episodes of hepatitis. Anemia was the only Grade 3 or higher 
treatment-emergent AE reported in more than 1 participant in Arm B. Out of the 6 DLT-evaluable 
participants in Arm B, 3 had PRs and 3 had stable disease (SD).
 
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The current protocol was designed to detect and manage AEs as early as possible. To maximize 
the safety of the participants enrolled in this study and to better characterize the risk for potential 
overlapping toxicities between immunotherapy and chemotherapy, a preliminary safety cohort was 
implemented for the 2L Cohort Treatment Arms C and D. Six participants per arm in both 
Treatment Arms C and D have been treated and monitored for 4 weeks. 
 
 
 
 
In addition, across the entire trial, special attention is given to liver enzyme alterations since they 
can be associated with either cabiralizumab, nivolumab, or chemotherapy. Guidelines for the 
management of laboratory abnormalities and immune-mediated adverse events (IMAEs) are 
included in the protocol (Appendix 7 and Appendix 8) as well as guidelines for dose reduction for 
chemotherapy and immunotherapy (Section 7.4).
Frequent safety assessments will be carried out by the Sponsor/BMS Medical Monitor (or 
designee) and investigators throughout the study to determine whether dose modification, 
additional safety measures, or termination of the study treatment combination arm is required at 
any time. The AEs and serious AEs (SAEs) will be reviewed regularly by the BMS Medical 
Monitor (or designee) and the Pharmacovigilance group to look for trends and potential safety 
signals. Treatment of AEs will follow institutional guidelines and recommended management 
algorithms, as listed in the Investigator Brochures (IB) and prescribing information, as applicable, 
for each combination agent and contemporaneous control comparator.
3.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of cabiralizumab and 
nivolumab are provided in the IB for each product.30,31
3.2.1
Cabiralizumab
3.2.1.1
Mechanism of Action
The TME, composed of non-cancer cells and stroma, is recognized as a major factor influencing 
the growth of tumor cells. TAMs are particularly abundant in the TME and are thought to play a 
key role in promoting tumor growth. Substantial evidence suggests that TAMs are polarized 
towards an anti-inflammatory phenotype and through the expression of cell surface T-cell 
inhibitors and immunosuppressive soluble factors play a major role in inhibiting anti-tumor 
immune responses.4 In the majority of tumors, TAMs are associated with a poor prognosis,5
making TAMs an attractive therapeutic target. Because CSF1 is a major survival factor for TAMs, 
targeting CSF1R with cabiralizumab should reduce TAM-mediated immune suppression.
Cabiralizumab is a recombinant, humanized IgG4 monoclonal antibody that binds to human 
CSF1R. Cabiralizumab contains a single amino acid substitution in the hinge region to prevent 
hemi-dimer exchange. Binding of cabiralizumab to CSF1R antagonizes its natural ligands, CSF1 
and IL34, thereby preventing activation of CSF1R. 
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Cabiralizumab inhibits both CSF1- and IL34-induced CSF1R phosphorylation in a cell line 
engineered to overexpress CSF1R (CHO-CSF1R), demonstrating that cabiralizumab blocks the 
activation of ligand-induced CSF1R 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.
CSF1R is expressed on cells of the monocyte/macrophage lineage, and signaling through CSF1R 
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.4
CSF1 is a major survival factor for TAMs, and targeting CSF1R with cabiralizumab should reduce 
TAM-mediated immune suppression, resulting in strengthening the anti-tumor response to 
immunotherapy. Therefore, a drug that inhibits CSF1R should limit the immunosuppressive 
influence of TAMs on the TME and could be complementary and augment current cancer 
therapies.
3.2.1.2
Preclinical Summary
The PK profile of cabiralizumab is complex and characterized by nonlinear clearance that is likely 
mediated by binding to CSF1R on cells. 
 
 As target-mediated clearance 
becomes saturated at high or repeat doses, cabiralizumab clearance is similar to other human IgG 
antibodies. 
 
 
 
 
 
 
 
 
In in vivo toxicology studies in cynomolgus monkeys, cabiralizumab was generally well tolerated. 
Test article-related findings included clinical observations, hematology and clinical chemistry 
changes, and histopathological changes. The majority of these observations were considered 
non-adverse. The most prominent clinical observation was reversible periorbital edema, seen after 
prolonged exposure to cabiralizumab. The onset of the edema did not show a clear relationship to 
exposure levels, but edema resolved after systemic clearance of the drug. Periorbital edema is a 
known side effect of drugs affecting the CSF1 pathway.10 The main hematologic change was a 
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reversible decrease 
, which was considered a pharmacodynamic 
effect. 
 
 
 These laboratory abnormalities were not associated with any 
histopathological evidence of liver, cardiac, or muscle tissue injury. Additionally, cardiac troponin, 
skeletal troponin, myoglobin, and aldolase did not show any changes, further confirming the lack 
of any liver or muscle injury. The increased serum levels are attributed to diminished clearance of 
ALT, AST, CK, and LDH molecules from serum due to a reduced number of liver Kupffer cells.32
 
The no-observable-adverse-effect level (NOAEL) for cabiralizumab was determined to be 
100 mg/kg when administered for 13 weekly doses to cynomolgus monkeys, which provided a 
32-fold safety factor based on body surface area calculation for the starting dose of 1 mg/kg in 
humans.
Since cabiralizumab does not cross-react to mouse CSF1R, a surrogate antibody, cmFPA008, was 
developed that binds and blocks mouse CSF1R with similar potency observed for cabiralizumab
against human CSF1R. Binding of cmFPA008 to mouse CSF1R was demonstrated in a direct 
binding enzyme-linked immunosorbent assay (ELISA), and cmFPA008 inhibitory activity was 
demonstrated by its ability to inhibit CSF1- and IL34-induced proliferation of a CSF1/IL34-
dependent cell line (mNFS60). The EC50 value for cmFPA008 binding to mouse CSF1R was 
2.4 ng/mL, and the IC50
values for inhibition of mouse CSF1-
and IL34-induced 
proliferation/survival of mNFS60 cells were 32.9 and 9.1 ng/mL, respectively. The ability of 
cmFPA008 to inhibit cancer growth in vivo was studied in an MC38 colon cancer model in 
immune-competent mice. These mice were selected to allow for the establishment of an intact 
tumor-immune interaction. 
 
 
 
 
 
 These data suggest that reduction of 
immunosuppressive macrophages by cmFPA008 results in a shift toward a greater cytotoxic T-
cell response in the tumor.
For more detailed information or background on cabiralizumab, please refer to the cabiralizumab
IB.30
3.2.1.3
Clinical Summary
The clinical summary of safety and efficacy is based on 4 clinical studies:
1) Study FPA008-001 evaluated the safety of cabiralizumab as single or double ascending doses 
in 48 healthy volunteers (36 received cabiralizumab and 12 received placebo). This study also 
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evaluated the safety and efficacy of cabiralizumab administered as 2 or 3 doses, 14 days apart, 
in 18 rheumatoid arthritis (RA) subjects. This study has been completed.
2) Study FPA008-002 is evaluating the safety and efficacy of cabiralizumab monotherapy in 
participants with pigmented villonodular synovitis (PVNS). As of 02-Jul-2018, approximately 
54 participants have been treated.
3) Study FPA008-003 is evaluating the safety and efficacy of cabiralizumab as monotherapy and 
in combination with nivolumab in participants with advanced cancers. As of 02-Jul-2018, 
approximately 312 participants have been treated
4) Study CA025001 is evaluating the safety and efficacy of cabiralizumab as monotherapy and 
in combination with nivolumab in Japanese participants with cancer. As of 16-Jul-2018, 
approximately 13 participants have been treated.
Clinical Pharmacology Summary (Pharmacokinetics, Immunogenicity, and 
Pharmacodynamics)
The available PK, ADA
 status following cabiralizumab 
treatment with either monotherapy or in combination with nivolumab were characterized in 
3 trials: FPA008-001, FPA008-002, and FPA008-003. The PK, ADA
 data from Study FPA008-003 are summarized below; data from Studies FPA008-001 
and FPA008-002 are presented in the cabiralizumab IB.30
 
 
 
 
 
Study FPA008-003 – Advanced Cancer (Cabiralizumab Monotherapy)
In Phase 1a, participants with cancer received cabiralizumab at doses of 2, 4, or 6 mg/kg every 
2 weeks (Q2W) as monotherapy or 1, 2, or 4 mg/kg Q2W in combination with nivolumab 3 mg/kg 
Q2W. There were a total of 25 participants (n = 16 for monotherapy and n = 9 for combination 
treatment) with PK data as of 15 December 2016. Blood samples for determination of serum 
cabiralizumab concentration were collected before dosing and at various times throughout the 
study. Blood samples for determination for anti-cabiralizumab antibodies were collected before 
dosing and at various time points from Day 15 to the end-of-treatment follow-up. 
 
 
 
 
 
 
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Assessment
 in Study FPA008-003 has been evaluated in cohorts 
receiving cabiralizumab 2, 4, or 6 mg/kg monotherapy. In addition, assessment 
 
 has been evaluated in cohorts receiving a combination of cabiralizumab 1, 2, or 
4 mg/kg with nivolumab 3 mg/kg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Safety Summary 
Study FPA008-001 – Healthy Volunteers and Rheumatoid Arthritis
Thirty-six
healthy 
volunteers 
and 
18 
RA 
participants 
received 
cabiralizumab 
in 
Study FPA008-001. No dose-limiting toxicities (DLTs) were reported and no unexpected 
treatment-related AEs have been reported in RA participants treated with 3 doses up to 6 mg/kg.
Details relating to safety are included in the latest version of the cabiralizumab IB.30
Study FPA008-002 – Pigmented Villonodular Synovitis
Study FPA008-002 is currently ongoing and is evaluating cabiralizumab as monotherapy in 
subjects with PVNS. Details relating to safety are included in the latest version of the 
cabiralizumab IB.30
Study FPA008-003 – Advanced Cancers (Cabiralizumab/Nivolumab Combination)
As of 02-Jul-2018, AEs have been experienced by 264 of 265 (99.6%) participants treated with 
cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Q2W across multiple cohorts, while 
treatment-related AEs were experienced in 245 of 265 (92.5%) participants treated with 
cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Q2W.
Treatment-related AEs are summarized in Table 3.2.1.3-1
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Table 3.2.1.3-1:
FPA008-003: Phase 1a and Phase 1b Combination Therapy (N = 
265) Summary of Incidence of Treatment-related Adverse Events 
Occurring in > 10% of Participants by Preferred Term Dosed with 
Cabiralizumab 4 mg/kg and Nivolumab 3 mg/kg
Phase 1a and 1b Combination Therapy 
Cabiralizumab 4 mg/kg + Nivolumab 3 mg/kg Q2W 
Cohorts 1aC3, 1b1-1b7, and 1aE2-1aE4
N=265
Preferred Term
All Grades
N (%)
Grade 3/4
N (%)
Grade 5
N (%)
Total subjects with a treatment-related AE
245 (92.5)
135 (50.9)
3 (1.1)
Treatment-related AEs reported in > 10% of subjects
Blood creatine phosphokinase increased
122 (46.0)
43 (16.2)
0
Periorbital edema
115 (43.4)
4 (1.5)
0
Fatigue
102 (38.5)
15 (5.7)
0
Aspartate aminotransferase increased
100 (37.7)
17 (6.4)
0
Alanine aminotransferase increased
51 (19.2)
3 (1.1)
0
Amylase increased
51 (19.2)
22 (8.3)
0
Rash
50 (18.9)
10 (3.8)
0
Pruritus
47 (17.7)
1 (0.4)
0
Lipase increased
44 (16.6)
20 (7.5) 
0
Diarrhea
41 (15.5)
8 (3.0)
0
Nausea
41 (15.5)
1 (0.4)
0
Blood lactate dehydrogenase increased
32 (12.1)
3 (1.1)
0
Anemia
28 (10.6)
9 (3.4)
0
Source: Investigator Brochure for Cabiralizumab.30
Notes: All participants received cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Q2W. Cohort 1aC3 is a Phase 1a 
combination therapy dose escalation part in participants (n=3) with selected advanced cancers. Cohorts 1b1-1b7 
are Phase 1b combination therapy dose expansion parts in participants with PD-1 naive NSCLC (1b1; n=30), PD-1 
resistant (de novo/acquired) NSCLC (1b2; n=31), SCCHN (1b3; n=30), pancreatic cancer (1b4; n=33), advanced 
ovarian cancer (1b5; n=31), RCC (1b6; n=30), or malignant glioma (1b7; n=30). Cohorts 1aE2-E4 are Phase 1a 
dose expansion parts in participants with melanoma (1aE2; n=11), anaplastic thyroid cancer (1aE3; n=1), or 
pancreatic cancer (1aE4; n=35).
Abbreviations: AE = adverse event; NSCLC = non-small cell lung cancer; PD-1 = programmed death-1; RCC = renal 
cell carcinoma; SCCHN = squamous cell carcinoma of the head and neck.
One hundred thirty-four of 265 participants (50.6%) receiving cabiralizumab 4 mg/kg + nivolumab 
3 mg/kg Q2W experienced a treatment-related SAE (cabiralizumab or nivolumab). Related SAEs 
reported in at least 2 participants included: increased blood creatine kinase and pneumonitis (8 
participants each), pneumonitis (5 participants each), colitis (4 participants each), acute respiratory 
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failure, brain edema, diarrhea, myocarditis, pancreatitis, pleural effusion, and troponin increase (2 
participants each). All other treatment-related SAEs were reported in 1 participant each.
A total of 128 of 265 (48.3%) participants receiving cabiralizumab 4 mg/kg + nivolumab 3 mg/kg 
Q2W died during the course of the study. A total of 17 of 265 (6.4%) participants died due to an 
AE, and treatment-related Grade 5 AEs were experienced by 3 of 265 (1.1%) participants and 
included acute respiratory failure (2 [0.8%] participants) and respiratory distress (1 [0.4%] 
participant).
Overall, the combination of cabiralizumab and nivolumab appears to be manageable with a safety 
profile consistent with the individual components, and the frequency and types of IMAEs appear 
to be similar across multiple tumor types. 
Details relating to safety are included in the latest version of the cabiralizumab IB.30
3.2.2
Nivolumab
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.33,34,35
Current immunotherapy efforts attempt to break the apparent 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).36 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.37 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.38 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).39 Binding of PD-1 to PD-L1 and programmed 
death-ligand 2 (PD-L2) has been shown to down-regulate T-cell activation in both murine and 
human systems.27,37,40,41 PD-1/PD-L1 interactions may also indirectly modulate the response to 
tumor antigens through T-cell/APC interactions. Therefore, PD-1 engagement may represent 1 
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means by which tumors evade immuno-surveillance and clearance.42 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 is currently being evaluated extensively across a wide range of 
solid tumors and hematological malignancies. These findings provided the rationale for expanding 
the evaluation of PD-1 pathway blockade in combination with novel immunotherapy agents in 
clinical studies.
Nivolumab (BMS-936558) is a fully human, immunoglobulin G4 (IgG4) [kappa] isotype mAb
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 (IC50 1 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. 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).43
The nonclinical safety of nivolumab was evaluated in a comprehensive toxicology program in 
mice and monkeys and was submitted as part of Biologics License Application 125527.22. Details 
of the in vitro and in vivo nonclinical pharmacology studies conducted to support the development 
of nivolumab can be found in Section 4.1 of the Nivolumab IB.31
There is a potential for enhanced toxicity when combined with other immunotherapeutic agents. 
Combination nonclinical toxicology studies with cabiralizumab and nivolumab have not been 
conducted and are not required by the International Council on Harmonisation S9 Note for 
Guidance on Nonclinical Evaluation for Anticancer Pharmaceuticals. The safety of the 
combination will be carefully monitored in the planned clinical trial.
The overall safety experience with nivolumab, as either monotherapy or in combination with 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 SCCHN with disease 
progression on or after a platinum-based therapy, 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. 
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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 IMAEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 7. 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. 
In addition, the 
combination of nivolumab and gemcitabine + nab-paclitaxel is currently being tested as 1L
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 were evaluable for efficacy. The preliminary ORR is 25% (5 out 
of 20 participants experienced a PR). 
 
Taken together, these data suggest that while nivolumab monotherapy may not be sufficient to 
provide 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. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are summarized in the Nivolumab IB.31
3.2.3
Clinical Experience Involving Serum Enzyme Elevations
The safety and preliminary efficacy of cabiralizumab is currently being evaluated in 4 clinical 
trials. A common feature observed across the clinical trials is an elevation of AST, CK, and LDH 
after the administration of cabiralizumab. These alterations are the consequence of the direct effect 
of anti-CSF1R antibodies on the Kupffer cell in the liver that results in a depletion of these cells. 
Depletion of Kupffer cells allows the enzymes, which are released following normally occurring 
liver cell turnover, to enter circulation (where they are measured by routine laboratory assessment) 
rather than being absorbed by the Kupffer cells. 
 
 The observed elevations were asymptomatic,
not permanent, and not associated with clinical sequelae. Similar effects have been observed across 
other CSF1R targeted agents (see cabiralizumab IB for additional details). The data with 
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cabiralizumab and with other agents in the class suggest that the observed serum enzyme 
elevations do not compromise the safety profile of cabiralizumab and therefore support 
modification of the safety monitoring criteria.
3.2.3.1
Serum Enzyme Elevations with Cabiralizumab
In Study FPA008-003, 34 participants have been dosed as part of Phase 1a dose escalation (24 in 
cabiralizumab monotherapy and 10 in cabiralizumab + nivolumab combination therapy) and 
195 participants have been dosed as part of Phase 1b dose expansion as of 01-Aug-2017. In 
Phase 1a, CK was elevated in 11 of 34 participants (32%), and 3 events (9%) were Grade 3 or 
higher. AST was elevated in 16 of 34 participants (47%), and 10 events (29%) were Grade 3 or 
higher. ALT was elevated in 4 of 34 participants (17%), and none of these were Grade 3 or higher. 
In Phase 1b, CK was elevated in 82 of 195 participants (42%), and 29 events (15%) were Grade 3 
or higher. AST was elevated in 76 of 195 participants (39%), and 14 events (7%) were Grade 3 or 
higher. ALT was elevated in 39 of 195 participants (20%), and 5 events (3%) were Grade 3 or 
higher.
The serum enzyme elevations for Studies FPA008-001 and FPA008-002 follow a similar pattern. 
Please refer to the cabiralizumab IB for more detailed information about these serum enzyme
elevations.
3.2.3.2
Management of Isolated Laboratory Abnormalities
 
 To rule out any potential hepatic injury in relation to 
elevated transaminases, additional monitoring following the Drug-Induced Liver Injury (DILI)
Guidance from the FDA44 will be performed for bilirubin, INR, and ALT/AST. In the case of 
elevated CK, additional assessments will be performed for CK isoenzymes (CK-MM, CK-MB, 
and CK-BB) and troponins (I or T). The investigator should notify the Sponsor of increased serum 
levels above specific cutoffs, but below those that would trigger drug modification or 
discontinuation. Additional monitoring of clinical signs and symptoms known to be associated 
with hepatic damage, per the FDA DILI Guidance, is recommended. These additional measures 
should be followed as per the guidance in Appendix 8.
3.3
Benefit/Risk Assessment
Patients with advanced/metastatic pancreatic cancer have a dismal prognosis due to the often 
advanced stage at diagnosis (see Section 3.1.1). 
Two combination regimens, FOLFIRINOX and gemcitabine + nab-paclitaxel, have gained 
acceptance as front-line treatments. While these chemotherapy regimens have shown to improve 
survival of patients with advanced/metastatic pancreatic cancer, more than three-fourths of 
pancreatic cancer patients progress within 1 year of diagnosis. In addition, for patients that 
progress after 1L therapies, limited options are available (see Section 3.1.1); therefore, better 
treatment options are clearly needed for subjects that progress after 1L treatments.
The combination of immunotherapy and chemotherapy has been tested in multiple settings, with 
a manageable safety profile reported using established safety guidelines.45,46 The combinations 
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also yielded substantial clinical efficacy as demonstrated by the combination of pembrolizumab 
with pemetrexed and carboplatin for the treatment of participants with previously untreated 
metastatic NSCLC.28
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 regimens 
being evaluated in this study. Preclinical evidence supports 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 and the lack of curative options support the need for 
novel combinatorial approaches.
The safety profile of cabiralizumab and nivolumab has been tested in > 250 participants. The 
frequency and types of immune-mediated adverse reactions are similar across multiple types of 
tumors and are described in the Reference Safety Information in the current cabiralizumab IB.30
Management algorithms for IMAEs involving gastrointestinal, renal, pulmonary, hepatic, 
endocrine, skin, and neurologic systems are included in the protocol. The safety of the 
chemotherapy combinations with cabiralizumab and nivolumab will be carefully monitored. A 
preliminary safety cohort was planned and has been completed in the 2L Cohort Treatment Arms 
C and D of the current study. Six participants per arm in both Treatment Arms C and D were
treated and monitored for 4 weeks. 
 
 
 
The mandated biopsies pose limited risk to the participant, which includes discomfort, pain, and 
bleeding. Because of the need to understand the effect of cabiralizumab and nivolumab with or 
without chemotherapy on the TME
 
 the limited risk of a research biopsy is 
considered appropriate in an early-phase clinical trial research setting.
Continuous safety assessments will be utilized by the Investigators and BMS to determine whether 
dose modification, additional safety measures, or termination of the study is required at any time. 
In addition, AEs and SAEs will be reviewed on an ongoing basis by the BMS Medical Monitor 
and Global Pharmacovigilance and Epidemiology representatives to monitor for any safety signals 
or trends. As the combination of cabiralizumab and nivolumab with or without chemotherapy is 
an experimental treatment, it is possible that unforeseen, unknown, or unanticipated reactions may 
occur. The protocol was developed carefully balancing risks and benefits of treatment of a novel 
therapy in this patient population with an unmet medical need.
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the PFS of cabiralizumab administered in 
combination with nivolumab with and without chemotherapy 
relative to investigator’s choice of chemotherapy in participants 
with advanced/metastatic pancreatic cancer who progressed on or 
after the first line of chemotherapy (either gemcitabine-based or 
5-FU-based chemotherapy).

PFS per RECIST v1.1 by BICR
Secondary

To evaluate the anti-tumor activity of cabiralizumab administered 
in combination with nivolumab with or without chemotherapy 
relative to investigator’s choice of chemotherapy in participants 
with advanced/metastatic pancreatic cancer who progressed on or 
after the first line of chemotherapy (either gemcitabine-based or 
5-FU-based chemotherapy) using RECIST v1.1.

PFS per RECIST v1.1 by investigator 
assessment; ORR, DOR, and PFSR at 
6, 9, and 12 months per RECIST v1.1 
by BICR and investigator assessment

To assess OS.

OS and OSR at 6 months, 1 year, and 
2 years

To assess the safety of cabiralizumab administered in 
combination with nivolumab with or without chemotherapy in 
participants with advanced/metastatic pancreatic cancer who 
progressed on or after the first line of chemotherapy (either 
gemcitabine-based or 5-FU-based chemotherapy).

Incidence of AEs, SAEs, AEs leading 
to 
discontinuation, 
death, 
and 
laboratory abnormalities
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Abbreviations: 5-FU = 5-fluorouracil; 
 AE = adverse event; BICR = blinded independent 
central review; 
ORR = objective response rate; OS = overall survival; OSR = overall survival rate; PFS = progression-free survival; 
PFSR = progression-free survival rate; 
 
RECIST = Response Evaluation Criteria In Solid 
Tumors; SAE = serious adverse event; 
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2, open-label, randomized study to evaluate the efficacy, safety, tolerability
of cabiralizumab in combination with nivolumab with or without
gemcitabine + nab-paclitaxel or oxaliplatin, 5-FU, and leucovorin (calcium folinate; FOLFOX), 
or an alternative choice of chemotherapy, in participants with locally advanced/metastatic 
pancreatic tumors who have progressed during or after no more than 1 line of systemic 
chemotherapy (either gemcitabine-based or 5-FU-based) in the metastatic setting.
The study design schematic for the study is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Note: ONIVYDE-based regimen can be substituted with FOLFIRI.
Abbreviations: ECOG = Eastern Cooperative Oncology Group; Q2W = every 2 weeks; Q4W = every 4 weeks; 
R = randomized.
The study will consist of 3 periods: Screening, Treatment, and Safety/Survival Follow-up. The 
study will end after the last participant completes the last visit.
5.1.1
Screening Period
The screening period will last for up to 30 days. The screening period begins by establishing the 
participant’s initial eligibility and signing of the informed consent form (ICF). The screening 
assessments are shown in Table 2-1. If a participant surpasses the 30-day window during the 
screening period due to a study-related procedure (eg, scheduling of a tumor biopsy or waiting 
time for a study-related laboratory value), the participant must be re-consented but does not need 
to be assigned a new participant identification (PID) number. In this situation, the least amount of 
repeat procedures from the initial screening to qualify the participant, while maintaining safety 
and eligibility under the discretion of the BMS Medical Monitor and investigator, may be done to 
reduce any undue burden of procedures in this participant population. Participants will be 
randomized and treated in 1 of 4 arms as described in Section 5.1.2 based on their 1L treatment 
for pancreatic cancer. Allocation will be based on availability of slots in each of the arms and 
participants meeting cohort-specific eligibility criteria.
Tumor tissue from a biopsy obtained during screening, or from a sample collected within 3 months 
prior to treatment, is required for enrollment. If the tumor sample is from a prior collection, 
participants should not have received any systemic anticancer therapy between collection and 
enrollment in the current study. Tumor samples must be obtained from a metastatic tumor lesion 
or from an unresectable primary tumor lesion. Tumor samples may be obtained from a core biopsy, 
excisional biopsy, or surgical specimen; formalin-fixed paraffin-embedded (FFPE) blocks or a 
minimum of 20 slides are required. Participants with lesions in a previously irradiated field as the 
sole site of measurable disease will be permitted to enroll, provided the lesion(s) has demonstrated 
Treatment Arm
R (A:B:D) 1:1:2
Stratified by ECOG 
Status (0 or 1)
R (A:B:C) 1:1:2
Stratified by ECOG 
Status (0 or 1)
Prior 5-fluorouracil-
based chemotherapy
B. Cabiralizumab Q2W + Nivolumab Q4W
D. Cabiralizumab Q2W + Nivolumab Q4W and
Oxaliplatin/5-Fluorouracil/Leucovorin (FOLFOX) Q2W
C. Cabiralizumab Q2W + Nivolumab Q4W and
Gemcitabine + Nab-paclitaxel (Abraxane®) D1, 8, and 15 Q4W
A. Investigator choice of chemotherapy: 
-
Gemcitabine + Nab-paclitaxel (ABRAXANE®)
-
5-Fluorouracil/Leucovorin/Irinotecan Liposome (ONIVYDE®)
Prior gemcitabine-
based chemotherapy
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clear progression and can be measured. Adequate tumor content must be documented by 
hematoxylin and eosin (H&E) stain, performed either locally or on samples submitted to the central 
laboratory, for participants to receive treatment. Local H&E or central laboratory results must be 
provided to the Interactive Response Technology (IRT) prior to randomization/treatment 
assignment.
5.1.2
Treatment Period
The randomization call is made into the IRT no more than 3 business days prior to the first day of 
treatment on Cycle 1 Day 1, unless otherwise agreed upon with the Medical Monitor. The 
participant will be randomly assigned to the open-label cohort dependent on their initial 
chemotherapy treatment (gemcitabine-based or 5-FU-based). Participants will not receive the same 
therapeutic combination that they received in the 1L setting.
Participants who have previously received gemcitabine-based chemotherapy will be stratified 
according to Eastern Cooperative Oncology Group (ECOG) status (0 or 1) and randomly assigned 
in a 1:1:2 ratio to 1 of the 3 following treatment options:

Treatment Arm A: Investigator choice of chemotherapy (gemcitabine + nab-paclitaxel 
[ABRAXANE]; 5-FU/leucovorin [calcium folinate]/irinotecan liposome [ONIVYDE]*);

Treatment Arm B: Cabiralizumab and nivolumab in combination;

Treatment 
Arm 
D: 
Cabiralizumab 
and 
nivolumab 
in 
combination 
with 
oxaliplatin/5-FU/leucovorin (calcium folinate; FOLFOX).
*ONIVYDE-based regimen can be substituted with FOLFIRI (irinotecan/leucovorin/5-FU)
Participants who have previously received 5-FU-based chemotherapy will be stratified according 
to ECOG status (0 or 1) and randomly assigned in a 1:1:2 ratio to 1 of the 3 following treatment 
options:

Treatment Arm A: Investigator choice of chemotherapy (gemcitabine + nab-paclitaxel 
[ABRAXANE]; 5-FU/leucovorin [calcium folinate]/irinotecan liposome [ONIVYDE]*);

Treatment Arm B: Cabiralizumab and nivolumab in combination;

Treatment 
Arm 
C: 
Cabiralizumab 
and 
nivolumab 
in
combination 
with 
gemcitabine + nab-paclitaxel (ABRAXANE).
*ONIVYDE-based regimen can be substituted with FOLFIRI
A total of 6 participants per arm were included in a preliminary safety cohort in Treatment Arms C 
and D. After the first 3 participants were treated with the combination of immunotherapy and 
chemotherapy, using an interval of 5 days between each participant, the subsequent 3 participants 
were enrolled competitively. The 6 participants were monitored for up to 4 weeks before additional 
participants were treated in the same arm.
 
 
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Blood, urine, tumor biopsy, fecal samples, and electrocardiograms (ECGs) will be collected and 
participants will receive study treatments as per the Schedule of Activities (Table 2-2). Participants 
will have baseline imaging within approximately 30 days before the start of the study and then 
every 8 weeks after starting combination treatment for reassessment. Tumor progression or 
response endpoints will be assessed using RECIST v1.1 for solid tumors. Participants will continue 
on treatment until withdrawal of consent, death, or initiation of another anti-cancer treatment. 
Participants who discontinue treatment will be followed for safety assessments and survival status 
as described in Section 5.1.4 and Table 2-3.
Physical examinations, vital sign measurements, 12-lead ECG and clinical laboratory evaluations 
will be performed at selected times throughout the dosing interval. In the event that multiple 
procedures are required at a single time point, the following is a list of procedures from highest to 
lowest priority: 
 ECG and vital signs, and laboratory tests. Participants will be 
closely monitored for AEs throughout the study. Blood samples will be collected at baseline and 
after study treatment administration for 
analyses according to the schedules outlined in 
Section 9.5.
Participants with a response of SD, PR, or complete response (CR) at the end of a given cycle will 
continue to the next treatment cycle. Participants will generally be allowed to continue study 
treatment until the first occurrence of either 1) progressive disease, 2) clinical deterioration 
suggesting that no further benefit from treatment is likely, 3) intolerability to therapy, 4) the 
participant meets criteria for discontinuation of study treatment as outlined in Section 7.4.4, or 5)
withdrawal of consent. 
Treatment beyond disease progression will be allowed in participants with initial 
RECIST v1.1-defined progressive disease in Treatment Arms B, C, and D, as described in Section 
5.1.3.
Participants who experience toxicities confirmed to be related to 1 of the study drugs in a 
combination therapy can continue treatment with the other drug(s) of the combination per protocol 
(see Section 7.4).
5.1.3
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of patients treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease per RECIST v1.1.
Participants treated with cabiralizumab and nivolumab combination therapy in Treatment Arms B,
C, and D will be permitted to continue cabiralizumab and nivolumab treatment beyond initial 
RECIST v1.1-defined progressive disease, as assessed by the investigator, as long as the following 
criteria are met:

Investigator-assessed clinical benefit and no rapid disease progression;

Participant is tolerating study treatment;
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
Stable performance status;

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Participants provides written informed consent prior to receiving additional study treatment, 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options;
The decision to continue treatment beyond initial investigator-assessed progression should be 
discussed with the BMS Medical Monitor and documented in the study records. A radiographic 
assessment/scan
should be performed approximately 4 weeks (7 days) after initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor size 
or continued progressive disease. The assessment of clinical benefit should be balanced by clinical 
judgment as to whether the participant is clinically deteriorating and unlikely to receive any benefit 
from continued treatment with cabiralizumab and nivolumab.
If the investigator feels that any participant receiving cabiralizumab and nivolumab will obtain 
clinical benefit by continuing treatment, the participant may remain on the trial and continue to 
receive monitoring according to the time and event schedules as per the protocol.
For participants who continue cabiralizumab and nivolumab study therapy beyond progression, 
confirmation of progression will be assessed based on 1) at least 5 mm of further increase in target 
or new target lesion burden, 2) further increase in the size of non-target lesion(s), 3) appearance of 
new lesion or additional new lesions in the next consecutive assessment. If complete or partial 
response, or stable disease criteria are met at the next assessment, then initial progression status is 
reset. Cabiralizumab and nivolumab treatment should be discontinued permanently upon 
documentation of confirmed progression.
5.1.4
Follow-up Period
5.1.4.1
Safety Follow-up Period
Once the decision is made to discontinue the participant from treatment, that is, at end of treatment 
(EOT), all participants will enter a Safety Follow-up Period.
For participants who will not complete all scheduled cycles of therapy, the EOT visit will be the 
most recent on-treatment visit (with all available safety and response data) and will not need to be 
repeated. Accordingly, for these participants, this visit will be considered the start of the safety 
follow-up period.
After the EOT visit, all participants will be evaluated for any new AEs for at least 100 days after 
the last dose of study treatment. Follow-up visits should occur at Days 30, 60, and 100 (7 days 
for all study visits) after the last dose or at the date of discontinuation (7 days). All participants 
should complete the 3 clinical safety follow-up visits regardless of whether new anti-cancer 
therapy is started, except those participants who will withdraw consent for study participation.
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5.1.4.2
Imaging Follow-up Period
At the time of study treatment discontinuation, participants will continue to have radiologic and 
clinical tumor assessments every 12 weeks (± 7 days) until withdrawal of consent, death, or 
initiation of another anti-cancer treatment, whichever occurs first. Radiological assessments for 
participants who have ongoing clinical benefit may continue to be collected after participants 
complete the Survival Follow-up Period of the study. Participants who have disease progression 
after an initial course of study therapy will be evaluated beyond the EOT visit and will be allowed 
to receive other tumor-directed therapy as required.
5.1.4.3
Survival Follow-up Period
In parallel with the safety follow-up period, all participants will start the survival follow-up period. 
Participants will be followed-up by telephone every 12 weeks (after completion of Safety Follow-
up Visit 3) for 2 years or until death, loss to follow-up, withdrawal of consent, or conclusion of 
the study, whichever comes first. Participants with SD, PR, or CR will have both the safety
follow-up period and survival follow-up period occur simultaneously during the 2-year follow-up 
period. The duration of this follow-up is up to 2 years following the last dose of study treatment, 
although a longer follow-up period could be considered in selected cases if an efficacy signal is 
apparent. Tumor assessment scans for participants who have ongoing clinical benefit beyond the 
2-year period following the first dose of study treatment, may continue to be collected as part of 
standard-of-care treatment. Subsequent therapies will also be recorded in this survival follow-up 
period.
5.1.5
Data Monitoring Committee and Other External Committees
Based on the key points listed and the comprehensive safety monitoring plan outlined below, BMS 
has elected to not use a Data Monitoring Committee (DMC) for this study.

This is an open label study.

The eligibility criteria exclude participants with disease characteristics that could predispose 
them to a higher risk of morbidity (eg, history of interstitial lung disease, recent history of 
thrombosis)

Exclusion of participants with known autoimmunity also applies as they could be at risk for 
exacerbation of their condition by the administration of therapies that relieve immune 
suppression such as nivolumab.

Participants will be observed frequently for clinical evaluation and blood counts.

Well-defined discontinuation criteria are established in the protocol for individual participants 
for both safety and treatment futility with clear criteria for treatment discontinuation, dose 
delay, and toxicity management.
 
 
 
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5.2
Number of Participants
Approximately 160 participants will be treated (approximately 40 participants in each treatment 
arm). Six participants from each of Treatment Arms C and D were evaluated for safety prior to 
continuation of enrollment in these treatment arms. The first 3 participants in the preliminary safety 
cohort were treated at intervals of at least 5 days; the enrollment for the additional 3 participants 
was competitive. 
 
 
 
Study enrollment is now open competitively. Refer to Section 10.1 for details regarding the sample 
size determination.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit or scheduled procedure shown in the Schedule of Activities for the last 
participant. Study completion is defined as the final date on which data for the primary endpoint 
was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
Cabiralizumab is being investigated in combination with nivolumab in subjects with advanced 
solid tumors. The study design includes the following:
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
30-day screening period

Treatment period

Safety/survival follow-up period
The rationale for the individual elements of the study design is provided below.
5.4.1
Rationale for Chemotherapy-only Regimens
Evaluating efficacy of a combination in a single arm study can be difficult due to many 
uncertainties, particularly if part of the combination has known anti-tumor activity. In addition, 
historical controls may not be fully representative of the patient population in this study. Therefore, 
stratified randomization is being used to avoid possible bias in treatment assignment and potential 
imbalance of baseline characteristics.
5.4.1.1
Treatment Arm A
Treatment options for patients with PDAC are usually very limited beyond 1L treatment. For 
patients with distant metastases who have received systemic chemotherapy and maintain an 
adequate performance status and comorbidity profile, a switch to an alternative regimen is 
considered reasonable. Patients who received a 5-FU-based chemotherapy regimen as 1L therapy 
are usually treated with a gemcitabine-based chemotherapy regimen as 2L; in contrast, patients 
who received a gemcitabine-based chemotherapy regimen are usually treated with a combination 
of fluorouracil/leucovorin (calcium folinate) and ONIVYDE after progression.
To align with the standard approach currently taken to treat patients that progress after initial 
chemotherapy, both gemcitabine + nab-paclitaxel and fluorouracil/leucovorin (calcium folinate) 
and ONIVYDE have been offered as treatment options in the 2L Cohort Treatment Arm A. Sites 
may substitute the ONIVYDE-based regimen with FOLFIRI if ONIVYDE is not available, per 
country/institution guidelines.
5.4.2
Rationale for Cabiralizumab and Nivolumab Combination Therapy
Please also refer to Section 3.2.1.3 and Section 3.1.4.
As of 02-Jul-2018, 32 participants with advanced/metastatic PDAC treated with 
cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Q2W in Cohort 1b4 of study FPA008-003 were 
evaluable for efficacy.30 Based on investigator-assessed responses, durable clinical benefit 
(PR + stable disease) was observed in 5 of 32 (15.6%) evaluable participants, with an ORR of 
9.4% (with 3 of 32 participants experiencing prolonged, sustained PR per investigator assessment). 
The duration of response for the 3 subjects with PR was: 14.1+, 9.3, and 8.4 months.
The initial blinded independent central review (BICR), as of 30-Oct-2017, showed an ORR of 
13%, with 4 of 31 participants experiencing prolonged PR. The updated BICR was available as of 
02-Sep-2018. Due to the need to change the team of readers, the scans of all active participants 
were re-analyzed. The most recent BICR assessment is now aligned with the investigator 
assessment, reporting an ORR of 9.4%, with 3 of 32 participants experiencing a durable PR. 
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Of note, all 3 PRs occurred in participants with microsatellite stable and low tumor mutational 
burden tumors. In addition, preliminary orthogonal immunohistochemistry (IHC) and 
transcriptome-wide analyses demonstrated that cabiralizumab induces CSF1R blockade in the 
periphery and tumor microenvironment in participants with advanced cancer.
In addition to the 32 participants treated in Cohort 1b4, additional participants with PDAC have 
been treated with the combination of cabiralizumab and nivolumab in study FPA008-003.30
Preliminary analysis of the data is available for the 34 participants with PDAC who were evaluated 
for response in Cohort 1aE4 (cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Q2W) and showed 6 
(17.6%) participants with stable disease. Preliminary analysis of the data is also available for the 
6 participants with PDAC who were evaluated for response in Cohort 1aC4 (cabiralizumab 6 
mg/kg + nivolumab 3 mg/kg Q2W) and showed 1 (16.7%) participant with a confirmed PR and 3 
(50.0%) participants with stable disease. Further follow up will reveal a more mature efficacy 
assessment with BICR confirmation.
These data support the need for further analysis of the combination of cabiralizumab and 
nivolumab for patients with metastatic PDAC.
5.4.3
Rationale for Cabiralizumab in Combination with Nivolumab and 
Gemicitabine + Nab-paclitaxel or FOLFOX
Please also refer to Section 3.1.5 above.
Gemcitabine + nab-paclitaxel is a global standard treatment for newly diagnosed PDAC.
In consideration of the potential synergy between gemcitabine and cabiralizumab + nivolumab, 
this combination has been included in Treatment Arm C of this protocol.
Historically, patients that received gemcitabine + nab-paclitaxel as their 1L of treatment have been 
treated with a 5-FU-based chemotherapy in 2L, while patients treated with a 5-FU-based 
chemotherapy in 1L have been treated with gemcitabine + nab-paclitaxel in 2L. 
In light of the activity of platinum-based chemotherapies and gemcitabine on macrophages, and 
considering the need to provide a different chemotherapy based on the initial treatment received 
by the patient, both gemcitabine + nab-paclitaxel and FOLFOX regimens have been included in 
this protocol in combination with immunotherapy. 
5.5
Justification for Cabiralizumab Dose
A cabiralizumab dose of 4 mg/kg has been tested in combination with nivolumab in 
195 participants across a number of tumors in Part 1b of Study FPA008-003. The safety profile of 
this dose is described in Section 3.2.1.3. The dose of 4 mg/kg was selected in this trial based on 
 a tolerable safety profile. 
Consistent with healthy subjects and RA and PVNS trials, a dose-dependent reduction 
 
 after cabiralizumab administration was observed in subjects with cancer in 
Study FPA008-003.
 
 
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the 4 mg/kg Q2W dose was associated with 
 
 consistent suppression 
 after dosing (Cabiralizumab IB30 Sections 6.1 and 6.2), as well 
as preliminary response signal in pancreatic cancer (see Section 5.4.1).
5.6
Justification for Nivolumab Dose
The nivolumab flat dose of 480 mg Q4W is approved in the US as monotherapy for unresectable 
or metastatic melanoma, metastatic NSCLC, advanced RCC, locally advanced or metastatic 
urothelial carcinoma, hepatocellular carcinoma, and as maintenance therapy for unresectable or 
metastatic melanoma after induction therapy with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 
every 3 weeks for 4 doses. In addition, nivolumab 480 mg Q4W monotherapy is approved in the 
EU for the treatment of unresectable or metastatic melanoma and advanced RCC. Flat dosing of 
nivolumab was supported using 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 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 AE profiles across body weight groups. Finally, initial evidence demonstrates that,
following administration of nivolumab 480 mg Q4W, nivolumab is well tolerated.
Nivolumab 480 mg Q4W is predicted to be approximately 16% lower steady-state trough 
concentrations (Cminss) compared to nivolumab 3 mg/kg Q2W. While these exposures are 
predicted to be lower, they are on the flat part of the exposure-response curves and are not predicted 
to affect efficacy. Exposure-efficacy analyses of multiple PK measures and efficacy endpoints 
(eg, OS, OR) indicated that, following administration of nivolumab 480 mg Q4W, efficacy is 
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predicted to be similar to that following administration of nivolumab 3 mg/kg Q2W across 
multiple tumor types. Based on these data, nivolumab 480 mg Q4W is expected to have similar 
efficacy and safety profiles to nivolumab 3 mg/kg Q2W, which has been studied in combination 
with cabiralizumab 4 mg/kg.
The doses for the additional investigational products (gemcitabine, nab-paclitaxel [ABRAXANE] 
and oxaliplatin/5-FU/leucovorin [calcium folinate; FOLFOX]) are in accordance with the 
Summary of Product Characteristics for these products.
5.6.1
Rationale for Infusion Times for Cabiralizumab and Nivolumab
Administration of nivolumab using a 30-minute infusion time has been evaluated in participants
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 or 2 and were 
manageable. An infusion duration of 30 minutes for nivolumab 3 mg/kg (30% of the dose provided 
at 10 mg/kg) is not expected to present any safety concerns compared to the prior experience at 
nivolumab 10 mg/kg infused over a 60-minute duration. The safety of nivolumab 3 mg/kg 
administered as a 30-minute infusion was assessed in Study CA209153 in patients with previously 
treated advanced NSCLC (see Nivolumab IB31 Section 5.5.1.2). 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.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1. Signed Written Informed Consent
a) 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.
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b) Consent for fresh pre-treatment, on-treatment, and upon progression biopsy samples at 
acceptable clinical risk, as judged by the investigator.
c) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Participants must be at least 18 years old.
b) Participants must have histological or cytological confirmed diagnosis of locally advanced 
or metastatic adenocarcinoma of the pancreas, which has progressed during or after no 
more than 1 line of systemic chemotherapy in the metastatic setting (gemcitabine or 5-FU-
based regimens).
i)
If a participant received adjuvant/neoadjuvant systemic therapy, and progressed within 
6 months, the adjuvant/neoadjuvant treatment will be considered as 1 line of systemic 
treatment.
c) In general, discontinuation of 1 drug in a multi-drug regimen and continuation of other 
drug(s), is considered part of the same line of treatment. Restarting the same regimen after 
a drug holiday or maintenance chemotherapy can also be considered part of the same line
of treatment. Switching from IV (5-FU) to an oral formulation (capecitabine) of the same 
drug is also considered part of the same line of treatment.
d) Minimum time from first systemic therapy for recurrent/metastatic adenocarcinoma of 
pancreas to progression should be at least 3 months.
3) General Inclusion Criteria
a) Participants must have measurable disease by RECIST v1.1 (Appendix 5) and have at least 
1 lesion accessible for biopsy in addition to the target lesion.
i)
Participants with lesions in a previously irradiated field as the sole site of measurable 
disease will be permitted to enroll provided the lesion(s) have demonstrated clear 
progression and can be measured.
b) Prior palliative radiotherapy must have been completed at least 2 weeks prior to the first 
dose of the study treatment. Participants with symptomatic tumor lesions at baseline that 
may require palliative radiotherapy within 4 weeks of the first dose of study treatment are 
strongly encouraged to receive palliative radiotherapy prior to enrollment.
c) ECOG performance status of 1
d) All participants will be required to undergo mandatory pre- and on-treatment biopsies. 
i)
An archival sample is acceptable only if there is no systemic therapy administered after 
the archival sample is collected. 
ii) Participants whose pretreatment biopsy yields inadequate tissue quantity or quality that 
do not have an appropriate archival sample will not be eligible (exception: Up to 
approximately 20% of the cohort will be allowed on treatment with a pre-treatment 
biopsy that does not yield adequate tissue quantity/quality).
iii) If a participant had a biopsy in the preceding 90 days with no intervening anti-cancer 
therapy, participants can be enrolled without needing a repeat biopsy after discussion 
with the BMS Medical Monitor and availability of FFPE blocks or unstained slides as 
delineated below. Participants will however be required to undergo on-treatment and 
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upon progression biopsies at acceptable clinical risk as judged by the investigator in all 
arms.
iv) Pretreatment tumor tissue will be assessed for adequate tumor content prior to 
participants receiving study treatment. Pretreatment tissue must be collected and 
confirmed for adequate tissue quantity (20 slides) and quality (100 viable tumor cells 
and 20% tumor content) during the screening period prior to first dose of study 
treatment. Participants who had a biopsy after signing consent which confirmed 
diagnosis but did not yield sufficient tissue for all correlative studies may be allowed 
after discussion with the BMS Medical Monitor. 
 
 
vi) Where possible, the biopsied lesion should be distinct from target lesions being 
evaluated for radiologic response, and the same lesion should be used for both the 
baseline and on-treatment sampling.
e) Adequate marrow function as defined by the following: 
i)
White blood cell (WBC) ≥2000/μL (stable off any growth factor within 4 weeks of 
first study treatment administration);
ii) Neutrophils ≥1500/μL (stable off any growth factor within 4 weeks of first study 
treatment administration);
iii) Platelets ≥100 × 103/μL (transfusion to achieve this level is not permitted within 
2 weeks of first study treatment administration);
iv) Hemoglobin ≥8.5 g/dL (transfusion to achieve this level is not permitted within 
2 weeks of first study treatment administration).
f)
Adequate other organ functions as defined by the following: 
i)
ALT and (AST) ≤2× institutional ULN
ii) Total bilirubin ≤1.5× institutional ULN (except participants with Gilbert’s Syndrome 
who must have normal direct bilirubin) 
iii) Serum creatinine ≤1.5× ULN or creatinine clearance (CLcr) ≥40 mL/min (measured 
using the Cockcroft-Gault formula below): 
Female CLcr ൌሺ140 െܽ݃݁݅݊ݕ݁ܽݎݏሻൈݓ݄݁݅݃ݐ݅݊݇݃ൈ0.85
72 ൈserum creatinine in mg/dL
Male CLcr ൌሺ140 െܽ݃݁݅݊ݕ݁ܽݎݏሻൈݓ݄݁݅݃ݐ݅݊݇݃ൈ1.00
72 ൈserum creatinine in mg/dL
g) Ability to comply with study visits, treatment, procedures
and required study follow-up.
4) Age and Reproductive Status
a) Males and females, ages 18 or age of majority or older.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
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c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study treatment(s) and for a total of 6 months posttreatment completion
for participants who received nab-paclitaxel (ABRAXANE), and 5 months posttreatment 
for participants who received any other study treatment(s).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 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. 
f)
Azoospermic males are required to use a condom for the duration of the study.
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception (Appendix 4)
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Target Disease Exclusions
a) Suspected or known CNS metastases (imaging required only if participants are 
symptomatic). 
2) Medical History and Concurrent Disease
a) Participants with active, known, or suspected autoimmune disease. Participants with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement, euthyroid participants with a history of Grave’s 
disease (participants with suspected autoimmune thyroid disorders must be negative for 
thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin 
prior to first dose of study treatment), psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll 
after discussing with the BMS Medical Monitor.
b) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days of start of study treatment. Inhaled or topical steroids and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active 
autoimmune disease.
Note: Treatment with a short course of steroids (< 5 days) for up to 7 days prior to initiating 
study treatment is permitted.
c) Interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected treatment-related pulmonary toxicity. 
d) Current or history of clinically significant muscle disorders (eg, myositis), recent 
unresolved muscle injury, or any condition known to elevate serum CK levels.
e) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following:
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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 (eg, 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.
f)
History of any chronic hepatitis as evidenced by the following:
i)
Positive test for hepatitis B surface antigen
ii) Positive test for qualitative hepatitis C viral load (by polymerase chain reaction [PCR]).
Note: Participants with positive hepatitis C antibody and negative quantitative hepatitis C 
by PCR are eligible. History of resolved hepatitis A virus infection is not an exclusion 
criterion.
g) 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.
h) Prior organ allograft or allogeneic bone marrow transplantation.
i)
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.
j)
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] v4.03) 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, such as neuropathy after platinum-based 
therapy, are permitted to enroll.
k) Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or 
anti-fungal therapy 7 days prior to administration of study medication.
l)
Any uncontrolled inflammatory GI disease including Crohn’s Disease and ulcerative 
colitis.
m) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (Testing for HIV must be performed at sites 
mandated by local requirements.)
n) Any uncontrolled medical condition or psychiatric disorder which, in the opinion of the 
Investigator, would pose a risk to participant safety or interfere with study participation or 
interpretation of individual participant results.
o) Not Applicable as per Revised Protocol 02 - Current or recent (within 3 months of study 
drug administration) gastrointestinal disease that could impact upon the absorption of study 
drug.
p) Transfusion completed within 72 hours prior to first dose of study drug administration
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q) Not Applicable as per Revised Protocol 01 - Any GI surgery that could impact upon the 
absorption of study drug.
r)
Not Applicable as per Revised Protocol 01 - Inability to tolerate oral medication.
s) Inability to be venipunctured and/or tolerate venous access.
t)
Positive test for latent tuberculosis (TB) at screening (eg, T-SPOT or Quantiferon test) or 
evidence of active TB.
3) Prior Therapies
a) Prior exposure to anti-CSF1R, anti-PD-1, anti-PD-L1, anti PD-L2, or anti-CTLA-4. 
b) For any anti-cancer therapy (eg, chemotherapy, biologics, vaccines, or hormonal 
treatment), including investigational drugs, 4 weeks or 5 half-lives (whichever is shorter) 
must have elapsed between last dose and first treatment with any study treatments; if 5 
half-lives are shorter than 4 weeks, agreement with the Medical Monitor must be obtained.
c) Treatment with botanical preparations (eg, 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.
d) Prior exposure to gemcitabine and 5-FU or gemcitabine and oxaliplatin co-administered as 
1L treatment.
4) Restricted Concomitant Therapies
a) 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.
b) Receipt of a live/attenuated vaccine within 30 days of first treatment. The inactivated 
seasonal influenza vaccine can be given to participants before treatment and while on 
therapy without restriction. 
5) Physical and Laboratories Test Findings
a) 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 (eg, hypokalemia or hyponatremia).
b) Evidence of coagulopathy or bleeding diathesis
c) Ascites needing paracentesis or medical management
d) Peripheral Neuropathy greater than Grade 1
e) Albumin less than 3 g/dL 
f)
Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG, or clinical laboratory determinations beyond what 
is consistent with the target population
6) Allergies and Adverse Drug Reactions
a) Known history of sensitivity to infusions containing Tween 20 (polysorbate 20) and Tween 
80 (polysorbate 80)
b) History of allergy to study treatments or any of their components
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7) Other Exclusion Criteria 
a) Not applicable per Revised Protocol 02 - Consumption of non-pasteurized milk while on 
study drug and for 30 days after discontinuing study drug
b) Pregnant or breastfeeding
c) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances and only in countries where local regulations permit, a person who has been 
imprisoned may be included as a participant. Strict conditions apply and BMS approval is 
required.
d) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Participants should abstain from consumption of alcoholic beverages while on study.
Male participants receiving gemcitabine, ABRAXANE, and fluorouracil should seek advice 
regarding cryoconservation of sperm prior to treatment because of the possibility of infertility.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities.
6.4.1
Retesting During Screening
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pretreatment failure (ie, participant has not been randomized / has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the BMS Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
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7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical study. 

Study required premedication

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy and rescue medications)
An IP, also known as IMP in some regions, is defined as a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical study, including products 
already with a marketing authorization but used or assembled (formulated or packaged) differently 
than the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-IP.
In this protocol, IPs are the following:

Cabiralizumab

Nivolumab
In this protocol, non-IPs are the following:

Gemcitabine

Irinotecan

Nab-paclitaxel

Oxaliplatin

5-FU

Leucovorin
Study treatment descriptions including dosage form, potency, IP/non-IMP, and storage conditions 
are presented in Table 7-1.
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Table 7-1:
Study treatments for CA025006
Product Description / Class 
and Dosage Form
Potency
IP/Non-IPa
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
Cabiralizumab (BMS-986227) 
Solution for Injection
100 mg/vial
(20 mg/mL)
IP
Open Label
Vial
Refer to the label on container 
and/or pharmacy manual
Cabiralizumab (BMS-986227) 
Solution for Injection
140 mg/vial
(20 mg/mL)
IP
Open Label
Vial
Refer to the label on container 
and/or pharmacy manual
Nivolumab Solution for 
Injection
100 mg/vial and
40 mg/vial (10 mg/mL)
IP
Open Label
Vial
Refer to the label on container 
and/or pharmacy manual
Gemcitabine
Powder for Concentrate for 
Solution for Infusiona
1000 mg/vial and 
various strengths
Non-IP
Open Label
Vial and various 
packaging configurations
Refer to the label on container or 
package insert / summary of 
product characteristics
Irinotecan Liposome Solution 
(ONIVYDE) for Concentrate 
for Solution for Infusiona
Various strengths
Non-IP
Open Label
Vial and various 
packaging configurations
Refer to the label on container or 
package insert / summary of 
product characteristics
Irinotecan Hydrochloride
Solution for Injectiona
Various strengths
Non-IP
Open Label
Vial and various 
packaging configurations
Refer to the label on container or 
package insert / summary of 
product characteristics
Nab-paclitaxel (ABRAXANE)
Powder for Suspension for 
Infusiona
Various strengths
Non-IP
Open Label
Vial and various 
packaging configurations
Refer to the label on container or 
package insert / summary of 
product characteristics
Oxaliplatin Concentrate for 
Solution for Infusiona
Various strengths
Non-IP
Open Label
Vial and various 
packaging configurations
Refer to the label on container or 
package insert / summary of 
product characteristics
5-Fluorouracil Solution for 
Injectiona
Various strengths
Non-IP
Open Label
Vial and various 
packaging configurations
Refer to the label on container or 
package insert / summary of 
product characteristics
Leucovorin (calcium folinate) 
Solution for Infusiona
Various strengths
Non-IP
Open Label
Vial and various 
packaging configurations
Refer to the label on container or 
package insert / summary of 
product characteristics
a These products may be supplied by BMS centrally or through investigating site’s standard prescribing procedures.
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7.1
Treatments Administered
The selection and timing of dose for each participant are as follows:
Table 7.1-1:
Selection and Timing of Dose
Treatment 
Arm(s)
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage Formulation
Frequency of 
Administration
(28-day Cycle)
Route of 
Administration
A
Investigator choice of 
chemotherapy
(see Section 5.1.2)
(see description in text 
following this table)
As appropriate
(see description in 
text following this 
table)
As appropriate
(see description in 
text following this 
table)
As appropriate
(see description 
in text following 
this table)
B, C, and D
Cabiralizumab
4 mg/kg IV
Days 1 and 15
IV Infusion
B, C, and D
Nivolumab
480 mg IV
Day 1
IV Infusion
C
Gemcitabine
1000 mg/m2 IV
Days 1, 8, and 15
IV Infusion
C
Nab-paclitaxel
(ABRAXANE)
125 mg/m2 IV
Days 1, 8, and 15
IV Infusion
D
Oxaliplatin
85 mg/m2 IV
Days 1 and 15
IV Infusion
D
5-FU
400 mg/m2 Bolus
AND
2400 mg/m2 IV
Days 1 and 15
Bolus and IV 
Infusion
D
Leucovorin (calcium 
folinate)
400 mg/m2 IV
Days 1 and 15
IV Infusion
Abbreviations: 5-FU = 5-fluorouracil; IV = intravenous.
For the combination arms, cabiralizumab 4 mg/kg and nivolumab 480 mg will be given on Day 1 
and cabiralizumab 4 mg/kg will be given alone on Day 15 (2 days) of each 28-day treatment 
cycle until progression of disease, discontinuation due to toxicity, withdrawal of consent, or study 
closure. Nivolumab will be administered as an IV infusion over 30 (5) minutes, and then, after 
a 30 minute rest period, cabiralizumab will be administered as an IV infusion over 30 (5) 
minutes. Premedication for chemotherapy (based on standard-of-care and local institutional 
standards) and chemotherapy will then be administered after a further 30 minute rest period.
The dosing regimen for irinotecan liposome injection (ONIVYDE) with 5-FU and leucovorin
(calcium folinate) is irinotecan liposome injection 70 mg/m2 over 90 minutes, followed by 
leucovorin (calcium folinate) 400 mg/m2 over 30 minutes, and 5-FU 2400 mg/m2 over 46 hours 
on Days 1 and 15 Q4W. The recommended starting dose of ONIVYDE in patients known to be 
homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by intravenous infusion over 
90 minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles. Sites 
may substitute the ONIVYDE-based regimen with FOLFIRI if ONIVYDE is not available, per 
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country/institution guidelines. Each site will use either ONIVYDE or FOLFIRI, but not both. The 
dose regimen for FOLFIRI is: irinotecan hydrochloride 180 mg/m2 over 90 minutes on Days 1 and 
15 of a 28-day cycle; leucovorin (calcium folinate) 400 mg/m2 over 90 to 120 minutes on Days 1 
and 15 of a 28-day cycle (leucovorin may be given concurrently with irinotecan hydrochloride); 
5-FU 400 mg/m2 bolus on Days 1 and 15, followed by 2400 mg/m2 over 46 hours (continuous 
infusion) on Days 1 and 15 of a 28-day cycle.
The recommended dose of nab-paclitaxel (ABRAXANE) is 125 mg/m2 administered as an IV 
infusion over 30 to 40 minutes on Days 1, 8, and 15 of each 28-day cycle. Administer gemcitabine 
1000 mg/m2 over 30 to 40 minutes immediately after nab-paclitaxel on Days 1, 8, and 15 of each 
28-day cycle.
FOLFOX (oxaliplatin 85 mg/m2 over 2 hours on Day 1 and Day 15 of a 28-day cycle; leucovorin
[calcium folinate] 400 mg/m2 over 2 hours on Day 1 and Day 15 of a 28-day cycle [leucovorin 
(calcium folinate) may be given concurrently with oxaliplatin]; 5-FU 400 mg/m2 bolus on Day 1
and Day 15, followed by 2400 mg/m2 over 46 hours continuous infusion) will be administered on 
Days 1 and 15 of a 28-day cycle.
7.2
Method of Treatment Assignment
All participants will be centrally randomized using an IRT. Before the study is initiated, each user 
will receive log-in information and directions on how to access the IRT.
Study treatment will be dispensed at the study visits as described in Section 7.1.
Enrolled participants, including those not dosed, will be assigned PID numbers comprised of the 
site number and participant number. For example, the first participant screened (ie, enrolled) at 
site number , will have a participant number of 
. Those enrolled participants meeting 
inclusion and exclusion criteria will be eligible to be dosed.
Participants will not be replaced if they are discontinued from the study.
7.3
Blinding
This is an open-label study; blinding procedures are not applicable.
7.4
Dosage Modification
7.4.1
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 8). 
Please discuss with the BMS Medical Monitor or designee as needed;

For dose delays or modifications for all other AEs, please refer to the AE management table in 
Appendix 7.
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
If symptoms or signs of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) 
appear, nivolumab should be withheld and the patient referred for specialized care for 
assessment and treatment
Participants who require a dose delay of cabiralizumab or cabiralizumab/nivolumab should be 
re-evaluated weekly or more frequently if clinically indicated and resume study drug dosing when 
re-treatment criteria are met. If a participant experiences an infusion reaction to cabiralizumab or 
nivolumab, or both study drugs, the infusion reaction should be treated following the infusion 
reaction treatment guidelines in Section 7.4.7 and Appendix 7. If the causality of the AE requiring 
a dose delay is confirmed to be due to one of the study drugs of the combination therapy, the 
non-offending drug may be continued per protocol taking into account the safety and clinical 
benefit to the participant.
7.4.2
Management Algorithms for Immuno-oncology Agents
Immuno-oncology (IO) agents are associated with AEs that can differ in severity and duration 
from AEs caused by other therapeutic classes. Nivolumab and cabiralizumab are considered IO 
agents in this protocol. Early recognition and management of AEs associated with IO 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 IMAEs:

GI

Renal

Pulmonary

Hepatic

Endocrinopathies

Skin

Neurological
Specific algorithms for the management of IMAEs are provided in Appendix 7 and are applicable 
to IMAEs for all IO study treatment combinations.
7.4.3
Dose Reduction for Cabiralizumab and Nivolumab
Dose reduction for cabiralizumab and nivolumab are not permitted.
7.4.4
Dose Discontinuation Criteria for Cabiralizumab and Nivolumab
For comprehensive discontinuation rules, refer to Appendix 7 (AE management) and Appendix 8 
(laboratory abnormalities).
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’s Medical Monitor 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:

Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation

Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 

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:

ALT or AST > 3ULN and total bilirubin > 2ULN or INR > 1.5ULN (in the absence 
of anticoagulation).
See Appendix 7 and Appendix 8 for guidelines and possibility of restarting therapy

ALT or AST > 20ULN (with or without concurrent liver metastases)

Total bilirubin > 3ULN (> 5ULN with concurrent liver metastases)

Any Grade 4 drug-related AE or laboratory abnormality, except for the following events which 
do not require discontinuation:

Grade 4 neutropenia < 7 days

Grade 4 lymphopenia or leukopenia < 7 days

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. The Sponsor’s Medical Monitor or designee should 
be consulted for Grade 4 amylase or lipase abnormalities.

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset

Grade 
4 
drug-related 
endocrinopathy 
AEs, 
such 
as 
adrenal 
insufficiency, 
adrenocorticotropic hormone deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, may not 
require discontinuation after discussion with and approval from the Sponsor’s Medical 
Monitor or designee. 
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
Grade 4 CK up to 20ULN (in the absence of clinical sequelae)

Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:

Dosing delays to manage drug-related AEs are allowed. Prior to re-initiating treatment in 
a participant with a dosing delay lasting > 6 weeks from the previous dose, the Sponsor’s 
Medical Monitor 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.

Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Sponsor’s Medical Monitor or designee. Prior 
to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the 
Sponsor’s Medical Monitor 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’s Medical Monitor

Any Grade 4 skin toxicity

Any Grade 4 renal toxicity

Any drug-related Grade 3 or higher pulmonary toxicity

Confirmed Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) will result 
in permanent discontinuation of nivolumab.

Any Grade 3 or higher myocarditis will result in permanent discontinuation of nivolumab.
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.
7.4.5
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 7 or the abnormal laboratory 
management table in Appendix 8. The BMS Medical Monitor or designee can be contacted at any 
time if further clarification is needed.
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7.4.6
Dose Modification for Chemotherapy
Since FOLFOX and gemcitabine + nab-paclitaxel are standard therapies for pancreatic cancers, 
sites may use their discretion for dosing these regimens based on a participant’s tolerability. Any 
laboratory-only abnormalities without clinical manifestations or electrolyte abnormalities that may 
be managed with supplementation also do not automatically need dose modification. In addition, 
if participants experience tolerability issues for 5-FU / leucovorin and ONIVYDE, and FOLFIRI, 
dose modifications for these 2 regimens should be performed according to their respective SmPCs 
and institutional guidelines.
7.4.6.1
Dose Modification for Gemcitabine + Nab-paclitaxel
Suggested dose modification will be performed according to the nab-paclitaxel (ABRAXANE) 
package insert (Table 7.4.6.1-1, Table 7.4.6.1-2, and Table 7.4.6.1-3).
If the causality of the AE requiring drug hold is confirmed to be due to 1 of the drugs in the 
chemotherapy regimen, the other drugs may be continued as per protocol schedule.
Table 7.4.6.1-1:
Dose Level Reductions for Participants with Adenocarcinoma of the 
Pancreas
Dose Level
Nab-paclitaxel (mg/m2)
Gemcitabine (mg/m2)
Full Dose
125
1000
1st dose reduction
100
800
2nd dose reduction
75
600
Source: Modified from Table 3 of nab-paclitaxel (ABRAXANE) US Package Insert47
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Table 7.4.6.1-2:
Dose Recommendation and Modifications for Neutropenia and/or 
Thrombocytopenia at the Start of a Cycle or within a Cycle for 
Participants with Adenocarcinoma of the Pancreas
Cycle Day
ANC (cells/mm3)
Platelet Count (cells/mm3)
Nab-paclitaxel / Gemcitabine
Day 1
< 1500
OR
< 100,000
Delay doses until recovery
Day 8
500 to < 1000
OR
50,000 to < 75,000
Reduce 1 dose level
< 500
OR
< 50,000
Withhold doses
Day 15: IF Day 8 doses were reduced or given without modification:
500 to < 1000
OR
50,000 to < 75,000
Reduce 1 dose level from Day 8
< 500
OR
< 50,000
Withhold doses
Day 15: IF Day 8 doses were withheld:
1000
OR
75,000
Reduce 1 dose level from Day 1
500 to < 1000
OR
50,000 to < 75,000
Reduce 2 dose levels from Day 1
< 500
OR
< 50,000
Withhold doses
Source: Table 4 of nab-paclitaxel (ABRAXANE) US Package Insert47
Abbreviations: ANC = absolute neutrophil count
Table 7.4.6.1-3:
Dose Modifications for Other Adverse Drug Reactions in Participants 
with Adenocarcinoma of the Pancreas
Adverse Drug Reaction
Nab-paclitaxel
Gemcitabine
Febrile Neutropenia:
Grade 3 or 4
Withhold until fever resolves and ANC 1500; resume at next lower dose level
Peripheral Neuropathy:
Grade 3 or 4
Withhold until improves to Grade 1; 
resume at next lower dose level
No dose reduction
Cutaneous Toxicity:
Grade 2 or 3
Reduce to next lower dose level; discontinue treatment if toxicity persists
Gastrointestinal Toxicity:
Grade 3 mucositis or diarrhea
Withhold until improves to Grade 1; resume at next lower dose level
Source: Table 5 of nab-paclitaxel (ABRAXANE) US Package Insert47
Abbreviations: ANC = absolute neutrophil count.
7.4.6.2
Dose Modification for FOLFOX
Suggested dose modifications of FOLFOX are provided in Table 7.4.6.2-1 and Table 7.4.6.2-2.
If the causality of the AE requiring drug hold is confirmed to be due to 1 of the drugs in the 
chemotherapy regimen, the other drugs may be continued per protocol schedule.
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Table 7.4.6.2-1:
Recommended Dose Modifications of FOLFOX
Drug
Starting Dose
Dose Modification
Dose Level - 1
Dose Level - 2
Oxaliplatin
85 mg/m2
70 mg/m2
50 mg/m2
5-FU
Bolus 5-FU: 
400 mg/m2 
Leucovorin (calcium folinate):
400 mg/m2
Infusion 5-FU: 
2400 mg/m2/46 hours
Bolus 5-FU: 
300 mg/m2 
Leucovorin (calcium folinate): 
300 mg/m2
Infusion 5-FU:
2000 mg/m2/46 hours
Bolus 5-FU: 
200 mg/m2 
Leucovorin (calcium folinate): 
200 mg/m2 
Infusion 5-FU:
1600 mg/m2/46 hours
Abbreviations: 5-FU = 5-fluorouracil
Table 7.4.6.2-2:
Dose Modifications of FOLFOX
Toxicity 
Definition
During a course of 
therapy
Dose adjustment for next 
treatments
Neutropenia
Grade 3 or greater
Interrupt until resolved to 
Grade 2
Dose level -1
*If treatment delayed for 
4 consecutive weeks, discontinue all 
treatment
Thrombocytopenia
Grade 2
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 2 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1 
Grade 3
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 3 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Grade 4
Interrupt until resolved to 
Grade 1
Dose level -2
*If Grade 4 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Neurologic toxicity
Grade 2 peripheral 
sensory neuropathy
Interrupt oxaliplatin until 
resolved to Grade 1 or 
management as per 
institutional standard
Oxaliplatin dose -1
Continue 5-FU and leucovorin
(calcium folinate)
*If oxaliplatin delayed for 
neurologic toxicity for 4 
consecutive weeks, discontinue
oxaliplatin, continue 5-FU and 
leucovorin (calcium folinate)
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Table 7.4.6.2-2:
Dose Modifications of FOLFOX
Toxicity 
Definition
During a course of 
therapy
Dose adjustment for next 
treatments
Grade 3 or greater 
peripheral sensory 
neuropathy
Discontinue oxaliplatin
Continue 5-FU and leucovorin
(calcium folinate)
Gastrointestinal 
toxicities
Grade 2 or greater 
diarrhea
Interrupt until resolved to 
Grade 1
Dose level -1
If dose delayed for diarrhea for 
4 consecutive weeks, discontinue all 
treatment
Abbreviations: 5-FU = 5-fluorouracil.
For toxicities not listed above, dose modifications are permitted per local standards.
Participants may also discontinue oxaliplatin following multiple cycles if, in the investigator’s 
judgment, cumulative toxicity is likely to increase over time.
7.4.7
Treatment of Cabiralizumab and Nivolumab-Related Infusion Reactions
Cabiralizumab and nivolumab may induce infusion or hypersensitivity reactions. If such reactions 
occur, they may manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension
or hypertension, bronchospasm, or other symptoms.
Infusion reactions should be graded according to CTCAE v4.03 guidelines. Any Grade 3 or 
Grade 4 infusion reaction should be reported within 24 hours to the BMS Medical Monitor or 
designee, and reported as an SAE if it meets the criteria.
The nivolumab 30 (5) minute infusion will be administered first, with a 30 minute rest, followed 
by the cabiralizumab 30 (5) minute infusion. It may be unclear if an infusion reaction is due to 
cabiralizumab, nivolumab, or to both study drugs. Therefore, 1 set of treatment recommendations 
(based on the most conservative treatments for infusion reactions due to either study drug) is 
provided below and may be modified based on clinical judgment, local treatment standards and 
guidelines, and/or specific symptoms, as appropriate:
For Grade 1 symptoms: Mild reaction (eg, localized cutaneous reactions including mild pruritus, 
flushing, and rash), requires infusion rate to be decreased; intervention may be indicated.

Decrease the rate of the study drug infusion until recovery from symptoms.

Remain at bedside and monitor the participant’s vital signs until resolution of symptoms. 
Diphenhydramine 50 mg may be administered at the discretion of the treating physician.

When symptoms resolve, restart the infusion at the original infusion rate.

If a participant has an infusion reaction with nivolumab, cabiralizumab can be given (without 
prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling 
purposes, the cabiralizumab infusion may be given the next day. Prophylactic pre-infusion 
medications should be given prior to all subsequent nivolumab infusions.
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
If a participant has an infusion reaction with cabiralizumab, prophylactic pre-infusion 
medications should be given prior to all subsequent cabiralizumab and nivolumab infusions.

The following prophylactic pre-infusion medications are recommended prior to future 
infusions of cabiralizumab and nivolumab: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol (acetaminophen) 325 mg to 1000 mg at least 30 minutes before additional study 
drug administrations.
For Grade 2 symptoms: Moderate reaction (ie, any symptom not listed above [mild symptoms] 
or below [severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, and hypotension 
with systolic blood pressure >80 mmHg), requires infusion interruption but responds promptly to 
symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, 
corticosteroids, and IV fluids); prophylactic pre-infusion medications indicated for 24 hours.

Interrupt the study drug infusion.

Begin an IV infusion of normal saline and treat the participant with diphenhydramine 50 mg 
IV (or equivalent) and/or paracetamol (acetaminophen) 325 mg to 1000 mg.

Remain at bedside and monitor the participant’s vital signs until resolution of symptoms. 
Corticosteroid therapy may be administered at the discretion of the treating physician.

When symptoms resolve, restart the infusion at 50% of the original infusion rate; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original 
infusion rate.

Monitor the participant closely. If symptoms recur, immediately discontinue the infusion; no 
further study drug will be administered at that visit. Administer diphenhydramine 50 mg IV, 
and remain at bedside and monitor the participant until resolution of symptoms.

If a participant has an infusion reaction with nivolumab infusion, cabiralizumab infusion can 
be given (without prophylactic medications) if the infusion reaction resolves within 3 hours. 
For scheduling purposes, the cabiralizumab infusion may be given the next day. Prophylactic 
pre-infusion medications should be given prior to all subsequent nivolumab infusions.

If a participant has an infusion reaction with cabiralizumab, prophylactic pre-infusion 
medications should be given prior to all subsequent cabiralizumab and nivolumab infusions.

The following prophylactic pre-infusion medications are recommended prior to future 
infusions of cabiralizumab and nivolumab: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol (acetaminophen) 325 mg to 1000 mg should be administered at least 30 minutes 
before additional study drug administrations. If necessary, corticosteroids (up to 25 mg of 
SoluCortef or equivalent) may be used.

The amount of study drug infused must be recorded.
For Grade 3 or Grade 4 symptoms: Severe reaction such as bronchospasm, generalized urticaria, 
systolic blood pressure <80 mmHg, or angioedema; Grade 3 symptoms including prolonged 
symptoms, which require 6 or more hours to respond to symptomatic medication and/or 
discontinuation of infusion; recurrence of symptoms following initial improvement; 
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hospitalization indicated for other clinical sequelae, such as renal impairment, pulmonary 
infiltrates; Grade 4: life-threatening; pressor or ventilation support indicated.

Immediately discontinue the study drug infusion. No further study drug will be administered. 
The amount of study drug infused must be recorded on the case report form (CRF).

Begin an IV infusion of normal saline and treat the participant as follows: Recommend 
bronchodilators, epinephrine 0.2 mg to 1.0 mg of a 1:1,000 solution for subcutaneous 
administration or 0.1 mg to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed.

Remain at bedside and monitor the participant’s vital signs until recovery from symptoms.

The participant should be monitored until the investigator is comfortable that the symptoms 
will not recur.

Investigators should follow their institutional guidelines for the treatment of anaphylaxis.
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
For nivolumab and cabiralizumab, please refer to the current version of the Investigator’s 
Brochures30,31 and/or pharmacy manual for complete storage, handling, dispensing, and infusion 
information. All other agents provided by BMS should be prepared/stored/administered in 
accordance with the package insert or summary of product characteristics. The IP should be stored 
in a secure area according to local regulations. It is the responsibility of the investigator to ensure 
that the IP must only be dispensed to study participants. The IP must be dispensed only from 
official study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed, and BMS should be contacted immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents and administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
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7.5.1
Dosing of Cabiralizumab and Nivolumab
For the combination therapy, nivolumab should always be administered first as a 30-minute 
(5 minutes) IV infusion followed by 30-minute (5 minutes) 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 Q2W (2days) and nivolumab 
will be administered Q4W (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 standard of care
(usually 10 mg).
Doses of study drugs may be interrupted, delayed, or discontinued depending on how the 
participant tolerates the treatment.
7.5.2
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable.
7.6
Concomitant Therapy
7.6.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
as follows (unless utilized to treat a drug-related AE or specified in Section 6):

Immunosuppressive agents;

Immunosuppressive doses of systemic corticosteroids;

Any live/attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella) during treatment and until 100 days post last dose;

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 CK 
elevations;

Other anti-neoplastic therapies including biologic, immunotherapy, extensive non-palliative 
radiation therapy, standard treatments, or investigational agents or devices.
No concomitant medications (prescription, over-the-counter, or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any concomitant 
therapies taken within 4 weeks prior to study drug administration must be recorded on the CRF.
7.6.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment 
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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 (eg, contrast dye allergy) or for treatment of 
non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact 
allergen) and also for the treatment of tumor-related AEs is permitted.
Concomitant palliative and supportive care for disease-related symptoms,
including 
bisphosphonates and RANK-L inhibitors, is allowed if initiated prior to the first dose of study drug 
administration. Transfusions are permitted as needed.
The inactivated seasonal influenza vaccine can be given to participants while on therapy without 
restriction.
Concomitant use of 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 CK elevations.
No routine premedication will be administered for initial cabiralizumab and nivolumab doses. If a 
participant develops nausea, vomiting, or other infusion-related AEs, the participant may be 
premedicated with anti-emetics, steroids, or antihistamines prior to subsequent infusions of study 
drugs at the discretion of the investigator. The treatment will be administered according to the 
institution’s standard practice, and should be captured on the participant’s CRF.
7.6.2.1
Imaging Restrictions and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether or not they should receive contrast and if so, what type and dose of contrast is appropriate. 
Specific to magnetic resonance imaging (MRI), participants with severe renal insufficiency (ie, 
estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) are at increased risk of 
nephrogenic systemic fibrosis. MRI contrast should not be given to this participant population. In 
addition, participants are excluded from MRI if they have tattoos, metallic implants, pacemakers, 
etc. The ultimate decision to perform MRI in an individual participant in this study rests with the 
site radiologist, the investigator, and the standard set by the local ethics committee.
7.7
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
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8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by the participant 
to provide this information

Any clinical AE, laboratory abnormality, or intercurrent illness which in the opinion of the 
investigator indicates that continued participation in the study is not in the best interest of the 
participant

Termination of the study by BMS

Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)

Documented disease progression or clinical deterioration while receiving active study therapy 
with exception as described in Section 5.1.3.

Pregnancy

Participants who are required to have prohibited concomitant medications

Inability to comply with the protocol
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 5.1.4. The only exception to this requirement is when a 
participant withdraws consent for all study procedures including post-treatment study follow-up 
or loses the ability to consent freely (ie, imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page.
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8.1.1
Follow-up after Conclusion of Study Treatment
In this study, safety and tolerability information are key endpoints of the study. Post study 
follow-up is of critical importance and is essential to preserving participant safety and the integrity 
of the study. Participants who discontinue study treatment must continue to be followed for 
collection of outcome and/or survival follow-up data as required and in line with Section 5 until 
death or the conclusion of the study.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by the participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain the date and cause of death.

If the investigator’s use of any third-party representative to assist in the follow-up portion of 
the study has been included in the participant’s informed consent, then the investigator may 
use a Sponsor retained third-party representative to assist site staff with obtaining the 
participant’s contact information or other public vital status data necessary to complete the 
follow-up portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
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
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical
records.
9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities (Section 2). 

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities (Section 2).
9.1
Efficacy Assessments
Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a CRF. Additional procedures and assessments may be performed as part of standard of 
care; however, data for these assessments should remain in the participant’s medical record and 
should not be provided to BMS, unless specifically requested.
9.1.1
Imaging Assessment for the Study
Images will be acquired up to 30 days prior to first dose, every 8 weeks (starting from first dose 
7 days) for the first 48 weeks, then every 12 weeks (7 days) until withdrawal of consent, death, 
or initiation of another anti-cancer treatment. These will be submitted to an imaging core 
laboratory for BICR. Sites should be trained prior to scanning the first study participant. Image 
acquisition guidelines and submission process will be outlined in the CA025006 Imaging Manual 
to be provided by the core lab. 
Efficacy assessments for the anti-tumor activity of cabiralizumab in combination with nivolumab 
with and without chemotherapy will be based on tumor measurements, using RECIST v1.1 per 
BICR and investigator assessment. Efficacy evaluation 
 
will be performed for each experimental arm.
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Screening images should be acquired as outlined in Table 2-1. On-study images should be acquired 
as outlined in Table 2-2 and Table 2-3 from the date of first dose until subsequent therapy is started, 
withdrawn consent, lost to follow-up, or death, whichever occurs first.
9.1.2
Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known/suspected sites of 
disease should be performed for tumor assessments. Images should be acquired with slice 
thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
time points. Tumor measurements should be made by the same investigator or radiologist for each 
assessment whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the investigator. 
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained.
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
Use of the CT component of a PET/CT scanner: Combined modality scanning such as with 
FDG-PET/CT is increasingly used in clinical care and is a modality/technology that is in rapid 
evolution; therefore, the recommendations outlined here may change rather quickly with time. At 
present, low dose or attenuation correction CT portions of a combined FDG-PET/CT are of limited 
use in anatomically-based efficacy assessments and it is therefore suggested that they should not 
be substituted for dedicated diagnostic contrast enhanced CT scans for anatomically-based 
RECIST measurements. However, if a site can document that the CT performed as part of a 
FDG-PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then 
the CT portion of the FDG-PET/CT can be used for RECIST v1.1 measurements. Note, however, 
that the FDG-PET portion of the CT introduces additional data which may bias an investigator if 
it is not routinely or serially performed.
Bone scan or PET scan is not adequate for assessment of RECIST v1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain non-
target organs, those non-target organs may be evaluated less frequently. For example, bone scans 
may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
Brain and/or bone scans may be collected per local standards, as clinically indicated. 
Screening assessments are to be performed within 30 days prior to first dose. In addition to the 
chest, abdomen, pelvis, and brain (to rule out brain metastases), all known sites of disease should 
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be assessed at baseline. Subsequent assessments should include chest, abdomen, pelvis, and all 
known sites of disease using the same imaging method and technique as was used at baseline.
In addition, participants receiving cabiralizumab and nivolumab treatment beyond progression 
must continue tumor assessments until such treatment has been discontinued. Treatment beyond 
disease progression with cabiralizumab and nivolumab in participants with solid tumors is reported 
in Section 5.1.3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s CRF.
Contacts for SAE reporting are specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until 
100 days after discontinuation of dosing or until starting a new anti-neoplastic therapy (whichever 
occurs first) at the time points specified in the Schedule of Activities (Section 2). Nonserious 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 participants.
Sections 5.6.1 and 5.6.2 in the Investigator’s Brochure (IB) for nivolumab,31 Section 6.4.1 of the 
cabiralizumab IB,30 and Section 4.8 of the SmPCs for gemcitabine,49 irinotecan (ONIVYDE),50
paclitaxel (ABRAXANE),51 oxaliplatin,52 5-FU,53 and leucovorin54 represent the Reference 
Safety Information to determine expectedness of SAEs for expedited reporting. Following the 
participant’s written consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected, including those thought to be associated with protocol-specified
procedures.
All SAEs that occur during the screening period and within 100 days after discontinuation of 
dosing must be collected except in cases where a study participant has started a new anti-neoplastic 
therapy. Any SAE occurring after the start of a new treatment that is suspected to be related to 
study treatment by the investigator will be reported. If applicable, SAEs that relate to any later 
protocol-specified procedure (eg, a follow-up biopsy) must be collected.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.

Medical occurrences that begin before the start of study treatment but occurred after obtaining 
informed consent will be recorded on the appropriate section of the electronic CRF.

All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the Sponsor within 24 hours of this data 
being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
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has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AE and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known 
adverse events, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs

Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment, as appropriate.

All identified non-serious AEs must be recorded and described on the nonserious AE page of 
the CRF. Completion of supplemental CRFs may be requested for AEs and/or laboratory 
abnormalities that are reported/identified during the course of the study.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
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5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy 
has ended), 
following approvals of 
participant/sponsor/IRB/EC, as applicable.
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 Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor or designee. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or electronic SAE Report Form, as appropriate (paper forms are only intended as a back-up 
option when the electronic system is not functioning):

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that, wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug-Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
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1) Aminotransferase (AT) (ALT or AST) elevation > 3ULN
AND
2) Total bilirubin > 2ULN, without initial findings of cholestasis (elevated serum ALP)
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a non-serious or SAE, as appropriate, and reported accordingly.
9.3
Overdose
For this study, any dose of cabiralizumab and/or nivolumab greater than the assigned dose and 
considered excessive and medically important by the investigator will be considered an overdose.
In the event of an overdose, the investigator should:
1) Contact the BMS Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
cabiralizumab and/or nivolumab can no longer be detected systemically (at least 5 days)
3) Obtain a plasma sample 
 within 5 days from the date of the last dose of study 
treatment if requested by the BMS Medical Monitor (determined on a case-by-case basis)
4) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the BMS Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a CRF. Additional procedures and assessments may be performed as part of standard of 
care; however, data for these assessments should remain in the participant’s medical record and 
should not be provided to BMS, unless specifically requested.
9.4.1
Physical Examinations
Refer to Schedule of Activities. Standard physical examination will be performed as determined 
by the investigator, particularly to follow physical findings to resolution. Targeted physical exams 
should be conducted at any time to follow-up on AE reports.
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9.4.2
Vital signs
Refer to Schedule of Activities. Vital signs include respiratory, heart rate, blood pressure, and 
temperature in the resting position for at least 5 minutes (sitting or supine). Vital signs to be 
measured for every treatment arm before infusion of the first study drug on Days 1 and 15 of each 
cycle at approximately the same time as the ECG is obtained. For cabiralizumab administration 
and nivolumab administration on Cycles 1 and 5, measure vital signs prior to dose and after 
completion of each IV infusion at the following time points: 15 (5) minutes, 30 (10) minutes, 
45 (10) minutes, 60 (15) minutes and 360 hours (24 hours) [Day 1 and Day 15] 
post-cabiralizumab administration; 10 (5) minutes post-nivolumab administration. If any vital 
sign is abnormal (based on clinician’s assessment) at the final check, the participant must be 
observed for a further period of time, as clinically indicated. 
9.4.3
Electrocardiograms
Refer to Schedule of Activities. A 12-lead ECG will be obtained at screening for all participants. 
12-lead ECGs will also be obtained for the initial 6 participants in Treatment Arms C and D, at 
predose and approximately 4 hours postdose of cabiralizumab and nivolumab (within 4 hours of 
completion of cabiralizumab) on Cycle 1 Day 1. Subsequent ECGs for these participants will be 
single-lead ECGs. Single-lead ECG tests will be obtained for all other participants prior to the start 
of the infusion of the first drug on Day 1 of each cycle. If clinically indicated, additional ECGs 
may be obtained during the study. To minimize variability, it is important that participants be in a 
resting position for at least 5 minutes prior to each ECG evaluation.
9.4.4
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report.

A local laboratory will perform the analyses and will provide reference ranges for these tests.

Results of clinical laboratory tests performed at Day 1, Day 8 (as appropriate), and Day 15 on 
each cycle for each treatment arm must be available prior to dosing to allow for dose 
modifications, if needed (unless obtaining assessment results are not possible due to local 
laboratory feasibility).
A local laboratory will perform the analyses and will provide reference ranges for these tests.
Results of clinical laboratory tests performed on Day 1 must be available prior to dosing.
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Table 9.4.4-1:
Clinical Laboratory Tests
Hematology
Hemoglobin
Hematocrit
CBC, including differential
Platelet count
Serum Chemistry
AST
ALT
Total bilirubin
Direct bilirubin
ALP
LDH
Creatinine
BUN
Uric acid
Glucose
Total protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase
Creatinine clearance (CLcr)- screening only
Thyroid Panel (Includes TSH, Free T3 and Free T4)
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, HBc antibody, interferon-gamma release assays for 
tuberculosis (eg, Quantiferon test), and HIV-1 and HIV-2 antibody (screening only)
Other Analyses
Pregnancy test (WOCBP only: screening, predose, discharge, and monthly during treatment and safety follow-up 
periods).
FSH (screening only for women)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CBC = complete blood count; CLcr = creatine clearance; FSH = follicle-stimulating 
hormone; Hbc = hepatitis B core; HIV; human immunodeficiency; LDH = lactate dehydrogenase; 
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing 
potential.
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If CK elevation is clinically significant, obtain troponins (cardiac), CK isoenzymes, aldolase, and 
ECG; repeat CK and these additional tests within 24 hours or other interval, as clinically indicated, 
until resolved or stable. If either AST or ALT is elevated, obtain total serum bilirubin and ALP; 
repeat within 24 hours or other interval, as clinically indicated, until resolved or stable. Additional 
tests may be obtained at any time, if clinically indicated. If a participant is being followed for a 
tumor marker (eg, CA-19-9 or others), a sample for the tumor marker should be obtained at 
screening and at every cycle, or if clinically indicated during the study.
9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study investigator as per standard 
medical/clinical judgment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
One purpose of the 2L Cohort is to evaluate the preliminary efficacy of cabiralizumab 
(BMS-986227) in combination with nivolumab with or without chemotherapy compared with the 
investigator’s choice of standard-of-care chemotherapy in participants with advanced or metastatic 
pancreatic cancer who progressed after the 1L of chemotherapy (gemcitabine-based or 5-FU-
based); additional rationale for the 2L Cohort can be found in Section 3.1.1.1 and Section 5.4. 
Participants who progressed after the 1L gemcitabine-based chemotherapy will be randomized in 
a 1:1:2 ratio to receive investigator’s choice of chemotherapy (Treatment Arm A), cabiralizumab 
in combination with nivolumab (Treatment Arm B), or cabiralizumab in combination with 
nivolumab and FOLFOX (Treatment Arm D). Participants who progressed after the 1L 5-FU-
based chemotherapy will be randomized in a 1:1:2 ratio to receive investigator’s choice of 
chemotherapy (Treatment Arm A), cabiralizumab in combination with nivolumab (Treatment Arm 
B), or cabiralizumab in combination with nivolumab and gemcitabine + nab-paclitaxel (Treatment 
Arm C). 
Randomization is used to avoid potential imbalance of baseline characteristics and will be stratified 
according to ECOG status (0 or 1) prior to treatment. There will be no formal statistical hypothesis 
testing and no multiplicity adjustment. Evaluation of efficacy will be based primarily on the PFS 
together with ORR, duration of response (DOR), time to response, depth of response, PFS rate 
(PFSR), and other aspects of effectiveness. 
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The sample size consideration is based on the following assumptions:
The false positive rate (FPR) is set at approximately 20%, and the false negative rate (FNR) is set 
at approximately 10%. The median PFS is assumed as 3.1 months in Treatment Arm A based on 
the NAPOLI-1 study55 and 5.4 months in Treatment Arms C and D by combining cabiralizumab 
and nivolumab with chemotherapy. In this setting, it will be required to observe at least 59 PFS 
events (see Note below). When the assessment of endpoint is “time-to-event” such as PFS, the 
number of participants needed to have the required number of PFS events depends on the accrual 
rate of participants. For example, assuming a fixed accrual rate of 16 participants per month with 
equal distribution across 4 treatment arms, a total of approximately 80 participants are needed to 
be treated for Treatment Arms A and C (or D) in order to achieve the 59 PFS events required. The 
enrollment will take approximately 10 months, and the duration of the study is estimated to be 
approximately 14 months. If enrollment rate is slower, for example, a fixed accrual rate is 
8 participants per month with equal distribution across 4 treatment arms, then a total of 
70 participants are needed for Treatment Arms A and C (or D) in order to have 59 PFS events. The 
accrual duration will be 17.5 months and the maximum duration of the study will be approximately 
22 months. Overall, approximately 40 participants in each treatment arm will be treated and 
followed until 59 PFS events are observed in Treatment Arms A and C combined, as well as in 
Treatment Arms A and D combined. In case a lower FPR is desired, a longer follow-up may be 
allowed or additional participants may be treated in order to observe additional PFS events.
NOTE: This sample size calculation is under the assumption that PFS follows an exponential 
distribution.
10.2
Populations for Analyses
For the purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent and are registered into the IRT.
Randomized
All participants who are randomized to any treatment arm.
Treated
All participants who take at least one dose of study drug and will be analyzed 
as treated.
Efficacy
Randomized population with at least one dose of study drug and will be 
analyzed as randomized.
Response-evaluable
Efficacy population with measurable disease at baseline and one of the 
following: (a) at least 1 post baseline tumor assessment, (b) clinical 
progression, (c) death.
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10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender, and race.
10.3.1
Efficacy Analyses
Efficacy analyses for the primary and secondary endpoints (Table 10.3.1-1) will be performed on 
the efficacy population for the final analysis. Efficacy analyses based on the response-evaluable 
population may be performed for interim analyses when the minimum follow-up period is less 
than sufficient to warrant adequate interpretation of the result. Details of the censoring scheme on 
time-to-event endpoints such as DOR, PFSR, and OSR will be described in the Statistical Analysis 
Plan.
Table 10.3.1-1:
Efficacy - Statistical Analyses
Endpoint
Statistical Analysis Methods
PFS and PFSR at 6, 9, and 12 months will be assessed per 
RECIST v1.1 by BICR and investigator assessment.
PFS for a participant is defined as the time from 
randomization date to the date of first objectively 
documented disease progression by BICR or investigator per 
RECIST v1.1 or death due to any cause, whichever occurs 
first. 
PFS curves for each randomized arm will be 
estimated and plotted using the K-M product 
limit method. Median PFS along with 95% CI 
will be constructed based on a log-log 
transformed CI for PFS. 
In addition, the hazard ratio and the 
corresponding 1-sided 80% CI for the HR (each 
experimental group versus combined 
chemotherapy) will be estimated in a Cox 
proportional hazards model.
ORR is defined as the proportion of participants whose BOR 
is either CR or PR per RECIST v1.1 in the population of 
interest.
BOR for a participant will be assessed per RECIST v1.1 by 
BICR and investigator assessment.
Estimate of ORR and corresponding 2-sided 
exact 95% CI using the Clopper-Pearson method.
OS and OSR at 6 months, 1 year, and 2 years
OS is defined as the time from randomization to the date
of death to any cause.
Estimate by the Kaplan-Meier method and 
corresponding 2-sided 95% CI using Brookmeyer 
and Crowley methodology (using log-log 
transformation) for the median and Greenwood
formula for the rate.
DOR will be assessed per RECIST v1.1 by BICR and 
investigator assessment.
DOR for a participant with a BOR of CR or PR is defined as 
the time between the date of first response and the date of the 
first objectively documented tumor progression by BICR or 
investigator per RECIST v1.1 or death, whichever occurs 
first.
Estimate by the Kaplan-Meier method and 
corresponding 2-sided 95% CI using Brookmeyer 
and Crowley methodology (using log-log 
transformation).
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Abbreviations: BICR = blinded independent central review; BOR = best overall response; CI = confidence interval; 
CR = complete response; DOR = duration of response; ORR = objective response rate; OSR = overall survival rate; 
PFS = progression-free survival; PFSR = PFS rate; PR = partial response; RECIST v1.1 = Response Evaluation 
Criteria in Solid Tumors version 1.1.
10.3.2
Safety Analyses
All safety analyses will be performed on the treated population.
Table 10.3.2-1:
Safety - Statistical Analyses
Endpoint
Statistical Analysis Methods
Incidence of AEs, SAEs, and AEs leading to 
discontinuation, and death
AEs will be graded according to CTCAE v4.03.
Frequency distribution of treated participants with AE 
using the worst CTC grade. Participants will only be 
counted (1) once at the PT level, (2) once at the SOC
level, and (3) once in the “Total subject” row at their 
worst CTC grade, regardless of SOC or PT.
Laboratory abnormalities
Laboratory values will be graded according to 
CTCAE v4.03.
Laboratory shift table using the worst CTC grade on 
treatment per participant.
Abbreviations: AE = adverse event; CTC = common terminology criteria; CTCAE = common terminology criteria 
for adverse events; PT = preferred term; SAE = serious adverse event; SOC = system organ class.
 
 
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10.3.7
Interim Analyses 
Interim analyses will be performed for administrative purposes or publications. No formal 
inferences requiring any adjustment to statistical significance level will be performed.
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11
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28 Langer CJ, Gadgeel SM, Borqhaei H, et al. Carboplatin and pemetrexed with or without 
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2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17(11):1497-508.
29 Wainberg ZA, Hochster HS, George B, et al. Phase I study of nivolumab (nivo) + nabpaclitaxel 
(nab-P) ± gemcitabine (Gem) in solid tumors: Interim results from the pancreatic cancer (PC) 
cohorts. J Clin Oncol 2017;35(Suppl):Abstract 412.
30 Cabiralizumab (FPA008; BMS-986227) Anti-CSF1R Humanized IgG4 Monoclonal Antibody 
Investigator’s Brochure v6. Oct 2018. Bristol-Myers Squibb, Inc. Document Control No. 
930110505.
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31 Nivolumab (BMS-936558; MDX1106; ONO-4538) Investigator Brochure v17. Jun 2018. 
Bristol-Myers Squibb Company. Document Control No. 930038243.
32 Radi ZA, Koza-Taylor PH, Bell RR, et al. Increased serum enzyme levels associated with 
kupffer cell reduction with no signs of hepatic or skeletal muscle injury. Am J Pathol 
2011;179(1):240-7.
33 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
34 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
35 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
36 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
37 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000; 192(7): 1027-34.
38 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
39 Keir M E, Butte M J, Freeman G J, Sharpe A H. PD-1 and Its Ligands in Tolerance and 
Immunity. Ann. Rev. Immunol. 2008;26:677–704.
40 Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T 
cell activation. Nat Immunol. 2001;2:261-8.
41 Carter LL, Fouser LA, Jussif J, et al. PD-1: PD-L1 inhibitory pathway affects both CD4+ and 
CD8+ T cells and is overcome by IL-1. Eur J Immunol. 2002;32:634-43.
42 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
2012;12:252-64.
43 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20.
44 FDA. Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
2009
45 Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based 
chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 
2016;34(25):2969-79.
46 Gadgeel SM, Stevenson J, Langer CJ, et al. Pembrolizumab (pembro) plus chemotherapy as 
front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. Proc Am Soc Clin 
Oncol. 2016;34:Abstr. 9016.
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47 ABRAXANE® US Package Insert. Celgene Corporation; 2015
 
49 Gemcitabine. United Kingdom Medicines and Healthcare Products Regulatory Agency 
Summary 
of 
Product 
Characteristics. 
Accessed 
September 
2018. 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1536897980572.pdf.
50 ONIVYDE (irinotecan). European Medicines Agency Summary of Product Characteristics. 
Accessed 
September 
2018. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/004125/WC500215029.pdf.
51 ABRAXANE (paclitaxel). European Medicines Agency Summary of Product Characteristics. 
Accessed 
September 
2018. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000778/WC500020435.pdf.
52 Oxaliplatin. United Kingdom Medicines and Healthcare Products Regulatory Agency 
Summary 
of 
Product 
Characteristics. 
Accessed 
September 
2018. 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1536897996039.pdf.
53 Fluorouracil. United Kingdom Medicines and Healthcare Products Regulatory Agency 
Summary 
of 
Product 
Characteristics. 
Accessed 
September 
2018. 
https://www.medicines.org.uk/emc/product/6041/smpc.
54 Leucovorin (calcium folinate). United Kingdom Medicines and Healthcare Products 
Regulatory Agency Summary of Product Characteristics. Accessed September 2018. 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1516943516232.pdf.
55 Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and 
folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy 
(NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016;387(10018):545-
57.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
1L
first line
5-FU
5-fluorouracil
ADA
anti-drug antibody
AE(s)
adverse event(s)
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APC
antigen-presenting cells
AST
aspartate aminotransferase
BICR
Blinded Independent Central Review
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best observed response
BUN
blood urea nitrogen
CBC
complete blood count
CDA
cytidine deaminase
CFR
Code of Federal Regulations 
CK
creatinine kinase
CI
confidence interval
CLcr
creatinine clearance
Cmaxss
steady-state peak concentration
Cminss
steady-state trough concentration
CMV
cytomegalovirus
CNS
central nervous system
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Term
Definition
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
Case Report Form, paper or electronic
CSF1R
colony-stimulating factor 1 receptor
CT
computerized tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte antigen-4
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
data monitoring committee
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
ELISA
enzyme-linked immunosorbent assay
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
FDG-PET
fluorodeoxyglucose positron emission tomography
FFPE
formalin-fixed paraffin-embedded
FNR
false negative rate
FOLFIRI
irinotecan/leucovorin/5-fluoruracil
FOLFIRINOX
folinic acid/5-fluoruracil/irinotecan/oxaliplatin
FOLFOX
oxaliplatin, 5-fluorouracil, and leucovorin
FPR
false positive rate
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Term
Definition
FSH
follicle stimulating hormone
GFR
glomerular filtration rate
GI
gastrointestinal
H&E
hematoxylin and eosin
HCG
beta-human chorionic gonadotrophin
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
IEC
Independent Ethics Committee
IFN-γ
interferon-γ
IgG4
immunoglobulin G4
IHC
immunohistochemistry
IMP
investigational medicinal product
INR
international normalized ratio
IO
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
Kd
dissociation constant
LDH
lactate dehydrogenase
mAb
monoclonal antibody
mmHg
millimeters of mercury
MRI
magnetic resonance imaging
N
number of subjects or observations
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Term
Definition
NCI
National Cancer Institute
NOAEL
no-observed adverse effect level
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OSR
overall survival rate
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PD-1
programmed cell death-1
PDAC
pancreatic ductal adenocarcinoma
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PET
positron emission tomography
PFS
progression-free survival
PFSR
progression-free survival rate
PID
participant identification
PK
pharmacokinetics
PPK
population pharmacokinetics
PR
partial response
PT
preferred term
PVNS
pigmented villonodular synovitis
Q2W
every 2 weeks
Q4W
every 4 weeks
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SCCHN
squamous cell carcinoma of the head and neck
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Term
Definition
SD
stable disease
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TAM
tumor-associated macrophages
TB
tuberculosis
TME
tumor microenvironment
ULN
upper limit of normal
US
United States
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the case report form (CRF) is intended to 
refer to a person (Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP),

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent form will receive approval/favorable opinion by the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) and regulatory authorities 
according to applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree 1 or more of the following: (1) the physical, safety, or mental integrity 
of 1 or more subjects/participants; (2) the scientific value of the trial (eg, reliability and robustness 
of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or Trial 
protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
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The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and, if 
applicable, also by the local health authority) except where necessary to eliminate any immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s), the deviation or change will be submitted, as 
soon as possible to:

IRB/IEC

Regulatory Authority(ies), if applicable by local regulations (per national requirements).
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and, if applicable, also by the local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given by subjects/participants, investigators must ensure that 
their legally acceptable representatives (as per country guidelines) are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in which the 
participant volunteers to participate. 
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Sponsor or designee will provide the investigator with an appropriate (ie, global or local) sample 
informed consent form, which will include all elements required by ICH, GCP, and other 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 

Allow time necessary for a participant, or a participant's legally acceptable representative, to 
inquire about the details of the study.

Obtain an informed consent form signed and personally dated by the participant or the 
participant's legally acceptable representative and by the person who conducted the informed 
consent discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant, or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue his or her participation in the study. This communication 
should be documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects'/participants’ signed ICF, and, in the US, the subjects’/participants’ signed HIPAA 
authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten on paper or entered 
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electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic health/medical records (EHRs/EMRs), 
adverse event (AE) tracking/reporting, protocol-required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of an electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a health authority.
If
Then
Supplied 
by 
BMS 
(including 
its 
vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each 
participant, including unique participant 
identifiers

amount transferred to another area/site for 
dispensing or storage

non-study disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 

dates and initials of person responsible for 
investigational product (IP) 
dispensing/accountability, as per the Delegation 
of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
The investigator or designee accepts responsibility 
for documenting traceability and study treatment 
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If
Then
sourced 
from 
the 
sites 
stock or 
commercial supply or a specialty 
pharmacy)
integrity in accordance with requirements 
applicable under law and the standard operating 
procedures (SOPs)/standards of the sourcing 
pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the case report form (CRF) must be consistent with the source documents, or the 
discrepancies must be explained. Additional clinical information may be collected and analyzed 
in an effort to enhance understanding of product safety. CRFs may be requested for AEs and/or 
laboratory abnormalities that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture (EDC) tool, eCRFs will be prepared 
for all data collection fields except for fields specific to serious adverse events (SAEs) and 
pregnancy, which will be reported on the electronic SAE form and Pregnancy Surveillance form, 
respectively. If an electronic SAE form is not available, a paper SAE form can be used. Spaces 
may be left blank only in those circumstances permitted by study-specific CRF completion 
guidelines provided by Sponsor or designee. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF and SAE/pregnancy CRFs must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. For eCRFs, review and approval/signature is completed electronically through the 
BMS EDC tool. The investigator must retain a copy of the CRFs including records of the changes 
and corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
Sponsor or designee. User accounts are not to be shared or reassigned to other individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
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Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site, they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, due to relocation, retirement), the records shall 
be transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). 
Notice of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS or a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials, and syringes may be destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors)
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor, 
unless study treatment containers must be 
immediately destroyed as required to meet 
safety and local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS or its vendors (examples include study 
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
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treatments sourced from the sites stock or 
commercial supply or a specialty pharmacy)
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal of study treatments, 
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. The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the study treatment.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs, and a copy must be provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor,
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Study 
Monitor to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty study 
treatment containers.
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, are solely the responsibility of the 
investigator or designee.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Participant recruitment (eg, among the top quartile of enrollers)

Involvement in the trial design

Regional representation (eg, among the top quartile of enrollers from a specified region or 
country)
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SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing study site participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to Sponsor or 
designee at the earliest practicable time prior to submission or presentation and otherwise within 
the time period set forth in the CTA.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor. Authorship of publications at BMS is aligned with the criteria of 
the International Committee of Medical Journal Editors (ICMJE, www.icmje.org). Authorship 
selection is based upon significant contributions to the study (ie, ICMJE criterion #1). Authors 
must meet all 4 ICMJE criteria for authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered. 
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING
ADVERSE EVENTS
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 treatment 
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 study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis..

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term.
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
SERIOUS ADVERSE EVENTS
A Serious Adverse Event (SAE) is defined as 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)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery planned prior to signing consent

admission as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, 
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, or administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
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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 participant or may require intervention [e.g., medical, 
surgical] to prevent 1 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.) 
Potential drug-induced liver injury (DILI) is also considered an important medical event. (See 
Section 9.2.7 for the definition of potential DILI.)
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see Section 9.2.5 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AEs AND SAEs
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term[s] initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SERIOUS ADVERSE EVENTS TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form.

The required method for SAE data reporting is through the eCRF.

The paper SAE Report Form is only intended as a backup option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
In this case, the paper form is transmitted via email or confirmed facsimile (fax)
transmission
When paper forms are used, the original paper forms are to remain on site.

Pregnancies must be recorded on a Pregnancy Surveillance Form and transmitted via email 
or confirmed facsimile (fax) transmission.
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

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

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout periods below are suggested guidelines, and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (eg, rings, creams, gels)

4 weeks minimum for transdermal products

8 weeks minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure

End of relevant systemic exposure is the time point where the investigational medicinal product 
(IMP), or any active major metabolites, has decreased to a concentration that is no longer 
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considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
the context of safety margins from the no-observed adverse effect level (NOAEL) or the time 
required for 5 half-lives of the IMP to pass.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 6 months after the end of nab-paclitaxel 
(ABRAXANE) study treatment, and 5 months after the end of any other study treatment(s).
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

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.
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
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence.
NOTES: 
a Typical-use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative 
methods of contraception should be utilized. 
c IUDs and IHSs are acceptable methods of contraception in the absence of definitive drug interaction studies 
when hormone exposures from IUDs do not alter contraception effectiveness.
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, postovulation methods)

Withdrawal (coitus interruptus).

Spermicide only

Lactation amenorrhea method
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
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
Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure, defined as 7 months after the end of treatment.

Female partners of male participants to consider use of effective methods of contraception until 
the end of relevant systemic exposure, defined as 7 months after the end of treatment of the 
male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of treatment.

Refrain from donating sperm for the duration of the study treatment and for 7 months after the 
end of treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of pregnancy information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and Procedures for Evaluating, Follow-up, and Reporting.
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APPENDIX 5
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST v1.1) guidelines with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of:
10 mm by computerized tomography (CT)/magnetic resonance imaging (MRI) scan (scan slice 
thickness no greater than 5 mm, or 2x slice thickness if greater than 5mm).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures, which may be 
visible by imaging even if not involved by a tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by a solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan, this is almost always the axial plane; for MRI, the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measurements is the short axis. 
For example, an abdominal node that is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded 
as the node measurement. All other pathological nodes (those with a short axis of 10 mm but 
< 15 mm) should be considered non-target lesions. Nodes that have a short axis of < 10 mm are 
considered nonpathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with 10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of the skin or lung, abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as target or non-target lesions.
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1.3
Special Considerations Regarding Lesion Measurability
1.3.1
Bone Lesions

Bone scan, positron emission tomography (PET) scan, and plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be used 
to confirm the presence or disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

Blastic bone lesions are non-measurable.
1.4
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only 1 or 2 organ sites involved, a maximum of 2 and 4 lesions, 
respectively, will be recorded).
Note: A maximum of 2 lesions can be selected per organ system. For example, a maximum of 
2 lung lesions can be selected (from 1 lung or 1 lesion from each lung). A maximum of 2 lymph 
nodes can be selected at baseline, as the lymphatic system is considered as 1 organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition, should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement, in which circumstance the next largest lesion that can 
be measured reproducibly should be selected.
A sum of the diameters (longest axis for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to 
be included in the sum, then, as noted above, only the short axis will be added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum during the study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 1 or more new 
lesions is also considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.

Not Evaluable (NE): If 1 or more target lesions cannot be measured or adequately assessed 
as either fully resolved or are too small to measure (due to missing or poor-quality images), 
and the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet PD as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to < 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be 0 even if the complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may, therefore, be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD, and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when measured to be very small 
(eg, 2 mm). However, sometimes lesions or lymph nodes that are recorded as target lesions at 
baseline become so faint on CT scan, such that the radiologist may not feel comfortable assigning 
an exact measurement and may report them as being ‘too small to measure’. When this occurs, it 
is important that a value be recorded on the case report form. 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 as the reference diameter. (Note: It is less likely that this rule will be used for 
lymph nodes since they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is 
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faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well.) This default value is derived from the 5 mm CT slice thickness (but should 
not be changed with varying CT slice thickness). The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is able to 
provide an actual measurement, that should be recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s).
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in the 
presence of SD or PR in the target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. A modest ‘increase’ in the size of 1 or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions, and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will, therefore, be extremely rare.
2.2.1.2
When the patient only has non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above; however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable), a useful test that can be applied when assessing patients 
for unequivocal progression is will be employed to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease: ie, an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase in 
diameter in a measurable lesion). Examples include an increase in lymphangitic disease from 
localized to widespread, or which be described as ‘sufficient to require a change in therapy’. If 
‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so; therefore, the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of preexisting lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event that a new 
fluid collection is seen on a post-baseline imaging exam, a comment may be made, but the 
appearance of a new fluid collection alone should not result in an assessment of PD. A lesion 
identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is a patient who 
has visceral disease at baseline and while on study has a CT or MRI scan of the brain ordered that 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have a brain imaging done at baseline. A lesion identified on chest X-Ray that was 
not present in a prior CT scan can be considered a new lesion and will result in PD.
If a new lesion is equivocal, for example, because of its small size, continued follow-up evaluation 
will clarify if it truly represents a new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While 
fluorodeoxyglucose PET (FDG-PET) response assessments need additional study, it is sometimes 
reasonable to incorporate the use of a FDG-PET scan to complement the CT scan in assessment 
of progression (particularly of a possible ‘new’ disease). New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is considered as PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a preexisting site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not considered as PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require a confirmatory measurement.
2.3.2
Time Point Response
At each protocol-specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore, non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients with Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
NE
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; NE = not evaluated; PD = progressive disease; PR = partial response; SD = stable disease
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Table 2.3.2-2:
Time Point Response: Patients with Non-Target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response; NE = not evaluated; PD = progressive disease
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some trials, hence it is not advisable to assign this category when no lesions can be 
measured.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in
Table 2.3.3-1. When SD is believed to be the best response, it must meet the protocol-specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (7 days) for a particular 
protocol, a best response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study). If the subject is not on-study for 
at least this amount of time, any tumor assessment indicating SD before this time period will have 
a best response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate a progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘0’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided that minimum criteria for SD duration are met; 
otherwise, PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
PD
SD provided that minimum criteria for SD duration are met; 
otherwise, PD
CR
NE
SD provided that minimum criteria for SD duration are met; 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided that minimum criteria for SD duration are met; 
otherwise, PD
PR
NE
SD provided that minimum criteria for SD duration are met; 
otherwise, NE
NE
NE
NE
CR = complete response; NE = not evaluated; PD = progressive disease; PR = partial response, SD = stable 
disease
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since the disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and, in fact, the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR, and the best 
response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a 
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only 1 intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have PD.
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 6
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS a
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, eg, 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.
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 7
ADVERSE EVENT MANAGEMENT FOR CABIRALIZUMAB AND NIVOLUMAB COMBINATION 
THERAPY ARMS
Gastrointestinal Adverse Event Management
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue study drugs. Opiates/narcotics may mask 
symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.
Grade of Diarrhea/Colitis
(NCI CTCAE v4.03)
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 
protocola
– Symptomatic treatment
If improves to Grade 1 in ≤4 days:
– Resume cabiralizumab and nivolumab therapy per protocol
If persists in ≥5–7 days or recurs:
– 0.5–1 mg/kg/day methylprednisolone or oral equivalent
– When symptoms improve to Grade 1, taper steroids over at least 1 month,
consider prophylactic antibiotics for opportunistic infections, and resume 
cabiralizumab and nivolumab therapy per protocol
If worsens or persists after >3-5 days with oral steroids:
– Treat as Grade 3 or 4
Grade 3–4: 
Diarrhea (G3): ≥7 stools per day 
over baseline; incontinence; IV 
fluids Ӌ24 hours; interfering with 
ADL; 
Colitis (G3): Severe abdominal 
pain, medical intervention 
indicated, and peritoneal signs
Grade 4: Life-threatening 
perforation
– Discontinue cabiralizumab and nivolumab 
therapy per protocolb
– 1 to 2 mg/kg/day methylprednisolone IV or 
IV equivalentc
– 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
If Grade 4:
– Permanently discontinue cabiralizumab and nivolumab
– Continue steroids until Grade 1, then taper steroids over at least 1 month
If persists for >3-5 days or recurs after improvement:
– Add infliximab 5 mg/kg (if no contraindications)
– Follow up until resolution
– Note: Infliximab should not be used in cases of perforation or sepsis
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient
b If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
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Renal Adverse Event Management
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue study drugs.
Grade of Creatinine Elevation
(NCI CTCAE v 4.03)
Management
Follow-Up
Grade 1: 
Creatinine > ULN and 
> baseline but 1.5x baseline 
– 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:
– Treated as Grade 2 or Grade 3/4
Grade 2-3: 
Creatinine >1.5x 6x ULN 
– Delay cabiralizumab and nivolumab
therapy per protocola
– Monitor creatinine every 2 to 3 days
– 0.5 to 1 mg/kg/day methylprednisolone
IV or oral equivalentb
– Consider renal biopsy if clinically indicated
If returns to Grade 1 or baseline before the next dosing visit:
– Taper steroids over at least 1 month, consider prophylactic antibiotics for
opportunistic infections, and resume cabiralizumab and nivolumab
therapy at the same dose level
– Routine creatinine monitoring per protocol
If elevations persist for >7 days or worsen:
– Treat as Grade 4
Grade 4: 
Creatinine >6.0x ULN
– Discontinue cabiralizumab and nivolumab
therapy per protocol c
– Monitor creatinine daily 
– 1 to 2 mg/kg/day methylprednisolone IV
or IV equivalentb
– Consult nephrologist
– Consider renal biopsy if clinically indicated
If returns to baseline or Grade 1:
– Taper steroids over at least 1 month and add prophylactic 
antibiotics for opportunistic infections
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient.
b Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
c If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient.
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Pulmonary Adverse Event Management
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue study drugs. Evaluate with imaging and pulmonary
consultation.
Grade of Pneumonitis
(NCI CTCAE v 4.03)
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 
protocola
– Pulmonary and infectious disease consults
– Monitor symptoms daily, consider hospitalization
– 1 mg/kg/day methylprednisolone IV or oral
equivalent
– Consider bronchoscopy and lung biopsy, if
clinically indicated
– Re-image every 1–3 days
If improves <14 days:
– When symptoms return to near baseline, taper steroids over at
least 1 month, consider prophylactic antibiotics for opportunistic
infections and resume cabiralizumab and nivolumab therapy per 
protocol
If does not improve after 2 weeks or worsens:
– Treat as Grade 3–4
Grade 3–4: 
Severe new symptoms;
New/worsening hypoxia;
Life-threatening
– Discontinue cabiralizumab and nivolumab therapy
per protocolb
– Hospitalization
– Pulmonary and infectious disease consults
– 2 to 4 mg/kg/day methylprednisolone IV or IV
equivalentc
– Add prophylactic antibiotics for opportunistic 
infections
– Consider bronchoscopy, lung biopsy if
clinically indicated
If improves to baseline:
– Taper steroids over at least 6 weeks
If does not improve after 48 hours or worsens:
– Add additional immunosuppression (eg, cyclophosphamide,
IVIG, or mycophenolate mofetil)
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient.
b If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by patient.
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
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Hepatic Adverse Event Management Without Liver Metastasis
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue study drugs. 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 Medical Monitor
– Evaluate for non-drug related causes of the laboratory abnormalities
(eg, obstruction, viral infection, Gilbert’s disease, etc.)
– Under selected circumstances (eg, alternative etiology is identified),
patient may receive additional therapy only after consultation and
agreement between the 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 Medical Monitor if there are clinical signs of muscle or 
hepatic injury or other clinical symptoms
– Contact the Medical Monitor if there is a concurrent increase of bilirubin,
AST, ALT, or alkaline phosphatase
– Notify the Medical Monitor 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 
protocola
– Increase frequency of monitoring of (including but
not limited to) AST, ALT, bilirubin, alkaline 
phosphatase, and INR (every 48-72 hours or more 
frequently, as clinically indicated)
– If there is a 2-fold ALT increase compared to the
previous measurement, start steroids immediately
– Consider steroid treatment on any total bilirubin
increase of over 2.0x ULN
– If there is a concurrent increase of alkaline
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 therapy per protocol
– 0.5-1 mg/kg/day methylprednisolone or oral equivalent, and when LFT
returns to Grade 1 or baseline, taper steroids over at least 1 month
– Consider prophylactic antibiotics for opportunistic infections
– Discuss with Medical Monitor
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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 study drugs. 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 therapyb
– Increase frequency of monitoring to every 1 to 2 
days
– Consider 1 to 2 mg/kg/day methylprednisolone IV 
or IV equivalentc
– Consider adding prophylactic antibiotics for 
opportunistic infections
– Consult gastroenterologist and hepatologist, if 
clinically indicated
If returns to Grade 2:
– Consider steroid taper over at least 1 month if they have been started
If does not improve in >3–5 days, worsens, or rebounds:
– Consider adding mycophenolate mofetil 1 g BID
– If no response within an additional 3–5 days, consider other 
immunosuppressants per local guidelines
– Follow up until resolution
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient.
b If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient.
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
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Hepatic Adverse Event Management with Liver Metastasis
Rule out noninflammatorycauses. If a noninflammatorycause is identified, treat accordingly and continue study drugs. 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
– Start steroids
– Continue LFT monitoring per protocol until resolution.
– Continue monitoring for and other associated clinical
signs or symptoms
– Contact the Medical Monitor
– 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 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 (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 Medical Monitor if there are clinical signs of 
muscle or hepatic injury or other clinical symptoms
– Contact the Medical Monitor if there is a concurrent
increase of bilirubin, AST, ALT, or alkaline 
phosphatase
– Notify the Medical Monitor 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 20
xULN
and
Total bilirubin 2 xULN
or
Isolated total bilirubin > 3.0 to
5 xULN
– Delay cabiralizumab and nivolumab therapy per protocola
– 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:
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BMS-986227
cabiralizumab
Hepatic Adverse Event Management with Liver Metastasis
Rule out noninflammatorycauses. If a noninflammatorycause is identified, treat accordingly and continue study drugs. 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/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 Medical Monitor
AST or ALT > 20 xULN
or
Total Bilirubin > 5 xULN
– Discontinue cabiralizumab and nivolumab therapyb
– Increase frequency of monitoring to every 1–2 days
– Consider 1 to 2 mg/kg/day methylprednisolone IV
or IV equivalentc
– Consider adding prophylactic antibiotics for
opportunistic infections
– Consult gastroenterologist and hepatologist, if clinically
indicated
If returns to Grade 2 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
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient.
b If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient.
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
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BMS-986227
cabiralizumab
Endocrinopathy Adverse Event Management
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue study drugs. 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 clinicallyindicated;
consider endocrinology consult
Symptomatic endocrinopathy
– Evaluate endocrine function
– Consider pituitary scan
Symptomatic with abnormal lab/pituitary scan:
– Delay cabiralizumab and nivolumab therapy per protocola
– 1 to 2 mg/kg/day methylprednisolone IV or PO equivalentb
– Initiate appropriate hormone therapy
No abnormal lab/pituitary MRI scan but symptoms
persist:
– Repeat labs in 1–3 weeks and MRI in 1 month
If improves within 28 days (with or without
hormone replacement):
– Taper steroids over at least 1 month and consider
prophylactic antibiotics for opportunistic infections
– Resume cabiralizumab and nivolumab therapy per protocol
– Patients with adrenal insufficiency may need to continue
steroids with mineralocorticoid component
If persists for over 28 days:
– Delay cabiralizumab and nivolumab therapy
– Continue steroids as needed
– Upon resolution, discuss with Medical Monitor if
patients are clinically stable on further dose delay and
discontinuation
– Follow up until resolution or return to baseline
Suspicion of adrenal crisis
(e.g. severe dehydration,
hypotension, shock out of
proportion to current illness)
– Delay or discontinue cabiralizumab and nivolumab
therapy per protocola,c
– Rule out sepsis
– Stress dose of IV steroids with mineralocorticoid activity
– IV fluids
– Consult endocrinologist
– If crisis is ruled out, treat as above for symptomatic
endocrinopathy
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient.
b Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
c If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient.
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BMS-986227
cabiralizumab
Skin Adverse Event Management
Rule out noninflammatory causes. If a noninflammatory cause is identified, treat accordingly and continue study drugs.
Grade of Rash
(NCI CTCAE v 4.03)
Management
Follow-Up
Grade 1–2:
Covering 30% BSAa
– Symptomatic therapy (e.g.
antihistamines, topical steroids)
– Continue cabiralizumab and nivolumab
therapy per protocol
If persists >1-2 weeks or recurs:
– Consider skin biopsy
– Delay cabiralizumab and nivolumab therapy per protocol
– Consider 0.5–1 mg/kg/day methylprednisolone IV or oral 
equivalent.
– Once improving ,taper steroids over at least 1 month, consider
prophylactic antibiotics for opportunistic infections, and resume 
cabiralizumab and nivolumab therapy per protocol
If worsens:
– Treat as Grade 3–4
Grade 3–4:
Covering > 30% BSA; life-
threatening consequencesd
– Delay or discontinue cabiralizumab and
nivolumab therapy per protocolb,c
– Consider skin biopsy and dermatology
consult
– 1 to 2 mg/kg/day IV methylprednisolone 
IV or IV equivalentd
If improves to Grade 1 within 28 days:
– Taper steroids over at least 1 month and add prophylactic 
antibiotics for opportunistic infections
– Resume cabiralizumab and nivolumab therapy per protocol
If persists > 28 days or worsens:
–Consider to discontinue cabiralizumab and nivolumab therapy per 
protocol
a Refer to NCI CTCAE v 4.03 for term-specific grading criteria.
b If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient
c If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient
d Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
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Neurological Adverse Event Management
Grade of Neurological
Toxicity (NCI CTCAE v
4.03)
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 or 3-4
Grade 2: 
Moderate symptoms; limiting
instrumental ADL
– Delay cabiralizumab and nivolumab
therapy per protocola
– Treat symptoms per local guidelines
– Consider 0.5 to 1 mg/kg/dayb
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 therapyc
– Obtain neurology consult
– Treat symptoms per local guidelines 1
to 2 mg/kg/day IV
methylprednisolone or POb
– Add prophylactic antibiotics for
opportunistic infections
If improves to Grade 2:
– Taper steroids over at least 1 month
If worsens or atypical presentation:
– Consider IVIG or other immunosuppressive therapies per local
guidelines
– Continue follow-up until resolution
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient.
b Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
c If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient.
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Periorbital Edema Adverse Event Management
Grade of Periorbital Edema
(NCI CTCAE v 4.03)
Management
Follow-Up
Grade 1
– Continue cabiralizumab and nivolumab therapy
per protocol
– Monitor edema weekly
If worsens:
–  Follow as stated below
Grade 2
– Delay cabiralizumab and nivolumab therapy per 
protocola
– Start systemic treatment including steroids, eye
drops, or analgesics as neededb
If returns to Grade 1 or baseline before the next dosing visit:
– Continue systemic treatment
– Resume cabiralizumab and nivolumab therapy at same dose level
without delay
– Routine eye monitoring per protocol, if clinically stable
If swelling persists >14 days but returns back to baseline or
normal within 28 days:
– Continue nivolumab and cabiralizumab dosing at same level
– If recurs at Grade 2 or above, discontinue cabiralizumab and 
nivolumab therapy
Grade ≥3
– Discontinue cabiralizumab and nivolumab
therapy per protocolc
– Systemic treatment including steroids, eye
drops, or analgesics as neededb
– Consult an ophthalmologist if needed
If returns to Grade 1 after discontinuation:
– Systemic treatment including tapering steroids as needed
– Any follow-up and ophthalmology consults, if clinically indicated
– Monitor and follow up until resolution
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient.
b Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
c If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient.
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Infusion Reaction Adverse Event Management
Grade of Infusion
Reactions
(NCI CTCAE v 4.03)
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 protocola,b
– Systemic treatment including NSAIDs, corticosteroids
andantihistaminesc
– 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
clinicallystable
– Resume cabiralizumab and nivolumab therapy at same dose
level and monitor per protocol
– Pre-infusion prophylactic medications are recommended for future
dosing, including antihistamines, NSAID, and corticosteroids up to
25 mg as needed.
If symptoms recur:
– Discontinue treatment at the visit
– Discuss with Medical Monitor as needed
Grade ≥3
– Discontinue cabiralizumab and nivolumab therapyper
protocolb
– Systemic treatment including NSAID , corticosteroids, and
antihistaminesc
– Normal saline infusion and constant monitoring of vitals
and other parameters
– Follow institutional guidelines for anaphylaxis
– Bronchodilators as clinically indicated with or without
hospitalization
If returns to Grade 1 after discontinuation:
– Systemic treatment including tapering steroids,
NSAIDs, and antihistamines until resolution, as needed
– Follow up until resolution
– Any other clinical referrals, if indicated
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient
b If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
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cabiralizumab
Uveitis Adverse Event Management
Grade of Uveitis
(NCI CTCAE v4.03)
Management
Follow-Up
Grade 1
– Observe symptoms
– Continue cabiralizumab and nivolumab
therapy
– Watch for worsening of symptoms including visual disturbances, light sensitivity,
decrease vision
– Monitor weekly
If worsens:
– Follow as stated below
Grade 2
– Delay or discontinue cabiralizumab and
nivolumab therapy per protocola,b
– Start antibiotics and inflammatory 
medications including steroidsc
– Ophthalmologic consult, if clinically
indicated
– Immunosuppressive agents (e.g, anti-
TNF agents such as Infliximab)
If symptoms resolve within 14 days:
– Continue cabiralizumab and nivolumab therapy at same dose level and start
tapering of steroid doses
If symptoms resolve between 14 -28 days:
– Consider continuing dosing at same dose level for nivolumab and a dose level
lower for cabiralizumab on resolution to baseline or Grade 1 and start tapering
of steroid doses.
– If it is Grade 2 drug-related uveitis that does not resolve within 14 days,
consider to discontinue study drug(s)
If symptoms persist or worsen in 28 days regardless of systemic treatment:
– Discontinue both cabiralizumab and nivolumab therapy
– Continue monitoring of symptoms including visual disturbances, eye pain, and
dimness of vision and follow up until resolution or return to baseline
– Continue steroids, antibiotics, and other medications such as infliximab, as
clinically indicated
Grade 3
– Discontinue cabiralizumab and
nivolumab therapy per protocolb
– Start antibiotics and inflammatory 
medications including steroidsc
– Ophthalmologic consult, if clinically
indicated
– Immunosuppressive agents (e.g, anti-
TNF agents such as Infliximab)
– Discontinue both cabiralizumab and nivolumab therapy
– Continue monitoring of symptoms including visual disturbances, eye pain, and
dimness of vision, and follow up until resolution or return to baseline
– Continue steroids, antibiotics, and other medications such as infliximab, as
clinically indicated
– Follow up until resolution
a If the AE requiring dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into account the safety and clinical benefit 
to the patient
b If the AE requiring discontinuation was due to one of the study drugs, the non-offending drug may be continued, if there is timely resolution of AE and clinical 
benefit is shown by the patient
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
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cabiralizumab
APPENDIX 8
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 protocola
Measure CK isoenzyme panel to identify
source of elevation
Increase frequency of monitoring (every
48-72 hours or more, as clinically
indicated)
Notify the BMS Medical Monitor
If CK or LDH returns to 15 xULN within 28
days:
Resume routine monitoring, resume cabiralizumab
and nivolumab therapy at same dose level as per 
protocol
If CK isoenzyme panel is normal continue monitoring 
the subject.
If CK isoenzyme panel is abnormal then consider
measuring troponins.
If troponins are abnormal, contact BMS Medical
Monitor to determine if the subject can be retreated.
If CK or LDH elevations persist at the same level
> 28 days or worsen:
Discontinue further dosing
Discuss with Medical Monitor
CK or LDH > 20
xULN
– Discontinue cabiralizumab and
nivolumab therapy per protocol
–  Follow up until resolution
a. If the AE requiring a dose delay was due to one of the study drugs, the non-offending drug may be continued, taking into
account the safety and clinical benefit to the patient.
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BMS-986227
cabiralizumab
APPENDIX 9
TNM STAGING
Because only a few patients with pancreatic cancer undergo surgical resection of the pancreas (and 
adjacent lymph nodes), a single TNM classification must apply to both clinical and pathologic 
staging.
Table 1:
American Joint Committee on Cancer TNM Staging of Pancreatic 
Cancer (2010)
Primary Tumor (T)
Regional Lymph Nodes (N)
TX
Primary tumor cannot be assessed
NX
Regional lymph nodes cannot be assessed
T0
No evidence of primary tumor
N0
No regional lymph node metastasis
Tis
Carcinoma in situ*
N1
Regional lymph node metastasis
T1
Tumor limited to the pancreas, 2 cm or less in 
greatest dimension
Distant Metastases (M)
T2
Tumor limited to the pancreas, more than 2 cm in 
greatest dimension
M0
No distant metastases
T3
Tumor extends beyond the pancreas but without 
involvement of the celiac axis or the superior 
mesenteric artery
M1
Distant metastases
T4
Tumor involves the celiac axis or the superior 
mesenteric artery (unresectable primary tumor)
Stage Grouping
Stage 0
Tis
N0
M0
Stage IA
T1
N0
M0
Stage IB
T2
N0
M0
Stage IIA
T3
N0
M0
Stage IIB
T1
N1
M0
T2
N1
M0
T3
N1
M0
Stage III
T4
Any N
M0
Stage IV
Any T
Any N
M1
*This also includes the “PanInIII” classification.
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APPENDIX 10
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 03, 24-Apr-2018
Some key changes to Revised Protocol 02 were not included in the final published document. 
These changes are applied to Revised Protocol 03. Minor clarifications have also been applied. 
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-1 Screening Procedural 
Outline
Addition of language to clarify the 
pretreatment tumor biopsy
Clarification of pretreatment tumor 
biopsy to ensure no participants are 
unnecessarily screen failed
Table 2-2 On-Treatment 
Procedural Outline
Addition of the collection of 
Chemistry, Hematology and 
Urinalysis on D8 for participants 
receiving Gemcitabine and Nab-
Paclitaxel (ABRAXANE) in 
subsequent cycles.
Omission of safety laboratories for 
participants receiving Gemcitabine 
and Nab-Paclitaxel (ABRAXANE)
Table 2-2 On-Treatment 
Procedural Outline
Update to the notes section for 
collection of Vital signs 
Clarifying Vital Signs collection. 
Table 2-2 On-Treatment 
Procedural Outline
Update to the notes section for 
collection of ECGs 
Clarifying ECG collection. 
Table 2-2 On-Treatment 
Procedural Outline
Inclusion of notes to describe the 
collection of optional on treatment 
tumor biopsy and the collection of 
On Progression tumor biopsy  
Clarification to the collection 
requirements of on treatment and on 
progression tumor biopsies 
Section 3.1.4 Rationale for 
Combining Cabiralizumab and 
Nivolumab, Section 5.4.2 
Rationale for Combining 
Cabiralizumab and Nivolumab 
Therapy 
Addition of data to support the 
combination of cabiralizumab and 
nivolumab 
To confirm the rationale for 
combining cabiralizumab and 
nivolumab.
Table 7-1 Study Treatments for 
CA025006
Minor updates to the dosage form of 
some products
Section 7.4.8, Crossover Post 
Disease Progression for 
Participants Treatment with 
Chemotherapy Only. 
Removed Section 7.4.8 and updated 
Section 5.1.2 Treatment period to 
reflect the change.
The population eligible for crossover 
will not meet the eligibility criteria for 
prior lines of treatment.  
Section 9.4.2 Vital Signs 
Updated to reflect Table 2-2
Clarifying Vital Sign collection
Section 9.4.3 
Electrocardiograms
Updated to reflect Table 2-2
Clarifying ECG collection
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Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Throughout protocol
Adding a 5 minute window for 
infusion period for cabiralizumab and 
nivolumab 
Window period was added to provide 
some logistical flexibility to the 
infusion period of cabiralizumab and 
nivolumab
Section 10.1 Sample Size 
Determination
Addition wording about the sample 
size calculation and the assumption 
of PFS value 
Clarification on the PFS assumption 
used.  
Throughout protocol
Minor corrections to add clarity as 
needed
Overall Rationale for the Revised Protocol 02, 09-Mar-2018
Changes were made to the protocol based on data collected from the preliminary safety cohort.
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 3, Introduction; Section 4, 
Objectives and Endpoints; Section 
5.1, Overall Design; Figure 5.1-1, 
Study Design Schematic; Section 6.1, 
Inclusion Criteria “2.b”; Section 6.2, 
Exclusion Criteria “3.d”
Eligible participants include those 
that have progressed after only 1 line 
of chemotherapy.
Changed to increase 
homogeneity of the treated 
population.
Section 5.1.2, Treatment Period; 
Section 10.1, Sample Size 
Determination
Participants will be stratified by 
ECOG status (0 or 1).
Changed to ensure similar 
distribution across cohorts and 
increase homogeneity of the 
treated population.
Table 2-1, Screening Procedural 
Outline; Section 5.1.1, Screening 
Period; Section 5.1.2, Treatment 
Period; Section 5.4, Scientific 
Rationale for Study Design; Section 
9.1.1, Imaging Assessment for the 
Study
Screening window updated from 28 
to 30 days.
Screening window was 
increased to provide more time 
to evaluate the participant 
without the need to repeat 
laboratory assessments and 
scans.
Table 2-1, Screening Procedural 
Outline; Section 5.1.1, Screening 
Period; Section 6.1, Inclusion 
Criteria “3.d.ii”
All participants must have fresh 
tumor biopsy taken during screening.
Up to approximately 
8 participants/cohort (~20%) will be 
allowed on treatment with 
To minimize the number of 
participants that are deemed 
ineligible based on the absence 
of adequate tumor sample after 
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Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
pretreatment biopsies that do not 
yield adequate tumor tissue.
already having undergone the 
procedure.
Section 7.1, Treatments 
Administered
For combination cohorts, 
cabiralizumab will be given on Day 1 
and Day 15 of each 28-day treatment 
cycle.
Corrected typographical error.
Table 2-1, Screening Procedural 
Outline; Table 9.4.4-1, Clinical 
Laboratory Tests
Removed fasting requirement for 
laboratory tests.
Removed, as study treatment is 
not expected to have a major 
influence on blood sugar.
Table 2-2, On-treatment Procedural 
Outline; Section 9.4.2, Vital Signs; 
Section 9.4.3, Electrocardiograms
Study assessments separated into 
Cycles 1 and 2 and subsequent 
cycles.
Edited to streamline the number 
of visits for the participants.
Section 5.1.2, Treatment Period; 
Section 5.4.1, Rationale for 
Chemotherapy Regimes in Treatment 
Arm A; Table 7-1, Study Treatments 
for CA025006; Section 7.1, 
Treatments Administered
ONIVYDE-based treatment regimens 
may be substituted with FOLFIRI.
To provide an alternative 
treatment option for sites where 
ONIVYDE is not commonly 
used.
Section 4, Objectives and Endpoints; 
Section 9.1, Efficacy Assessments
Edited and added to primary, 
secondary, 
 
endpoints.
Edited to streamline the 
endpoints.
Section 5.1.3.1, Safety Follow-up 
Period; Section 5.1.3.2, Imaging 
Follow-up Period
Follow-up text edited to match 
current BMS programs.
Edited to align with BMS 
processes.
Section 6.1, Inclusion Criteria “3.f.i”
Adequate organ function is defined 
as ALT and AST 2 ULN.
Decreased to minimize the 
number of participants that may 
need to hold/discontinue study 
treatments due to pre-existing 
liver alterations.
Section 6.1, Inclusion Criteria; 
Section 6.2, Exclusion Criteria; 
Section 6.3, Lifestyle Restrictions; 
Section 7.4.4, Dose Discontinuation 
Criteria for Cabiralizumab and 
Changes to study restrictions based 
on current study data:
Upon progression biopsy added
Study restrictions were updated 
based on current safety 
information.
Revised Protocol No.: 04
Date: 17-Jun-2019
156
6.0
Aproved
93019361
6.0v
Approved
1.0
v

Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Nivolumab; Section 7.4.6.1, 
Gemcitabine + Nab-paclitaxel; 
Section 7.4.6.2, Dose Modification 
for FOLFOX; Section 7.6.1, 
Prohibited and/or Restricted 
Treatments; Section 9.4.4, Clinical 
Safety Laboratory Assessments; 
Section 9.8.1, Tumor Tissue 
Specimens
Clarified that participants may 
only have 1 previous line of 
therapy
Progressive CNS metastases not 
excluded
Removed exclusion of 
participants with current or 
recent gastrointestinal disease
Added exclusion of participants 
with prior exposure to 
gemcitabine and 5-FU or 
gemcitabine and oxaliplatin co-
administered as first line 
treatment
Removed restriction of 
consumption of non-pasteurized 
milk while on study
Added restriction of alcoholic 
beverage consumption while on 
study
Table 7.4.6.2-1, Recommended Dose 
Modifications of FOLFOX
5-FU infusions updated to 46 hours 
at all dose levels.
Aligned to standard of care 
guidelines.
Section 7.4.7, Treatment Beyond 
Disease Progression
Imaging language updated.
Aligned to BMS standards.
Section 7.4.8, Crossover Post-
Disease Progression for Participants 
Treatment with Chemotherapy Only
Removed section.
The population eligible for 
crossover will not meet the 
eligibility criteria for prior lines 
of treatment.
Appendix 9
TNM Staging added.
Added to better characterize the 
baseline characteristic of the 
treated population.
Throughout
Instances of “leucovorin” updated to 
“leucovorin (calcium folinate)”.
Clarified for generic drug 
naming conventions.
Throughout
General edits for clarity.
Corrected errors
Revised Protocol No.: 04
Date: 17-Jun-2019
157
6.0
Aproved
93019361
6.0v
Approved
1.0
v

Clinical Protocol
CA025006
BMS-986227
cabiralizumab
Overall Rationale for the Revised Protocol 01, 28-Nov-2017
Changes were made to the protocol based on data collected from the preliminary safety cohort.
Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 1 Synopsis
Revision to Objectives
Revision to Objectives align 
with protocol body
Section 2 Schedule of 
Activities
Added Hematology and urinalysis in 
Laboratory Tests; Added Fresh 
On-Treatment Tumor Biopsy
Added to correct omission
Section 3.1.5 Rationale for 
Combining Immunotherapy 
and Chemotherapy 
Regimens
Expanded rationale for combining 
immunotherapy and chemotherapy agents
Added 
Section 6.2 Exclusion 
Criteria
Removed criteria excluding participants who 
had any GI surgery and an inability to 
tolerate oral medication
Removed 
Section 7.4.4 Dose 
Discontinuation Criteria for 
Cabiralizumab and 
Nivolumab
Added criteria for permanent dose 
discontinuation and exceptions
Added 
Section 7.4.8 Treatment 
Beyond Disease Progression 
with Chemotherapy in 
Subjects with Solid Tumors
Correction to re-assignment of treatment to 
participants receiving platinum-based 
chemotherapy
Correction of error
Section 9.4.2 Vital Signs
Added description of vital sign time points
Clarified vital sign time points 
in the Preliminary Safety 
Cohorts
Revised Protocol No.: 04
Date: 17-Jun-2019
158
6.0
Aproved
93019361
6.0v
Approved
1.0
v