A Phase 1 Study of Cabiralizumab (BMS-986227, FPA008) Administered Alone or in Combination With Nivolumab (BMS-936558) in Advanced Malignancies
Phase: PHASE1
Conditions: Advanced Malignancies
Sponsor: Bristol-Myers Squibb

Page: 1
Protocol Number: CA025001
IND Number: N/A
Ex-US: Non-IND
EUDRACT Number: N/A
Date: 17-Jan-2017
Revised Date: 22-Mar-2018
Clinical Protocol CA025001
A Phase 1 Study of Cabiralizumab (BMS-986227, FPA008) Administered Alone or in 
Combinationwith Nivolumab (BMS-936558) in Advanced Malignancies
Revised Protocol Number: 05
Study Director
Medical Monitor
Naoko Murakami 
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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 ethicscommittee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (e.g., 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 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, e.g., a Contract Research 
Organization (CRO).

Clinical Protocol
CA025001
BMS-986227
cabiralizumab
Revised Protocol No.: 05
Date: 22-Mar-2018
2
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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.

Clinical Protocol
CA025001
BMS-986227
cabiralizumab
Revised Protocol No.: 05
Date: 22-Mar-2018
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 05
22-Mar-2018
Added Clarification inbone marrow sample for efficacy 
assessments in subject with Multiple Myeloma
Revised Protocol 04
17-Oct-2017
RemovedSurvival follow-up after Follow up Period
Revised Protocol 03
12-Sep-2017
Incorporate DLT criteria with other ongoing studies. 
Providedsome clarifications in the protocol
Revised Protocol 02
06-Jul-2017
Added Clarification of the allowance on treatment phase 
procedural outline
Added Correction and clarification of pharmacokinetic 
sampling schedule 
Provided some clarifications in the protocol
Administrative Letter 01
26-Apr-2017
Clarifications in laboratory test
Revised Protocol 01
08-Mar-2017
Incorporates Amendment 01
Amendment 01
08-Mar-2017
Addedclarification of DLT evaluable participants

 
Added the clarification of pulse oximetry requiremenet.
Provided some clarifications in the protocol 
Original Protocol
17-Jan-2017
Not Applicable
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Clinical Protocol
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BMS-986227
cabiralizumab
OVERALL RATIONALE FOR REVISED PROTOCOL 05:
The main purpose of this revised protocol is to clarifybone marrow sample for efficacy 
assessments in subject with Multiple Myelomain order to reduce ambiguity regarding study 
procedures:
The revised protocol applies to all participants.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number 
& Title
Description of Change
Brief Rationale
Section
9.1.2.1:
Laboratory 
Assessments
1)Include the detailed explanation 
regarding FISH
2)Added Minimal Residual Disease 
(MRD)to Table 9.1.2.1-1
All
Minor formatting and typographical 
corrections
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TABLE OF CONTENTS 
TITLE PAGE 
................................................................................................................ 
DOCUMENT HISTORY 
.............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 05: 
..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05 
......................... 
TABLE OF CONTENTS 
.............................................................................................. 
1 SYNOPSIS 
................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 OBJECTIVES AND ENDPOINTS 
........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design 
.................................................................................................. 
5.1.1 Cabiralizumab monotherapy dose escalation 
.......................................... 
5.1.1.1 Dose Limiting Toxicity 
.................................................................... 
5.1.2 Cabiralizumab in Combination with nivolumab: .................................... 
5.1.3 Data Monitoring Committee and Other External Committees 
................ 
5.2 Number of Participants 
..................................................................................... 
5.3 End of Study Definition 
.................................................................................... 
 
 
 
 
 
 
 
 
 
 
 
6 STUDY POPULATION 
............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
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6.2 Exclusion Criteria 
............................................................................................. 
6.3 Lifestyle Restrictions 
........................................................................................ 
6.4 Screen Failures 
.................................................................................................. 
6.4.1 Retesting During Screening Period 
......................................................... 
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 Criteria to Resume Treatment with Cabiralizumab and Nivolumab 
....... 
7.4.3 Dose Reduction with Cabiralizumab and Nivolumab 
.............................. 
7.4.4 Treatment beyond Disease Progression with Cabiralizumab and 
Nivolumab in Subjects with Solid Tumor 
.................................................... 
7.4.5 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 
........................... 
7.6 Treatment Compliance 
...................................................................................... 
 
 
 
7.8 Treatment After the End of the Study 
............................................................... 
8 DISCONTINUATION CRITERIA 
........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Dose Discontinuation Criteria for Cabiralizumab and Nivolumab ........ 
8.1.2 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study 
........................................................................ 
8.3 Lost to Follow-Up 
............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES 
..................................................... 
9.1 Efficacy Assessments 
........................................................................................ 
9.1.1 Efficacy Assessment in Subjects with Solid Tumor 
.................................. 
9.1.1.1 Imaging Assessment 
........................................................................ 
9.1.2 Efficacy Assessments in Subjects with Multiple Myeloma 
....................... 
9.1.2.1 Laboratory Assessments 
.................................................................. 
9.1.2.2 Skeletal Survey 
................................................................................ 
9.1.2.3 Assessment of Extramedullary Plasmacytoma................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
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 (DILI) 
............................................ 
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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 Optional Liver Biopsy 
.............................................................................. 
9.4.6 Imaging Safety Assessment 
...................................................................... 
9.5 Pharmacokinetic and Anti-Drug Antibody (ADA) 
........................................... 
 
 
 
 
 
 
 
 
9.7 Health Economics OR Medical Resource Utilization and Health Economics 
. 
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....................................................................................... 
10.3.3 Pharmacokinetic Analyses 
..................................................................... 
10.3.4 Immunogenicity 
...................................................................................... 
 
10.3.6 Other Analyses 
....................................................................................... 
10.3.7 Interim Analyses 
..................................................................................... 
 
12 APPENDICES 
......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERANCE CONSIDERATIONS 
.................................... 
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 SIMULATION TO EXAMINE MTPI VS. TRADITIONAL 3+3 FOR 
DOSE ESCALATION STUDY WITH 2 DOSE LEVELS 
.................................... 
APPENDIX 6 AE MANAGEMENT FOR CABIRALIZUMAB MONOTHERAPY 
COHORTS
 ..............................................................................................................
 
APPENDIX 7 AE MANAGEMENT FOR CABIRALIZUMAB AND NIVOLUMAB 
COMBINATION THERAPY COHORTS 
............................................................. 
APPENDIX 8 LABORATORY ABNORMALITIES MANAGEMENT TABLE 
...... 
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APPENDIX 9 ECOG PERFORMANCE STATUS 
..................................................... 
APPENDIX 10 RESPONSE CRITERIA (RECIST 1.1) 
.............................................. 
APPENDIX 11 DEFINITIONS OF RESPONSE AND PROGRESSION CRITERIA 
(MODIFIED FROM IMWG) ................................................................................. 
APPENDIX 12 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY 
...... 
APPENDIX 13 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY 
...... 
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CA025001
cabiralizumab
Revised Protocol No.: 05
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
1
SYNOPSIS
Protocol Title: A Phase 1 Study of Cabiralizumab (BMS-986227, FPA008) Administered Alone or in Combination 
with Nivolumab(BMS-936558) in Advanced Malignancies
Study Phase:1
Study Population:
Advanced solid tumorsand hematologic malignancies who is refractory to or have relapsed after standard therapies, 
or have no known effective treatment. 
Objectives and Endpoints:
Objective
Endpoint
Primary
To assess the safety and tolerability of 
cabiralizumabas monotherapy in subjects with 
advanced solid tumors.
Incidence of AEs, SAEs, AEs meeting protocol-
defined DLT criteria, AEs leading to 
discontinuation, 
death 
and 
laboratory 
abnormalitiesin monotherapy cohorts.
Secondary
To assess the safety of cabiralizumab in 
combination with nivolumab in subjects with 
advanced solid tumors and hematologic 
malignancies.
To characterize the PK profile of cabiralizumab 
administered alone and in combination with 
nivolumab.
To characterize the immunogenicity of 
cabiralizumaband nivolumab
To assess the preliminary anti-tumor activity of 
cabiralizumab administered alone and in 
combination with nivolumab in subjects with 
advanced solid tumors.
To assess the preliminary anti-tumor activity of 
cabiralizumab administered in combination with 
nivolumab in subjects with hematologic 
malignancies.
Incidence of AEs, SAEs, AEs leading to 
discontinuation, 
death 
and 
laboratory 
abnormalities
Summary measures of PK parameters (Section 
9.5) of cabiralizumab
Incidence of ADA to cabiralizumaband 
nivolumab
BOR, DOR assessed per RECIST 1.1 by 
investigator
BOR, DOR assessed per IMWG Response 
criteriaby investigator
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
Abbreviations: ADA, anti-drug antibody AE, adverse event; DLTs, dose limiting toxicities; BOR, best overall 
response, DOR,duration of response;PK, pharmacokinetic; SAE, serious adverse event
Overall Design:
This study is a Phase 1, open-label, dose escalation study to evaluate the safety, tolerability, PK, PD and preliminary 
anti-tumor activity of cabiralizumab as monotherapy in subjects with advanced solid tumor. In addition, the study will 
evaluate the safety profile, PK, PDand preliminary anti-tumor activityof cabiralizumab in combination with 
nivolumab in subjects with advanced solid tumors and hematologic malignancies.
For the monotherapy cohorts of the study, cabiralizumab will be given on Day 1 of each 14-day treatment cycle until 
the progression of disease, discontinuation of toxicity, withdrawal of consent or study closure. For the combination 
cohorts of the study, cabiralizumab and nivolumab will be given on Day 1 of each 14-day treatment cycle until the 
progression of disease, discontinuation of toxicity, withdrawal of consent or study closure. Nivolumab will be 
administered as an IV infusion over 30 minutes, and then cabiralizumab will be administered as an IV infusion over 
30 minutes.This study consists of 2 planned cabiralizumab monotherapycohorts (M1: 2 mg/kg and M2: 4 mg/kg) 
and 2 cohorts of cabiralizumab in combination with nivolumab (C1: 4 mg/kg cabiralizumab and 3 mg/kg nivolumab 
in subjects with solid tumor and C2: 4 mg/kg cabiralizumab and 3 mg/kg nivolumab in subjects with hematologic 
malignancies).The study design schematic is presented in Figure 1 and Figure 2.
Figure1:
Dose Escalation Schema
Figure 2.
Study Design Schema
A modified Toxicity Probability Interval (mTPI) design will be used to assess the tolerabilityofcabiralizumab in 
monotherapy. The DLT evaluation periodbegins on the first day of treatment andcontinues for 28 days.Participants
who receive at least 2 doses of study drug during the 28-day evaluation interval or participants who discontinue study 
treatment for drug-related AEs before receiving 2 doses of study drug will be considered evaluable for DLT 
determination. Dose escalation will be basedon the number of DLTs experienced during theDLT evaluation period
as determined by the Investigators and MedicalMonitor in consultation with Efficacyand SafetyReview Committee.
Number of Participants: 
This is a Phase 1 study and the sample size cannot be precisely determined and depends on the observed toxicities. 
Between 6 and 12 subjects are expected to be treatedduring dose escalation, assuming 2 mg/kg and 4mg/kg 
cabiralizumabmonotherapy are explored.On the combination cohorts, 6 subjects in each cohort are expected to be 
treated with 4 mg/kg cabiralizumabin combination with 3 mg/kg nivolumab following the dose escalationpart of 
monotherapy. In additio
n, Sponsor has the option to expand combination cohorts(up to 12 subjects in total per each 
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Clinical Protocol
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combination cohort)at the dose previously established to be safe in order to obtain additional data or to investigate 
alternative dose levels.
Treatment Arms and Duration:
Cohort M1: cabiralizumab2 mg/kg will be administered every 2 weeks until progression of disease, 
discontinuation due to toxicity, withdrawal of consent, or study closure.
Cohort M2:cabiralizumab4 mg/kg will be administered every 2 weeks until progression of disease, 
discontinuation due to toxicity, withdrawal of consent, or study closure.
Cohort C1/C2: cabiralizumab4 mg/kg in combination with nivolumab3 mg/kg will be administered every 2 
weeks until progression of disease, discontinuation due to toxicity, withdrawal of consent, or study closure.
Study treatment: 
Study Drug for CA025001
Medication
Potency
IP/Non-IP
Cabiralizumab(BMS-986227)
Solution for Injection
100 mg/vial (20 mg/mL)
IP
Nivolumab Solution for Injection
100 mg/vial (10 mg/mL)
IP
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA025001)
Procedure
Screening
Visit
Within 28 days prior to 
treatment assignment
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol specific informed 
consent is signed.
Inclusion/Exclusion Criteria
X
Medical History
X
Include any toxicities or allergy related to previous treatments.
Baseline Tumor Assessment
X
Prior/Concomitant Medications
X
Safety Assessments
Physical Examination (PE)
X
If the screeningPE is performed within 1 dayprior to dosing on Day 1 then a 
single exam may count as both the screening and pre-dose evaluation.
Physical Measurements
X
Includes height and weight.
ECOG P.S.
X
Assessment of Signs and Symptoms
X
Vital Signs
X
Includes body temperature, respiratory rate, and blood pressure and heart rate 
(sitting or supine). Blood pressure and heart rate should be measured after the 
participant has been resting quietly for at least 5 minutes. 
Pulse oximetry is performed at restand after exertion prior to nivolumab 
dosing at each dosing visit only for the combination cohorts.
Refer to Section 9.4.2
Electrocardiogram (ECGs)
X
ECGs should be recorded after the participant has been supine for at least 5 
minutes. 
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Clinical Protocol
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cabiralizumab
Table 2-1:
Screening Procedural Outline (CA025001)
Procedure
Screening
Visit
Within 28 days prior to 
treatment assignment
Notes
Laboratory Tests
X
Hematology: CBC with differential, platelets, hemoglobin, hematocrit, RBC
Chemistry: CK, AST, ALT, alkaline phosphatase, bilirubin (direct and total), 
BUN, calcium, chloride, creatinine, glucose, cholinesterase , LDH, 
phosphorus, potassium, sodium, albumin, amylase, lipase, thyroid panel (TSH, 
Free T3 and Free T4), PT/INR, PTT (aPTT)and Troponins
Urinalysis: Glucose, Protein, Blood
Serology
X
Includes hepatitis C antibody, hepatitis B surface antigen/hepatitis B core 
antibody, and Interferon-Gamma Release Assays (e.g. Quantiferon test).
Pregnancy Test
X
For WOCBP only.
Follicle Stimulating Hormone (FSH)
X
Women only. Refer to Appendix 4.
Baseline Tumor Assessment
For Solid tumor : Tumor Assessments
X
Refer to Section 9.1.1
For Multiple Myeloma
Refer to Section 9.1.2
  Myeloma Urine and Serum Lab tests
  (SPEP/UPEP/sFLC)
X
  Bone Marrow Aspiration/Biopsy
X
Refer to Table 9.1.2.1-1
  Skeletal survey
X
  Documentation of extramedullary soft 
  tissue plasmacytomas, if clinically 
  indicated
X
Perform CT or MRI at screening if clinicallyindicated or if patient had a 
previous extramedullary or bone plasmacytoma.
 
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Clinical Protocol
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Table 2-1:
Screening Procedural Outline (CA025001)
Procedure
Screening
Visit
Within 28 days prior to 
treatment assignment
Notes
Adverse Event Reporting
Monitor for Serious Adverse Events
X
All SAEs must be collected from the date of participant’s written consent 
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Clinical Protocol
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Table 2-2:
Treatment Phase Procedural Outline (CA025001)
Procedure
Cyclea1
Cycle 2~
EOTb
Follow-up 
Period
28 days and 100 
days post-last 
dose
D 1
D 2 
D 4 
D 8 
D 1
Notes
Safety Assessments
Physical Examination (PE)
X
X 
X
X
X
ECOG P.S.
X
X
X
X
Physical Measurementsc
X
X
X
X
Weight only
Within 72 hours prior to 
dosing.
Vital Signs
X
X 
X
X
X
See note in screening 
procedures and Section9.4.2.
Cohort C1, C2: measure Pulse 
oximetry at rest and after 
exertion prior to nivolumab 
dosing 
Electrocardiogram (ECGs) Refer to 
the DM ECG Study Guidelines
X
C2D1
X
See note in screening 
procedures and Section 9.4.3
Pre dose and within 1 hour of 
completion of cabiralizumab 
dosing on C1D1 and C2D1
Laboratory Tests
c
X
X 
X
X
X
See note in screening 
procedures and Section 9.4.4. 
Pre-dose on Day 1 on each 
cycle.
Within 72 hours prior to 
dosing.
Pregnancy Testc
X
X
X
X
Every 2 cycles D1within 72
hoursprior to dosing
Adverse Event Reporting
X
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Clinical Protocol
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Table 2-2:
Treatment Phase Procedural Outline (CA025001)
Procedure
Cyclea1
Cycle 2~
EOTb
Follow-up 
Period
28 days and 100 
days post-last 
dose
D 1
D 2 
D 4 
D 8 
D 1
Notes
Monitor for Non-Serious Adverse 
Events
X
Monitor for Serious Adverse Events
X
All SAEs must be collected 
from the date of participant’s 
written consent until 100 days 
of discontinuation of dosing 
Concomitant Medications Collection
X
Pharmacokinetic (PK)/ADA 
Assessments
Serial Blood PK Sampling
X 
X 
X 
X
Xd
X
X
See Section 9.5. 
ADA sampling
X
Xe
X
X
See Section 9.5.
 
 
Efficacy Assessments
Tumor Assessments (for Solid 
tumor)
X
Xf
Every 8 weeks (7 days) for 
first 48 weeks, then ever 12 
weeks (7 days) thereafter 
See Section 9.1.1
For Multiple Myeloma
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Clinical Protocol
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Table 2-2:
Treatment Phase Procedural Outline (CA025001)
Procedure
Cyclea1
Cycle 2~
EOTb
Follow-up 
Period
28 days and 100 
days post-last 
dose
D 1
D 2 
D 4 
D 8 
D 1
Notes
Myeloma Urine and Serum Lab tests
(SPEP/UPEP/sFLC)
X
Xf
Day 1 on every 2 cycles 
starting from C3D1
Bone Marrow Aspiration/Biopsy
For confirmation of CR/sCR if applicable or, if clinically indicated at time of 
suspected disease progression
Refer to Table 9.1.2.1-1
Skeletal survey
If clinically indicated
Documentation of extramedullary 
soft tissue plasmacytomas, if 
clinically indicated
As clinically indicated and at the time of CR/sCR assessments
Flow Cytometry 
For confirmation of CR/sCR if applicable or, if clinically indicated at time of 
suspected disease progression
Subsequent Treatment (Anti-cancer)
X
Survival Status
X
Clinical Drug Supplies
Study Drug Administrationg
X
X
Those supplied by BMS 
a Each cycle is 14-days.
b End of treatment (EOT) is defined as the visit where the decision is made to discontinue the participant from treatment.
c Physical measurements and laboratory tests do not need to be repeated if completed within the last 72 hours
d Cycles 2-9, 13, 21
e Cycles 2, 3, 5, 9, 13, 21
f Only participants who have not discontinued study treatment for progressive disease.
g Every 14 days ( 2days), subjects may be dosed no less than 12 days from the previous dose.
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the safety and tolerability ofcabiralizumab as 
monotherapy in subjects with advanced solid tumors.
Incidence  of AEs, SAEs, AEs meeting 
protocol-defined DLT criteria, AEs leading to 
discontinuation, death and laboratory 
abnormalitiesin monotherapy cohorts
Secondary
To assess the safety of cabiralizumab in combination 
with nivolumab in subjects with advanced solid tumors 
and hematologic malignancies.
To characterize the PK profile of cabiralizumab 
administered alone and in combination with nivolumab.
To characterize the immunogenicity of cabiralizumab
and nivolumab
To assess the preliminary anti-tumor activity of 
cabiralizumab administered alone and in combination 
with nivolumab in subjects with advanced solid tumors.
To assess the preliminary anti-tumor activity of 
cabiralizumab administered in combination with 
nivolumab in subjects with hematologic malignancies.
Incidence of AEs, SAEs, AEs leading to 
discontinuation, death and laboratory 
abnormalities
Summary measures of PK parameters (Section 
9.5) of cabiralizumab
Incidence of ADA to cabiralizumab and 
nivolumab
BOR, DOR assessed per RECIST 1.1 by 
investigator
BOR, DOR assessed by IMWG Response 
criteria by investigator
 
 
 
 
 
 
 
 
5
STUDY DESIGN
5.1
Overall Design
This study is a Phase 1, open-label, dose escalation study to evaluate the safety, tolerability, PK, 
and PD and preliminary anti-tumor activity of cabiralizumab as monotherapy in subjects with 
advanced solid tumor.  In addition, the study will evaluate thesafety profile, PK, PDand 
preliminary anti-tumor activityof cabiralizumab in combination with nivolumab in subjects with 
advanced solid tumors and hematologic malignancies.
For the monotherapy cohorts of the study, cabiralizumab will be given on Day 1 of each 14-day 
treatment cycle until the progression of disease, discontinuation of toxicity, withdrawal of consent 
or study closure. For the combination cohorts of the study, cabiralizumab and nivolumab will be 
given on Day 1 of each 14-day treatment cycle until the progression of disease, discontinuation of 
toxicity, withdrawal of consent or study closure. Nivolumab will be administered as an IV infusion 
over 30 minutes, and then cabiralizumab will be administered as an IV infusion over 30 minutes. 
This study consists of 2 planned cabiralizumab monotherapy cohorts (M1: 2 mg/kg and M2: 
4mg/kg) and 2 cohorts of cabiralizumab in combination with nivolumab (C1: 4mg/kg 
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cabiralizumab and 3 mg/kg nivolumab in subjects with solid tumor and C2: 4 mg/kg cabiralizumab 
and 3 mg/kg nivolumab in subjects with hematologic malignancies).
The study will consist of 3 periods: Screening, Treatment and Follow-up.The study will end after 
the last subject completes the last visit.
Screening begins by establishing the subject’s initial eligibility and signing of the informed consent
form(ICF). Subjects must have treatment assignment within 28 days after signing the informed 
consent.
The Treatment Phase begins when the treatment cohort is assigned to the subjects. The subjectwill 
be assigned to the open cohort (M1, M2, C1, or C2) at the timing of the treatment assignment.First 
dose should be started within 3 days of treatment assignment. The subjects will be required to be 
hospitalized for safety evaluation at least for 8 days from the first dose. The subjects can be 
discharged at the investigator’s discretion at Day 8.
The Follow-Up Phase begins when the decision to discontinue a subject from all treatment is made.
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to baseline, 
or are deemed irreversible. All adverse events will be documented for a minimum of 100 days 
after the last dose of study medication.The study design schematic is presented in Figure 5.1-1
andFigure 5.1-2.
Figure 5.1-1:
Dose EscalationSchematic
Figure 5.1-2:
Study Design Schematic
5.1.1
Cabiralizumabmonotherapy dose escalation
Enrollment of subjects in dose escalation part will be guided bythemTPI design. The study design 
sets a 25% target DLT rate with an equivalence interval of 20 -30%. Doses of cabiralizumabto 
be explored in this part of the study will be 2 mg/kg and 4 mg/kg. Decisions regarding dose 
escalation will be guided by the incidence of DLTs (see Section 5.1.2) occurring within the DLT 
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evaluation period (28-days) based on the modified Toxicity Probability Interval (mTPI) design. 
Subjects will be enrolled in successive cohorts of 3 or6 subjects. The first 3 subjects will receive 
2mg/kg of cabiralizumabevery 2 weeks. A decision to proceed to the next higher dose level 
(4mg/kg), to add 3 subjects at 2 mg/kg cohort or to stop the enrollmentwill be made once the first 
3subjects have completed DLT evaluation period. Guided by mTPI, the dose escalation needs to 
be agreed by the Efficacy and Safety Evaluation Committee after clinical assessment of the totality 
of available safety data from all treated participants. An additional dose level may also be evaluated 
if agreed upon by the Investigators, the Sponsor/Medical Monitor and the Efficacyand Safety 
Evaluation Committee.The performance of the design is reported in Appendix 5.Basically 3 or 
6subjects will be enrolled in a cohort. However, if additional subject will be enrolled in a cohort 
(e.g. 4 or 7 subjects), dose escalation will be guided by Table 1 in the Appendix 5.
Table 5.1.1-1:
Guidance for Dose Escalation/De-escalationBased on Observed 
Toxicity Outcomes
Number of Subjects Treated
3
6
Number of Subjects with DLTs
0
E
E
1
S
E
2
D
S
3
DU
D

DU
At Starting dose (2 mg/kg):
E: The current dose level is safe. Escalate and enroll subjects to the next higher dose level (4 mg/kg). If the next 
higher dose level (4 mg/kg) is deemed to be unacceptably toxic (DU) or has already enrolled 6 or more subjects 
with D, accept the current dose (2 mg/kg). 
S: If 6 or more subjects have already enrolled at this dose level, accept the current dose level (2 mg/kg). Otherwise, 
stay current dose and enroll 3 additional subjects.
D/DU: The current dose (2 mg/kg) is toxic, stop the enrollment.
At Maximum dose (4 mg/kg):
E: The current dose level is safe. Accept the current dose (4 mg/kg). 
S:If 6 or more subjects have already enrolled at this dose level, accept the current dose level (4 mg/kg). Otherwise, 
stay current dose and enroll 3 additional subjects.
D: De-escalate to the lower dose level (2 mg/kg). Accept the lower dose level (2 mg/kg) if 6 or more subjects have 
already been enrolled at the lower dose level (2 mg/kg).
DU: The current dose is unacceptably toxic. De-escalate to the lower dose level (2 mg/kg) without re-escalation to 
the current dose level (4 mg/kg). Accept the lower dose level (2 mg/kg) if 6 or more subjects have already been 
enrolled at the lower dose level (2 mg/kg).
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5.1.1.1
Dose Limiting Toxicity
Non-HematologicDLT
A DLT is defined as a study drug-related Non-Hematologic≥Grade 3 AE (using National Cancer 
Institute [NCI]Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) occurring 
during the first28-days, excluding: 
Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sitesof known or 
suspected tumor), 
Grade 3 rash, 
Grade 3 immune-related adverse event (irAE) thatresolved to a Grade 1 or less within 14 days, 
or a transient (resolving within 6 hours of onset)Grade 3 infusion-related AE.
Grade 3 or 4 increase in amylase and/or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis.
In the absence of clinical symptoms and other accompanying changes in bilirubin or ALT (as 
noted in appendices 6, 7and 8), serum elevations of AST/ALT > 12 ULN and 20 ULN 
that last for < 7 days will not be considered a DLT and serum elevations of CK and/or LDH > 
15 ULN and 20 ULNthat last for < 7 days will not be considered a DLT.
Any recurrence of Grade 3 rash, Grade 3 immune-related AE, orGrade 3 infusion-related AE will 
be considered a DLT. An irAE is defined as a clinicallysignificant AE that is associated with study 
drugexposure, of unknown etiology, and is consistentwith an immune-mediated mechanism.
Definition of Hematologic DLT
Any of the following study drug-related AEswill be considered a hematologic DLT:
Febrile neutropenia meeting the following criteria: body temperature 38.3C at a single 
measurement, or hyperthermia 38C with duration 1 hour AND neutrophil count 
<500/mm3or < 1,000/mm3and predicted to decrease to < 500/mm3within 48 hours
Grade 4 neutropenia that lasts > 5 days 
Grade 4 thrombocytopenia 
Grade 4 anemia
Grade 3 thrombocytopenia associated with clinically significant bleeding
Grade 3 or 4 hemolysis
Hemotoxicities requiring red blood cell or platelet transfusions.
If the events described above or any other clinically significant events occur, these events will be 
discussed by the investigator, Sponsor/Medical Monitor and the Efficacy and Safety Review 
Committee to determine whether they qualify as DLT considering its clinical significance.
Participantswho receive atleast two doses of study drug during the 28-dayevaluation interval or 
participantswho discontinue study treatment due to study drug-related AEs before receiving two 
doses of study drug will be considered as evaluable for DLT determination.
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If doses of cabiralizumabare delayedfor more than 28days during the DLT evaluation period
because of study drugrelated AEs, the Investigator and Sponsor/Medical Monitor will consult the 
Efficacy and Safety Review Committee and decide whether such events should be classified as a 
DLT or not, and whether subjects with such events should be considered to be “evaluable” or not.
Unevaluable subjects may be replaced at the same dose level. Subjects who miss a dose during the 
DLT evaluation period may continue on treatment if the subject does not otherwise meet the 
criteria for permanent discontinuation in Section 8.
Subjects who withdraw from the study during the DLT evaluation periodfor reasons other than a 
DLT are not evaluable for DLT and arereplaced at the same dose level. The dose escalation to the 
next dose level and initiation of combination cohort should be determined in considerationof all 
safety information, including information on adverse events occurred in subjects excluded from 
DLT evaluation.
5.1.2
Cabiralizumabin Combination with nivolumab:
After tolerability of a dose of 4 mg/kg cabiralizumabmonotherapy has been confirmed in the DLT 
evaluation period of the study, combination cohorts for both subjects with solid tumor and subjects 
with hematologic malignancies will open in parallel. 6 subjectsper each cohortwill be enrolled. 
The start of combination cohortsneeds to be agreed by the Efficacy and Safety Evaluation 
Committee. Subjects will undergo screening evaluations to determine eligibility within 28 days 
prior to the first doses of cabiralizumaband nivolumab on Day 1 of Cycle 1. Cabiralizumabat a 
dose of 4 mg/kg and nivolumab at a dose of 3 mg/kg will be administered every 2 weeks.
Sponsor has the option to expand the combination cohortsin order to obtain additional data or to 
investigate alternative dose levels to those defined in the protocol. Upon completion of 28 days 
follow-up from the first dose on initial 6 subjects on each combination cohort and afteragreed by 
the Efficacy and Safety Evaluation Committee, up to 24patients(12patients with advanced solid 
tumor and 12patients with hematologic malignancies) may be enrolled in combination cohortsto 
fully characterize safety, PK, and PD.
5.1.3
Data Monitoring Committee and Other External Committees
Efficacy and Safety Review Committee will be established in this study.
5.2
Number of Participants
Between 6 and 12 subjects are expected to be treated during dose escalation, assuming 2mg/kg 
and 4 mg/kg cabiralizumab monotherapy are explored. On the combinationcohorts, 6subjects 
each cohort are expected to be treated with 4 mg/kg cabiralizumab in combination with 3mg/kg 
nivolumab following the dose escalation part of monotherapy. In addition, Sponsor has the option 
to expand combination cohorts (up to 12 subjects in total per each combination cohort) at the dose 
previouslyestablished to be safe in order to obtain additional data or to investigate alternative dose 
levels tothose defined in the protocol.
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5.3
End of Study Definition
The start of the trial is defined as first visit for 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6 
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/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 subject care.
b) Consent for tumor biopsy samplesin subjects with solid tumor
i) Subject must consent to allow the acquisition of existing formalin-fixed paraffin-
embedded (FFPE) tumor tissue, either a block or unstained slides, for performance of 
correlative studies.An archival sample is acceptable only if there is not systemic 
immune-oncology therapy administered after the archival sample is collected.If an 
archived sample is not available, subject must consent to allow a pre-treatment tumor 
biopsy. In either case, study personnel must ensure that the tissue block or slides 
physically exist prior to initiating therapy. 
Subjects unable to provide an archived tumor 
sample and who either do not consent to a pre-treatment tumor biopsy or do not have 
accessible lesions are not eligible. Subjects whose pre-treatment biopsy yields 
inadequate tissue quantity or quality will not be ineligible on this basis alone.
ii)Where possible, the biopsied lesion should be distinct from target lesions being 
evaluated for radiologic response.
c) Subjects must be willing and able to comply with scheduled visits, treatment schedule, and 
laboratorytesting.
2) Type of Participant and Target Disease Characteristics
a) Cohort M1, M2 and C1: Subjects must have histologic or cytologic confirmation of an 
advanced (metastatic and/or unresectable) malignant solid tumor. Primary CNS 
malignancy is not allowed.
b) Cohort C2: Documented refractory or relapsed multiple myeloma
c) Subjects must be refractory to or have relapsed after standard therapies, or have no known 
effective treatment. Subjects who refuse or are ineligible for standard therapy will be 
allowed to enroll provided their refusal/ineligibility is documented in medical records.
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d) Subjects cannot have had dose reduced or therapy discontinued due to serious and/or 
life-threatening IOs-related toxicity (e.g., dose-limiting toxicity in prior study) per 
Investigator
's assessment in consultation with the BMS Medical Monitor.
IO: such as, but not limited to, anti-LAG-3, anti-CTLA-4, anti-PD-1, anti-PD-L1, 
anti-PD-L2, anti-KIR, anti-CD137, or anti-OX40 antibodies
e) Cohort M1, M2 and C1: Measurable disease according to Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1)
i) Target lesions may be located in a previously irradiated field if there is documented 
(radiographic) disease progression in that site after the completion of radiation therapy.
f) Cohort C2: Measurable disease at screeningwithin 28 days of treatment assignment, 
defined as one or more of the following:
i) Serum IgG, IgA, or IgM M-protein 0.5 g/dL
ii)Urine M-Protein 200 mg excreted in a 24-hour collection sample
iii)Involved serum freelight chain (sFLC) 100 mg/L provided the FLC ratio is abnormal
g) Eastern Cooperative Group (ECOG) Performance Status 0-1(Appendix 9)
h) Cohort M1, M2 and C1: Screening laboratory values must meet the following criteria 
(using CTCAE v4):
i) Neutrophils 1500/uL
ii)Platelet 100x103/uL
iii)Hemoglobin 9.0 g/dL
iv)Serum creatinine 1.5 x ULN or calculated creatinine clearance 50 mL/min (using 
the Cockcroft Gault formula)
Female CrCl = (140-age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl= (140-age in years) x weight in kg x 1.0
72 x serum creatinine in mg/ dL
v) PT/INR 1.5 x ULN and PTT (aPTT) ≤1.5 x ULN
vi)AST 3.0 x ULN 
vii)ALT 3.0 x ULN 
viii)
Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome who must 
have a total bilirubinlevel of < 3.0 x ULN)
ix)Albumin >3.0 g/dL (pancreatic cancer patients only)
i) Cohort C2: Screening laboratory values must meet the following criteria (using CTCAE 
v4):
i) Neutrophils 750/uL (stable off any growth factor within 2 weeks of first study drug 
administration)
ii)Platelet 50x103/uL (transfusion to achieve this level is not permitted within 2 weeks 
of first study drug administration)
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iii)Hemoglobin ≥ 8.5 g/dL (transfusion to achieve this level is not permitted within 1 week 
of first study drug administration)
iv)Serum creatinine 1.5 x ULN or calculated creatinine clearance 40 mL/min (using 
the Cockcroft Gault formula)
Female CrCl = (140-age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl = (140-age in years) x weight in kgx 1.0
72 x serum creatinine in mg/ dL
v) PT/INR 1.5 x ULN and PTT (aPTT) 1.5 x ULN
vi)AST 3.0 x ULN 
vii)ALT 3.0 x ULN 
viii)
Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome who must 
have a total bilirubin level of < 3.0 x ULN)
3) Age and Reproductive Status
a) Males and Females, ages 20
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) within1 day
prior to the start of study treatment.
c) Women must notbe breastfeeding(Even if breastfeeding is suspended, participation in the 
study is not allowed)
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s)and for a 
total of 5 monthspost-treatment completion.
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 monthspost-treatment completion.In addition, male 
participants must be willing to refrain from sperm donation during this time. 
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
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) Medical Conditions
a) Cohort M1, M2, and C1: Untreated or active central nervous system (CNS) or 
leptomeningeal metastases. Patients are eligible if metastases have been treated and 
patients are neurologically returned to baseline or neurologically stable (except for residual 
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signs or symptoms related to the CNS treatment) for at least 2 weeks prior to treatment 
assignment. In addition, patients must be either off corticosteroids, or on a stable dose or 
decreasing dose of <10 mg daily prednisone or prednisone equivalent
b) CohortM1, M2, and C1: Subjects with hepatocellular carcinoma (HCC)
c) Cohort C2: Subjects with solitary bone or extramedullary plasmacytoma as the only
evidence of plasma cell dyscrasia
d) Cohort C2: Subjects with monoclonal gammopathy of undetermined significance (MGUS), 
smoldering multiple myeloma (SMM), amyloidosis, Waldenstrom’s macroglobulinemia, 
or POEMS syndrome (plasma cell dyscrasia withpoly neuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes)
e) Cohort C2: Subjects with active plasma cell leukemia (defined aseither 20% of peripheral 
blood white blood cell count comprised of plasma/CD138+ cells or an absolute plasma cell 
count of 2 x 109/L)
f) Current or history of clinically significant muscle disorders (e.g., myositis), recent 
unresolved muscle injury, or any condition known to elevate serum CK levels
g) Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
h) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
treatment assignmentInhaled or topical steroids, and adrenal replacement steroid > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
i) Subjects with active or history of interstitial pneumonia or pulmonary fibrosis as diagnosed 
clinically or by imaging. Patients with radiation pneumonitis will be eligible if stabilization 
from fibrosis is confirmed and there is no concern for recurrence.
j) Decreased cardiac function with NYHA > Class 2
k) Uncontrolled or significant heart disorder such as unstable angina
l) Current unresolved infection or history of chronic, active, clinically significant infection 
(viral, bacterial, fungal, or other) which, in the opinion of the Investigator, would preclude 
the patient from exposure to a biologic agent or pose a risk to patient safety
m) Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or study drug administration or interfere with the 
interpretation of safety results
n) Evidence of coagulopathy or bleeding diathesis
o)Any major surgery within 4 weeks of study drug administration
p) Participants with a prior malignancy are excluded (except non-melanoma skin cancers, and 
in situ cancers such as the following: bladder, colorectal, cervical/dysplasia, melanoma, or 
breast). Participants with other second malignancies diagnosed more than 2 years ago who 
have received therapy with curative intent with no evidence ofdisease during the interval 
who are considered by the investigator to present a low risk for recurrence will be eligible.
q) Other active malignancy requiring concurrent intervention
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2) Prior/Concomitant Therapy
a) Cohort M1 and M2 (cabiralizumabmonotherapy), subjects with prior exposure to anti-
CSF1R therapy
b) Cohort C1 and C2(cabiralizumaband Nivolumab combination therapy), subjects with 
prior exposure to both ofanti-CSF1Rtherapyand anti-PD-1/PD-L1 antibody as either 
combination or sequential. 
c) Concomitant use of statins while on study. However, a patient using statins for over 3 
months prior to study drug administration and in stable status without CK rise may be 
permitted to enroll
d) Treatment with any anti-cancer therapy or participation in another investigational drug or 
biologics trial within 28 days prior to first dose of study drug administration
e) Non-oncology vaccine therapies for prevention of infectious diseases (e.g., HPV vaccine) 
within 4 weeks of study drug administration. The inactivated seasonal influenza vaccine 
can be given to patients before treatment and while on therapywithout restriction. 
Influenza vaccines containing live virus or other clinically indicated vaccinations for 
infectious diseases (i.e., pneumovax, varicella, etc.) may be permitted,but must be 
discussed with the Sponsor’s Medical Monitor and may require a study drug washout 
period prior to and after administration of vaccine.
f) Transfusion completed within 72 hours prior to first dose of study drug administration
g) Cohort C2: Subject has undergone any allogeneic transplant
h) Cohort C2: Subject has undergoneautologous transplantwithin 100 days of initiation of 
study drugs.
3) Physical and Laboratory Test Findings
a) 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
b) Significant abnormalities on ECG at screening.
i) QTcF > 450 msec for males
ii)QTcF > 470 msec for females
c) Positive bloodscreen for hepatitis C antibody, hepatitis B surface antigen, or HIV-1 and -
2 antibody 
d) Positive test for latent tuberculosis (TB) at screening [Interferon-Gamma Release Assays 
(e.g. Quantiferon test)] or evidence of active TB
4) Allergies and Adverse Drug Reaction
a) History of allergy to components of cabiralizumaband/or nivolumab.
b) History of any significant drug allergy
 (such as anaphylaxis or hepatotoxicity)
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
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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
LifestyleRestrictions
Not applicable.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequentlyassigned to treatment. A minimal setof screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening Period
Participant Re-enrollment: This study permits the re-enrollment of a participantthat has 
discontinued the study as a pre-treatment failure (i.e., participanthas not had treatment 
assignment). If re-enrolled, the participantmust be re-consented
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatoryvalue).
The most current result prior to treatment assignmentis the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
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:
Cabiralizumab
Nivolumab
An investigational product, also known as investigational medicinal product in some regions, is 
defined 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.
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Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standardof care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1:
Study treatments for CA025001
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
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
Nivolumab Solution for 
Injection
100 mg/vial
(10 mg/mL)
IP
Open Label
Vial
Refer to the label on 
container and/or pharmacy 
manual
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1: 
Selection and Timing of Dose
Cohort
Study Treatment
Unit dose 
strength(s)/
Dosage level(s)
Dosage formulation
Frequency of 
Administration
Route of 
Administration
M1a
Cabiralizumab
2 mg/kg
Every 2 weeks
Intravenous
M2
Cabiralizumab
4 mg/kg
Every 2 weeks
Intravenous
C1/C2
Cabiralizumab
4 mg/kg
Every 2 weeks
Intravenous
Nivolumab
3 mg/kg
Every 2 weeks
Intravenous
a A lower dose may be tested if appropriate.
Sponsor has the option to expand combination cohorts(up to 12 subjects in total per each 
combination cohort)at the dose previously established to be safe in order to obtain additional data 
or to investigate alternative dose levels to those defined in the protocol. 
No within-subject dose escalations will be permitted. If a dose level is found to exceed the MTD 
subjects enrolled in that dose level may be treated at a lower dose following consultation and 
agreement between Investigators,the Sponsorand Efficacy and Safety Review Committee.
7.2
Method of Treatment Assignment
All participants will be centrally assigned to treatment. Complete instructions will be providedin 
a separate manual.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
Enrolled participants, including those not dosed, will be assignedparticipant numbers comprised 
of the site number and subject number. For example, the first subject screened (ie, enrolled) at site 
number 1, will have a participant number of 0001 00101.Those enrolled participants meeting 
inclusion and exclusion criteria will be eligible to be dosed.
7.3
Blinding
Not applicable.
7.4
Dosage Modification
7.4.1
Dose Delayfor Cabiralizumaband Nivolumab
Administration of cabiralizumaband/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
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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 Sponsor’s Medical Monitor or designee as needed.
Fordose delays or modifications for all other AEs please refer to the AE management tables 
in Appendix 6and Appendix 7.
Patients who require a dose delay of cabiralizumabor cabiralizumab/nivolumab should be re-
evaluated weekly or more frequently if clinically indicated and resume study drug dosing when 
re-treatment criteria are met. If a patient experiences an infusion reaction to cabiralizumab, or 
nivolumab, or both study drugs, the infusion reaction should be treated following the infusion 
reaction treatment guidelines in Section 7.4.5, Appendix 6, 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 patient.
7.4.2
Criteria to Resume Treatment with Cabiralizumaband Nivolumab
Patients may resume treatment with cabiralizumaband/or nivolumab when the drug-related AE 
resolves as noted in the AE management tables in Appendix 6and Appendix 7or the abnormal 
laboratory management table in Appendix 8. The Sponsor’s Medical Monitor or designee can be 
contacted at any time if further clarification is needed.
7.4.3
Dose Reduction with Cabiralizumaband Nivolumab
Dose reduction for cabiralizumab and Nivolumab are not permitted.
7.4.4
Treatment beyond Disease Progression with Cabiralizumaband 
Nivolumabin Subjects with Solid Tumor
Accumulating evidence indicates a minority of patients treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease.
Patients treated with cabiralizumaband nivolumab combination therapy will be permitted to 
continue cabiralizumaband nivolumab treatment beyond initial RECIST v1.1 defined progressive 
disease, assessed by the Investigator, as long as the following criteria are met:
Patients who will be treated beyond disease progression must review and sign an ICF before 
continuing on study drug
The patient demonstrates investigator-assessed clinical benefit, and do not have rapid disease 
progression
Tolerance of study drugs
Stable performance status
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases)
A radiographic assessment/scan should be performed approximately 8 weeks (7 days) after initial 
Investigator-assessed progression to determine whether there has been a decrease in the tumor size 
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or continued progressive disease. The assessment of clinical benefit should be balanced by clinical 
judgment as to whether the patient is clinically deteriorating and unlikely to receive any benefit 
from continued treatment with cabiralizumaband nivolumab.
If the Investigator feels that any patient receiving cabiralizumaband nivolumab will obtain clinical 
benefit by continuing treatment, the patient may remain on the trial and continue to receive 
monitoring according to the time and event schedules per protocol.
For the patients who continue cabiralizumaband nivolumab study therapy beyond progression, 
further progression is defined as an additional 10% increase in tumor burden from time of initial 
progression. This includes an increase in the sum of diameters of all target lesions and/or the 
diameters of new measurable lesions compared to the time of initial progression. cabiralizumab
and nivolumab treatment should be discontinued permanently upon documentation of further 
progression.
7.4.5
Treatment of Cabiralizumaband Nivolumab-Related Infusion Reactions
Cabiralizumaband nivolumab may induce infusion or hypersensitivity reactions. If such reactions
were to occur, it may manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, hypo-
or hypertension, bronchospasm, or other symptoms.
Infusion reactions should be graded according to CTCAE v4guidelines. Any Grade 3 or Grade4 
infusion reaction should be reported within 24 hours to the Sponsor’s Medical Monitor 
or designee, 
and reported asan SAE if it meets the criteria.
The nivolumab 30-minute infusion will be administered first, with a 30-minute rest, followed by 
the cabiralizumab30-minute infusion. It may be unclear if an infusion reaction is due to 
cabiralizumab, nivolumab, or to both study drugs. Therefore, one set of treatment 
recommendations (based on the most conservative treatments for infusion reactions due to either 
study drug) is provided below and may be modified based on clinical judgment, local treatment 
standards and guidelines, and/or specific symptoms, as appropriate:
For Grade 1 symptoms: Mild reaction (e.g., localized cutaneous reactions including mild 
pruritus, flushing, rash), requires infusion rate to be decreased; intervention may be indicated.
Decrease the rate of the study drug infusion until recovery from symptoms.
Remain at bedside and monitor the patient’s vital signs until resolution of symptoms. 
Diphenhydramine 50 mg may be administered at the discretion of the treating physician.
When symptoms resolve, restartthe infusion at the original infusion rate.
If a patient has an infusion reaction with nivolumab, cabiralizumabcan be given (without 
prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling 
purposes, cabiralizumabinfusion may be given the next day. Prophylactic pre-infusion 
medications should be given prior to all subsequent nivolumab infusions.
If a patient has an infusion reaction with cabiralizumab, prophylactic pre-infusion medications 
should be given prior to all subsequent cabiralizumaband nivolumab infusions.
The following prophylactic pre-infusion medications are recommended prior to future 
infusions of cabiralizumaband nivolumab: diphenhydramine 50 mg (or equivalent) and/or 
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paracetamol (acetaminophen) 325 to 1000 mg at least 30 minutes before additional study drug 
administrations.
For Grade 2 symptoms: Moderate reaction (i.e., any symptom not listed above [mild symptoms] 
or below [severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension 
with systolic blood pressure >80 mmHg), requires infusion interruption but responds promptly to 
symptomatic treatment (e.g., antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, 
corticosteroids, IV fluids); prophylactic pre-infusion medications indicated for ≤24 hours.
Interrupt the study drug infusion.
Begin an IV infusion of normal saline, and treat the patient with diphenhydramine 50 mg IV 
(or equivalent) and/or paracetamol (acetaminophen) 325 to 1000 mg.
Remain at bedside and monitor the patient’s vital signs until resolution of symptoms. 
Corticosteroid therapy may be administered at the discretion of the treating physician.
When symptoms resolve, restart the infusion at 50% of the original infusion rate; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original 
infusion rate.
Monitor the patient closely. If symptoms recur, immediately discontinue the infusion; no 
further study drug will be administered at that visit. Administer diphenhydramine 50 mg IV, 
and remain at bedside and monitor the patient until resolution of symptoms.
If a patient has an infusion reaction with nivolumab infusion, cabiralizumabinfusion can be 
given (without prophylactic medications) if the infusion reaction resolves within 3 hours. For 
scheduling purposes, the cabiralizumabinfusion may be given the next day. Prophylactic pre-
infusion medications should be given prior to all subsequent nivolumab infusions.
If a patient has an infusion reaction with cabiralizumab,prophylactic pre-infusion medications 
should be given prior to all subsequent cabiralizumaband nivolumab infusions.
The following prophylactic pre-infusion medications are recommended prior to future 
infusions of cabiralizumaband nivolumab: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol (acetaminophen) 325 to 1000 mg should be administered at least 30 minutes 
before additional study drug administrations. If necessary, corticosteroids (up to 25 mg of 
SoluCortef or equivalent) may be used.
The amount of study drug infused must be recorded.
For Grade 3 or Grade 4 symptoms: Severe reaction such as bronchospasm, generalized urticaria, 
systolic blood pressure <80 mmHg, or angioedema; Grade 3 symptoms including prolonged 
symptoms, which require 6 or more hours to respond to symptomatic medication and/or 
discontinuation of infusion; recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae, such as renal impairment, pulmonary 
infiltrates; Grade 4: life-threatening; pressor or ventilation support indicated.
Immediately discontinue the study drug infusion. No further study drug will be administered. 
The amount of study drug infused must be recorded on the CRF.
Begin an IV infusion of normal saline, and treat the patient as follows: Recommend 
bronchodilators, epinephrine 0.2 to 1.0 mg of a 1:1,000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, 
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and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed.
Remain at bedside and monitor the patient’s vital signs until recovery from symptoms.
The patient should be monitored until the Investigator is comfortable that the symptoms will 
not recur.
Investigators should follow their institutional guidelines for the treatment of anaphylaxis.
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatmentis 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 treatmentarise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatmentnot supplied by BMS will be stored in accordance with the package insert.
Investigational product 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 (e.g., required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and pharmacy manual.
7.5.1
Dosing of Cabiralizumaband Nivolumab
For patients in the monotherapy cohorts, cabiralizumabinfusion will be administered as a 
30-minute IV infusion on Day 1 of each 14-day treatment cycle. For the combination therapy, 
nivolumab should always be administered first as a 30-minute IV infusion followed by a 30-minute 
infusion of cabiralizumab. The time in between infusions is expected to be approximately 
30minutes butman be more or less depending on the situation.Cabiralizumab ± Nivolumab will 
be administered every 2 weeks in 14-day (2days).Subjects may be dosed no less than 12 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 study drug administration. If the subject’s weight on the day of dosing differs by 
>10% from the weight used to calculate the prior dose, the dose must be recalculated. All doses 
should be rounded to the nearest milligram.
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The calculated dose for Cabiralizumab may be mixed in 5% Dextrose Injection, USP or 
0.9%Sodium Chloride Injection, USP to nominal concentrations of 1.0 mg/mL to 10mg/mL 
which can be infused over a period of 30 minutes through an intravenous line containing a sterile 
0.22micron in-line filter.  Further guidance and information for the preparation of the study 
medication is provided in the pharmacy manual.
The calculated dose for Nivolumab may be mixed in 5% Dextrose Injection, USP or 0.9% Sodium 
Chloride Injection, USP to nominal concentrations of 1 mg/mL –10 mg/mL which can be infused 
over a period of 30 minutes through an intravenous line containing a sterile, non-pyrogenic, 
low-protein binding in-line filter.Further guidance and information for the preparation of the 
study medication is provided in the pharmacy manual.
Doses of study drugs may be interrupted, delayed, or discontinued depending on how the patient 
tolerates the treatment.  
7.5.2
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit.
 
 
 
 
 
 
 
 
 
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7.8
TreatmentAfter the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatmentto 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participantreceives 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 investigational product (and non-investigational product 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 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 Bristol-Myers Squibb (BMS)
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Documented disease progression or clinical deterioration while receiving active study therapy 
with exception as described in section7.4.4.
Pregnancy
Patients who are required to have prohibited concomitant medications
Inability to comply with 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
All participants who discontinue study treatmentshould comply with protocol specified follow-up 
procedures as outlined in Section 2. 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 (i.e., is imprisoned or involuntarily incarcerated for the treatment of either
a psychiatric or physical illness).
If study treatmentis 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 case report form (CRF) page.
8.1.1
Dose Discontinuation Criteria for Cabiralizumaband Nivolumab
Discontinuation rules may be different for monotherapy and combination therapy and not all rules 
will apply to both arms of the study. For comprehensive discontinuation rules,refer to Appendix6
(monotherapy) and Appendix 7(combination therapy) or Appendix 8(laboratory abnormalities).
Treatment of cabiralizumabin monotherapy or cabiralizumabin combination with nivolumab 
should be discontinued in the following cases unless otherwise specified:
Any Grade 3 or higher uveitis or any Grade 2 drug-related uveitis, eye pain, or blurred vision 
that does not respond to topical therapy and does not improve to Grade 1 within the second re-
treatment period or that requires systemic treatment
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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, including drug-related uveitis, 
pneumonitis, hypoxia, bronchospasm, and endocrinopathies with the following exceptions:
o Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do notrequire discontinuation
o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia >7 days or associated with Grade ≥2 
bleeding requires discontinuation
Any drug-related liver function test (LFT) abnormality that meets any one of the following 
criteria requires discontinuation:
o ALT or AST >3x ULN and total bilirubin 
>2x ULN or INR > 1.5 xULN (in the absence 
of anticoagulation).
See Appendix 6and Appendix 7forguidelines and possibility of restarting 
therapy
o ALT or AST > 20x ULN (with or without concurrent liver metastases)
o Total bilirubin >3x ULN (>5x ULN with concurrent liver metastases)
Any Grade 4 drug-related AE or laboratory abnormality, except for the following events which 
donot require discontinuation:
o Grade 4 neutropenia <7 days
o Grade 4 lymphopenia or leukopenia <7 days
o 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.
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset
o Grade 4 drug-related endocrinopathy AEs, such as adrenal insufficiency, 
adrenocorticotropic hormone (ACTH) deficiency, hyper-or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic 
hormonereplacement (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.
o Grade 4 CK up to 20 xULN (in the absence of clinical sequelae)
Any event that leads to delay in dosing lasting >6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
o Dosing delays to manage drug-related adverse events are allowed. Prior to re-initiating 
treatment ina patient 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.
o Dosing delays lasting >6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Sponsor’s Medical Monitor or designee. 
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Prior to re-initiating treatment in a patient with a dosing delay lasting >6 weeks, the 
Sponsor’s Medical Monitor must be consulted. Tumor assessments should continue per 
protocol every 8weeks (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 patient with continued cabiralizumab
and/or nivolumab dosing
Any 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 3 or higher drug-related diarrhea or colitis, which does not resolve to Grade 1 or 
baseline within 28 days.
Any Grade 4 skin toxicity
Any Grade 4 renal toxicity
Any Grade 3 or higher pulmonary toxicity
If the causality of the adverse event requiring discontinuation is confirmed to be due to one of 
the study drugs in the combination therapy, the other drug may be continued per protocol 
schedule under the following scenarios:
o Timely resolution of the adverse event based on the treatment modification table
o Clinical benefit is shown by the patient based on Investigator assessment
8.1.2
Post Study Treatment Study Follow-up
In this study, safety and tolerability informationis a key endpoint 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 for at least 100 days after the last dose of study therapy.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatmentwill 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 participantto provide this information. 
Participantsshould 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 treatmentonly 
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.
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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 participantto one 
registered mail letter. All attempts should be documented in the participant’s medical records.
If it is determined that the participanthas died, the site will use permissible local methods to 
obtain date and cause of death.
If investigator’s use of 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 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.
If after all attempts, the participant remains lost tofollow-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.
Protocol waivers or exemptions are not allowed.
Allimmediate safety concerns must bediscussed 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 treatment assignment. 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 (e.g., 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.
9.1
Efficacy Assessments
BOR and DOR per RECIST 1.1(Appendix 10) orIMWG Response criteria(Appendix 11) by 
investigator evaluation per each participants will be assessed for efficacy.
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9.1.1
Efficacy Assessment in Subjects with Solid Tumor
9.1.1.1
Imaging Assessment 
Tumor assessments will be performed at Screening (within 28 days prior to first dose), then every 
8weeks (7 days) from the first dose, for the first 12 months, and then every 12 weeks (7 days) 
thereafter.All patients should have tumor response parameters assessed at the End-of-Treatment 
visit unless a tumor assessment has been performed within 8 weeks prior to an End-of-Treatment 
Visit or if tumor progression was previously determined. Patients who enter Long-Term Follow-
up while showing clinical benefit should have tumor assessments every 12 weeks (7 days) for 
duration of response. The same measuring modality should be preferably used by the site to 
maintain consistency across the study.
Response will be evaluated using RECIST v1.1 for measurable disease. Clinical lesions will only 
be considered measurable when they are superficial and 10 mm diameter as assessed using 
calipers. For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As previously noted, when lesions can be evaluated 
both by clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study. These assessments will follow the 
same schedule as the radiological assessments.
At the sponsor’s discretion, scans may be collected for review.
Contrast enhanced CT with PO/IV contrast or contrast enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. If a subject has a known allergy to contrast 
material, please use local prophylaxis standards to obtain the assessment with contrast if at all 
possible, or use the alternate modality. In cases where contrast is strictly contraindicated, a 
non-contrast scan will suffice. Should a subject have a contraindication for CT IV contrast, a 
non-contrast CT of the chest and a contrast enhanced MRI of the abdomen and pelvis may be 
obtained. Every attempt should be made to image each subject using an identical acquisition 
protocol on the same scanner for all imaging time points.
Use of 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 1.1 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 1.1 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 
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may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
Screening assessments are to be perform performedwithin 28 days prior to treatment assignment. 
In addition to the chest, abdomen, pelvis, and brain (to rule out brain metastases), all known sites 
of disease should be assessed at baseline. Subsequent assessments should include chest, abdomen, 
pelvis, andall known sites of disease using the same imaging method and technique as wasused 
at baseline.
In addition, subjects 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 Subjects with Solid Tumor is reported in7.4.4.
9.1.2
Efficacy Assessments in Subjects with Multiple Myeloma
9.1.2.1
Laboratory Assessments
All efficacy laboratory assessments (SPEP, UPEP, serum/urine immunofixation, and sFLC)and 
bone marrow assessment will be done locally. M protein absolute quantification (eg, g/dL or g/L) 
or sFLC (eg, mg/L or mg/dL) must be performed. Any laboratory samples analyzed locally be 
entered on the appropriate CRF/eCRF as requested by the Sponsor to properly assess efficacy per 
protocol criteria.
1) Serum: SPEP for M protein quantification, total serum protein, serum immunofixation, and 
quantitative immunoglobulin assay
a) Serum Immunofixation (IFE) is required at screeningand to confirm CR regardless of 
whether measurable M-protein was present at screening.
b) Subjects with measurable disease in SPEP will be assessed for response based on SPEP 
and not by the serum FLC assay.
c) Subjects with measurable disease in both SPEP and UPEP will be assessed for response 
based on these two tests and not by the serum FLC assay.
d) Subjects with FLC only disease should be monitored by sFLC only; SPEP, UPEP and IFE 
are required only to code CR in those subjects
2) Serum free light chain (sFLC)
a) Subjects without measurable serum M-protein (ie, < 0.5 g/dL (5 g/L)) or urine M-protein 
(ie, < 200 mg (0.2 g) per 24 hours) and considered oligosecretory must have sFLC assessed 
at every 2cycles starting from C3D1.
b) Serum for sFLC analysis must be collected at screening and time of serum and urine IFE 
negativity to confirm CR. This measurement is required to assess for sCR
3) Urine: 24-hour urine collection for M protein quantification and immunofixation. 24-hour 
urine must be collected with every 2 cyclesstarting from C3D1for all subjects (except FLC 
only disease subjects).
a) Urine Immunofixation (IFE) is required at screeningand to confirm CR, regardless or 
whether measurable M-protein was present at screening.
b) Subjects with measurable disease in UPEP will be assessed for response based on UPEP 
and not by the serumFLC assay.
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c) Subjects with FLC only disease should be monitored by sFLC only; SPEP, UPEP and IFE 
are required only to code CR in those subjects
4) Bone marrow aspiration/biopsy: percentage of plasma cell
Table 9.1.2.1-1:
Bone Marrow Sample
Aspirate
1) Samples required at the following times to evaluate percentage plasma cells:
a. Screening (within 28 days of treatment assignment)
b. When subject is immunofixation negative in both serum and urine (second bone marrow 
sample not required for confirmation)
i.In addition, evaluate flow cytometry to assess plasma cell clonality (ie, lambda 
and kappa IHC or flow cytometry to assess light chain restriction.
c. At time of suspected disease progression, if needed (see Appendix 11) to assess PD in 
subjects whose myeloma become nonsecretory.
Evaluation of percentage of plasma cells should be performed locally perinstitution standard practice;
Plasma cell percentage and light chainrestriction assessments are required. Ifnot available, IHC can 
be performed of bone marrow core biopsy.
2) Genetic assessments (FISH) should be performed on a fresh bone marrow sample locally at 
screening (within 28 days of treatment assignment),which may include but are not limited to:
t(4 ;14), t(14 ;16), and del(17p).
3) Samples should be collected and sent to the central lab at the following timesto evaluate
Minimal Residual Disease(MRD) status at times of potential CR.
a. Screening (within 28 days of treatment assignment)
b. At time of confirmation of CR/sCR if applicable
Biopsy
Not required by protocol unless an aspirate sample (at any time point above) is not available due to a 
dry tap or due to laboratory preferences of the local pathologist
5) Serum Corrected Calcium: Serum corrected calcium should be collected with eachcycle for 
all subjects until disease progression.
Corrected Calcium, mg/dL = (0.8 x [Normal Albumin, g/dL -Subject’s Albumin, g/dL] + 
Serum Ca, mg/dL
9.1.2.2
Skeletal Survey
Skeletal survey, by conventional radiography, for metastatic disease will be performedduring 28 
days prior toinitiationof study drugs. Skeletal survey will be performed on study if clinically 
indicated (development of compression fracture does not exclude response). Use of conventional 
or low dose CT scan (ie, of the spine) or MRI bone survey is acceptable. If imaging is performed 
on treatment for assessment of progression, the site 
must use the same modality of imaging as used 
in screening. The number and location of skeletal lesions and whether they are lytic should be 
recorded on the eCRF. On treatment survey should record whether there is an increase in the 
number or size of lytic lesions.
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9.1.2.3
Assessment of Extramedullary Plasmacytoma
Computed tomography or MRI should be performed at screening, if clinically indicated or if 
patient had a previous extramedullary or bone plasmacytoma. To minimize unnecessary radiation 
in myeloma subjects where progression is primarily based on serum and urine M-protein, on study 
assessments should only be performed if clinically indicated (ie, pain, concern for disease 
progression), whether or not present at baseline, and at the time of CR/sCR assessment.
A sum of the products of the longest diameters and longest perpendicular diameter for all 
measurable lesions will be calculated at screening. This sum will beused as the reference for on 
study assessments by which to characterize the objective tumor response.
All documented measurable and non-measurable lesions are to be followed throughout the trial. 
All assessments to be used for tumor response evaluation, including the baseline assessment, must 
be performed using the same method for repeat assessment. CT and MRI scanning are the 
preferable methods of assessment. Conventional CT and MRI should be performed with 
contiguous cuts of 10 mm or less or with cuts of5 (or 10) mm if spiral CT scanning is used. 
Imaging-based evaluation is preferred to evaluation by clinical examination. Evaluation by chest 
x-ray is less preferable than CT or MRI, and should only be used for well-defined lesions 
surrounded by aerated lung. Clinical examination is only acceptable when lesions are superficial, 
such as a skin nodule or palpable lymph node. Skin lesions must be documented by a photograph 
with a ruler. Ultrasound is not acceptable for documentation of measurable disease.
At the sponsor’s discretion, scans may be collected for review.
Measurable disease are lesions that can be accurately measured in 2 dimensions and both diameters 
must be 20 mm when evaluated by standard CT scanning or 10 mm when evaluated by spiral 
CT scanning or MRI. The minimum diameter size should be at least twice the slice thickness.
Non-measurable disease are all other lesions (or sites of disease), including those that are too small 
(ie, do not meet above criteria), occur within a previously irradiated area (unless they are 
documented as new lesions since the completion of radiation therapy), bone lesions,
leptomeningeal disease, ascites, pleural or pericardial effusion (exception for effusions 
documented by cytology as not malignant or present at baseline without progression), lymphangitis 
cutis/pulmonis, abdominal masses that are not pathologically/cytologically confirmed and 
followed by imaging techniques, and cystic lesions.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant
's legally authorized representative). 
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. 
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Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonseriousAE information should begin at initiation of study treatment until 
within 100days of discontinuation of dosing,at the timepoints specified in the Schedule of 
Activities (Section2). Nonserious AEinformation 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.
Investigator Brochure (IB) represent the Reference Safety Information to determine expectedness 
of serious adverse events 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 must be collected that occur during the screening period and within 100days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (e.g., a follow-up skin biopsy).
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 after obtaining informed 
consent will be recorded on the appropriate section of the eCRFsection.
All SAEs will be recorded and reported to 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 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 
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
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participantsshould 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
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All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2will 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 sothat 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 (e.g., 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 designeewill be reporting adverse events 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 
5half-lives(5 months) 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
In most cases, the study treatmentwill be permanently discontinued in an appropriate manner (e.g., 
dose tapering if necessary for participantsafety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy.
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.
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Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designeeto 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 nonserious AE CRF 
page or SAE Report Form electronic,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 participantto have study treatment
discontinued or interrupted
Any laboratory test result abnormality that required the participantto receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2and Appendix 3 for reporting 
details).
Potential drug induced liver injury
 is defined as: 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),or INR > 1.5 xULN (in the absence of anticoagulation)
AND
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
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 nonserious or serious AE, as appropriate, and reported accordingly.
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9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section9.2).
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.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
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.
9.4.2
Vital signs
Refer to Schedule ofActivities.Vital signs includerespiratory,heart rate, blood pressure, and 
temperature in the resting position (sitting or supine). Measure prior to dose and after completion 
of each IV infusion at the following time points: 10 (±5) minutes, 30 (±10) minutes, and 60 (±15) 
minutes, 168 hours (±24 hours) [Cycle 1 only] post cabiralizumabadministration; 10 (±5) minutes 
post nivolumab administration. Pulse oximetry is performed at rest and after exertion prior to 
nivolumab dosing at each dosing visit only for the combination cohorts.
9.4.3
Electrocardiograms
Refer to Schedule of Activities.12-lead ECG will be obtained at screening, pre dose and post dose 
of cabiralizumab(within one hour of completion of cabiralizumab)on C1D1 and C2D1, and end 
of treatment.If clinically indicated, additional ECGs may be obtained during the study. To 
minimize variability, it is important that patients 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 on each cycle must be available priorto 
dosing(unless obtaining assessment results are not possible due to local laboratoryfeasibility).
Hematology
Hemoglobin
Hematocrit
CBC including differential
Platelet count
RBC
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Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Glucose
Cholinesterase
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Creatine kinase
Troponins
Amylase
Lipase
TSH
FT3, FT4
PT/INR
PTT(aPTT)
Urinalysis
Protein
Glucose
Blood
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, HBc antibody, and Interferon-
Gamma Release Assays (e.g. Quantiferon test)(screening only)
Other Analyses
Pregnancy test (WOCBP only: screening, predose).
Follicle stimulating hormone (FSH) (screening only for women only) if required
If CK elevation is clinically significant, obtaintroponins (cardiac), CK isoenzymes, aldolase, and 
ECG; repeat CK and these additional tests within 48 hours or other interval as clinically indicated, 
until resolved or stable. If either AST or ALT is elevated, obtain total serum bilirubin, alkaline 
phosphatase; repeat within 48 hours or other interval, as clinically indicated, until resolved or 
stable. Additional tests may be obtained at any time, if clinically indicated. If a patient is being 
followed for a tumor marker (e.g. CA-125, or others), a sample for the tumor marker should be 
obtained at screening and every other cycle,or if clinically indicated during the study.
9.4.5
Optional Liver Biopsy
Optional liver biopsy may be performed at the discretion of the Investigator with an agreement 
with the Sponsor in the presence of significant liver enzyme elevations. It is performed to 
understand whether or not such elevations are clinically/pathologically relevant.
9.4.6
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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9.5
Pharmacokineticand Anti-Drug Antibody (ADA)
Pharmacokinetics of cabiralizumab and nivolumabwill be derived from serumconcentration 
versus time data. The pharmacokinetic parameters of cabiralizumabto be assessed, following the 
intensive PKcollection after first dose, are shown in below.
AI_Ctrough
CtroughAccumulation Index; ratio of Ctroughat steady-state(i.e. 
Cycle 8)to Ctroughafter the first dose
AUC(0-T)
Area under the serum concentration-time curve from time zero to 
time of last quantifiable concentrationafter the first dose
AUC(TAU)
Area under the serum concentration-time curve in one dosing 
interval
Cmax
Maximum observed serum concentration
Ctrough
Trough observed serum concentration(predose at each cycle)
T-HALFeff_Ctrough Effective elimination half-life that explains the degree of Ctrough
accumulation observed 
Tmax
Time of maximum observed serum concentration
Individual participant pharmacokinetic parameter values will be derived by non-compartmental 
methods by a validated pharmacokinetic analysis program. Actual times will be used for the 
analyses.
Table 9.5-1and Table9.5-2are listedthe sampling schedulefor Cohort M1/M2 and C1/C2to be 
the assessment of pharmacokineticsand immunogenicity respectively. Treatment assignments will 
be released to the bioanalytical laboratory in order to minimize unnecessary analysis of samples.
Additional samples for immunogenicity assessments, referred to as “ADA Event Driven” samples 
may be justified in cases of Grade 3/4 infusion or hypersensitivity reactions. The immunogenicity 
(and corresponding drug exposure) data from these samples will be reported as part of a subject’s 
overall immunogenicity assessment. Uniquely identified specimen collection kits and instructions 
for collection of “ADA Event Driven” samples will be provided by the central laboratory vendor
Table 9.5-1:
Pharmacokinetic Sampling Schedule forCohort M1 and M2
Study Cycle
(Study Day)
Event
Time 
Hour: Min
Sampling for 
cabiralizumab
Sampling for ADA 
(cabiralizumab)
Cycle 1
(Day 1)
Prior to infusion
00:00
X
X
EOIa
00:30
X
4 hrpost-start of
infusion
04:00
X
Cycle 1
(Day 2)
24 hr post-start of 
infusion
24:00
X
Cycle 1
(Day 4)
72hr post-start of 
infusion
72:00
X
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Table 9.5-1:
Pharmacokinetic Sampling Schedule forCohort M1 and M2
Study Cycle
(Study Day)
Event
Time 
Hour: Min
Sampling for 
cabiralizumab
Sampling for ADA 
(cabiralizumab)
Cycle 1
(Day 8)
168hr post-start of 
infusion
168:00
X
Cycle 2 –3
(Day 1)
Prior to infusion
00:00
X
X
Cycle 4
(Day 1)
Prior to infusion
00:00
X
Cycle 5
(Day 1)
Prior to infusion
00:00
X
X
Cycle 6 –8
(Day 1)
Prior to infusion
00:00
X
Cycle 9, 13, 21
(Day 1)
Prior to infusion
00:00
X
X
End of Treatment
Post treatment
X
X
Follow-up
-
X
X
a EOI=End of Infusion, This sample should be taken immediately prior to stopping the infusion (preferably within 2 
minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly.
Table9.5-2:
Pharmacokinetic Sampling Schedule forCohort C1and C2
Study Cycle
(Study Day)
Event
(Relative to 
cabiralizumab)
Time 
(Relative to 
start of 
cabiralizumab 
infusion)
Hour: Min
Sampling for 
cabiralizumab
Sampling for 
Nivolumab
Sampling for 
ADA 
(cabiralizumab
and 
Nivolumab)
Cycle 1
(Day 1)
Prior to infusion
00:00
X
X
X
EOIa
01:30
X
X
4 hr post-start of  
infusion
04:00
X
Cycle 1
(Day 2)
24 hr post-start 
of infusion
24:00
X
Cycle 1
(Day 4)
72 hr post-start 
of infusion
72:00
X
Cycle 1
(Day 8)
168 hr post-start 
of infusion
168:00
X
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Table9.5-2:
Pharmacokinetic Sampling Schedule forCohort C1and C2
Study Cycle
(Study Day)
Event
(Relative to 
cabiralizumab)
Time 
(Relative to 
start of 
cabiralizumab 
infusion)
Hour: Min
Sampling for 
cabiralizumab
Sampling for 
Nivolumab
Sampling for 
ADA 
(cabiralizumab
and 
Nivolumab)
Cycle 2 –3
(Day 1)
Prior to infusion
00:00
X
X
X
Cycle 4
(Day 1)
Prior to infusion
00:00
X
Cycle 5
(Day 1)
Prior to infusion
00:00
X
X
X
Cycle 6 –8
(Day 1)
Prior to infusion
00:00
X
Cycle 9, 13, 21
(Day 1)
Prior to infusion
00:00
X
X
X
End of 
Treatment
Post treatment
X
X
X
Follow-up
-
X
X
X
a
EOI=End of Infusion, This sample should be taken within 15 min after end of infusionfor both cabiralizumab 
and nivolumab.
PKsamples will be analyzed for cabiralizumaband nivolumab by validated immunoassays.
Immunogenicity samples will be analyzed for anti-cabiralizumaband anti-nivolumab antibodies 
byvalidated immunoassays.
Serum samples may be used for potential exploratory bioanalysis (e.g., analysis of drug-ADA 
immune complexes); exploratory results will not be reported. Serum samples designated for 
immunogenicity, PK or biomarker assessments from the same collection time point may be used 
interchangeably, if required (eg, insufficient volume for complete assessment or to follow up on 
suspected immunogenicity related AE). In addition, serum samples will be archived, if the need 
arises and to the extent possible.
Detailed instructions for the pharmacokinetic blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
 
 
 
 
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
 
  
 
 
 
 
 
9.7
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
This is a Phase 1 safety study and the sample size cannot be precisely determined and depends on 
the observed toxicities. Between 6 and 12 participants are expected to be treated during dose 
escalation(Part 1), assuming 2mg/kg and 4 mg/kg cabiralizumabmonotherapy are explored. On 
the combination cohorts, 6 subjects each cohort are expected to be treated with 4mg/kg 
cabiralizumab in combination with 3 mg/kg nivolumab following the dose escalation part of 
monotherapy. 
In addition, Sponsor has the option to expand combination cohorts (up to 12subjects 
in total per each combination cohort) at the dose previously established to be safe in order to obtain 
additional data or to investigate alternative dose levels to those defined in the protocol.
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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Treated
All participants who take at least 1 dose of study treatment.
Pharmacokinetic
All treated participants who have evaluable concentration-time data
Immunogenicity
All treated participants who have baseline and at least one post baseline 
immunogenicity assessment
10.3
Statistical Analyses
Part 1 (cabiralizumabmonotherapy) and Part 2 (cabiralizumaband nivolumab combination 
therapy) willbeanalyzed separately.
The statistical analysis plan will be developed and finalized before database lock.
10.3.1
Efficacy Analyses
The efficacy analyses of best overall response (BOR) will be listed on treated population. Duration 
of response (DOR) will be listed for participants with a BOR of CR or PR. 
Endpoint
Statistical Analysis 
Methods
BOR
BOR for a participant will be assessed per RECIST 1.1 or IMWG by investigator
Listing
DOR
DOR for a participant with a BOR of CR or PRor better, is defined as the time between 
the date of first response and the date of the first objectively documented tumor 
progression per RECIST 1.1/IMWGor death, whichever occurs first.
Listing
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10.3.2
Safety Analyses
All safety analyses will be performed on the Treated population.
Endpoint
Statistical Analysis Methods
Incidence of AEs, SAEs, AEs leading to 
discontinuation, deaths
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 preferred term (PT) level, (2) once at the system 
organ class (SOC) level, and (3) once in the ‘Total subject’ 
row at their worst CTC grade, regardless of SOC or PT.
Lab abnormalities
Laboratory values will be graded according to 
CTCAE v4.03.
Lab shift table using the worst CTC grade on treatment per 
participant
10.3.3
Pharmacokinetic Analyses
The following parmacokinetic parameters of cabiralizumab will be summarized.
Endpoint
Statistical Analysis Methods
Cmax, AUC(0-T), AUC(TAU), AI-Ctrough, 
T-HALFeff_Ctrough
Summary statistics: geometric meansand coefficients of 
variation
Tmax.
Summary statistics: medians and ranges
Ctrough.
Summary statistics to assess attainment of steady state: geometric 
means and coefficients of variation; plots vs time by dose
PK time-concentration data may be pooled with data from other studies for population PK analysis, 
which will be presented in a separate report.
10.3.4
Immunogenicity
Endpoint
Statistical Analysis Methods
Incidence of ADA to Cabiralizumab/Nivolumab
Baseline ADA-positive subject is defined as a subject who has a 
ADA detected sample at baselinea. ADA-positive subject is a subject 
with at least 1 ADA-positive sample relative to baseline after 
initiation of the treatment
Frequency distribution of baseline ADA-
positive subjects and ADA-positive 
subjects after initiation of the treatment
a Baseline sample is the last sample before initiation of the treatment
 
10.3.6
Other Analyses 
Not Applicable.
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10.3.7
Interim Analyses 
Not Applicable.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
AI
accumulation index
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
-HCG
beta-human chorionic gonadotrophin
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimumobserved concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
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Term
Definition
Ctrough
Trough observed serumconcentration
CV
coefficient of variation
D/C
discontinue
dL
deciliter
DMC
Data monitoring committee
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ESR
Expedited Safety Report
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
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Term
Definition
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K+
potassium
kg
kilogram
L
liter
LAM
Lactation amenorrhea method
LDH
lactate dehydrogenase
ln
natural logarithm
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
mmHg
millimeters of mercury
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
PD
pharmacodynamics
PK
pharmacokinetics
PTT
partial thromboplastin time
QC
quality control
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
Subj
subject
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Term
Definition
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
T-
HALFeff_Ctrough
Effective elimination half life that explains the degree of Ctrough
accumulation observed)
Tmax, TMAX
time of maximum observed concentration
Vss/F (or Vss)
apparent volume of distribution at steady state
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP
women notof childbearing potential
x g
times gravity
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APPENDIX 2
STUDY GOVERANCE 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 eCRF is intended to refer to a person 
(Participant) who has consented to participate in theclinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
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 participantinformed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulationsprior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
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 (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEWBOARD/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, participantrecruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. 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 and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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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 local health authority)except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
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 for 
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 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 
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 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 yearafter completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects 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 to subjects, 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 participantvolunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., 
Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and 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:
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Provide a copy of the consent form and written information about the study in the language 
in which the participantis most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
Allow time necessary for participantor participant's legally acceptable representative to 
inquire about the details of the study.
Obtain an informed consent signed and personally dated by the participantor 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, 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 participantsubsequently 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 participantor 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 participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participantrecords. 
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant 
must also be informedabout the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, andwell-being of the study subjects 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 hand-written 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 medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of 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 treatmentintegrity 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.
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If
Then
Supplied by BMS (or 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
nonstudy disposition (e.g., lost, wasted) 
amount destroyed at study site, if 
applicable
amount returned to BMS
retain samples for 
bioavailability/bioequivalence, if 
applicable 
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:
label identification number or batch 
number 
amount dispensed to and returned by each 
participant, including unique participant
identifiers
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site doesnot have an 
established system that meets these requirements.
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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 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 designeeelectronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
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 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, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
taskFor electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designeetraining 
requirements and must only access the BMS electronic data capture 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 designeerepresentatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
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.
In addition, the study may be evaluated by Sponsoror designeeinternal 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.
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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 (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., anotherinvestigator, 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, 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 treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
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 treatments sourced from the sites stock 
or commercial supply, or a specialty 
pharmacy)
It is the investigator’s or designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, 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:
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On-site disposal practices must not expose humans to risks from the drug.
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 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, i.e., 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 Monitor 
to review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty 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, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
Participant recruitment (e.g., among the top quartile of enrollers)
Involvement in trial design
Other criteria (as determined by the study team)
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 publicationrequirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] 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.
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APPENDIX 3
ADVERSE EVENTSAND 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 participantadministered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
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SERIOUS ADVERSE EVENTS
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 participantwas 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: 
o 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)
o elective surgery, planned prior to signing consent
o admissions as per protocol for a planned medical/surgical procedure
o routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)
o medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason)
o admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participantor may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7for the definition of potential DILI.) 
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Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatmentis an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as 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 causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug 
administration and the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
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 drug 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.
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REPORTING OF SAES TOSPONSOR OR DESIGNEE
SAEs, whether related or not related to study drug, and pregnancies must be 
reported to BMS (or designee) within 24 hours of awareness of the event.
SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms).
The preferred method for SAE data reporting collection is through the eCRF.
The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning.
o In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
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 post-menopausal 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 folliclestimulating 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 period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
1 week minimum for vaginal hormonal products (rings, creams, gels)
4 week minimum for transdermal products
8 week 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.
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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 5 months after the end of study 
treatment.
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 EffectiveMethods That Are User Independent
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
Intrauterine device (IUD)c
Intrauterine hormone-releasing system (IUS)
c
Bilateral tubal occlusion
Vasectomizedpartner 
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. 
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 drug, 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 Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
* Not approved in Japan
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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.
Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure defined as 7 monthsafter the end of treatment in the maleparticipant.
Female partners of males participating in the study to consider use of effectivemethods of 
contraception untilthe end of relevant systemic exposure, defined as 5 monthsafter the end of 
treatment in the male participant.
Male participantswith 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 treatmentand until 7 monthsafter the end of treatment.
Refrain from donating sperm for the duration of the study treatment and for 7 monthsafter 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
SIMULATION TO EXAMINE MTPI VS. TRADITIONAL3+3 FOR 
DOSE ESCALATION STUDY WITH 2 DOSE LEVELS
The dose escalation part of the study utilizes the mTPI method. The mTPI uses a set of decision 
rules guided by simple Bayesian models and requires a definition of an equivalence interval (EI), 
in which any dose is considered close to the true maximum tolerated dose (MTD). For this study, 
the EI is defined as [20%, 30%] with the target toxicity rateof 25%. With this method, there are 3 
intervals in the toxicity probability scale: (0, 20%) that is considered lower than the target toxicity 
rate, [20, 30%] that is considered within the toxicity target range, and (30, 100%) that is considered 
toxic. 
Using this mTPI design, initially 3 eligible subjects will be treated at the dose level of 2 mg/kg. 
An additional 3 subjects may be added to the same dose level, and hence a total number of 3 to 
6subjects will be treated for a given dose level. A decision to consider the next higher dose level 
(4 mg/kg) or stop the enrollment will be guided by the number of subjects with dose-limiting 
toxicities (DLTs) observed (see Table 1).Basically 3 or 6 subjects will be enrolled in a cohort. 
However, if additional subject willbe enrolled in a cohort (e.g. 4 or 7 subjects), dose escalation 
will be guided by Table 1.
Table 1:
Guidance for Dose Escalation/De-escalation Based on Observed 
Toxicity Outcomes
Number of Subjects Treated
3
4
5
6
7
8
Number 
of 
Subjects 
with 
DLTs
0 
E
E
E
E
E
E
1 
S
E
E
E
E
E
2 
D
D
S
S
S
S
3
DU 
DU 
DU
D
S
S
4
DU 
DU
D
5
DU
6
At Starting dose (2 mg/kg):
E: The current dose level is safe. Escalate and enroll subjects to the next higher dose level (4 mg/kg). If the next 
higher dose level (4 mg/kg) is deemed to be unacceptably toxic (DU) or has already enrolled 6or moresubjects 
with D, accept the current dose (2 mg/kg). 
S:If 6 or more subjects have already enrolled at this dose level, accept the current dose level (2 mg/kg). Otherwise, 
stay current dose and enroll 3 additional subjects.
D/DU: The current dose (2 mg/kg) is toxic, stop the enrollment.
At Maximum dose (4 mg/kg):
E: The current dose level is safe. Accept the current dose (4 mg/kg). 
S:If 6 or more subjects have already enrolled at this dose level, accept the current dose level (4mg/kg). Otherwise, 
stay current dose and enroll 3 additional subjects.
D: De-escalate to the lower dose level (2 mg/kg). Accept the lower dose level (2 mg/kg) if 6or moresubjects have 
already been enrolled at the lower dose level (2 mg/kg).
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DU: The current dose is unacceptably toxic. De-escalate to the lower dose level (2 mg/kg) without re-escalation to 
the current dose level (4 mg/kg). Accept the lower dose level (2 mg/kg) if 6or moresubjects have already been 
enrolled at the lower dose level (2 mg/kg).
DU: The current dose is unacceptably toxic. De-escalate to the lower dose level (2 mg/kg) without re-escalation to 
the current dose level (4 mg/kg). Accept the lower dose level (2 mg/kg) if the maximum of 6 subjects have already 
been enrolled at the lower dose level (2 mg/kg).
Simulations were conducted to examinethe performances of the mTPI design and the traditional 
escalation A+B designs (including a 3+3 design) for this study. The 3+3 design starts from the 
lower dose level (2 mg/kg); adapts every cohort of 3 patients; considers the next dose level if 
unacceptable toxicity rate observed.  The “1/3” rule has been used in the designs, in the way that:
If the observed toxicity rate is < 1/3 in the initial cohort of subjects (3 subjects for the 3+3 
design), then this dose level will be considered safe, and proceeding with the next higher dose 
level will be discussed
If the observed toxicity rate is < 1/3 in the last cohort of subjects (3 subjects for the 3+3 design), 
then another 3 subjects will be enrolled to evaluate the safety at a max cohort.
If the observed toxicity rate is 1/3 in the first cohort of subjects, then another 3 subjects will be 
enrolled to evaluate this dose level further;
If the observed toxicity rate is > 1/3 in the first cohort of subjects, then this dose level will be 
considered too toxic and stop enrollment;
If the observed toxicity rate is < 1/3 at a max cohort size (6 subjects in total for the 3+3 design), 
then this dose level will be considered safe and proceeding with the next higher dose level will 
be discussed;
If the observed toxicity rate is 1/3 at a max cohort size (6 subjects in total for the 3+3 design), 
then this dose level will be considered as too toxic.
The mTPI design is knowledge-driven, which assumes a target toxicity rate. On the contrary, the 
traditional 3+3 design is algorithm-driven, which uses the “1/3” rule.
Simulation Implementation:
10,000 simulated trials
Target toxicity rate for the mTPI design: 25% with EI = [20, 30%]
mTPI design as described above
Traditional 3+3 design as described above
Table 2
Dose-Toxicity Scenarios
Scenario
True DLT Rate
2 mg/kg
4 mg/kg
1
0.1
0.15
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Table 2
Dose-Toxicity Scenarios
Scenario
True DLT Rate
2 mg/kg
4 mg/kg
2
0.1
0.2
3
0.15
0.25
4
0.20
0.25
5
0.25
0.33
Simulation Results:
Simulation results are summarized from all the simulated trials per scenario, and include the 
following statistics:
Selected (%): Frequency of each dose level being selected as acceptable dose level.
DLT rate: The average number of subjects who have DLT across all dose levels.
Average Sample Size: The average number of subjects across all dose levels.
Table 3
Simulation Results
Scenario
Designs
Items
Selected (%)
DLT Rate
Average 
Sample 
Size
Under
2 mg/kg
2 mg/kg 
4 mg/kg
1
True DLT rate
0.1
0.15
mTPI
Selected (%)
3.49
10.74 
85.77
12.4
7.6
3+3
Selected (%)
9.93
19.84 
70.23
12.8
9.5
2
True DLT rate
0.1 
0.2
mTPI
Selected (%)
3.55
15.29 
81.16
14.9
8.0
3+3
Selected (%)
10.16 
30.36 
59.48
15.3
9.6
3
True DLT rate
0.15 
0.25
mTPI
Selected (%)
8.19
25.13 
66.69
19.6
8.1
3+3
Selected (%)
20.49 
36.15 
43.36
19.8
9.3
4
True DLT rate
0.2
0.25
mTPI
Selected (%)
14.65 
27.50 
57.85
22.1
7.7
3+3
Selected (%)
31.84 
30.66 
37.50
22.3
8.8
5
True DLT rate
0.25 
0.33
mTPI
Selected (%)
22.46 
37.17 
40.36
28.0
7.6
3+3
Selected (%)
44.17 
34.17 
21.67
28.0
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In summary, the mTPI design selects the correct dose level more frequently than the traditional 
3+3 designs for under the true toxicity rate within EI evaluated. The average toxicity rates for 
mTPI design are slightly lower than the rates of the traditional designs. The traditional 3+3 designs 
are more conservative and may select sub-optimal dose frequently.
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APPENDIX 6
AE MANAGEMENT FOR CABIRALIZUMABMONOTHERAPY COHORTS
Hepatic Adverse EventManagement withoutLiverMetastasis
Grade ofLiver TestElevation Management
Follow-Up
ASTor ALT>3.0xULN
and
Totalbilirubin>2xULNor
INR>1.5
–  Discontinue cabiralizumabtherapyper protocol
–ContinueLFTmonitoringper protocoluntilresolution.
–Continuemonitoring forandotherassociatedclinicalsignsor
symptoms
–Contactthe MedicalMonitor
–Evaluate fornon-drugrelatedcausesofthelaboratoryabnormalities
(e.g.obstruction,viralinfection,Gilbert’sdisease,etc)
–Under selectedcircumstances(e.galternative etiologyis identified),
patientmayreceive additional therapyonlyafterconsultationand
agreementbetweentheSponsor/MMandthe investigatorifreceiving 
additionaltreatmentwithcabiralizumabis inthe bestinterestofthe
patient(e.g ifthe subjecthas demonstratedaresponsetotherapy)
ASTor ALT>5to≤ 12xULN
and
Totalbilirubin≤2xULN
–Continuecabiralizumabtherapyifthereare no
clinicalsignsofsignificantmuscle or hepatic
damage
–IncreasefrequencyofmonitoringofAST,ALT,
bilirubin, alkalinephosphataseandINR(every
48-72hoursormore frequently,asclinically
indicated)
–Monitor forother clinicalsymptoms(fatigue,
nausea,vomiting,abdominalpain,fever,
rash,and/oreosinophilia)
–Contactthe MedicalMonitorifthere are clinicalsignsof muscle or 
hepaticinjuryor otherclinicalsymptoms
–Contactthe MedicalMonitorifthere is aconcurrentincrease of
bilirubin,AST,ALT,or alkaline phosphatase frombaseline.
–NotifytheMedical Monitor ifthere is anASTincrease>5xULN
–Frequencyofretesting candecrease toonce aweek or lessif
abnormalitiesstabilize or the trialdrughasbeen discontinuedandthe 
subjectisasymptomatic
–Consider gastroenterologyor hepatologyreferral
ASTorALT>12to≤20xULN
and
Totalbilirubin≤2xULN
or
Isolatedtotalbilirubin>2to
≤3xULN
–Delaycabiralizumabtherapyper protocol
–Increasefrequencyofmonitoring(includingbut
notlimitedto) ofAST,ALT,bilirubin,alkaline 
phosphataseandINR(every48-72hoursor 
more frequently,asclinicallyindicated)
–Monitor forother clinicalsymptoms(fatigue,
nausea,vomiting,abdominalpain,fever,
rash,and/oreosinophilia)
–Considerimaging toruleoutobstruction
IfASTandALT≤ 12xULN for≤ 28days:
–Resume routinemonitoring
–Resume cabiralizumabtherapyatsamedoselevelper protocol
Ifelevationspersistatsame level for >28daysorworsen:
–Discontinue cabiralizumabtherapyper protocol
–DiscusswithMedical Monitor
ASTorALT >20xULN
or
Totalbilirubin>3xULN
–  Discontinue cabiralizumabtherapy
–ContinueLFTmonitoringper protocoluntilresolution
–Continuemonitoring forandotherassociatedclinicalsignsor
symptoms
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Hepatic Adverse EventManagement withLiver Metastasis
Grade ofLiver TestElevation Management
Follow-Up
ASTorALT>3.0xULN
and
Totalbilirubin>2xULNor
INR>1.5
–  Discontinue cabiralizumabtherapyper protocol –ContinueLFTmonitoringper protocoluntilresolution.
–Continuemonitoring forandotherassociatedclinicalsignsorsymptoms
–Contactthe MedicalMonitor
–Evaluate fornondrugrelatedcausesofthelaboratoryabnormalities
(e.g.obstruction,viralinfection,Gilbert’sdisease,etc)
–Under selectedcircumstances(e.galternative etiologyis identified),
patientmayreceive additional therapyonlyafterconsultationand
agreementbetweentheSponsor/MMandthe investigatorifreceiving 
additionaltreatmentwithcabiralizumabis inthe bestinterestofthe
patient(e.g ifthe subjecthas demonstratedaresponsetotherapy)
ASTor ALT>5to≤ 12xULN
and
Totalbilirubin≤2xULN
–Continuecabiralizumabtherapyifthereare no
clinicalsignsofsignificantmuscle or hepatic
damage
–IncreasefrequencyofmonitoringofAST,ALT,
bilirubin, alkalinephosphataseandINR(every
48-72hoursormore frequently,asclinically
indicated)
–Monitor forother clinicalsymptoms(fatigue,
nausea,vomiting,abdominalpain,fever,
rash,and/oreosinophilia)
–Contactthe MedicalMonitorifthere are clinicalsignsof muscle or 
hepaticinjuryor otherclinicalsymptoms
–Contactthe MedicalMonitorifthere is aconcurrentincrease of
bilirubin,AST,ALT,or alkaline phosphatase frombaseline.
–NotifytheMedical Monitor ifthere is anASTincrease>5xULN
–Frequencyofretesting candecrease toonce aweek or lessif
abnormalitiesstabilize or the trialdrughasbeen discontinuedandthe 
subjectisasymptomatic
–Consider gastroenterologyor hepatologyreferral
ASTorALT >12to≤20xULN
and
Totalbilirubin≤2xULN
or
Isolatedtotalbilirubin>3.0to
≤5xULN
–Delaycabiralizumabtherapyper protocol
–Increasefrequencyofmonitoring(includingbut
notlimitedto) ofAST,ALT,bilirubin,alkaline 
phosphataseandINR(every48-72hoursor as
clinicallyindicated)
–Monitor forother clinicalsymptoms(fatigue,
nausea,vomiting,abdominalpain,fever,
rash,and/oreosinophilia)
–Considerimaging toruleoutobstruction
IfASTandALT≤ 12xULN for≤ 28days:
–Resume routinemonitoring
–Resume cabiralizumabtherapyatsamedoselevelper protocol
Ifelevationspersistatsame level for >28daysorworsen:
–Discontinue cabiralizumabtherapyper 
protocolDiscusswithMedicalMonitor
ASTorALT>20xULN
or
Totalbilirubin>5xULN
–  Discontinue cabiralizumabtherapy
–ContinueLFTmonitoringper protocoluntilresolution
–Continuemonitoring forandotherassociatedclinicalsignsorsymptoms
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PeriorbitalEdemaAdverseEventManagement
GradeofPeriorbitalEdema
(NCICTCAE v4.03)
Management
Follow-Up
Grade 1
–Continuedosing cabiralizumabtherapyper protocolIfworsens:
–  Followasstatedbelow
Grade 2
–Delaycabiralizumabtherapyper protocol
IfreturnstoGrade 1or baseline before thenext dosingvisit:
–Resume cabiralizumabtherapyatsamedoselevelwithoutdelay
–Routine eyemonitoringperprotocol,ifclinicallystable
Ifswellingpersists>14daysbutreturnsbacktobaselineorGrade
1within28days:
–Continuecabiralizumabtherapyuponresolution
–Ifit recursatGrade 2or above,discontinue cabiralizumabtherapy
Grade ≥3
–Discontinue cabiralizumabtherapyper protocol.
Ifreturns toGrade1afterdiscontinuation:
–  Followupuntilresolution
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InfusionReactionsAdverseEventManagement
GradeofInfusionReactions
(NCICTCAEv4.03)
Management
Follow-Up
Grade 1
–Decrease infusionrate ofcabiralizumabtherapy
per protocolandrestartatnormalinfusionrate
oncesymptomssubside.
–Monitorpatientandstartsymptomatic treatment
asclinicallyindicatedwhichincludes
antihistaminesandNSAIDs
Ifinfusionreactionsymptomssubside within3hoursof
cabiralizumabtherapy:
–Subsequentdosing shouldincludeprophylacticpre-infusion
medicationsforcabiralizumabtherapy
–Continuecabiralizumabdosing atsamelevel
Grade 2
–Interruptcabiralizumabinfusion
–Systemic treatmentincludingNSAIDs,
corticosteroids,andantihistamines
–Normalsaline infusionandconstantmonitoring of
vitalsandotherparameters
–Ifsymptomsresolve,resumeinfusionat50%ofthe
infusionrateandthenincreaseto100%ifclinically
stable
–Resume cabiralizumabtherapyatsamedoselevel
–Futuredosing withpre-infusion prophylacticmedications
recommendedincludingantihistamines,NSAIDs,and
corticosteroidsupto25mgasneeded
Ifsymptomsrecur:
–Discontinue treatmentatthevisit
Grade≥3
–Discontinue cabiralizumabtherapyper protocol
–Followinstitutionalguidelinesfor
hypersensitivityreaction
–Systemic treatmentincludingNSAIDs,
corticosteroidsandantihistamines
–Normalsaline infusionandconstantmonitoring of
vitalsandotherparameters
–Bronchodilatorsasclinicallyindicatedwithor 
without hospitalization
Ifreturns toGrade1afterdiscontinuation:
–Systemic treatmentincludingtapering steroids,NSAIDs,and
antihistaminesuntilresolutionasneeded
–Followupuntilresolution
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APPENDIX 7
AE MANAGEMENT FOR CABIRALIZUMABAND NIVOLUMAB COMBINATION THERAPY 
COHORTS
GastrointestinalAdverse EventManagement
Ruleoutnoninflammatorycauses.Ifanoninflammatorycause is identified,treataccordinglyandcontinue nivolumabtherapy.Opiates/narcoticsmay 
mask symptomsof perforation.Infliximabshould notbeused incasesofperforation orsepsis.
Grade ofDiarrhea/Colitis
(NCICTCAEv4.03)
Management
TreatmentandFollow-Up
Grade1:Diarrhea:<4 stools/day
overbaseline;Colitis:
asymptomatic
–Continuecabiralizumaband nivolumab
therapyperprotocol
–Symptomatic treatment
–Close monitoring forworsening symptoms
–Educatepatienttoreportworsening immediately
Ifworsens:
–Treat as Grade 2 or 3/4
Grade 2: Diarrhea:4–6stools
perdayoverbaseline;IVfluids
indicated
<24hours;notinterferingwith 
ADL;Colitis:abdominalpain;
bloodinstool
–Delaycabiralizumaband nivolumabper 
protocola
–Symptomatic treatment
IfimprovestoGrade1≤4days:
–Resume cabiralizumabandnivolumabtherapyper protocol
Ifpersists≥5–7daysorrecurs:
–0.5–1mg/kg/day methylprednisolone ororal equivalent
–When symptomsimprovetoGrade1,tapersteroidsoveratleast1month,
considerprophylactic antibiotics foropportunisticinfections,andresume 
cabiralizumabandnivolumabtherapyper protocol
Ifworsensorpersists>3-5dayswithoralsteroids:
–TreatasGrade 3or4
Grade 3–4: Diarrhea (G3): ≥7 
stools per day over baseline; 
incontinence; IV fluids ≥24 
hours; interfering with ADL; 
Colitis (G3): Severe abdominal 
pain, medical intervention 
indicated, peritoneal signs
Grade 4:Life-threatening 
perforation
–Delay or Discontinue cabiralizumaband 
nivolumabtherapy per protocolb
–1 to 2 mg/kg/day methylprednisolone IV or 
IVequivalentc
–Add prophylactic antibiotics for opportunistic
infections
–Consider lower endoscopy if clinically 
indicated
If Grade 3 AE improves to Grade 1 or baseline within 28 days:
–Taper steroids over at least 1 month
–Resume dosing of cabiralizumaband Nivolumab
If Grade 4:
–Permanently discontinue cabiralizumaband Nivolumab
–Continue steroids until Grade 1, then taper steroids over at least 1 month
If persists >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 patient
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 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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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
RenalAdverse EventManagement
Ruleoutnoninflammatorycauses.Ifanoninflammatorycause is identified,treataccordinglyandcontinue nivolumabtherapy.
GradeofCreatinineElevation
(NCICTCAEv4.03)
Management
Follow-Up
Grade 1: Creatinine >1.0xto
1.5xbaseline;>1xULNto 
1.5xULN
–Continuecabiralizumaband nivolumab
therapyatthesame doselevelper protocol
–Monitor creatinine weekly
Ifreturnstobaseline :
–Resume routinecreatinine monitoring per protocol
Ifworsens:
–Followasstatedbelow
Grade2: Creatinine>1.5x to 
3.0xbaseline;>1.5xULNto 
3.0xULN
–Delaycabiralizumaband nivolumab
therapyperprotocola
–Monitor creatinine every2to3days
–0.5to1mg/kg/daymethylprednisoloneIV
ororalequivalentc
–Consider renalbiopsyifclinicallyindicated
IfreturnstoGrade1or baseline before thenext dosingvisit:
–Tapersteroids overatleast1month,considerprophylactic antibioticsfor
opportunisticinfections,andresume cabiralizumabandnivolumab
therapyatthesamedoselevel
–Routine creatinine monitoringper protocol
Ifelevationspersist>14daysor worsen:
–TreatasGrade 4
Grade3:Creatinine>3.0x
baseline;
>3.0xULNto 6.0xULN
–Delaycabiralizumaband nivolumab
therapyperprotocola
–Monitor creatinine every2to3days
–0.5to1mg/kg/daymethylprednisoloneIV
ororalequivalentc
–Consider renalbiopsyifclinicallyindicated
IfreturnstoGrade1or baseline before thenext dosingvisit:
–Tapersteroids overatleast1month,considerprophylactic antibioticsfor
opportunisticinfections,andresume cabiralizumabandnivolumab
therapyatthesamedoselevel
–Routine creatinine monitoringper protocol
Ifelevationspersist>14daysorworsen:
–TreatasGrade 4
Grade4: Creatinine >6.0xULN
–Discontinue cabiralizumabandnivolumab
therapyperprotocolb
–1to2mg/kg/day methylprednisolone IV
or IVequivalentc
–Consultnephrologist
–Consider renalbiopsyifclinicallyindicated
IfreturnstobaselineorGrade 1:
–Tapersteroids overatleast1monthandaddprophylactic 
antibioticsforopportunisticinfections
Ifworsens:
–Followupuntilresolution
–Clinicalreferralsasneeded
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 (e.g. 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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6.0
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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
PulmonaryAdverseEventManagement
Ruleoutnoninflammatorycauses.Ifanoninflammatorycauseisidentified,treataccordinglyandcontinuenivolumab therapy.Evaluatewith imagingand
pulmonaryconsultation.
GradeofPneumonitis
(NCICTCAEv4.03)
Management
Follow-Up
Grade 1: Radiographicchanges
only
–Considerdelayofcabiralizumaband nivolumab
therapy
–Monitor forsymptomsevery2to3days
–Considerpulmonaryandinfectiousdisease consults
–Re-image atleastevery 3weeks
Ifworsens:
–TreatasGrade 2or3–4
Grade2: Mildtomoderate 
newsymptoms
–Delaycabiralizumaband nivolumabtherapyper 
protocola
–Pulmonaryandinfectiousdisease consults
–Monitor symptomsdaily,considerhospitalization
–1mg/kg/day methylprednisoloneIV or oral
equivalent
–Considerbronchoscopy,lungbiopsy,if
clinicallyindicated
–Re-image every 1–3days
Ifimproves<14days:
–When symptomsreturntonearbaseline,tapersteroidsoverat
least
1month,considerprophylacticantibioticsforopportunistic
infections,andresume cabiralizumabandnivolumabtherapy
per protocol
Ifdoesnotimprove after 2weeksor worsens:
–TreatasGrade 3–4
Grade3–4: Severenew
symptoms;New/worsening
hypoxia;
Life-threatening
–Discontinue cabiralizumabandnivolumabtherapy
perprotocolb
–Hospitalization
–Pulmonaryandinfectiousdisease consults
–2to4mg/kg/day methylprednisolone IVorIV
equivalentc
–Addprophylactic antibiotics foropportunistic 
infections
–Considerbronchoscopy,lungbiopsyif
clinicallyindicated
Ifimprovestobaseline:
–Tapersteroids overatleast6weeks
Ifdoesnotimprove after48hoursor worsens:
–Addadditionalimmunosuppression(e.g.cyclophosphamide,
IVIG,ormycophenolate mofetil)
–Followupuntilresolution
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 (e.g. 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 oforal corticosteroids.
6.0
Approved
930110647
6.0
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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
Hepatic Adverse EventManagement withoutLiver Metastasis
Ruleoutnoninflammatorycauses.Ifanoninflammatorycauseis identified,treataccordinglyandcontinue nivolumabtherapy.Considerimagingforobstruction.
Grade ofLiver 
TestElevation
Management
Follow-Up
ASTor ALT>3.0x ULN
and
Totalbilirubin>2xULN
or
INR>1.5
–Discontinue cabiralizumabandnivolumabper 
protocol
–Startsteroids
–ContinueLFTmonitoringper protocoluntilresolution.
–Continuemonitoring forandotherassociatedclinicalsignsorsymptoms
–Contactthe MedicalMonitor
–Evaluate fornondrugrelatedcausesofthelaboratoryabnormalities
(e.g.obstruction,viralinfection,Gilbert’sdisease,etc)
–Under selectedcircumstances(e.galternative etiologyis identified),
patientmayreceive additional therapyonlyafterconsultationand
agreementbetweentheSponsor/MMandtheinvestigatorifreceiving 
additionaltreatmentwith cabiralizumaband nivolumabis inthebest
interestofthepatient (e.g ifthe subjecthas demonstratedaresponseto
therapy)
ASTor ALT>5to≤12
xULN
and
Totalbilirubin≤2xULN
–Continuecabiralizumaband nivolumabtherapy
ifthereare noclinicalsignsofsignificantmuscle 
or hepaticdamage
–Increasefrequencyofmonitoring ofAST, ALT,
bilirubin,alkaline phosphatase andINR(every48-
72 hours or more frequently, as clinically
indicated)
–Monitor forother clinical symptoms(fatigue,
nausea, vomiting,abdominalpain, fever,rash,
and/oreosinophilia)
–Contactthe MedicalMonitorifthere are clinicalsignsof muscle or 
hepaticinjuryor otherclinicalsymptoms
–ContacttheMedicalMonitorifthereisaconcurrentincreaseofbilirubin,
AST, ALT,or alkaline phosphatase
–NotifytheMedical Monitor ifthere is anAST or ALTincrease >5xULN
–Frequencyofretesting candecrease toonce aweek or lessifabnormalities
stabilizeorthetrialdrughasbeendiscontinuedandthesubjectis
asymptomatic
–Consider gastroenterologyor hepatologyreferral
ASTorALT>12to
≤ 20xULN
and
Totalbilirubin≤2xULN
or
Isolatedtotalbilirubin>
2to≤3xULN
–Delaycabiralizumaband nivolumabtherapyper 
protocola
–Increasefrequencyofmonitoringof(includingbut
notlimitedto) AST,ALT,bilirubin,alkaline 
phosphatase andINR(every48-72hours or more 
frequently,asclinicallyindicated)
–Ifthereis a2-foldALTincreasecomparedtothe
previousmeasurement,startsteroidsimmediately
–Consider steroid treatmentonanytotalbilirubin
increaseofover2.0xULN
–Ifthereis aconcurrentincrease ofalkaline
phosphatasealongwithALT,startsteroids 
immediately
IfAST/ALTreturnto≤ 12xULNwithin≤ 7days:
–Resume routinemonitoring
–Resume cabiralizumabandnivolumabtherapyatsame doselevelper 
protocol
Ifelevationspersistandremainatthe same level>7daysbut28days:
–Startsteroidsimmediatelyanddiscontinuefurtherdosing
–Continuemonitoringandconsiderdosingthesubjectwithnivolumab
therapyatthesamedoselevel.
–Considertaperingsteroidsoveratleast1month
Ifelevationspersistatthesamelevel>28daysorworsen:
–Discontinue cabiralizumabandnivolumabtherapyper protocol
–0.5-1mg/kg/day methylprednisolone ororal equivalentandwhen LFT
returnstoGrade 1orbaseline,tapersteroidsoveratleast1month
–Consider prophylactic antibioticsforopportunistic infections
–DiscusswithMedical Monitor
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
Hepatic Adverse EventManagement withoutLiver Metastasis
Ruleoutnoninflammatorycauses.Ifanoninflammatorycauseis identified,treataccordinglyandcontinue nivolumabtherapy.Considerimagingforobstruction.
Grade ofLiver 
TestElevation
Management
Follow-Up
–Monitor forother clinicalsymptoms(fatigue,
nausea,vomiting,abdominalpain,fever,rash,
and/oreosinophilia)
AST or ALT > 20 xULN
or
Total bilirubin >3 
xULN
–Discontinue cabiralizumaband nivolumab therapyb
–Increase frequency of monitoring to every 1 to 2 
days
–Consider 1 to 2 mg/kg/day methylprednisolone IV 
orIV equivalentc
–Consider adding prophylactic antibiotics for 
opportunisticinfections
–Consult gastroenterologist and hepatologist, if 
clinicallyindicated
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 patient.
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 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.
6.0
Approved
930110647
6.0
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Revised Protocol No.: 05
Date: 22-Mar-2018
114

Clinical Protocol
CA025001
BMS-986227
cabiralizumab
HepaticAdverseEventManagement withLiverMetastasis
Ruleoutnoninflammatorycauses.Ifanoninflammatorycauseisidentified,treataccordinglyandcontinuenivolumabtherapy.Considerimagingforobstruction.
GradeofLiverTest
Elevation
Management
Follow-Up
ASTor ALT>3.0x ULN
and
Totalbilirubin>2xULNor 
INR>1.5
–Discontinue cabiralizumabandnivolumabtherapyper 
protocol
–Startsteroids
–ContinueLFTmonitoringper protocoluntilresolution.
–Continuemonitoring forandotherassociatedclinical
signsorsymptoms
–Contactthe MedicalMonitor
–Evaluate fornondrugrelatedcausesofthelaboratory
abnormalities(e.g.obstruction,viralinfection,Gilbert’s
disease,etc)
–Under selectedcircumstances(e.galternative etiologyis 
identified),patient mayreceive additional therapyonly
afterconsultationandagreementbetweentheSponsor/MM
andtheinvestigatorifreceivingadditionaltreatmentwith
cabiralizumabandnivolumabis inthebestinterestofthe
patient(e.g ifthesubjecthasdemonstratedaresponseto
therapy)
ASTor ALT>5to≤ 12xULN
and
Totalbilirubin≤2xULN
–Continuecabiralizumaband nivolumabtherapyifthere
are noclinicalsignsofsignificantmuscle or hepatic 
damage
–Increase frequencyofmonitoringofAST,ALT,bilirubin,
alkalinephosphatase andINR(every48-72hoursor more 
frequently,asclinicallyindicated)
–Monitor forother clinicalsymptoms(fatigue,nausea,
vomiting,abdominalpain,fever,rash,and/or
eosinophilia)
–Contactthe MedicalMonitorifthere are clinicalsignsof 
muscle orhepaticinjuryor otherclinicalsymptoms
–Contactthe MedicalMonitorifthere is aconcurrent
increase ofbilirubin,AST,ALT,or alkaline 
phosphatase
–NotifytheMedical Monitorifthere is anASTor ALT
increase >5xULN
–Frequencyofretesting candecrease toonce aweek or lessif
abnormalitiesstabilizeorthetrialdrughasbeen
discontinuedandthesubject is asymptomatic.
–Consider gastroenterologyor hepatologyreferral
ASTorALT>12to≤ 20
xULN
and
Totalbilirubin ≤2xULN
or
Isolatedtotalbilirubin>3.0to
≤5xULN
–Delaycabiralizumaband nivolumabtherapyper protocola
–Increasefrequencyofmonitoring of(includingbutnot
limitedto)AST,ALT,bilirubin,alkaline phosphatase and
INR(every48-72 hours or more frequently,asclinically
indicated)
–Ifthereis a2-foldALTincreasecomparedtothe
previousmeasurement,startsteroidsimmediately
–Consider steroid treatmentonanytotalbilirubinincrease 
ofover2.0xULN
IfAST/ALTreturnto≤ 12xULNwithin≤ 7days:
–Resume routinemonitoring,resume cabiralizumaband
nivolumabtherapyatsame doselevelper protocol
Ifelevationspersistandremainatthe same level>7
daysbut28days:
–Startsteroidsimmediatelyanddiscontinuefurtherdosing
–Continuemonitoringandconsiderdosingthesubjectwith
nivolumabtherapyatthesame doselevel
–Considertaperingsteroidsoveratleast1month
Ifelevationspersistatthe samelevel>28daysorworsen:
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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
HepaticAdverseEventManagement withLiverMetastasis
Ruleoutnoninflammatorycauses.Ifanoninflammatorycauseisidentified,treataccordinglyandcontinuenivolumabtherapy.Considerimagingforobstruction.
GradeofLiverTest
Elevation
Management
Follow-Up
–Ifthereisaconcurrentincreaseofalkalinephosphatase
alongwith ALT,startsteroids immediately
–Monitor forother clinicalsymptoms(fatigue,nausea,
vomiting,abdominalpain,fever,rash,and/or
eosinophilia)
–Discontinue cabiralizumabandnivolumabtherapyper 
protocol
–0.5–1mg/kg/day methylprednisolone ororal equivalent
andwhenLFTreturns toGrade 1orbaseline,taper
steroidsoveratleast1month
–Considerprophylactic antibioticsforopportunistic infections
–DiscusswithMedical Monitor
ASTorALT>20xULN
or
TotalBilirubin>5xULN
–Discontinue cabiralizumabandnivolumabtherapy
b
–Increasefrequencyofmonitoringtoevery1–2days
–Consider1to2mg/kg/day methylprednisolone IV
or IVequivalentc
–Consider adding prophylactic antibiotics for
opportunisticinfections
–Consultgastroenterologistandhepatologist,ifclinically
indicated
IfreturnstoGrade 2or baseline:
–Consider steroid taperoveratleast1monthiftheyhave 
beenstarted
Ifdoesnotimprove in>3–5days,worsens,or rebounds:
–Consider adding mycophenolatemofetil1gBID
–Ifnoresponse withinanadditional3–5 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 patient.
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 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.
6.0
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930110647
6.0
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Revised Protocol No.: 05
Date: 22-Mar-2018
116

Clinical Protocol
CA025001
BMS-986227
cabiralizumab
EndocrinopathyAdverse EventManagement
Ruleoutnoninflammatorycauses.Ifanoninflammatorycause is identified,treataccordinglyandcontinue nivolumabtherapy.Considervisualfield
testing,endocrinology consultation,andimaging.
Description
Management
Follow-Up
AsymptomaticTSHelevation
–Continuecabiralizumaband nivolumabtherapyper 
protocol
IfTSH<0.5xLLN,or TSH>2x ULN,orconsistentlyoutof
rangein2subsequentmeasurements:
–  IncludefreeT4atsubsequentcyclesasclinicallyindicated;
considerendocrinologyconsult
Symptomatic endocrinopathy
–Evaluate endocrinefunction
–Considerpituitaryscan
Symptomatic withabnormallab/pituitaryscan:
–Delaycabiralizumaband nivolumabtherapyper protocola
–1to2mg/kg/day methylprednisolone IVorPOequivalentc
–Initiateappropriate hormone therapy
No abnormallab/pituitaryMRI scanbutsymptoms
persist:
–Repeatlabs in1–3weeksandMRI in1month
Ifimproveswithin28days(with or without
hormonereplacement):
–Tapersteroids overatleast1monthandconsider
prophylacticantibioticsforopportunistic infections
–Resume cabiralizumabandnivolumabtherapyper protocol
–Patientswithadrenalinsufficiency mayneedtocontinue
steroidswithmineralocorticoidcomponent
Ifpersistsfor over 28days:
–Delaycabiralizumaband nivolumabtherapy
–Continuesteroidsasneeded
–Uponresolution,discusswithMedicalMonitorif
patients areclinicallystable onfurtherdose delayand
discontinuation
–Followupuntilresolutionorreturntobaseline
Suspicionofadrenalcrisis
(e.g.severedehydration,
hypotension,shockoutof
proportiontocurrentillness)
–Delayor discontinuecabiralizumabandnivolumab
therapyperprotocola,b
–Ruleoutsepsis
–StressdoseofIV steroidswithmineralocorticoidactivity
–IVfluids
–Consultendocrinologist
–crisisis ruledout,treatasabove forsymptomatic
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 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 (e.g. 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 oforal corticosteroids.
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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
SkinAdverse EventManagement
Ruleoutnoninflammatorycauses.Ifanoninflammatorycause is identified,treataccordinglyandcontinue nivolumabtherapy.
Grade ofRash
(NCICTCAEv4.03)
Management
Follow-Up
Grade1–2:Covering ≤30%BSAd
–Symptomatic therapy(e.g.
antihistamines,topical steroids)
–Continuecabiralizumaband nivolumab
therapyperprotocol
Ifpersists>1-2weeksorrecurs:
–Consider skin biopsy
–Delaycabiralizumaband nivolumabtherapyper protocol
–Consider0.5–1mg/kg/day methylprednisolone IVor oral 
equivalent.
–Onceimproving,tapersteroidsoveratleast1month,consider
prophylacticantibioticsforopportunistic infections,andresume 
cabiralizumabandnivolumabtherapyper protocol
Ifworsens:
–TreatasGrade 3–4
Grade3–4:Covering>30%
BSA;Life-threatening
consequencesd
–Delayor discontinuecabiralizumaband
nivolumabtherapyper protocola,b
–Consider skin biopsyanddermatology
consult
–1to2mg/kg/dayIVmethylprednisolone 
IV orIVequivalentc
IfimprovestoGrade 1within28days:
–Tapersteroids overatleast1monthandaddprophylactic 
antibioticsforopportunisticinfections
–Resume cabiralizumabandnivolumabtherapyper protocol
Ifpersists >28daysor worsens:
–Considertodiscontinuecabiralizumaband nivolumabtherapyper 
protocol
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 (e.g. 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.
d Refer to NCI CTCAE v 4.03 for term-specific grading criteria.
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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
NeurologicalAdverse EventManagement
Grade ofNeurological
Toxicity(NCICTCAEv
4.03)
Management
Follow-Up
Grade1: Asymptomaticormild
symptoms;Interventionnotindicated
–Continuecabiralizumaband nivolumab
therapyperprotocol
Ifworsens:
–  TreatasGrade 2,3,or4
Grade2: Moderate symptoms;
LimitinginstrumentalADL
–Delaycabiralizumaband nivolumab
therapyperprotocola
–Treatsymptomsper localguidelines
–Consider0.5to1mg/kg/dayc 
methylprednisolone IV orPO
Ifimprovestobaseline within28days:
–Resume cabiralizumabandnivolumabtherapyatsame doselevel
per protocolwhenimprovedtobaseline
Ifworsensorpersistsafter 28days:
–TreatasGrade 3-4
Grade3–4:Severesymptoms;
limitingself-care ADL;life-
threatening
–Discontinue cabiralizumaband
nivolumabtherapy
b
–Obtain neurologyconsult
–Treatsymptomsper localguidelines1
to2mg/kg/dayIV
methylprednisolone orPOc
–Addprophylactic antibiotics for
opportunisticinfections
IfimprovestoGrade 2:
–Tapersteroids overatleast1month
Ifworsensor atypicalpresentation:
–Consider IVIGorother immunosuppressive therapiesper local
guidelines
–Continuefollowupuntilresolution
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 discontinuationwas 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 (e.g. 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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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
PeriorbitalEdemaAdverseEventManagement
GradeofPeriorbitalEdema
(NCICTCAEv4.03)
Management
Follow-Up
PeriorbitalEdema >baseline but
<Grade 2
–Continuecabiralizumaband nivolumabtherapy
per protocol
–Monitor edemaweekly
Ifworsens:
–  Followasstatedbelow
Grade2
–Delaycabiralizumaband nivolumabtherapyper 
protocola
–Startsystemic treatmentincluding steroids,eye
drops,or analgesicsasneededc
IfreturnstoGrade 1or baseline before thenext dosingvisit:
–Continuesystemictreatment
–Resume cabiralizumabandnivolumabtherapyatsame doselevel
without delay
–Routine eyemonitoringperprotocol,ifclinicallystable
Ifswellingpersists>14daysbutreturnsbacktobaseline or
normalwithin28days:
–Continuenivolumabandcabiralizumabdosingatsamelevel
–IfrecursatGrade 2or above,discontinuecabiralizumaband 
nivolumabtherapy
Grade ≥3
–Discontinue cabiralizumabandnivolumab
therapyperprotocolb
–Systemic treatmentincludingsteroids,eye
drops,oranalgesicsasneededc
–ConsultOphthalmologistifneeded
Ifreturns toGrade1afterdiscontinuation:
–Systemic treatmentincludingtapering steroids asneeded
–Anyfollowupandophthalmology consults,ifclinicallyindicated
–Monitor andfollowupuntilresolution
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 (e.g. 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 oforal corticosteroids.
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Revised Protocol No.: 05
Date: 22-Mar-2018
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Clinical Protocol
CA025001
BMS-986227
cabiralizumab
InfusionReactionAdverseEventManagement
GradeofInfusion
Reactions
(NCICTCAEv4.03)
Management
Follow-Up
Grade1
–Decreaseinfusionrateofcabiralizumabandnivolumab
therapyperprotocolandrestartatnormalinfusionrate
oncesymptomssubside
–Monitorpatientandusesymptomatictreatmentas
clinicallyindicated(whichincludesantihistaminesand
NSAIDs)
Ifinfusionreactionsymptomssubside within3hoursof
nivolumab
–cabiralizumabtherapycanbegivenwithoutanyprophylactic
medications ifthereactionisnivolumabrelated
–Subsequentdosingshouldincludeprophylacticpre-
infusionmedicationsfornivolumab
–Iftheinfusionreactionisrelatedtocabiralizumabtherapy,
prophylacticmedicationshouldbegivenpriortodosingof
cabiralizumabandnivolumab
–Continuecabiralizumabandnivolumabdosingatsamelevel
Grade2
–Interruptcabiralizumaband/ornivolumab
infusionperprotocola,b
–SystemictreatmentincludingNSAIDs,corticosteroids
andantihistaminesc
–Normalsalineinfusionandconstantmonitoringofvitals
andotherparameters
–Ifsymptomsresolvewithin3hours,continueinfusionat
50%ratefor30minutesandthenincreaseto100%if
clinicallystable
–Resumecabiralizumabandnivolumabtherapyatsamedose
levelandmonitorperprotocol
–Pre-infusionprophylacticmedicationsarerecommendedforfuture
dosing,includingantihistamines,NSAIDandcorticosteroidsupto
25mgasneeded.
Ifsymptomsrecur:
–Discontinuetreatmentatthevisit
–DiscusswithMedicalMonitorasneeded
Grade≥3
–Discontinuecabiralizumabandnivolumabtherapyper
protocolb
–SystemictreatmentincludingNSAID,corticosteroidsand
antihistaminesc
–Normalsalineinfusionandconstantmonitoringofvitals
andotherparameters
–Followinstitutionalguidelinesforanaphylaxis
–Bronchodilatorsasclinicallyindicatedwithorwithout
hospitalization
Ifreturns toGrade1afterdiscontinuation:
–Systemictreatmentincludingtaperingsteroids,
NSAIDs, antihistaminesuntilresolution,asneeded
–Followupuntilresolution
–Anyotherclinicalreferrals,ifindicated
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 (e.g. 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 oforal corticosteroids.
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UveitisAdverse EventManagement
GradeofUveitis
(NCICTCAEv4.03)
Management
Follow-Up
Grade1
–Observe symptoms
–Continuecabiralizumaband nivolumab
therapy
–Watch forworsening ofsymptomsincludingvisualdisturbances,lightsensitivity,
decreasevision
–Monitor weekly
Ifworsens:
–Followasstatedbelow
Grade 2
–Delayor discontinuecabiralizumaband
nivolumabtherapyper protocola,b
–Startantibioticsandinflammatory 
medications includingsteroidsc
–Ophthalmologic consult,ifclinically
indicated
–Immunosuppressive agents(e.g,anti-
TNFagentssuchasInfliximab)
Ifsymptomsresolve within14days:
–Continuecabiralizumaband nivolumabtherapyatsame doselevelandstart
taperingofsteroiddoses
Ifsymptomsresolve between14-28days:
–Consider continuing dosing atsamedoselevelfornivolumabandadoselevel
lowerforcabiralizumabonresolution tobaselineor Grade 1andstarttapering
ofsteroid doses.
–Ifit is Grade 2drugrelateduveitiswhichdoes notresolve within 14days,
consider todiscontinuestudydrug(s)
Ifsymptomspersistorworsenin28daysregardlessofsystemictreatment:
–Discontinue both cabiralizumabandnivolumabtherapy
–Continuemonitoringofsymptomsincludingvisualdisturbances,eye pain,and
dimnessofvisionandfollowupuntilresolution or returntobaseline
–Continuesteroids,antibiotics,and other medicationssuchasinfliximab,as
clinicallyindicated
Grade ≥3
–Discontinue cabiralizumaband
nivolumabtherapyper protocolb
–Startantibioticsandinflammatory 
medications includingsteroidsc
–Ophthalmologic consult,ifclinically
indicated
–Immunosuppressive agents(e.g,anti-
TNFagentssuchasInfliximab)
–Discontinue both cabiralizumabandnivolumabtherapy
–Continuemonitoringofsymptomsincludingvisualdisturbances,eye pain,and
dimnessofvisionandfollowupuntilresolution or returntobaseline
–Continuesteroids,antibiotics,and other medicationssuchasinfliximab,as
clinicallyindicated
–Followupuntilresolution
a If the AErequiring 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 shownby patient
c Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 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 oforal corticosteroids.
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APPENDIX 8
LABORATORY ABNORMALITIES MANAGEMENT TABLE
LaboratoryAbnormalitiesManagement (CKandLDH)
GradeofLiverTest
Elevation
Management
Follow-Up
CK>10xULN
–ConsidermeasuringCKisoenzymesasclinically
indicated
IfCKisoenzymesareabnormal
–Consider checking troponinlevels
–Considerotherassessments (includinguromyoglobin)asclinically
indicated
IfCKisoenzymesarenormal
–Continuedosing,perprotocol
–Monitor CKlevelasclinicallyindicated
CKorLDH>15to≤20
xULN
–Delaycabiralizumaband nivolumabtherapyper 
protocola
–Measure CKisoenzyme panel toidentify
sourceofelevation
–Increasefrequencyofmonitoring(every48-72
hours,ormore,asclinicallyindicated)
–NotifytheMedical Monitor
Ifreturnsto≤ 15xULNwithin≤ 28days:
–Resume routinemonitoring,resume cabiralizumabandnivolumab
therapyatsamedoselevelper protocol
–IfCKisoenzyme panel is normalcontinuemonitoring the subject.
–IfCKisoenzyme panel is abnormalthenconsidermeasuring troponins.
–Iftroponins are abnormal,contactMedical Monitortodetermine if the
subjectcanberetreated.
Ifelevationspersistatthesamelevel>28daysorworsen:
–Discontinue furtherdosing
–DiscusswithMedical Monitor
CKor LDH>20xULN
–Discontinue cabiralizumabandnivolumabtherapy
per protocol
–  Followupuntilresolution
a.IftheAErequiringdosedelay wasduetoone ofthestudydrugs,the non-offending drugmaybecontinued,taking intoaccountthe safetyandclinicalbenefittothe patient.
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APPENDIX 9
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUSa
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able tocarry out work ofa 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a
 
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APPENDIX 10
RESPONSE CRITERIA (RECIST 1.1)
1
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2. 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3. 20 mm by chest x-ray
Malignant lymph nodes:To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reportedas two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis 10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
<10mm 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, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques.
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2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two 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 one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
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 nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
3
RESPONSE CRITERIA
3.1
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 on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered 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.
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3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
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 below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if 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.
3.1.1.2
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 very small (eg,2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure 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 (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 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 measure, 
that should be recorded, even if it is below 5 mm.
3.1.1.3
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’.
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3.2
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 and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD:Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD):Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered progression).
3.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
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 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy (see examples in Appendix 2 and further details below). A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. 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.
3.2.1.2
When the patient has only 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 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 beapplied 
when assessing patients for unequivocal progression is 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 diameter in a measurable lesion). Examples include an increase in a pleural effusion 
from ‘trace’ to ‘large’, an increasein lymphangitic disease from localized to widespread, or may 
be described in protocols 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.
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3.2.2
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 inscanning 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 pre-existing 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.
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 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly 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 FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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 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-upcorresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
3.3
Response Assessment
3.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into considerationthe appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
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3.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
3.3.2-1provides 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 3.3.2-2is to be used. 
Table 3.3.2-1:
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
Not evaluated
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, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 3.3.2-2:
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, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
3.3.3
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 
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of 4 weeks later. In this circumstance, the best overall response can be interpreted as inTable 
3.3.3-1.
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 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 ‘zero’ on the case report 
form (CRF).
Table 3.3.3-1:
Best Overall Response (Confirmation of CR&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 minimum criteria for SD durationbmet, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationbmet, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationbmet, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration bmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD =stable disease, PD = progressive disease, and 
NE=inevaluable
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 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.
b Minimum criteria for SD duration is 6 weeks.
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3.3.4
Confirmation Scans
Verification of Response:To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
28days after thecriteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
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 
progressive disease.
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APPENDIX 11
DEFINITIONS OF RESPONSE AND PROGRESSION CRITERIA 
(MODIFIED FROM IMWG)
Response 
Subcategory
Response Criteriaa
Stringent Complete 
Response (sCR)
CR, as defined below, plus the following:
Normal FLC ratioband absence of clonal cellscin bone marrow by 
immunohistochemistry or immunofluorescence.
Complete Response 
(CR)b
Negative immunofixation of serum and urine and disappearance of any soft tissue 
plasmacytomas, and < 5% plasma cells in bone marrow.
Very Good Partial 
Response (VGPR)b
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
90% reduction in serum M-protein level plus urine M-protein level < 100 mg per 24hour.
Partial Response 
(PR)
50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 
90% or to < 200 mg per 24 hour.
If serum and urine M-proteinare unmeasurable, a 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria.
In addition to the above criteria, if present at baseline, 50% reduction in the size of soft 
tissue plasmacytomas is also required
Minor (Minimal) 
Response (MR)
25-49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50-
89%, which still exceeds 200 mg per 24 hours. In addition, if present at baseline, 25-49% 
reduction in the size of soft tissue plasmacytomas is also required. No increase in the size 
or number of lytic bone lesions (development of compression fracture does not exclude 
response).
Stable Disease (SD)
Not meeting criteria for CR, VGPR, PR, MR, or progression.
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Response 
Subcategory
Response Criteriaa
Progressive disease
Any of the following: 
1. Increase of 25% from lowest response value in any one or more of the following:
a. Serum M-component (absolute increase must be 0.5g/dL(5g/L))d
and/or
b. Urine M-component (absolute increase must be 200 mg (0.2g) per 24 
h) and/or
c. Only in patients without measurable serum and urine M-protein levels: 
the difference between involved and uninvolved FLC levels (absolute 
increase must be >10mg/dL(100mg/L))
d. Bone marrow plasma cell percentage (absolute % must be 10%)
2. Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas
3. Development of hypercalcemia (corrected serum calcium >11.5mg/100mL) 
that can be attributed solely to the plasma cell proliferative disorder
a All response categories require 2 consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies 
were performed. Radiographic studies are notrequired to satisfy these response requirements. Bone marrow 
assessments need not be confirmed.
b Note clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients is defined as a normal FLC ratio of 0.26-1.65 in addition to CR criteria 
listed above. VGPR in such patients is defined as a > 90% decrease in the difference between involved and 
uninvolved FLClevels.
c Presence or absence of clonal cells is based upon the /ratio. An abnormal /ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is /of > 4:1 or < 1:2.
d For progressive disease, serum M-component increase of 1 g/dL (10g/L) is sufficient to define progression if 
starting M-component is 5 g/dL(50 g/L).
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APPENDIX 12
REVISED PROTOCOL SUMMARY OF CHANGEHISTORY
Overall Rationale for the Revised Protocol 03, 12-Sep-2017
The main purpose of this revised protocol isto incorporate DLT criteria with other ongoing studies.
In addition, administrative changes are incorporated in the revised protocol.
The revised protocol applies to all participants.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section 
Number & 
Title
Description of Change
Section2:
SCHEDULE 
OF 
ACTIVITIES
Table 2-1
Table 2-2
Notes of Physical Examination 
(PE) and Tumor Biopsy (for solid 
tumor) were modified from 
24hours to 1day.
Section2:
SCHEDULE 
OF 
ACTIVITIES
Table 2-2
Section 
9.1.1.1:
Imaging 
Assessment
9.1.2.1:
Laboratory 
Assessments
Regarding Follow-up period, 
Tumorassessment, Myeloma 
Urine and Serum Lab tests, and
Subsequent Treatment in Table 2-
2 were updated.
The first sentence in the first 
paragraph of Section 9.1.1.1and 
2)-a. of Section 9.1.2.1 were 
modified.
Section2:
SCHEDULE 
OF 
ACTIVITIES
Table 2-2
Section 7.5.1:
Dosing of 
Cabiralizumab 
and 
Nivolumab
Study Drug Administration in 
Table 2-2 and The first paragraph 
of Section 7.5.1 were modified to
add the allowance of 
Cabiralizumab and Nivolumab 
dosing.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section 
Number & 
Title
Description of Change
Section 3.1.1:
Tumor-
Associated 
Macrophages 
and Colony 
Stimulating 
Factor 1 
Receptor
The first sentence in the third 
paragraph was modified to include 
multiple myeloma.
Section3.2.1.2
:Clinical 
Summary
Section3.2.3.1
:Serum 
Enzyme 
Elevations in 
Cabiralizumab
Clinical Study and Safety 
Summary of Cabiralizumabwas 
updated
Section3.3:
Benefit/Risk 
Assessment
The fifth and sixth paragraph were
updated.
Section 
5.1.1.1:Dose-
limiting 
toxicity 
The last bullet inNon-
Hematologic DLTsection was 
modified.
Section 7.4.1:
Dose Delay 
for 
Cabiralizumab 
and 
Nivolumab
The last sentence of the last 
paragraph was added.
 
   
 
 
Section 7.4.3:
Dose 
Reduction 
with 
Cabiralizumab 
and 
Nivolumab
1) The title was modified to 
include in Nivolumab
2) The sentence was modified 
not to permit dose reduction 
for Cabiralizumab
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section 
Number & 
Title
Description of Change
Section 8.1:
Discontinuatio
n from Study 
Treatment
1) Add the reasons Participants 
must discontinue 
investigational product
2) Deleted the instruction in the 
case of pregnancy
Section 9.4.4: 
Clinical Safety 
Laboratory 
Assessments
Delete skeletal from troponin 
obtained if CK elevation is 
clinically significant.
Appendix 
6.7.8
Modified in accordance with the 
changes in FPA008-003 protocol
All
Minor formatting and 
typographical corrections
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Overall Rationale for the Revised Protocol02, 06-Jul-2017
The main purpose of this revised protocol is to clarify and correct the following points in orderto 
reduce ambiguity regarding study procedures:
Clarify the allowance for physical measurements and laboratory tests on treatment phase 
Correct and clarify time and event for pharmacokinetic sampling schedule to be collected 
relative to start of cabiralizumab infusion
In addition, administrative changes are incorporated in the revised protocol.
The revised protocol applies to all participants. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section 
Number & 
Title
Description of Change
Section2:
SCHEDULE 
OF 
ACTIVITIES
Table 2-1
1) Laboratory Tests was 
modified to include Troponin.
2) Documentation of 
extramedullary soft tissue 
plasmacytomaswas modified 
to add notes to table.
Section2:
SCHEDULE 
OF 
ACTIVITIES
Table 2-2
5) Physical 
Measurements, 
pregnancy test and Laboratory 
Tests were modified to include 
within 72 hours prior in notes 
and add footnote.
6) Vital signs was modified to add 
notes to table.
7) EOT was removed from 
exploratory 
biomarker 
assessment 
Section 6.1: 
Inclusion 
Criteria
1)-b)Consent for tumor biopsy 
samples in subjects with solid 
tumor was modified
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section 
Number & 
Title
Description of Change
Section 6.2: 
Exclusion 
Criteria
Exclusion Criteria was modified 
to include 1)-p)and q).
Section 7.2: 
Method of 
Treatment 
Assignment
Method of Treatment Assignment 
was modified to update participant 
numbers assignment.
Section 
9.1.1.1:Imagin
g Assessment 
11)The first sentence in the first 
paragraph was modified to 
include the mention of the end 
tumor assessment. 
12)The last sentence in the last 
paragraph was added to 
include the mention of 
Treatment beyond Disease 
Progression.
Section
9.1.2.1:
Laboratory 
Assessments
1) “Baseline” was modified in 
wording to “screening”
15)Serum free light chain and 
Urine parts were modified to 
include “starting from C3D1 
to every 2 cycles”
Section 
9.1.2.2:
Skeletal 
Survey
The first sentence in the first 
paragraph was modified to include 
“during 28 days prior to initiation 
of study drugs” in
Section
9.4.4:
Clinical Safety 
Laboratory 
Assessments
16)Themention on local 
laboratory feasibility was 
added on the third bullet.
17)(APTT) was added to Serum 
chemistry.
18)Discharge was removed from 
pregnancy test.
Section9.5:Ph
armacokinetic 
and Anti-Drug 
22)The pharmacokinetic 
parameters to be assessed was 
modified to AUC (TAU) from
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cabiralizumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section 
Number & 
Title
Description of Change
Antibody 
(ADA)
Section10.3.3:
:Pharmacokin
etic Analyses
AUC (INF), and CLT and Vss 
were removed.
23)Event, Time and footnote of
Table9.5-1 and Table9.5-2 
were modified.
Section9.6.1:
Tumor Tissue 
Specimens
The second paragraph was 
modified to include notification to 
BMS Medical Monitor regarding 
On-treatment biopsies.
Section10.2:
Population for 
analyses
Removed the mention of IRT
Section10.3.4:
Immunogenici
ty
Added Nivolumab to Incidence of 
ADA
All
Minor formatting and 
typographical corrections
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CA025001
BMS-986227
cabiralizumab
APPENDIX 13
REVISED PROTOCOL SUMMARY OF CHANGEHISTORY
Overall Rationale for the Revised Protocol 04, 17-Oct-2017
The main purpose of the modification to the CA025001 is to remove Survival follow-up after 
Follow up Period from the study. Since 1) the number of subjects enrolled in the study will be 36 
at a maximum; and 2) enrolled subjects will have various type of cancer, it does not expect survival 
follow-up to obtain mature data.
Summary of key changes of Revised Protocol 04
Section Number & Title
Description of Change
Section 1: SYNOPSIS
Section 2:
SCHEDULE OF 
ACTIVITIES
Section 5.1:
Overall Design
Figure 2.Study Design 
Shema has been updated
Table 2.2 Treatment Phase 
Procedural Outline has 
been updated.
Figure 5.1-2 Study Design 
Shema hasbeen updated.
Section 8.1.2
Post study Treatment 
Study Follow-up
The last sentence was 
modified 
All
Minor formatting and 
typographical corrections
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