A Phase 3, Randomized, Open-Label Study of Nivolumab Combined With Cabozantinib Versus Sunitinib in Participants With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
Phase: PHASE3
Conditions: Renal Cell Carcinoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 3, Randomized, Open-Label Study of Nivolumab Combined with Cobazantinib Versus 
Sunitinib in Participants with Previously Untreated Advanced or Metastatic Renal Cell 
Carcinoma 
 
 
NCT Number: NCT03141177 
 
Document Date (Date in which document was last revised): May 3, 2019 
 

Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 03-May-2019
2
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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Revised Protocol No.: 02
Date: 03-May-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 02
03-May-2019
Major Changes:
•
Revised protocol 02 adjusts the timing of the PFS and 
OS interim analyses with modified hypothesized OS 
hazard ratio (HR). The number of randomized 
participants is increased. 
•
The interim analysis for ORR is removed, resulting in 
revised overall alpha for PFS and OS endpoints.
•
No change in eligibility or study procedure. 
•
Clinical data for nivolumuab + ipilimumab in renal cell 
carcinoma (RCC) has been updated. 
Other changes include more detail on PRO measures and 
updates to align with BMS standards for the nivolumab 
program.
Administrative Letter 02
08-Feb-2018
Clarification to the sites on the implementation of 
CA2099ER Global Revised Protocol 01 which stopped
further randomization into Arm B, and the timing of  IRB 
approval and impact on randomization. Protocol text was 
not changed.
Revised Protocol 01
18-Dec-2017
Primary revisions: (i) To stop enrollment into Arm B 
(nivolumab, ipilimumab and cabozantinib triplet) and (ii) to 
include favorable risk participants (capped at 25%) in the 
primary data analysis.  
Secondary items include: (i) to add a Data Monitoring 
Committee review after 30 participants are treated for 6 
weeks, (ii) to adjust, clarify and add exclusion criteria, (iii) 
to add treatment restrictions, (iv) to clarify criteria 
associated with hemorrhage with regard to resuming 
treatment, (v) to specify an additional precaution when 
sunitinib dosing is resumed, and (vi) to apply newly 
updated Sponsor standards for nivolumab clinical protocols.
Tertiary items include (i) incorporation of Administrative 
Letter 01 and (ii) correction of typographical and 
grammatical errors.
Administrative Letter 01
20-Jul-2017
To notify of a change of Medical Monitor and Study 
Director. To correct typographical errors and resolve 
inconsistencies found in the original protocol.
Original Protocol
08-Mar-2017
Not applicable
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APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 6 INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA .......................................... 
APPENDIX 7 PERFORMANCE STATUS SCORES ................................................. 
APPENDIX 8 RADIOLOGIC EVALUATION CRITERIA IN SOLID TUMOURS 
VERSION 1.1 (RECIST CRITERIA 1.1) .............................................................. 
 
APPENDIX 10 SUPPORTIVE CARE GUIDELINES FOR THE MANAGEMENT 
OF HAND FOOT SYNDROME (HFS) ................................................................. 
APPENDIX 11 SUPPORTIVE CARE GUIDELINES FOR THE MANAGEMENT 
OF DIARRHEA FOR CABOZANTINIB .............................................................. 
APPENDIX 12 COUNTRY SPECIFIC REQUIREMENTS ....................................... 
APPENDIX 13 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
141
152
153
154
163
164
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Clinical Protocol
BMS-936558
CA2099ER
nivolumab
Revised Protocol No.: 02
Date: 03-May-2019
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Clinical Protocol
CA2099ER
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nivolumab
•
Participants with favorable, intermediate, and poor risk categories will be eligible for the study. 
Participants must be categorized according to favorable versus intermediate versus poor risk 
status at registration as per International Metastatic RCC Database Consortium (IMDC) 
criteria.
•
Negative pregnancy test and able to meet protocol-specified reproductive requirements
Key Exclusion Criteria
•
Any active central nervous system (CNS) metastases. Participants with treated, stable CNS 
metastases for at least 1 month are eligible
•
Any tumor invading the superior vena cava (SVC), other major blood vessels, or GI tract; any 
evidence of endotracheal or endobronchial tumor
•
Prior systemic treatment with VEGF, MET, AXL, KIT or RET targeted therapy (including, 
but not limited to, sunitinib, pazopanib, axitinib, tivozanib, sorafenib, lenvatinib, bevacizumab,
and cabozantinib)
•
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways
•
Any active, known or suspected autoimmune disease or any condition requiring systemic 
treatment with corticosteroids
(> 10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of randomization
•
Uncontrolled adrenal insufficiency
•
Poorly controlled hypertension despite antihypertensive therapy
•
History of unstable angina, myocardial infarction, symptomatic peripheral vascular disease, 
congestive heart failure (CHF, Class III or IV as defined by the New York Heart Association
[NYHA]), or cerebrovascular accident (CVA)
•
Deep vein thrombosis (DVT) or pulmonary embolism (PE) unless adequately treated with low 
molecular weight heparin (LMWH)
•
Any unstable cardiac arrhythmia; prolonged QTcF > 450 msec for males and > 470 msec for 
females
•
Serious, non-healing wound or ulcer; evidence of active bleeding or bleeding susceptibility; 
history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel or 
gastric outlet obstruction 
•
Concomitant strong CYP3A4 inducers or inhibitors within 14 days prior to randomization
•
Ejection fraction ≤ 50% on screening echocardiogram or multigated acquisition scan (MUGA)
•
Major surgery less than 6 weeks, nephrectomy less than 4 weeks, prior to randomization,  with 
complete wound healing and no ongoing post-operative complications.
•
Participants who have received a live/attenuated vaccine within 30 days of first treatment.
Revised Protocol No.: 02
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Clinical Protocol
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nivolumab
Objectives and Endpoints:
Objective
Endpoint
Primary
To compare progression-free survival (PFS) 
per blinded independent central review 
(BICR) of nivolumab plus cabozantinib 
(Arm A, doublet) with sunitinib (Arm C) in 
all randomized participants. 
The primary endpoint of this study is to compare the PFS per BICR 
of Arm A versus Arm C in all randomized participants. PFS is 
defined as the time between the date of randomization and the first 
date of the documented progression, or death due to any cause, 
whichever occurs first. Participants who die without a reported 
progression (and die without start of subsequent anti-cancer 
therapy) will be considered to have progressed on the date of their 
death. Participants who did not progress or die will be censored on 
the date of their last evaluable tumor assessment on or prior to 
initiation of subsequent anti-cancer therapy. Participants who did 
not have any on study tumor assessments and did not die will be 
censored on their date of randomization. Participants who started 
anti-cancer therapy without a prior reported progression will be 
censored on the date of their last evaluable tumor assessment on or
prior to the initiation of first subsequent anti-cancer therapy.
Secondary
To compare overall survival (OS) of Arm A 
with Arm C in all randomized participants.
The first secondary endpoint is to compare the OS of Arm A versus 
Arm C in all randomized participants. OS is defined as the time 
between the date of randomization and the date of death due to any 
cause. A participant who has not died will be censored at the last 
known alive date.
To evaluate the objective response rate 
(ORR) per BICR in all randomized 
participants.
The second secondary endpoint is to describe ORR per BICR in all 
randomized participants. ORR is defined as the proportion of 
randomized participants who achieve a best response of complete 
response (CR) or partial response (PR) using the RECIST 1.1 
criteria. Best overall response (BOR) is defined as the best response 
designation recorded between the date of randomization and the 
date of objectively documented progression per RECIST 1.1 or the 
date of subsequent therapy (including tumor-directed radiotherapy 
and tumor-directed surgery), whichever occurs first.
For 
participants
without documented progression or subsequent 
therapy, all available response designations will contribute to the 
BOR assessment. Duration of response (DOR) is defined as the time 
between the date of first confirmed documented response (CR or 
PR) to the date of first documented tumor progression (per RECIST 
1.1) or death due to any cause, whichever occurs first. Participants 
who neither progress nor die will be censored on the date of their 
last tumor assessment. Responders who started anti-cancer therapy 
without a prior reported progression will be censored on the date of 
their last evaluable tumor assessment prior to the initiation of first 
subsequent anti-cancer therapy. Time to response (TTR) is defined 
as the time from randomization to the date of the first confirmed 
documented response (CR or PR), as assessed by BICR. DOR and 
TTR will be evaluated for responders (CR or PR) only.
To assess overall safety and tolerability in 
all treated participants.
As measured by the incidence of adverse events (AEs), serious 
adverse events (SAEs), AEs leading to discontinuation, deaths, 
laboratory abnormalities and changes from baseline.
Revised Protocol No.: 02
Date: 03-May-2019
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Overall Design:
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm 
B. Participants previously randomized to Arm B continue with Arm B treatment and continue with 
Arm B clinical planned events, per protocol.
This is an open label, randomized trial of nivolumab combined with cabozantinib (doublet 
regimen) versus sunitinib in participants with previously untreated (first line) advanced or 
metastatic RCC. Participants will be randomized between Arm A and Arm C in a 1:1 ratio with 
approximately 638 participants (319 per Arms A and C, respectively), and capped at 25% 
favorable risk participants. Participants will be stratified for randomization by IMDC prognostic 
score (0 [favorable risk] versus 1-2 [intermediate risk] versus 3-6 [poor risk]), PD-L1 tumor 
expression ( 1% versus < 1% or indeterminate),
and region (US/Canada/Western
Europe/Northern Europe versus rest of the world [ROW]).
The study design schematic is presented below.
Abbreviations: DMC= data monitoring committee; IMDC= International Metastatic Renal Cell Carcinoma 
Database Consortium; IV=intravenous;; PD-L1= programmed death-ligand 1; PO= orally by mouth; 
Pts=participants; Q2W=every 2 weeks; Q3W=every 3 weeks; QD= once daily; RCC=renal cell carcinoma.
Arm B is shown in the design schematic because after implementation of Revised Protocol 01, there will be patients 
on Arm B treatment from the original protocol version 08 Mar 2017.
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nivolumab
Number of Participants: Approximately 850 participants will enroll in order to randomize 
638 participants into Arms A and C (319 per Arm A and per Arm C) capped at 25% favorable risk
participants.
Treatment Arms and Duration:
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm 
B. Participants previously randomized to Arm B continue with Arm B treatment and continue with 
Arm B clinical planned events, per protocol.
•
Arm A (Doublet): Nivolumab 240 mg flat dose intravenously (IV) every 2 weeks (Q2W) + 
Cabozantinib 40 mg orally by mouth (PO) once daily (QD)
o
Nivolumab treatment until disease progression or unacceptable toxicity with maximum
treatment of 2 years
o
Cabozantinib treatment until disease progression or unacceptable toxicity
•
Arm C: Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off-treatment, per cycle. 
Cycles to be continued until progression or unacceptable toxicity 
Note - Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into 
Arm B. Participants previously randomized to Arm B continue with Arm B treatment and continue 
with Arm B clinical planned events, per protocol.
o
Arm B (Triplet): Nivolumab 3mg/kg IV Q3W x 4 doses + Ipilimumab 1 mg/kg IV
Q3W x 4 doses + Cabozantinib 40 mg PO QD 

Then, Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD

Nivolumab to be continued until disease progression or unacceptable toxicity 
with maximum treatment of 2 years from the start of first dose in Cycle 1

Cabozantinib until disease progression or unacceptable toxicity
Refer to Section 7.1 Treatments Administered for additional details.
Revised Protocol No.: 02
Date: 03-May-2019
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Study treatment: 
Study Drugs for CA2099ER
Medication
Potency
IP/
Non-IP
BMS-936558-01
(Nivolumab) Solution for Injection
100 mg (10 mg/mL)
IP
Ipilimumab Solution for Injection*
200 mg (5 mg/mL)
IP
Cabozantinib Tablet
20 mg
IP
Sunitinib Malate Capsule
12.5 mg
IP
Abbreviation: IP=investigational product
*Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm B. Participants 
previously randomized to Arm B continue with Arm B treatment and continue with Arm B clinical planned events, 
per protocol.
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Date: 03-May-2019
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2099ER)
Procedure
Screening Visita
Notes
Eligibility Assessments
Informed Consent
X
Register in Interactive Response Technology (IRT) system to obtain participant 
number. The participant should sign the Informed consent prior to any study 
related assessment is performed.
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization.
Medical History
X
International Metastatic RCC Database 
Consortium (IMDC) Prognostic Score
X
See Appendix 6.
Tumor tissue sample
(for stratification by PD-L1 tumor expression)
X
Tumor tissue (preferably obtained within 3 months but no more than 12 months 
prior to enrollment, with an associated pathology report) will be collected. 
Formalin-fixed paraffin-embedded (FFPE) block or 20 unstained slides: a 
minimum of 10 slides will be acceptable if tumor tissue is limited. See Section 
9.8.2.
Central lab will determine PD-L1 tumor expression. Participants must have an 
evaluable PD-L1 result from the central lab in order to be randomized.
Safety Assessments
Full Physical Examination, Measurements, Vital 
Signs, and Performance Status
X
Height, weight, Karnofsky Performance Status (KPS) (Appendix 7), BP, HR,
RR, and temperature within 14 days prior to randomization.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Serious Adverse Events Assessment
X
Serious Adverse Events from time of consent. See Section 9.2
Electrocardiogram (ECG)
X
Within 28 days prior to randomization. Fridericia corrected QT (QTcF) 
required. If any time there is an increase in QTcF interval to an absolute value > 
500 msec, 2 additional ECGs must be performed each with intervals 
approximately 3 minutes apart.
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099ER)
Procedure
Screening Visita
Notes
Cardiac Ejection Fraction (via Echocardiogram or 
MUGA)
X
Within 28 days prior to randomization.
Laboratory Tests
(includes blood and urine samples)
X
See Section 9.4.1 for additional details on tests required. To be completed 
locally at each site. Must be performed within 14 days prior to randomization.
•
CBC w/differential
•
PT/INR, PTT
•
Chemistry panel (includes AST, ALT, total bilirubin, ALP, LDH, 
creatinine, BUN, glucose, albumin, Na, K, Cl, Ca (also corrected), P, Mg, 
amylase, lipase)
•
Thyroid panel (includes TSH with free T3 and free T4)
•
Hepatitis B/C (HBVsAg, HCV antibody or HCV RNA)
•
HIV if mandated locally (sites in Germany, see Appendix 12)
•
Urine protein and urine creatinine (for urine protein/creatinine ratio
[UPCR]). If UPCR ≥ 1.0, obtain 24 hour urine protein.
Pregnancy Test
X
WOCBP only. Serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) to be done at screening visit and within 24 hours of 
first dose of study therapy.
Follicle Stimulating Hormone (FSH)
X
For women under the age of 55 years to confirm menopause as needed.
Efficacy Assessments
Baseline Tumor Assessments
X
CT/MRI of the chest, abdomen, pelvis, brain, and all known sites of disease, 
performed within 28 days prior to randomization. 
All scans need to be submitted for blinded independent central review (BICR). 
See Section 9.1.
Abbreviations: For abbreviations on lab tests refer back to Section 9.4.1.
a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline for Arm A Nivolumab Combined with Cabozantinib, Doublet  
(CA2099ER) 
Procedure
Cycle 1, Day 1 
Cycle=2 wks
C2 and
subsequent visitsa
Each Cycle=2 wks
Notes
Randomize
X
Begins with call to Interactive Response Technology (IRT). Participants must 
have an evaluable PD-L1 result from the central lab in order to be randomized.
Administer Nivolumab and 
Cabozantinib
X
X
See Section 7. Dispense study treatment as appropriate.
Day 1 Treatment must begin within 3 days (72 hours ) of Randomization)
Abbreviations: C=cycle; D=day; wks= weeks. For abbreviations on lab tests refer back to Section 9.4.1.
Notes: Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the 
treating physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
a If a dose is delayed, the procedures scheduled for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs.
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline for Arm B Nivolumab and Ipilimumab Combined with 
Cabozantinib, Triplet (CA2099ER)
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm B. Participants previously 
randomized to Arm B continue with Arm B treatment and continue with Arm B clinical planned events, per protocol.
Procedure
Part 1
Part 2
Notes
(Please note differences in cycle durations
between Part 1 and Part 2)
Cycle 1 
(Each 
Cycle=3 
wks)
C2-C4a
(Each 
Cycle= 3 
wks)
C5 and 
Subsequent 
visits a
(Each Cycle=2 
wks)
Safety Assessments
Targeted Physical Examination, 
Vital Signs, Performance Status
X
X
X
Weight, BP, HR, RR, temperature, and Karnofsky Performance Status 
(KPS) (Appendix 7). Performance Status to be performed within 72 hours 
prior to dosing.
Assessment of Signs and 
Symptoms
X
X
X
Adverse Events and Serious 
Adverse Events Assessment
X
X
X
Record at each visit. Participants 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 last 
dose (Appendix 3).
Electrocardiogram (ECG)
X
X
(See notes)
X
(See notes)
Fridericia corrected QT (QTcF) required. Only Cycles 1, 3, 5, then every 6 
cycles (ie, Cycles 11, 17, 23, etc). If any time there is an increase in QTcF 
interval to an absolute value > 500 msec, 2 additional ECGs must be 
performed each with intervals approximately 3 minutes apart.
Laboratory Tests
(includes blood and urine 
samples)
X
X
X
(See notes)
See Section 9.4.1 for additional details on tests required. Laboratory tests
do not need to be repeated at C1D1 if performed within 14 days prior to first
dose. After C1D1, within 72 hours prior to dosing.
•
CBC w/differential at every cycle
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline for Arm B Nivolumab and Ipilimumab Combined with 
Cabozantinib, Triplet (CA2099ER)
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm B. Participants previously 
randomized to Arm B continue with Arm B treatment and continue with Arm B clinical planned events, per protocol.
Procedure
Part 1
Part 2
Notes
(Please note differences in cycle durations
between Part 1 and Part 2)
Cycle 1 
(Each 
Cycle=3 
wks)
C2-C4a
(Each 
Cycle= 3 
wks)
C5 and 
Subsequent 
visits a
(Each Cycle=2 
wks)
•
Chemistry panel at every cycle (includes AST, ALT, total bilirubin, 
ALP, LDH, creatinine, BUN, glucose, albumin, Na, K, Cl, Ca, P, Mg)
•
Amylase and lipase at every cycle until Cycle 5 then every 3 cycles (ie,
Cycles 8, 11, 14, etc)
•
Thyroid panel (includes TSH with reflexive free T3 and free T4) at 
every cycle until Cycle 5, then every 3 cycles (ie, Cycles 8, 11, 14, etc)
•
Urine protein and urine creatinine (for UPCR, preferred) or urine 
dipstick for protein at Cycles 1, 3, and 5, then every 3 cycles 
(ie, Cycles 8, 11, 14, etc)
Pregnancy Test
X
X
X
Within 24 hours prior to the initial administration of study drug, then every
4 weeks ± 7 days. Serum or Urine. WOCBP only.
Efficacy Assessments
Tumor Assessments
First tumor assessment post-baseline should 
be performed Week 12 (± 7 days) following 
randomization. Use same imaging method 
as was used at baseline.
Subsequent tumor assessments should occur 
at every 6 weeks (± 7 days) until Week 60, 
then every 12 weeks (± 14 days) until 
radiographic progression, assessed by the 
investigator and confirmed by the BICR. 
CT/MRI of the chest, abdomen, pelvis, and all known sites of disease.
Tumor assessments should be performed at the specified time points 
regardless of dosing delays. See Section 9.1 for additional details.
Treatment Beyond Progression
A radiographic assessment/ scan should be performed within 6 weeks of 
initial investigator-assessed progression. Refer to Section 8.1.4 for tumor 
assessment associated with Treatment beyond progression.
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Clinical Protocol
CA2099ER
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline for Arm B Nivolumab and Ipilimumab Combined with 
Cabozantinib, Triplet (CA2099ER)
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm B. Participants previously 
randomized to Arm B continue with Arm B treatment and continue with Arm B clinical planned events, per protocol.
Procedure
Part 1
Part 2
Notes
(Please note differences in cycle durations
between Part 1 and Part 2)
Cycle 1 
(Each 
Cycle=3 
wks)
C2-C4a
(Each 
Cycle= 3 
wks)
C5 and 
Subsequent 
visits a
(Each Cycle=2 
wks)
Randomize
X
Begins with call to Interactive Response Technology (IRT). Participants 
must have an evaluable PD-L1 result from the central lab in order to be 
randomized.
Implementation of CA2099ER Global Revised Protocol 01 stops further 
randomization into Arm B. Participants previously randomized to Arm B 
(Triplet) continue with Arm B treatment and continue with Arm B 
clinically planned events, per protocol.
Administer Nivolumab, 
Ipilimumab, and  Cabozantinib
X
X
Cycles 1 to 4 are 3 week cycles. See Section 7.
Implementation of CA2099ER Global Revised Protocol 01 stops further 
randomization into Arm B. Participants previously randomized to Arm B 
(Triplet) continue with Arm B treatment and continue with Arm B 
clinically planned events, per protocol.
Administer Nivolumab and  
Cabozantinib
X
Day 1 Treatment must begin within 3 days (72 hours ) of Randomization)
Cycle 5 and subsequent cycles are 2 week cycles. See Section 7.
Dispense Study Treatment
X
X
X
See Section 7.
Abbreviations: C=cycle; D=day; wks= weeks. For abbreviations on lab tests refer back to Section 9.4.1.
Notes: Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the 
treating physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
a If a dose is delayed, the procedures scheduled for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs.
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Clinical Protocol
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nivolumab
Table 2-4:
On Treatment Procedural Outline for Arm C Sunitinib (CA2099ER) 
Procedure
Cycle 1
Each Cycle=6wks
Cycle 2 a
Each Cycle=6 
wks
C3 and 
Subsequent visitsa
Each Cycle=6 wks
Notes
Day 1
Day 22
(+/- 3 
days)
Day 1
Day 22
(+/- 3 
days)
Day 1
Day 22
(+/- 3 
days)
•
Chemistry panel on Day 1 and Day 22 (+/- 3 days) of 
every cycle (includes AST, ALT, total bilirubin, 
ALP, LDH, creatinine, BUN, glucose, albumin, Na, 
K, Cl, Ca, P, Mg)
•
Amylase and lipase on Day 1 and Day 22 (+/- 3 days) 
of Cycle 1 and 2, then on Day 1 of Cycle 3 and all 
subsequent cycles.
•
Thyroid panel (includes TSH with reflexive free T3 
and free T4) on Day 1 and Day 22 (+/- 3 days) of 
Cycle 1 and 2, then on Day 1 of Cycle 3 and all 
subsequent cycles.
•
Urine protein and urine creatinine (for UPCR, 
preferred) or urine dipstick for protein on Day 1 of 
every cycle
Pregnancy Test
X
X
X
X
X
X
Within 24 hours prior to the initial administration of study
drug, then every 4 weeks ± 7 days. Serum or Urine. 
WOCBP only.
Efficacy Assessments
Tumor Assessments
First tumor assessment post-baseline should be performed 
Week 12 (± 7 days) following randomization. Use same 
imaging method as was used at baseline. 
Subsequent tumor assessments should occur at every 6 weeks 
(± 7 days) until Week 60, then every 12 weeks (± 14 days) until 
radiographic progression, assessed by the investigator and 
confirmed by the BICR.
CT/MRI of the chest, abdomen, pelvis, and all known 
sites of disease.
Tumor assessments should be performed at the specified 
time points regardless of dosing delays. See Section 9.1
for additional details.
Treatment Beyond Progression
A radiographic assessment/ scan should be performed 
within 6 weeks of initial investigator-assessed 
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Table 2-5:
Follow-Up Procedural Outline for All Arms (CA2099ER) 
Procedure
Safety Follow-up
(Follow up 
Visit 1 (FU1) and Visit 2 
(FU2)a
Survival
Follow-
upb
Notes
Safety Assessments
Targeted Physical Examination, Vital 
Signs, Performance Status
X
Weight, BP, HR, RR, temperature, and Karnofsky Performance Status 
(KPS) (Appendix 7).
Assessment of Signs and Symptoms
X
Adverse Events and Serious Adverse 
Events Assessment
X
Record at each visit. Participants 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 last dose (Appendix 3).
Electrocardiogram (ECG)
X
Fridericia corrected QT (QTcF) required. If any time there is an increase 
in QTcF interval to an absolute value > 500 msec, 2 additional ECGs 
must be performed each with intervals approximately 3 minutes apart.
Laboratory Tests
(includes blood and urine samples)
FU1 -yes
FU2 - if toxicities are 
present
See Section 9.4.1 for additional details on tests required.
•
CBC w/differential, PT/INR, and PTT
•
Chemistry panel (includes AST, ALT, total bilirubin, ALP, LDH, 
creatinine, BUN, glucose, albumin, Na, K, Cl, Ca, P, Mg, amylase, 
lipase)
•
Thyroid panel (includes TSH with reflexive free T3 and free T4) 
•
Urine protein and urine creatinine (for UPCR, preferred) or urine 
dipstick for protein
Pregnancy Test
X
Serum or Urine. WOCBP only.
Efficacy Assessments
Tumor Assessments
First tumor assessment post-baseline 
should be performed Week 12 (± 7 days) 
following randomization. Use same 
imaging method as was used at baseline. 
Participants who discontinue study treatment without radiographic 
progression, confirmed by BICR, will continue tumor assessments 
according to the protocol specified schedule, even if new anti-tumor 
therapy has been initiated in the Follow-Up phase, until radiographic
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a Participants must be followed for at least 100 days after last dose of study treatment. Follow-up visit #1 (FU1) should occur 30 days from the last dose (+/- 7) 
days or can be performed on the date of discontinuation if that date is greater than 42 days from last dose. Follow-up visit #2 (FU2) occurs approximately 100 
days (+/- 7 days) from last dose of study drug. Both Follow Up visits should be conducted in person.
b Survival Follow-up visits to occur every 3 months from Follow-up Visit #2. Survival visits may be conducted in person or by telephone. BMS may request that 
survival data be collected on all treated participants outside of the 3 month specified window. At the time of this request, each participant will be contacted to 
determine their survival status unless the participant has withdrawn consent for all contact.
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3
INTRODUCTION
Renal cell carcinoma (RCC) is the eighth most common cancer in the world with an increasing 
incidence.1 Globally, RCC occurs in more than 330,000 cases with approximately a third of the 
patients succumbing to their disease. More than 100,000 deaths occur annually, as a result of 
progression of metastatic disease. Despite the earlier detection of smaller kidney tumors, the rate 
of RCC-related mortality has increased suggesting that recurrence and advanced disease are 
responsible for mortality.2,3 With the rise in RCC incidence, as well as mortality and morbidity 
associated with advanced RCC, medical need in this population remains a priority. 
Over the last decade, an increased understanding of the biology of RCC has led to development of 
multiple agents that target specific growth pathways. The vascular endothelial growth factor 
(VEGF) pathway and targeted serine/threonine protein kinase therapies that block the mammalian 
target of rapamycin (mTOR) have been found to be important targets in RCC disease. Global 
health authorities (HAs) have approved multiple drugs targeting these pathways, including anti-
VEGF agents, such as pazopanib, sorafenib, sunitinib, cabozantinib, and bevacizumab, and mTOR 
pathway inhibitors, such as temsirolimus and everolimus.4 Additionally, recent innovation of 
treating cancer with immunotherapies has also expanded treatment options. Nivolumab, an anti-
PD-1 antibody, given as monotherapy or in combination with the anti-CTLA-4 antibody, 
ipilimumab, has demonstrated clinical activity in multiple tumor types, including RCC. 
To better understand treatment and patient outcomes, several academic groups have identified 
variables associated with survival and created prognostic models in mRCC. These risk models are 
commonly used for choosing therapies or selecting patients for treatment in clinical trials. The 
International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model stratifies 
patients into 3 prognostic groups, based on 6 adverse prognostic factors, into favorable (0 factors), 
intermediate (1-2 factors), and poor risk (3-6 factors) groups.5 The currently available first-line 
agents for mRCC, which target the VEGF pathway, have shown limited efficacy in the 
intermediate and poor risk populations, yielding median overall survival of approximately 2 years
or less. 
Cabozantinib and nivolumab both share category 1 NCCN guideline recommendations 
(ie, uniform consensus that the treatment is appropriate, based on high-level evidence) for the 
treatment of previously treated mRCC patients.6 Therefore, it is an appropriate next step to 
combine these agents and move them to the first-line setting in an attempt to improve clinical 
outcomes in patients with advanced RCC. This protocol CA2099ER will test the clinical activity 
of nivolumab combined with cabozantinib (doublet regimen). Given the different mechanisms of 
action of each of these agents, there is potential for distinct improvement in clinical efficacy.7  
 
 
 
 
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objective
Endpoint
Primary
To compare progression-free survival (PFS) 
per BICR of nivolumab combined with 
cabozantinib (Arm A: doublet) with sunitinib
(Arm C) in all randomized participants. 
The primary endpoint of this study is to compare PFS per BICR of 
Arm A versus Arm C in all randomized participants. PFS is 
defined as the time between the date of randomization and the first 
date of the documented progression, or death due to any cause, 
whichever occurs first. Participants who die without a reported 
progression (and die without start of subsequent anti-cancer
therapy) will be considered to have progressed on the date of their 
death. Participants who did not progress or die will be censored on 
the date of their last evaluable tumor assessment on or prior to 
initiation of subsequent anti-cancer therapy. Participants who did 
not have any on study tumor assessments and did not die will be 
censored on their date of randomization. Participants who started 
anti-cancer therapy without a prior reported progression will be 
censored on the date of their last evaluable tumor assessment on or
prior to the initiation of first subsequent anti-cancer therapy.
Secondary
To compare overall survival (OS) of Arm A 
with Arm C in all randomized participants.
The first secondary endpoint is to compare OS of Arm A versus 
Arm C in all randomized participants. OS is defined as the time 
between the date of randomization and the date of death due to any 
cause. A participant who has not died will be censored at the last 
known alive date.
To evaluate the objective response rate 
(ORR) per BICR in all randomized 
participants.
The second secondary endpoint is to describe ORR per BICR in 
all randomized participants. ORR is defined as the proportion of 
randomized participants who achieve a best response of complete 
response (CR) or partial response (PR) using the RECIST 1.1 
criteria. Best overall response (BOR) is defined as the best 
response designation recorded between the date of randomization 
and the date of objectively documented progression per RECIST 
1.1 or the date of subsequent therapy (including tumor-directed 
radiotherapy and tumor-directed surgery), whichever occurs first. 
For participants without document progression or subsequent 
therapy, all available response designations will contribute to the 
BOR assessment. Duration of response (DOR) is defined as the 
time between the date of first confirmed documented response (CR 
or PR) to the date of first documented tumor progression (per 
RECIST 1.1) or death due to any cause, whichever occurs first. 
Participants who neither progress nor die will be censored on the 
date of their last tumor assessment. Responders who started anti-
cancer therapy without a prior reported progression will be 
censored on the date of their last evaluable tumor assessment prior 
to the initiation of first subsequent anti-cancer therapy. Time to 
response (TTR) is defined as the time from randomization to the 
date of the first confirmed documented response (CR or PR), as 
assessed by BICR. DOR and TTR will be evaluated for responders 
(CR or PR) only.
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2 [intermediate risk] versus 3-6 [poor risk]), PD-L1 tumor expression ( 1% versus < 1% or 
indeterminate), and region (US/Canada/Western Europe/Northern Europe versus rest of the world 
[ROW]). 
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
Abbreviations: DMC= data monitoring committee; IMDC= International Metastatic Renal Cell Carcinoma Database 
Consortium; IV=intravenous; PD-L1= programmed death-ligand 1; PO= orally by mouth; Pts=patients/participants; 
Q2W=every 2 weeks; Q3W=every 3 weeks; QD= once daily; RCC=renal cell carcinoma.
Arm B is shown in the design schematic because after implementation of Revised Protocol 01, there will be be patients 
on treatment from the original protocol version 08 Mar 2017.
This study will consist of 3 stages: screening, treatment, and follow up phase.
Screening stage: Screening begins by establishing the participant’s initial eligibility and signing of 
the informed consent (ICF). Sufficient, recent tumor tissue, preferably obtained within 3 months
but no more than 12 months prior to enrollment, from a metastatic tumor lesion or from a primary 
tumor lesion which has not been previously irradiated (formalin-fixed paraffin-embedded block or 
20 unstained slides: a minimum of 10 slides, obtained from core biopsy, punch biopsy, excisional 
biopsy or surgical specimen) will be submitted to the central laboratory. Upon receipt of the tumor 
sample, the central lab will determine PD-L1 expression level by immunohistochemistry (IHC) 
testing (see Section 9.8.2). In order to be randomized in the Interactive Response Technology 
(IRT) system, a participant must be classified as PD-L1 expression  1%, PD-L1 expression < 1%, 
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or PD-L1 expression indeterminate. Sites will be informed when the submitted tumor sample is 
insufficient for PD-L1 testing by the central lab. 
Participants will be assessed for complete study eligibility prior to randomization as specified in 
Section 2. 
The Screening stage ends with either confirmation of full eligibility and randomization for the 
participant or with the confirmation that the participant is a screen failure. This study permits the 
re-enrollment of a participant that has discontinued the study as a pre-treatment failure prior to 
randomization. If re-enrolled, the participant must be re-consented. A new participant
identification number will be assigned by IRT at the time of re-enrollment. 
Treatment stage: 
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm 
B. Participants previously randomized to Arm B continue with Arm B treatment and continue with 
Arm B clinical planned events, per protocol.
The Treatment stage begins when the randomization call is made into the IRT. The participant is 
randomly assigned to 1 of the 2 treatment arms as noted in the study schematic above.
•
Arm A (Doublet): Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD
o
Nivolumab to be continued until disease progression or unacceptable toxicity with 
maximum treatment of 2 years from the first dose in Cycle 1
o
Cabozantinib to be continued until disease progression or unacceptable toxicity
•
Arm C: Sunitinib 50 mg PO QD for 4 weeks, followed by 2 weeks off, per cycle. Cycles to be 
continued until progression or unacceptable toxicity
•
Note - Randomization to Arm B stops with implementation of approved CA2099ER Global 
Revised Protocol 01. Treatment B (below) continues only for participants randomized to Arm 
B prior to implementation of Global Revised Protocol 01 
o
Arm B (Triplet): Nivolumab 3mg/kg IV + Ipilimumab 1 mg/kg IV, both Q3W x 4 doses 
+ Cabozantinib 40 mg PO QD 

Then Nivolumab 240 mg flat dose IV Q2W + Cabozantinib 40 mg PO QD

Nivolumab to be continued until disease progression, unacceptable toxicity, or 
a maximum of 2 years from the first dose in Cycle 1

Cabozantinib to be continued until progression or unacceptable toxicity
Study treatment must begin within 3 days (72 hours) of randomization. Participants in Arm A will 
continue nivolumab until progression, unacceptable toxicity, withdrawal of consent, or a 
maximum of 2 years from the first dose in Cycle 1, whichever occurs first. Cabozantinib (Arm A) 
may be continued until progression, unacceptable toxicity, or withdrawal of consent, whichever 
occurs first, and may extend beyond 2 years from the first dose in Cycle 1. See Table 7.1-1 and 
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Table 7.1-2 for the dosing schedule. Study drugs may be delayed for toxicity (See Section 7.4.1).
Treatment may be continued beyond investigator-assessed progression if the investigator confirms 
that the participant meets the criteria specified in Section 8.1.4.
A negative pregnancy test should be documented within 24 hours prior to the initial dose of the 
investigational product and then performed every 4 weeks ± 7 days during treatment. On-study 
laboratory assessments should be drawn within 72 hours prior to dosing and will be assessed at the 
local laboratory.
Tumor assessments will occur in accordance with Section 2 and Section 9.1.2 until progression 
has been assessed by the investigator and confirmed by the blinded independent central review 
(BICR). Each site must submit scans on a rolling basis, preferably within 7 days of image 
acquisition, to a third-party vendor for BICR. If progression is assessed by the investigator, the 
site will inform the radiology vendor so that the BICR assessment of progressioncan be performed. 
The BICR assessment of progression will be completed, and the results provided to the site, within 
approximately 14 days, as specified in Section 9.1.2. 
 
Adverse event assessments should be documented at each clinic visit. 
 
 
The Treatment stage ends when the participant is discontinued from study therapy. 
Follow-up stage: The Follow-up stage begins when the decision to discontinue a participant from 
study therapy is made (no further treatment with study therapy). Participants must be followed for 
at least 100 days after last dose of study treatment. Follow-up visit #1 (FU1) should occur 30 days 
from the last dose (+/- 7) days or can be performed on the date of discontinuation if that date is 
greater than 42 days from last dose. Follow-up visit #2 (FU2) occurs approximately 100 days (+/-
7 days) from last dose of study drug. Both Follow Up visits should be conducted in person. AEs 
will be followed until the toxicities resolve, return to baseline, or are deemed irreversible. 
 
Participants who discontinued study treatment without BICR confirmed radiographic progression
will continue to have tumor assessments performed according to the frequency described in 
Sections 2 and 9.1.2, even if new anti-tumor therapy has been initiated. If progression is assessed 
by the investigator, the site will inform the radiology vendor, so that the BICR assessment of 
progression can be performed. Participants whose progression is not confirmed by the BICR will 
be required to continue tumor assessments (if clinically feasible) according to the protocol-
specified schedule or sooner if clinically indicated until BICR confirms progression on a 
subsequent tumor assessment (See Section 9.1.2.2 for additional details).
After the Follow-up 2 Visit, all participants will be followed for overall survival status every 
3 months (+/- 14 days) until death, withdrawal of consent, loss to follow-up, or end of study. 
Survival status can be ascertained in person or by telephone contact. If new anti-tumor therapy is 
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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) Participants 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 
participant care. 
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Histological confirmation of RCC with a clear-cell component, including participants who 
may also have sarcomatoid features
b) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC 
Stage IV) RCC
c) No prior systemic therapy for RCC with the following exception:
i)
One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such 
therapy did not include an agent that targets VEGF or VEGF receptors and if 
recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant 
therapy.
d) Karnofsky Performance Status (KPS) ≥70% (See Appendix 7)
e) Measurable disease as per RECIST v1.1 per investigator. (See Appendix 8)
f)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections, preferably obtained within 3 months but no more than 12 months prior to 
enrollment, with an associated pathology report, must be submitted to the central laboratory 
during screening. Biopsy should be excisional, incisional or core needle. Fine needle 
aspiration is unacceptable for submission. In participants who received prior adjuvant or
neoadjuvant therapy, the tumor sample must have been obtained after completion of 
adjuvant or neoadjuvant therapy. Upon receipt of the tumor sample, the central lab will 
determine PD-L1 expression level by IHC testing (see Section 9.8.2). In order to be 
randomized in the IRT system, a participant must be classified as PD-L1 expression ≥ 1%, 
PD-L1 expression < 1%, or PD-L1 expression indeterminate. Sites will be informed when 
the submitted tumor sample is insufficient for PD-L1 testing by the central lab.
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g) Participants with favorable, intermediate and poor risk categories will be eligible for the 
study. To be eligible for the Intermediate and Poor-Risk cohort, at least one of the following 
prognostic factors as per International Metastatic RCC Database Consortium (IMDC) must 
be present: (See Appendix 6)
i)
KPS equal to 70%
ii)
Less than 1 year from initial diagnosis (including original localized disease if 
applicable) to randomization
iii)
Hemoglobin < lower limit of normal (LLN)
iv)
Corrected calcium concentration > 10 mg/dL
v)
Absolute neutrophil count > ULN
vi)
Platelet count > ULN
If none of the above factors are present, participants are only eligible for the favorable-risk 
cohort. Approximately 160 favorable risk participants will be randomized. Enrollment of 
favorable risk participants may be closed earlier than enrollment for intermediate and poor 
risk participants.
3) Age and Reproductive Status
a) Males and Females, ages 18 or age of majority 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study treatment and 5 months after the last 
dose of study treatment (ie, 30 days [duration of ovulatory cycle] plus the time required for 
the investigational drug to undergo approximately five half-lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment and 7 months after the last 
dose of study treatment (ie, 90 days [duration of sperm turnover] plus the time required for 
the investigational drug to undergo approximately five half-lives).
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) Any active CNS metastases. Participants with treated, stable CNS metastases for at least 1 
month are eligible as long as they meet the following criteria:
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Treated CNS metastases are defined as having no ongoing requirement for corticosteroids 
for at least 2 weeks prior to randomization and no evidence of progression or hemorrhage 
after treatment completed at least 1 month prior to randomization, as ascertained by clinical 
examination and brain imaging (MRI or CT). (Stable dose of anticonvulsants is allowed). 
Treatment for CNS metastases may include whole brain radiotherapy, radiosurgery (eg, 
RS, gamma knife, LINAC, or equivalent) or a combination as deemed appropriate by the 
treating physician. Participants with CNS metastases treated by neurosurgical resection or 
brain biopsy performed within 1 month prior to randomization are not eligible. Baseline 
imaging of the brain is required within 28 days prior to randomization.
b) Any active, known or suspected autoimmune disease. Participants 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 (e.g. celiac disease) are permitted to enroll.
c) Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
d) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast
e) Any tumor invading the SVC or other major blood vessels
f)
Any tumor invading the GI tract or any evidence of endotracheal or endobronchial tumor 
within 30 days prior to randomization
g) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally (sites in Germany, see Appendix 12).
h) Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis, 
aortic aneurysm, aortic dissection) 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
i)
History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel 
obstruction, or gastric outlet obstruction within the past 6 months prior to randomization
j)
Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of cabozantinib or sunitinib (eg, malabsorptive disorder, ulcerative 
disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection)
k) Serious, non-healing wound or ulcer within 30 days prior to randomization
l)
Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage 
within prior 3 months prior to randomization
m) Uncontrolled adrenal insufficiency
n) History of cerebrovascular accident (CVA) including transient ischemic attack within the 
past 6 months prior to randomization
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c) Neutrophils < 1500/μL
d) Platelets < 100 x 103/μL
e) Hemoglobin < 9.0 g/dL (support with transfusion is acceptable)
f)
Serum creatinine > 1.5 x ULN unless calculated creatinine clearance ≥40 mL/min (using 
the Cockcroft-Gault formula)
g) AST/ALT > 3.0 x ULN
h) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 x ULN)
i)
Urine protein/creatinine ratio (UPCR) > 1.5, unless 24-hour urine protein is ≤ 1.5 g
j)
INR > 1.5
k) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, hepatitis B surface antigen (HBsAg) positive, or hepatitis C antibody (anti-HCV) 
positive (except if HCV-RNA negative)
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) No history of severe hypersensitivity to a monoclonal antibody
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included as a participant. Strict conditions apply and Bristol-Myers 
Squibb approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
6.3.1
Meals and Dietary Restrictions
For participants in Arms A (and Arm B participants enrolled prior to Revised Protocol 01), 
cabozantinib should not be taken with grapefruit/grapefruit juice or Seville oranges.
For participants in Arm C, sunitinib should not be taken with grapefruit/grapefruit juice.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
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6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1 Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the BMS Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
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:
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.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1:
Study treatments for CA2099ER 
Product Description / 
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
BMS-936558-01
(Nivolumab) Solution for
Injection*
100 mg (10 mg/mL)
IP
Open Label
Vial
(multiple vials per carton)
Store at 2° - 8 °C. Protect 
from light and freezing
Ipilimumab Solution for
Injection (see Note)
200 mg (5mg/mL)
IP
Open Label
Vial
(multiple vials per carton)
Store at 2° - 8 °C. Protect 
from light and freezing
Cabozantinib
Tablet
20 mg
IP
Open Label
Tablets in a bottle
Refer to storage 
conditions on container 
label
Sunitinib Malate
Capsule**
12.5 mg
IP
Open Label
Capsules in various 
packaging configurations
Refer to storage 
conditions on container 
label/package insert
*May be labeled as “BMS-936558-01” or “Nivolumab”
** Sunitinib may be obtained by the investigational sites in certain countries as local commercial product (which may be available as a different potency/package 
size than listed above) if local regulations allow and agreed to by BMS.
Note: Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm B. Participants previously randomized to Arm B continue 
with Arm B treatment and continue with Arm B clinically planned events, per protocol
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and
permitted by local regulations. Solutions used as diluent (ie, 0.9% Sodium Chloride Injection or 5% Dextrose Injection) should also be
sourced by investigative sites if available and permitted by local regulations.
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7.1
Treatments Administered
The selection and timing of dose for each participant is presented in Table 7.1-1 and the dosing 
scheduled by cycle is presented in Table 7.1-2.
Table 7.1-1:
Selection and Timing of Dose
Arm
Study 
Treatment
Dosage level(s) and 
Formulation
Frequency of Administration
Route of 
Administration
A
(Doublet)
Nivolumab
240 mg IV
Every 2 weeks
IV
Cabozantinib
40 mg (20 mg tablets)
Once daily (QD)
PO
B
(Triplet)
See Note
Nivolumab 
3 mg/kg IV for 4 doses
then 240 mg IV
Every 3 weeks (Q3W) for 4 doses 
then every 2 weeks (Q2W)
IV
Ipilimumab
1 mg/kg IV for 4 doses
Every 3 weeks (Q3W) for 4 doses
IV
Cabozantinib
40 mg (20 mg tablets)
Once daily (QD)
PO
C
Sunitinib
50 mg (12.5 mg capsules)
A 6 week cycle, consisting of
once daily (QD) regimen for 4 
weeks followed by no treatment 
for 2 weeks.
PO
Abbreviations: IV=intravenous; PO= by mouth.  
Note: Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm B. Participants 
previously randomized to Arm B continue with Arm B treatment and continue with Arm B clinically planned events, 
per protocol
Table 7.1-2:
Dosing Schedule for CA2099ER
Arm
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 and 
subsequent 
cycles
Arm A
Nivolumab +
Cabozantinib
(each cycle = 2 weeks)
Nivolumab 
240 mg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Nivolumab 
240 mg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Nivolumab 240 
mg IV on Day 
1
+
Cabozantinib
40 mg PO QD
Nivolumab 
240 mg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Nivolumab 
240 mg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Arm B
Nivolumab +
Ipilimumab + 
Cabozantinib (see Note)
(Cycle 1 to 4 = 3 
weeks, 
Cycle 5 and subsequent 
cyces = 2 weeks)
Nivolumab
3 mg/kg IV on 
Day 1
+
Ipilimumab 
1 mg/kg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Nivolumab
3 mg/kg IV on 
Day 1
+
Ipilimumab 
1 mg/kg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Nivolumab
3 mg/kg IV on 
Day 1
+
Ipilimumab 
1 mg/kg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Nivolumab
3 mg/kg IV on 
Day 1
+
Ipilimumab 
1 mg/kg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
Nivolumab
240 mg IV on 
Day 1
+
Cabozantinib
40 mg PO QD
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Table 7.1-2:
Dosing Schedule for CA2099ER
Arm
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 and 
subsequent 
cycles
Arm C
Sunitinib
(each cycle = 6 weeks, 
treatment for 4 weeks 
then 2 weeks off each 
cycle)
Sunitinib
50 mg PO QD 
x 4 weeks
Sunitinib
50 mg PO QD 
x 4 weeks
Sunitinib
50 mg PO QD 
x 4 weeks
Sunitinib
50 mg PO QD 
x 4 weeks
Sunitinib
50 mg PO QD 
x 4 weeks
Abbreviations: IV=intravenous; PO= by mouth; QD= once daily
Note: Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm B. Participants 
previously randomized to Arm B continue with Arm B treatment and continue with Arm B clinically planned events, 
per protocol
Participants should begin study treatment within 3 days (72 hours) of randomization. 
For Arm A, participants should receive nivolumab at a dose of 240 mg as an approximately 
30 minute infusion on Day 1 of each treatment cycle until progression, unacceptable toxicity, 
withdrawal of consent, completion of 24 months of treatment (from the first dose on Cycle 1), or
the end of the study, whichever occurs first. The first cabozantinib dose should be given in the 
evening on Day 1, Cycle 1 (after the Cycle 1 nivolumab dose).
For Arm B (Note: only applicable to participants who randomized to Arm B prior to Revised 
Protocol 01), when nivolumab and ipilimumab are to be administered on the same day, nivolumab 
is to be administered first. Nivolumab infusion (approximately 30 minutes) must be promptly 
followed by a flush of diluent to clear the line of nivolumab before starting the ipilimumab 
infusion. The second infusion will always be the ipilimumab study drug (approximately 30 minutes
infusion) and will start after the infusion line has been flushed, filters changed and participant has 
been observed to ensure no infusion reaction has occurred. The time in between infusions is 
expected to be at least 30 minutes (from the end of the nivolumab infusion to the start of the 
ipilimumab infusion). The first cabozantinib dose should be given in the evening on Day 1, Cycle 
1 (after the Cycle 1 nivolumab and ipilimumab doses).
Starting with Cycle 5 in Arm B, participants should receive nivolumab at a dose of 240 mg as a 
30 minute infusion on Day 1 of each treatment cycle until progression, unacceptable toxicity, 
withdrawal of consent, completion of 24 months of treatment (from the first dose on Cycle 1), or 
the end of the study, whichever occurs first.
Dosing calculations for nivolumab and ipilimumab should be based on the body weight assessed 
at baseline. It is not necessary to re-calculate subsequent doses if the participant weight is within 
10% of the weight used to calculate the previous dose. All doses should be rounded up or to the 
nearest milligram per institutional standard.
There will be no dose escalations or reductions of nivolumab or ipilimumab allowed. Participants 
may be dosed with nivolumab no less than 12 days from the previous dose during q2w cycles. 
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Participants may be dosed with nivolumab and ipilimumab no less than 19 days from the previous 
dose during q3w cycles (ie, Cycles 1-4 in Arm B). Participants in Arm B may be dosed with the 
first nivolumab maintenance dose (Cycle 5) no less than 19 days from the previous nivolumab and 
ipilimumab doses. Premedications are not recommended for the first dose of nivolumab or 
ipilimumab. 
Participants should be carefully monitored for infusion reactions during nivolumab and/or 
ipilimumab administration. If an acute infusion reaction is noted, participants should be managed 
according to Section 7.4.4.
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending 
on how well the participant tolerates the treatment. Dosing visits are not skipped, only delayed.
The only exception is Cycle 4 in Arm B, which may be skipped (omitted) only for the reasons 
specified in Section 7.4.3.1and Section 8.1.1 below.
7.1.1
Nivolumab
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is to be administered as an IV infusion through 
a 0.2-micron to 1.2-micron pore size, low-protein binding in-line filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. Please refer to the 
Investigational Brochure/pharmacy manual for further details regarding storage, preparation and 
administration. Care must be taken to assure sterility of the prepared solution as the product does 
not contain any antimicrobial preservative or bacteriostatic agent. 
7.1.2
Ipilimumab (Participants Randomized to Arm B Prior to Revised 
Protocol 01)
For details regarding ipilimumab storage, preparation, and administration, please refer to the 
instructions in the ipilimumab IB and/or pharmacy manual.
Separate infusion bags and filters should be used when administering nivolumab and ipilimumab 
on the same day.
Care must be taken to assure sterility of the prepared solutions, since the drug product does not 
contain any antimicrobial preservatives or bacteriostatic agents.  
7.1.3
Cabozantinib
Cabozantinib is taken orally on an empty stomach, preferably at bed time. Participants should fast
(with the exception of water) for at least 2 hours before until 1 hour after each dose of cabozantinib. 
Cabozantinib tablets should not be crushed or chewed. Cabozantinib should not be taken with 
grapefruit/grapefruit juice or Seville oranges. Missed doses of cabozantinib should not be taken 
within 12 hours of the next dose.
Dispense cabozantinib tablets in their original containers.
7.1.4
Sunitinib
Sunitinib is taken orally without regard to meals. Participants are to avoid grapefruit/grapefruit 
juice while on treatment with sunitinib.
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7.2
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT. Specific instructions for using IRT will be provided to the investigational site in a 
separate document. 
The investigator or designee will register the participant for enrollment by following the 
enrollment procedures established by BMS. 
Once enrolled in IRT, enrolled participants that have met all eligibility criteria, including 
determination of PD-L1 expression in the tumor sample submitted to and evaluated by the central 
laboratory, will be ready to be randomized through the IRT prior to the start of study treatment 
administration for each participant. The site will record the treatment assignment on the applicable 
case report form, if required.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
7.3
Blinding
Not applicable as this is an open-label study; however, the specific treatment to be taken by a 
participant will be assigned using an Interactive Response Technology (IRT). 
Treatment assignments will be released to the bioanalytical laboratory in order to minimize 
unnecessary analysis of samples.
BICR will remain blinded to treatment assignment.
7.4
Dosage Modification 
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm 
B. Participants previously randomized to Arm B continue with Arm B treatment and continue with 
Arm B clinical planned events, per protocol.
In Arm A and Arm B, the assessment of causality for any AE should be performed independently 
for each study drug in the combination regimen.
In the doublet treatment arm (Arm A), cabozantinib and nivolumab will be administered at Cycle 
1. After Cycle 1, modifications in cabozantinib dosing (delay, reduction/escalation, and 
discontinuation) may occur as outlined in Section 7.4.1, Section 7.4.2, and Section 8. After Cycle 
1, nivolumab may be modified as outlined in Section 7.4.1, Section 7.4.2, and Section 8.
In the triplet treatment arm (Arm B), cabozantinib, nivolumab, and ipilimumab will be 
administered at Cycle 1. After Cycle 1, modifications in cabozantinib dosing (delay, 
reduction/escalation, and discontinuation) may occur as outlined in Section 7.4.1, Section 7.4.2, 
and Section 8. After Cycle 1, nivolumab or ipilimumab may be modified as outlined in 
Section 7.4.1, Section 7.4.2, and Section 8.
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•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The management algorithms recommended for use in CA2099ER are included in Appendix 5.
7.4.1.2
Dose Delay Criteria for Cabozantinib
Cabozantinib dosing should be delayed for the following: 
•
Urine protein/creatinine ratio (UPCR) > 2.0 or urine dipstick protein ≥ 3+ or urine protein >
2.0 g / 24 hours. Obtain 24 hour urine protein prior to next dosing visit.
•
Grade 3 prolonged QTc interval (ie, QTcF interval > 500 msec on at least 2 out of 3 separate 
ECGs performed at least 3 minutes apart)
•
Any Grade 2 or 3 drug-related venous thrombosis requiring anticoagulation, with the following 
exception:
−
Any recurrent or worsening venous thromboembolic event after restarting cabozantinib 
will require discontinuation
•
Any other Grade 2 drug-related adverse event or grade 2 drug-related laboratory abnormality 
(e.g., AST, ALT, total bilirubin) that persists for more than 1 week or worsens despite 
supportive care management, with the following exception:
−
Any Grade 2 drug-related hemorrhage requires dose delay
−
Grade ≥ 2 arterial thromboembolic events, including cerebrovascular ischemia, cardiac 
ischemia/infarction, peripheral or visceral arterial ischemia, require discontinuation
•
Sustained Grade 3 drug-related hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥100 
mm Hg). NOTE: Stopping or reducing the dose of cabozantinib is expected to cause a decrease 
in BP. The treating physician should monitor the participant for hypotension and adjust the 
number and dose of antihypertensive medications accordingly.
•
Any other Grade 3 drug-related adverse event or laboratory abnormality, with the following 
exceptions:
−
Grade ≥3 drug-related hemorrhage requires discontinuation (Section 8.1.2).
−
Drug-related AST or ALT > 8 x ULN requires discontinuation (Section 8.1.2).
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN, consistent with potential 
drug-induced liver injury (see Section 9.2.7), requires discontinuation (Section 8.1.2)
−
Grade 3 drug-related amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis do not require dose delay. In such cases, more 
frequent monitoring (eg, weekly) of amylase and lipase is recommended. If amylase or 
lipase worsen to Grade 4 severity or the participant develops symptoms or clinical 
manifestations of pancreatitis, dosing should be delayed.
•
Grade 4 drug-related amylase or lipase abnormalities require dose delay. Participants should 
be monitored for development of symptoms or clinical manifestations of pancreatitis.
•
Grade 4 drug-related electrolyte abnormalities require dose delay. Electrolyte correction with 
supplementation/appropriate management should be promptly initiated.
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•
Grade 4 drug-related neutropenia, lymphopenia, leukopenia, anemia, or thrombocytopenia
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying cabozantinib dosing
•
For participants scheduled for major surgery, including dental surgery which may impact bone 
healing, cabozantinib dosing should be delayed at least 28 days prior to scheduled surgery. The 
treating physician should use clinical judgment with regard to the risks and benefits of the 
planned surgical procedure if it is not possible to delay cabozantinib dosing for 28 days prior 
to the procedure. A delay of cabozantinib dosing of 5 to 7 days is recommended for healing 
for minor surgery.
As a general approach, all AEs related to cabozantinib should be managed with supportive care 
when possible at the earliest signs of toxicity. Calcium, magnesium, potassium, and phosphorus 
should be kept above the lower limits of the laboratory normal values. Please refer to the 
cabozantinib IB, Appendix 10, and Appendix 11 for additional information regarding dose 
modifications and AE management.21
7.4.1.3
Dose Delay Criteria for Sunitinib
Sunitinib dose delays should be based on instructions in the approved product label and should be 
considered for any severe or intolerable drug-related adverse events.
Within a cycle, missed doses of sunitinib should be skipped. Participants should never be dosed 
during the 2-week off period of each 6-week cycle, even if treatment delays occurred earlier in the 
cycle and therapy is ready to be resumed. If treatment is delayed past the end of the 6-week cycle, 
the start of the next cycle should be delayed until treatment with sunitinib resumes.
Prior to resuming therapy after a dose delay, refer to Section 7.4.2 for dose reduction 
recommendations and Section 8 for discontinuation criteria.
For this protocol, sunitinib dosing should be delayed for any of the following:
•
Urine protein/creatinine ratio (UPCR) ≥ 2.0 or urine dipstick protein ≥ 3+ or urine protein 
≥2.0 g / 24 hours. Obtain 24 hour urine protein prior to next dosing visit.
•
Grade 3 prolonged QTc interval (ie, QTcF interval > 500 msec on at least 2 out of 3 separate 
ECGs performed at least 3 minutes apart)
•
Any Grade 2 or 3 drug-related venous thrombosis requiring anticoagulation, with the following 
exception:
−
Any recurrent or worsening venous thromboembolic event after restarting sunitinib will 
require discontinuation
•
Any other Grade 2 drug-related adverse event that persists or worsens despite supportive care 
management, with the following exception:
−
Any Grade 2 drug-related hemorrhage requires dose delay
−
Grade ≥ 2 arterial thromboembolic events, including cerebrovascular ischemia, cardiac 
ischemia/infarction, peripheral or visceral arterial ischemia, require discontinuation
•
Grade 3 drug-related hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg). 
NOTE: Stopping or reducing the dose of sunitinib is expected to cause a decrease in BP. The 
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treating physician should monitor the participant for hypotension and adjust the number and 
dose of antihypertensive medications accordingly.
•
Any other Grade 3 drug-related adverse event or laboratory abnormality, with the following 
exceptions:
−
Grade ≥3 drug-related hemorrhage requires discontinuation (Section 8.1.2).
−
Drug-related AST or ALT > 8 x ULN requires discontinuation (Section 8.1.2).
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN, consistent with potential 
drug-induced liver injury (see Section 9.2.7), requires discontinuation (Section 8.1.2)
−
Grade 3 drug-related amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis do not require dose delay. In such cases, more 
frequent monitoring (eg, weekly) of amylase and lipase is recommended. If amylase or 
lipase worsen to Grade 4 severity or the participant develops symptoms or clinical 
manifestations of pancreatitis, dosing should be delayed.
•
Grade 4 drug-related amylase or lipase abnormalities require dose delay. Participants should 
be monitored for development of symptoms or clinical manifestations of pancreatitis.
•
Grade 4 drug-related electrolyte abnormalities require dose delay. Electrolyte correction with 
supplementation/appropriate management should be promptly initiated.
•
Grade 4 drug-related neutropenia, lymphopenia, leukopenia, anemia, or thrombocytopenia
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying sunitinib dosing
•
For participants scheduled for major surgery, including dental surgery which may impact bone 
healing, sunitinib dosing should be delayed at least 28 days prior to scheduled surgery. The 
treating physician should use clinical judgment with regard to the risks and benefits of the 
planned surgical procedure if it is not possible to delay sunitinib dosing for 28 days prior to 
the procedure. A delay of sunitinib dosing of 5 to 7 days is recommended for healing for minor 
surgery.
As a general approach, all AEs related to sunitinib should be managed with supportive care when 
possible at the earliest signs of toxicity. Calcium, magnesium, potassium, and phosphorus should 
be kept above the lower limits of the laboratory normal values. Please refer to the sunitinib 
approved product label and Appendix 10 for additional information regarding AE monitoring and
management.
7.4.2
Dose Reductions and Escalations
Dose reductions are permitted for cabozantinib and sunitinib but not for nivolumab and ipilimumab 
(see Table 7.4.2-1). 
Table 7.4.2-1:
Dose Level Modifications Table
Dose Level
Cabozantinib 
(tablet dose 
expression)
Sunitinib 
(capsule dose 
expression)
Nivolumab
(IV)
Ipilimumab
(IV)
Nivolumab
(IV)
0 (starting dose)
40 mg daily
50 mg daily
3mg/kg
1 mg/kg
240 mg
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Table 7.4.2-1:
Dose Level Modifications Table
Dose Level
Cabozantinib 
(tablet dose 
expression)
Sunitinib 
(capsule dose 
expression)
Nivolumab
(IV)
Ipilimumab
(IV)
Nivolumab
(IV)
-1
20 mg daily
37.5 mg daily
-
-
-
-2
20 mg every other day
25 mg daily
-
-
-
7.4.2.1
Dose Reduction and Escalation for Nivolumab and Ipilimumab
No dose reductions or dose escalations of nivolumab or ipilimumab are allowed.
7.4.2.2
Dose Reduction and Escalation for Cabozantinib
Dose reductions and dose escalations for adverse event management are allowed for cabozantinib 
(Table 7.4.2-1). Cabozantinib doses will not be re-escalated once reduced, unless a concomitant 
strong CYP3A4 inducer is started (see below). The only exception is participants who continue on 
cabozantinib alone after discontinuation of nivolumab alone (Arm A) or discontinuation of both 
nivolumab and ipilimumab (Arm B) who may re-escalate one dose level if the prior dose reduction 
was due to a toxicity felt by the investigator to have been mainly related to nivolumab and/or 
ipilimumab.
After toxicity requiring a dose delay has improved and meets the criteria to resume dosing (Section 
7.4.3.2), participants who were receiving cabozantinib 40 mg daily prior to the delay will resume 
cabozantinib at 20 mg daily. Participants who were receiving cabozantinib 20 mg daily prior to 
the delay and require another dose delay will resume cabozantinib at 20 mg every other day. If 
more than 2 dose reductions are necessary (ie, reduction to less than 20 mg every other day), 
cabozantinib must be permanently discontinued (Section 8.1.2). 
Participants who required a dose delay due to Grade 3 hypertension, which improved with 
antihypertensive medications, or any Grade 2 or 3 drug-related adverse event or asymptomatic 
laboratory abnormality that improved to Grade ≤ 1 within 7 days with supportive medical care 
may resume cabozantinib at the same dose or a reduced dose, at the discretion of the investigator.
Participants with asymptomatic Grade 2 drug-related AST, ALT or total bilirubin elevation, or 
Grade 3 drug-related lipase or amylase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis may reduce cabozantinib by one dose level, without delaying 
dosing, at the discretion of the investigator.  See also section 7.4.1.2.
In Participants Who Start Taking a Concomitant Strong CYP3A4 Inhibitor: Reduce the daily 
cabozantinib dose by 20 mg (for example, from 40 mg to 20 mg daily). Resume the dose that was 
used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong 
inhibitor (see Prescribing Information for cabozantinib).
7.4.2.3
Dose Reduction and Escalation for Sunitinib
Sunitinib Dose Reductions are permitted as per the approved product label for safety reasons or 
when a concomitant strong CYP3A4 inhibitor is needed (Appendix 9). Selection of an alternative 
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For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional study drug administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for ≤24 
hours):
•
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms recur, 
then no further study dug will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before study drug infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Study drug will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given be given (eg, 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 
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7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration specified in 
protocol Section 7.1. Study treatment will be provided via an extension of the study, a rollover 
study requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of the nivolumab, 
ipilimumab, cabozantinib, or sunitinib is terminated for other reasons, including but not limited to 
lack of efficacy and/or not meeting the study objectives; c) the participant can obtain medication 
from a government sponsored or private health program. In all cases BMS will follow local 
regulations.
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:
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•
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 adverse event (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 (eg, infectious disease) illness. (Note: Under 
specific circumstances, and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
•
Criteria listed in 8.1.1
•
Disease progression of RCC or occurrence of a secondary malignancy which requires systemic 
therapy for treatment
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study treatment will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for participant safety). Please 
call the BMS Medical Monitor within 24 hours of awareness of the pregnancy. If the investigator 
determines a possible favorable benefit/risk ratio that warrants continuation of study treatment, a 
discussion between the investigator and the BMS Medical Monitor/designee must occur.
All participants who discontinue study treatment should 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 (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.1
Nivolumab and Ipilimumab Dose Discontinuation (Arms A and B)
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm 
B. Participants previously randomized to Arm B continue with Arm B treatment and continue with 
Arm B clinical planned events, per protocol.
The assessment for discontinuation of nivolumab, ipilimumab, and cabozantinib should be made 
separately for each study drug. Although there is overlap among the discontinuation criteria, if 
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discontinuation criteria are met for one study drug but not the other(s), it may be acceptable to 
continue treatment with the study drug(s) that are not felt to be related the toxicity, as specified 
below. If the investigator considers the toxicity to be related to all study drugs or is unable to 
determine which of the study drug(s) in Arm A or Arm B are the cause of toxicity, then all study 
drugs in the treatment regimen should be discontinued, and the recommendations for management 
of toxicity related to all study drugs should be promptly initiated.
Nivolumab and/or ipilimumab treatment should be permanently discontinued for any of the
following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation. NOTE: The diagnosis of colitis should be supported by findings 
on colonoscopy whenever possible.
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be 
permanently discontinued. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug(s), a discussion 
between the investigator and the BMS Medical Monitor/designee must occur.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤ 7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
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−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor or designee.
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor or designee. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks, the BMS 
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 every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing.
Participants in Arm B who meet any of the discontinuation criteria above prior to Cycle 3 must 
discontinue both nivolumab and ipilimumab and may not receive nivolumab monotherapy 
maintenance. 
Participants in Arm B who meet any of the discontinuation criteria above after Cycle 3 or Cycle 4 
may be able to proceed to Cycle 5 (skipping Cycle 4 if needed) to begin nivolumab monotherapy 
maintenance if the toxicity is felt to be related mainly to ipilimumab, only after discussion with 
and approval by the BMS Medical Monitor or designee.
8.1.2
Cabozantinib Dose Discontinuation
Permanently discontinue cabozantinib for participants with any of the following:
•
Any requirement for more than 2 cabozantinib dose reductions (ie, reduction to less than 20 
mg every other day)
•
Any Grade ≥2 drug-related arterial thromboembolic events, including cerebrovascular 
ischemia, cardiac ischemia/infarction, peripheral or visceral arterial ischemia
•
Any Grade ≥ 3 drug-related hemorrhage
•
Grade 4 hypertension or persistent Grade 3 hypertension despite optimal medical management 
and cabozantinib dose reduction
•
Drug-related reversible posterior leukoencephalopathy syndrome
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•
Development of drug-related fistula or GI perforation
•
Drug-related nephrotic syndrome
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
−
AST or ALT > 8 x ULN.
−
Concurrent AST or ALT > 3 x ULN and total bilirubin >2 x ULN, consistent with potential 
drug-induced liver injury (see Section 9.2.7).
•
Any Grade 4 drug-related adverse event or laboratory abnormality, with the following 
exceptions:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis
−
Isolated Grade 4 electrolyte abnormalities that are not associated with clinical sequelae and 
are corrected with supplementation/appropriate management within 72 hours of their onset
•
Any dosing interruption lasting > 6 weeks unless the BMS Medical Monitor or designee is 
consulted and agrees with the rationale for resuming therapy after a delay > 6 weeks. Note that
tumor assessments should continue as per protocol even if dosing is interrupted.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued 
cabozantinib dosing.
8.1.3
Sunitinib Dose Discontinuation
Treatment with sunitinib should be permanently discontinued for any of the following:
•
Any requirement for more than 2 sunitinib dose reductions (ie, reduction to less than 25 mg 
daily)
•
Any Grade drug-related arterial thrombosis.
•
Grade 4 drug-related hemorrhage or recurrent Grade 3 drug-related hemorrhage after dose 
reduction.
•
Grade 4 drug-related symptomatic venous thrombosis.
•
Grade 4 drug-related cardiac toxicity.
•
Grade 4 hypertension or persistent Grade 3 hypertension despite optimal medical management 
and sunitinib dose reduction
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
o
AST or ALT > 8 x ULN.
o
Concurrent AST or ALT > 3 x ULN and total bilirubin >2 x ULN, consistent with 
potential drug-induced liver injury (see Section 9.2.7).
•
Any other Grade 4 drug-related adverse event or laboratory abnormality, with the following 
exceptions:
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−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis
−
Isolated Grade 4 electrolyte abnormalities that are not associated with clinical sequelae and 
are corrected with supplementation/appropriate management within 72 hours of their onset
•
Any dosing interruption lasting > 6 weeks unless the BMS Medical Monitor or designee is 
consulted and agrees with the rationale for resuming therapy after a delay > 6 weeks. Note that 
tumor assessments should continue as per protocol even if dosing is interrupted.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued sunitinib 
dosing.
8.1.4
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy or 
anti-angiogenic therapy may derive clinical benefit despite initial evidence of PD.19,51,52
Participants, regardless of study arm, will be permitted to continue treatment beyond initial 
RECIST 1.1 defined PD, assessed by the investigator, up to a maximum of 24 months from the 
date of first dose, as long as they meet the following criteria:
•
Investigator-assessed clinical benefit
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional treatment with the 
study drug regimen. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply.
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with nivolumab.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities Schedule in Section 2.  Treatment may be continued beyond 
investigator-assessed progression if the investigator confirms that the participant meets the criteria 
specified in Section 8.1.4.
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time 
of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the 
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diameters of new measurable lesions compared to the time of initial PD. It is recommended that 
study treatment should be discontinued permanently upon documentation of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least15 
mm). Any new lesion considered non-measureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
8.1.5
Post-Study Treatment Follow-up
In this study, overall survival is a key endpoint of the study. Post-study treatment follow-up is of 
critical importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed for collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (See Section 2). At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
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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 participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain 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 to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
CA2099ER Global Revised Protocol 01
Implementation of CA2099ER Global Revised Protocol 01 stops further randomization into Arm 
B. Participants previously randomized to Arm B continue with Arm B treatment and continue with 
Arm B clinical planned events, per protocol.
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
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evaluated to rule out pulmonary toxicity,
 
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
CA2099ER Imaging Manual to be provided by the core lab. 
9.1.1
Methods of Measurements
The following imaging assessments should be performed at pre-specified intervals: CT of the 
chest, CT or MRI of the abdomen, pelvis, and other known sites of disease.
•
CT scans should be acquired with slice thickness of 5 mm or less with no intervening gap 
(continuous) 
•
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest 
and a contrast enhanced MRI of the abdomen and pelvis and other sites of disease may be 
obtained. MRIs should be acquired with slice thickness of 5 mm or less with no gap 
(continuous).
•
Every attempt should be made to image each participant using an identical acquisition protocol 
on the same scanner for all imaging time points
•
PET alone will not be considered for the disease assessment. Complementary CT and/or MRI 
or biopsy must be performed in such cases. 
Note: 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 (Appendix 8) 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. 
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9.1.2
Imaging and Clinical Assessment 
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
CA2099ER Imaging Manual to be provided by the core lab. 
Baseline imaging, including CT/MRI of the chest, abdomen, pelvis, and all known sites of disease
performed within 28 days prior to randomization, should be submitted to the imaging core lab.
Baseline brain MRI (preferred) or CT scan should also be performed within 28 days prior to 
randomization and submitted to the imaging core lab. Participants who are found to have untreated 
brain metastases on the baseline brain scan may not be randomized.
9.1.2.1
Investigator Assessment of Progression
The same method of assessment used at Screening should be used for on-study time points. Brain 
MRI or CT scans during on-study time points and the follow-up phase are only required in 
participants with a history of CNS metastases prior to randomization or if clinically indicated for 
new signs or symptoms that suggest new or worsening CNS metastases. 
Post-baseline tumor assessments will be performed at the time points described below until 
progression assessed by the investigator and confirmed by BICR, death, or withdrawal from the 
study, whichever occurs first. 
•
First tumor assessment post-baseline should be performed at Week 12 (± 7 days) following 
randomization. Use same imaging method as was used at screening/baseline. 
•
Subsequent tumor assessments should occur at every 6 weeks until Week 60. Allowable 
window for assessments is ± 7 days until Week 60. After Week 60, tumor assessments should 
occur every 12 weeks (± 14 days) until radiographic progression, assessed by the investigator 
and confirmed by the BICR. 
•
Additional imaging of potential disease sites should be performed whenever disease 
progression or a secondary malignancy is suspected. In participants with no history of brain 
lesions prior to randomization, brain MRI or CT on-study treatment should be obtained if 
clinically indicated. Bone imaging during on-study treatment and follow-up periods should be 
obtained if clinically indicated.
•
Tumor assessments are to continue for all randomized participants according to the protocol 
schedule until radiographic progression has been assessed by the investigator and confirmed 
by the BICR, regardless of whether study drug dosing is delayed, reduced, or discontinued.
The investigator (in consultation with the local radiologist as needed) will complete tumor 
assessments using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria on all 
imaging time points specified in the protocol. Any additional imaging that may demonstrate tumor 
response or progression, including scans performed at unscheduled time points and/or at an outside 
institution, should also be collected for the investigator to complete RECIST 1.1 tumor 
assessments on these images and to submit them for BICR review.
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All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment.
9.1.2.2
BICR Assessment of Progression
Sites should submit all scans to a BICR on a rolling basis, preferably within 7 days of scan 
acquisition, throughout the duration of the study. BICR will review scans on a rolling basis and 
remain blinded to treatment arm and investigator assessment of submitted scans. When progression
per RECIST 1.1 criteria is assessed by the investigator, the site will inform the imaging core lab,
so that the BICR assessment of progression can be performed. The BICR review will be completed 
and the results provided to the site within approximately 14 days of receipt of the scans, provided 
there are no pending imaging queries to the site. 
Participants whose progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule or sooner if 
clinically indicated until the BICR confirms progression on a subsequent tumor assessment. Also, 
if participants discontinue treatment without radiographic progression, tumor assessments will 
continue according to the protocol specified schedule, as noted in Section 2, until progression has 
been confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment. The BICR assessment of progression is only relevant for determining 
when tumor assessments for a given participant are no longer required to be submitted to the 
imaging vendor.
9.1.3
Imaging Restriction and Precautions
Table 9.1.3-1 provides a summary of the alternative methods, acceptable per protocol, in the event 
of contraindications for use of IV and oral contrast, and or/MRI. 
Table 9.1.3-1:
Acceptable Imaging Assessment Methods for Different Anatomic 
Regions
Anatomic Region
Preferred Method
Alternative Methods
Chest, abdomen, 
and pelvis
Note: Scan must 
cover lung apices to 
diaphragm, 
diaphragm through 
entire liver, and to 
below the pubic 
symphysis
CT with IV contrast
For chest:
• CT without contrast can be used only if the participant has a 
clinical contraindication for iodine-based IV contrast (eg,
hypersensitivity, renal insufficiency)
For abdomen and pelvis:
• MRI with gadolinium-based IV contrast is the first alternative 
method if the participant has a clinical contraindication for 
iodine-based IV contrast
• CT without contrast can be used as the second alternative 
method only if the participant has a clinical contraindication 
for both contrast-enhanced CT and MRI.
Brain
MRI with IV contrast
•
CT with IV contrast is the first alternative method if IV 
gadolinium is clinically contraindicated. 
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9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
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. 
Contacts for SAE reporting specified in Appendix 3
Immune-mediated adverse events (IMAEs, imAEs) are AEs consistent with an immune-mediated 
mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection 
or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology 
which were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the participant’s case report form.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until the 
timepoints specified in the Schedule of Activities (Section 2). Nonserious AE information should 
also be collected from the start of a placebo lead-in period or other observational period intended 
to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochures (IBs) for Nivolumab28 and Ipilimumab29
represent the Reference Safety Information (also Appendix K in the IB for cabozantinib21) 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.
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All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized to treatment and never treated with study 
drug, SAEs should be collected for 30 days from the date of randomization. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure (eg, 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 eCRF section.
•
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. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 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 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
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9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will 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 5 
months (5 half-lives + 30 days) after product administration for WOCBP, 7 months (5 half lives + 
90 days) after product administration for male participants with partners who are WOCBP, 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 treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). 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.
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 designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the 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.
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•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (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 9.2 and 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),
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.
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 SAEs (see Section 9.2).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (see Section 
2).
9.4.1
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Hematology (CBC)
Hemoglobin
Hematocrit
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Total leukocyte count, including differential
Platelet count
Prothrombin time (PT)/ International normalized ratio (INR)
Partial thromboplastin time (PTT)
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (MLR)
Creatinine
Blood Urea Nitrogen (BUN)
Glucose
Albumin
Sodium (Na)
Potassium (K)
Chloride (Cl)
Calcium (Ca)
Corrected calcium (Screening only)
Phosphorus (P)
Magnesium (Mg)
Amylase
Lipase
Urinalysis
Creatinine
Protein
Urine protein/creatinine ratio (UPCR)
Serology
Serum for hepatitis C antibody, HCV RNA, hepatitis B surface antigen (screening only).
HIV, if mandated locally. (Sites in Germany, see Appendix 12)
Other Analyses
Thyroid stimulating hormone (TSH) with free thyroxine (fT3) and free triiodothyronine (fT4)
(screening only); TSH with reflexive fT3 and fT4 during study and follow up
Pregnancy test (WOCBP only: screening and during study)
Follicle stimulating hormone (FSH) (screening only for women under 55 years old to confirm 
menopause as needed)
9.4.2
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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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will be 
evaluated in this study as noted in Section 2.
Medical resource utilization and health economics data, associated with medical encounters, will 
be collected in the CRF by the investigator and study-site personnel for all participants throughout 
the study. Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include:
•
Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)
•
Duration of hospitalization (total days length of stay, including duration by wards; eg, intensive 
care unit)
•
Number and character of diagnostic and therapeutic tests and procedures
•
Outpatient medical encounters and treatments (including physician or emergency room visits, 
tests and procedures, and medications)].
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The sample size of this study accounts for the primary endpoint of progression-free survival (PFS) 
per BICR in all randomized participants. Assuming a 25% screen failure rate, it is expected that 
approximately 850 participants will need to be enrolled in order to randomize 638 participants 
(319 per arm) in a 1:1 ratio. To represent the normal frequency of the favorable risk group in 
mRCC, the favorable risk participants are capped at approximate 25%; thus, at most 212 favorable 
risk participants (106 per arm) will be enrolled to randomize 160 favorable risk participants in a 
1:1 ratio. The rest of the enrolled participants will provide approximately 478 intermediate/poor 
risk randomized participants (239 per each arm).
The overall alpha for this study is 0.05 (two-sided). PFS will be evaluated for treatment effect at 
an alpha of 0.05 (two-sided), with at least 95% power. No interim analysis of PFS is planned. OS 
will be evaluated for treatment effect at an alpha level of 0.05 (two-sided) with 80% power, 
accounting for two formal interim analyses to assess efficacy.
Sample Size Justification for Primary PFS Endpoint
The primary endpoint of PFS per BICR of Arm A versus Arm C analysis will be conducted on all 
randomized participants. The PFS analysis will occur after approximately 9-10 months minimum 
follow-up on all randomized subjects by which approximately 350 events from Arm A and Arm 
C are expected. The 350 PFS events provide at least 95% power to detect a HR of 0.68 for PFS of 
Arm A versus Arm C with a type I error of 0.05 (two-sided). The HR of 0.68 corresponds to a 47% 
increase in the median PFS, assuming a median PFS of 18.2 months for Arm A and 12.4 months 
for Arm C. It is projected that an observed HR of 0.811 or less, which corresponds to a 2.89 month 
or greater improvement in median PFS (12.4 versus 15.3 months), would result in a statistically 
significant improvement in PFS for the Arm A versus Arm C comparison. 
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If the formal analysis of PFS among all randomized participants is statistically significant, the 
formal interim analysis of OS among all randomized participants will be tested, as per hierarchical 
testing procedure. 
Sample Size Computation for Secondary OS Endpoint
The secondary endpoint of OS in all randomized participants specifies the comparison of Arm A 
versus Arm C. Among all randomized participants, approximately 254 events (ie, deaths) in Arm 
A and Arm C provides at least 80% power to detect a HR of 0.70 for OS of Arm A and Arm C 
with an overall type 1 error of 0.05 (two-sided) for each test. The HR of 0.70 corresponds to a 43% 
increase in the median OS, assuming a median OS of 47.1 months for Arm A and 33 months for 
Arm C.
Two formal interim analyses of OS are planned for this study. The first interim analysis is planned 
at the time of final PFS analysis and it is expected to observe 165 OS events (65% of the targeted 
OS events for final analysis) and the second interim analysis is planned to occur after observing
approximately 211 events (83% of targeted OS events needed for final analysis). The stopping 
boundaries at interim and final analyses will be derived based on the number of deaths using 
O’Brien and Fleming α spending function. For example, with 165, 211, and 254 observed events 
in Arm A and Arm C at the first interim, second interim, and final analyses, the respective stopping 
boundaries would be α=0.011 (two-sided), α=0.025 (two-sided), and α=0.041 (two-sided). If the 
first interim analysis is performed exactly at 165 deaths, it is projected that an observed HR of 
0.673 or less, which corresponds to a 16.0 month or greater improvement in median OS (33 versus 
49 months), would result in a statistically significant improvement in OS for the Arm A versus 
Arm C comparison. At the second interim analysis with 211 deaths, it is projected that an observed 
HR of 0.734 or less, which corresponds to a 12.0 month or greater improvement in median OS (33
versus 45 months), would result in a statistically significant improvement in OS for the Arm A 
versus Arm C comparison. At the time of final OS analysis when there are 254 deaths, it is 
projected that an observed HR of 0.774 or less, which corresponds to a 9.6 month or greater 
improvement in median OS (33 versus 42.6 months), would result in a statistically significant 
improvement in OS for the Arm A versus Arm C comparison.
Assuming a constant accrual rate (an average rate of 3 participants/month in the first 4 months, 
afterwards an average rate of 42 participants/month), the accrual will take approximately 19 
months. The final PFS analysis will not occur prior to these conditions being met:
•
at least 8 months minimum follow-up on all randomized subjects;
•
at least 283 PFS events, which provide at least 90% power to detect a HR of 0.68 for PFS of 
Arm A versus Arm C; and 
•
at least 149 OS events, which provide 66% power if the target HR for OS was 0.60. (Note that 
if the analysis of first interim analysis OS takes place with 149 OS events, the alpha spending 
for the OS comparison would be 0.007 with a critical HR=0.643.)
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This expected PFS analysis will occur at approximately 29 months from FPFV. The second interim 
and final analyses of OS are expected to occur approximately 34 months and 40 months from 
FPFV, respectively. Table 10.1-1 summarizes the results of these calculations.
Table 10.1-1:
Summary of sample size parameters and schedule of analyses
Primary/Secondary 
Endpoints
PFS (Primary)
OS (Secondary)a
Primary analysis population
All Randomized Participants
Accrual rate per month for all 
randomized population
3 participants/month in the first 4 months, afterwards an average rate of 42 
participants/month
Power
95%
80%
Alpha
0.05 2-sided
0.05 2-sided (0.011 at IA1, 0.025 at IA2, 
0.041 at FA)
Hypothesized median control 
vs exp (months) 
12.4 vs 18.2
33 vs 47.1
Hypothesized hazard ratio
0.68
0.70
Critical hazard ratio (observed 
hazard ratio at which a 
statistically significant 
difference would be observed) / 
Difference in median (months) 
Corresponding to a minimal 
clinically significant effect size 
(FA)b
0.811 / 2.89
0.774 / 9.6
Critical HR at interim analysis-
1(IA1) /effect size
N/A
0.673 / 16.0
Expected number of event for 
IA1 (percentage of target 
events)
N/A
165 (65%) 
Timing of IA1 from FPFV 
(months)
N/A
29
Critical HR at interim analysis-
2(IA2) /effect size
N/A
0.734 / 12.0
Expected number of event for 
IA2 (percentage of target 
events)
N/A
211 (83%) 
Timing of IA2 from FPFV 
(months)
N/A
34
Accrual duration (months)
19
19
Timing of final analysis (FA) 
from FPFV (months)
29
40
Sample size
638
638
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10.3.1
Efficacy Analyses
The efficacy analyses will be performed in all randomized participants in Arm A and Arm C. 
Descriptive summary of efficacy will be provided for participants randomized in Arm B.
Table 10.3.1-1:
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint of this study is to compare PFS per BICR of Arm A (doublet) versus 
Arm C (single agent), in all randomized participants. 
PFS is defined as the time between the date of randomization and the first date of the 
documented progression, or death due to any cause, whichever occurs first. Participants who 
die without a reported progression (and die without start of subsequent anti-cancer therapy)
will be considered to have progressed on the date of their death. Participants who did not 
progress or die will be censored on the date of their last evaluable tumor assessment on or prior 
to initiation of subsequent anti-cancer therapy. Participants who did not have any on study 
tumor assessments and did not die will be censored on their date of randomization. Participants 
who started anticancer therapy (including tumor-directed radiotherapy and tumor-directed 
surgery) without a prior reported progression will be censored on the date of their last evaluable 
tumor assessment on or prior to the initiation of first subsequent anti-cancer therapy.
The primary formal comparisons of PFS will be conducted using a two-sided 0.05 stratified 
log-rank test for each comparison, with IMDC scores, PD-L1 tumor expression, and region at 
screening per IRT as stratification factors among all randomized participants.
Median PFS will be estimated via the Kaplan-Meier product limit method. Two-sided 95% CI 
for the median PFS will be computed for each randomized arm. 
Kaplan-Meier plots of PFS will be presented. Hazard ratios (HR) and corresponding two-sided 
95% confidence intervals (CI) will be estimated using a Cox proportional hazards model, with 
treatment arm as a single covariate, stratified by the stratification factors, corresponding to the 
comparison of PFS.
The totality of PFS results will be presented in a single graphical display that includes Kaplan-
Meier curves for all treatment arms, the log-rank p-values for the formal comparisons, the HRs 
and corresponding CIs, and the median PFS estimates and corresponding CIs.
The following supportive analyses of PFS will also be conducted: 
A stratified multivariate Cox regression model will be used in order to estimate the treatment 
effect after adjustment for possible imbalances in known or potential prognostic factors. The 
covariates included in this model will be specified in the statistical analysis plan. 
PFS using an un-stratified log rank test. The hazard ratio associated with treatment will be 
presented along with the associated two-sided 95% CIs.
PFS accounting for missing tumor assessment prior to PFS event (progression or death). This 
analysis will be performed only if at least 10% of events have missing prior tumor assessment. 
It will apply the following restriction to the primary definition: If the elapsed time between the 
PFS event and the last assessment immediately prior to the event is two or more missed visits 
(more than 12 weeks - 10 days), the participant’s PFS will be censored at his/her last tumor 
assessment prior to the PFS event.
Secondary
The first secondary endpoint is to compare OS of Arm A versus Arm C in all randomized 
participants. OS is defined as the time between the date of randomization and the date of 
death due to any cause. A participant who has not died will be censored at the last known 
alive date. 
At the time of the primary endpoint analysis, there will be a first interim analysis of OS. The 
second interim analysis and the final analysis of OS are planned to occur approximately 34
months and 40 months from FPFV, respectively. OS will be compared between these 
treatment arms using a two sided, 0.05 level log-rank test (adjusted for interim analyses), 
stratified using IMDC scores, PD-L1 tumor expression, and region at screening as 
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Table 10.3.1-1:
Efficacy Analyses
Endpoint
Statistical Analysis Methods
stratification factors among all randomized participants. A similar analysis as in PFS will be 
conducted for OS. Hazard ratio (HR) and corresponding two-sided 95% confidence intervals 
(CI) will be estimated using a Cox proportional hazards model, with treatment arm as a single 
covariate, stratified by the stratification factors, corresponding to the comparison of OS.
The second secondary endpoint evaluates ORR per BICR for all randomized participants. 
ORR is defined as the proportion of randomized participants who achieve a best response of 
complete response (CR) or partial response (PR) using the RECIST 1.1 criteria. Best overall 
response.
(BOR) is defined as the best response designation recorded between the date of randomization 
and the date of objectively documented progression per RECIST 1.1 or the date of subsequent 
therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs 
first. For participants without document progression or subsequent therapy, all available 
response designations will contribute to the BOR assessment. Duration of response (DOR) is 
defined as the time between the date of first confirmed documented response (CR or PR) to the 
date of first documented tumor progression (per RECIST 1.1) or death due to any cause, 
whichever occurs first. Participants who neither progress nor die will be censored on the date 
of their last tumor assessment. Responders who started anti-cancer therapy without a prior 
reported progression will be censored on the date of their last evaluable tumor assessment prior 
to the initiation of first subsequent anti-cancer therapy. TTR is defined as the time from 
randomization to the date of the first confirmed documented response (CR or PR), as assessed 
by BICR. DOR and TTR will be evaluated for responders (CR or PR) only.
Tumor assessments are scheduled to be performed at Week 12 following randomization, every 
6 weeks for the first 12 months and then every 12 weeks until progression.
ORR will be analyzed at the time of the final PFS analysis. ORRs and corresponding 95% exact 
CIs will be calculated using the Clopper Pearson method within each treatment arms. An 
estimate of the response rate and an associated exact two-sided 95% CI (Clopper and Pearson) 
will be presented, by treatment group. Sensitivity analysis based on investigator-determined 
ORR may also be performed. DOR and TTR will also be evaluated.
10.3.2
Safety Analyses
The safety analyses will be performed in all treated participants in Arm A and Arm C. Participants 
treated in Arm B will be considered in select safety analyses.
Table 10.3.2-1:
Safety Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint is related to efficacy and there are no primary safety endpoints.
Secondary
Safety will be analyzed at the time of the primary endpoint analysis. Descriptive statistics of 
safety will be presented using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 by treatment arm. All AEs, drug-related 
AEs, SAEs and drug-related SAEs, imAEs, and select AEs will be tabulated using the worst 
grade per NCI CTCAE version 4.0 criteria by system organ class and preferred term. On-
study lab parameters including hematology, coagulation, chemistry, liver function and renal 
function will be summarized using worse grade per NCI CTCAE version 4.0 criteria.
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is expected after observing 211 deaths (approximately 83% of the targeted OS events) have been 
observed among all randomized participants based on above accrual rate and the exponential 
distribution in each arm. The boundary for declaring superiority in terms of statistical significance 
for the second interim analysis after 211 events would be 0.025 (HR=0.734 with 12 months 
improvement in median OS for the doublet versus sunitinib comparison (33 versus 45 months).
The boundary for declaring superiority in terms of statistical significance for the final analysis 
after 254 events would be 0.041 (HR=0.774 with 9.6 months improvement in median OS for the 
Arm A versus Arm C comparison (33 versus 42.6 months). More details are summarized in Table 
10.1-1. An independent statistician external to BMS will perform interim analysis in conjunction 
with a review by a data monitoring committee.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ACLS
advanced cardiac life support
AHA
alpha hydroxy acid
AI
accumulation index
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
APC
antigen-presenting cell
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
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
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
AXL
member of the TAM (Tyro-3, Axl, Mer) receptor tyrosine kinases (RTK) 
subfamily
β-HCG
beta-human chorionic gonadotrophin
Bcl-xL
anti-apoptotic member of the B-cell lymphoma 2 (BCL-2) protein family
BICR
blinded independent central review
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
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Term
Definition
BOR
best overall response
BP
blood pressure
BTLA
B and T lymphocyte attenuator
BUN
blood urea nitrogen
C
Celsius
C
cycle
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca, Ca++
calcium
Cavg
average concentration
Cavgss
average concentration at steady state
CBC
complete blood count
CD
cluster of differentiation
CD3, CD8, CD14, 
CD28
cluster of differentiation 3, 8, 14, 28
CD137
member of the tumor necrosis factor (TNF) receptor family. Alternative 
names are TNF receptor superfamily member 9 (TNFRSF9), 4-1BB and 
induced by lymphocyte activation (ILA)
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CHF
congestive heart failure
CI
confidence interval
Cl, C1-
chloride
CLcr
creatinine clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu 
or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
centimeter
Cmax, CMAX
maximum observed concentration
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Term
Definition
c-MET
tyrosine-protein kinase mesenchymal-epithelial transition (MET) or 
hepatocyte growth factor receptor, is a protein that in humans is encoded 
by the MET gene
CMH
Cochran-Mantel-Haenzel
Cmin, CMIN
minimum observed concentration
CMV
cytomegalovirus
CNS
central nervous system
CONSORT
Consolidated standards of reporting trials
CR
complete response
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CT
computed tomography
CTAg
clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte antigen-4
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CVA
cerebrovascular accident
CYP
cytochrome p-450
D
day
DBP
diastolic blood pressure
D/C
discontinue
DILI
drug induced liver injury
dL
deciliter
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
DVT
deep vein thrombosis
EA
extent of absorption
EC50
half maximal effective concentration
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Term
Definition
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
e.g., eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EOI
end of infusion
EQ-5D-3L
EuroQoL Group’s instrument to measure general health status
ESR
Expedited Safety Report
F
bioavailability
FA
final analysis 
FDA
Food and Drug Administration
FDG-PET
fludeoxyglucose- positron emission tomography
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescent in-situ hybridization
FKSI-19
Functional Assessment of Cancer Therapy - Kidney Symptom Index
FLT-3
Fms-related tyrosine kinase 3
FSH
follicle stimulating hormone
fT3, fT4
free thyroxine (fT3), free triiodothyronine (fT4)
FU
follow up
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
GI
gastrointestinal
h
hour
HA
health authorities
HBsAg
hepatitis B surface antigen
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Term
Definition
HBV
hepatitis B virus
hCG, HCG
human chorionic gonadotropin
HCO3-
bicarbonate
HCV
hepatitis C virus
HFS
hand foot syndrome
HIV
Human Immunodeficiency Virus
HR
heart rate, hazard ratio
HrQoL
health-related quality of life
HRT
hormone replacement therapy
ICD
International Classification of Diseases
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonisation 
ICOS
inducible co-stimulator
i.e., ie
id est (that is)
IEC
Independent Ethics Committee
IFN-γ
interferon-γ
IFN-alpha
interferon alphas
IgG1
immunoglobulin G1
IHC
Immunohistochemistry
IL
interleukin
IL-2
interleukin-2
IMAEs, imAEs
immune-mediated adverse events
IMDC
International Metastatic Renal Cell Carcinoma Database Consortium
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INR
international normalized ratio
IP
investigational product
ipi
ipilimumab
iRAEs
immune-related adverse events
IRB
Institutional Review Board
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Term
Definition
IRC
independent radiologic review committee
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K, K+
potassium
kg
kilogram
KIT
platelet-derived growth factor receptors (PDGFRs)
KPS
Karnofsky Performance Status
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LC-MS-MS
liquid chromatography tandem-mass spectrometry
LDH
lactate dehydrogenase
LFT
liver function test
LINAC
linear accelerator 
LLN
lower limit of normal
LMWH
low molecular weight heparin
ln
natural logarithm
MDSCs
myeloid-derived suppressor cells
MER
proto-oncogene tyrosine-protein kinase MER is an enzyme that in 
humans is encoded by the MERTK gene
MET
mesenchymal-epithelial transition factor, a tyrosine kinase receptor
mg
milligram
Mg, Mg++
magnesium
MHC
major histocompatibility complex
min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
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Term
Definition
mmHg
millimeters of mercury
mOS
median overall survival
mRCC
metastatic renal cell carcinoma
MRI
magnetic resonance imaging
MS
mass spectrometry
MSKCC
Memorial Sloan Kettering Cancer Center
MTD
maximum tolerated dose
mTOR
mammalian target of rapamycin
mUC
metastatic urothelial carcinoma
MUGA
multigated acquisition scan
mWHO
modified World Health Organization
μg
microgram
N
number of subjects or observations
N/A, NA
not applicable
Na, Na+
sodium
NaF
Sodium fluoride
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
not evaulable
ng
nanogram
NIMP
non-investigational medicinal products 
nivo
nivolumab
NK
natural killer
NKG2D
encoded by KLRK1 gene which is located in the NK-gene complex 
(NKC)
NR
not reached
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
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Term
Definition
P
phosporous
PCR
polyermase chain reaction
PD
progressive disease, disease progression
PD
pharmacodynamics
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PE
pulmonary embolism
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Q2W, Q3W
every 2 weeks, every 3 weeks
QC
quality control
QD, qd
quaque die, once daily
qRT-PCR
quantitative real time polyermase chain reaction
QTcF
Fridericia corrected QT
R2
coefficient of determination
RBC
red blood cell
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RET
proto-oncogene encodes a receptor tyrosine kinase for members of the 
glial cell line-derived neurotrophic factor family of extracellular 
signalling molecules
RNA
ribonucleic acid
ROS1
proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans 
is encoded by the ROS1 gene
ROW
rest of the world
RR
respiratory rate
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Term
Definition
RS
radiosurgery
RTK
receptor tyrosine kinases
SAE
serious adverse event
SBP
systolic blood pressure
SCC
squamous cell carcinoma
SD
standard deviation, stable disease
SNP
single-nucleotide polymorphism
SOP
Standard Operating Procedures
Subj
subject
SVC
superior vena cava
t
temperature
T
time
TAMs
tumor-assisted macrophages
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
T-HALF
Half life
TID, tid
ter in die, three times a day
TIE-2
tunica interna endothelial cell kinase 2
TIL
tumour-infiltrating lymphocyte,
TKIs
tyrosine kinase inhibitors
Tmax, TMAX
time of maximum observed concentration
Tregs
regulatory T cells
TRKB
tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor 
kinase B
TSH
thyroid stimulating hormone
TTR
time to response
TYRO3
tyrosine-protein kinase receptor TYRO3 is an enzyme that in humans is 
encoded by the TYRO3 gene
ULN
upper limit of normal
UPCR
urine protein to creatinine ratio
UV
ultraviolet
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Term
Definition
VAS
visual analog rating scale
VEGF
vascular endothelial growth factor
VEGFR2
vascular endothelial growth factor receptor 2
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
washout
WBC
white blood cell
WHO
World Health Organization
wks
weeks
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
x g
times gravity
XL184
cabozantinib
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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 CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following: (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (eg,
advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
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The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC 
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects//participants currently enrolled in the study if they are affected by the amendment; and 
(3) the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given to subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant
volunteers to participate. 
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Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects'/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects/participants unable to give their written consent (eg, stroke or subjects/participants with 
or severe dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The participant must also be informed about 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 
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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, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
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 treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
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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 (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, if 
applicable 
•
dates and initials of person responsible for 
Investigational Product 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.   
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture 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 
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only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, 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 
task For 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 designee training 
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 designee representatives 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. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
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If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, 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 (eg,
cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study 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:
•
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, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
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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
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
•
Other criteria (as determined by the study team)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) 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 CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
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4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study 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 participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
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 participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
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Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is 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 TO SPONSOR 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 follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
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.
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 
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•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
•
Intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study 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
Unacceptable as a Sole Method of Contraception
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
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•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
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 end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment.
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
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 6
INTERNATIONAL METASTATIC RCC DATABASE 
CONSORTIUM (IMDC) PROGNOSTIC CRITERIA
Adverse Prognostic Factors
Clinical 
KPS < 80%
Time from initial diagnosis (including original localized disease if applicable) to treatment < 1 year
Laboratory 
Hemoglobin < LLN
Corrected calcium > 10 mg/dL
Absolute neutrophil count > ULN
Platelet count > ULN
Note: The corrected calcium criterion was adapted from to Heng et al, 2009 to account for local laboratories that may 
not provide an ULN for corrected calcium.
Abbreviations: KPS= Karnofsky Performance Status; LLN = Lower limit of normal; ULN = Upper limit of normal
Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]), where 
4.0 represents the average albumin level in g/dL.
Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 (40 - serum albumin [g/L]), 
where 40 represents the average albumin level in g/L
Risk Group Based on Number of Adverse Prognostic Factors
Number of Adverse Prognostic Factors Present
Risk Group
0
Favorable
1-2
Intermediate
3-6
Poor
 
 
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APPENDIX 7
PERFORMANCE STATUS SCORES
SCALES
STATUS
KARNOFSKY
ZUBROD-ECOG-WHO
STATUS
Normal, no complaints
100
0
Normal activity
Able to carry on normal 
activities Minor signs or 
symptoms of disease
90
0
Normal activity with effort
80
1
Symptoms, but fully 
ambulatory
Cares for self. Unable to 
carry on normal activity or 
to do active work
70
1
Requires occasional 
assistance, but able to care 
for most of his needs
60
2
Symptomatic, but in bed 
< 50% of the day.
Requires considerable 
assistance and frequent 
medical care
50
2
Disabled. Requires special 
care and assistance
40
3
Needs to be in bed 
> 50% of the day, but 
not bedridden
Severely disabled. 
Hospitalization indicated 
though death non imminent
30
3
Very sick. Hospitalization 
necessary. Active 
supportive treatment 
necessary
20
4
Unable to get out of bed
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 8
RADIOLOGIC EVALUATION CRITERIA IN SOLID TUMOURS 
VERSION 1.1 (RECIST CRITERIA 1.1)
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
Subjects must have measureable disease to be eligible for this study.
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least 1 measurable tumor lesion. When computed tomography (CT)
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or nonmeasurable, which 
are discussed below.
1.1
Measurable Lesions
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
•
10 mm by CT/magnetic resonance imaging (MRI) scan - (CT/MRI scan slice thickness no 
greater than 5 mm)
•
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as nonmeasurable)
•
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). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable Lesions
•
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥10 to < 15 mm short axis), as well as truly non-measurable lesions
•
Lesions considered truly nonmeasurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
1.3
Special Considerations Regarding Lesion Measurability
1.3.1
Bone Lesions
•
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be used 
to confirm the presence or disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can be evaluated by cross sectional imaging techniques such as CT or MRI, can be considered
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measurable lesions if the soft tissue component meets the definition of measurability described 
above.
•
Blastic bone lesions are nonmeasurable.
1.3.2
Cystic Lesions
•
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 
•
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions.
1.3.3
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area or in an area subjected to other locoregional 
therapy are usually not considered measurable, unless there has been demonstrated progression in 
the lesion. Measurable lesions may be in an irradiated field as long as there is documented 
progression, and the lesion(s) can be reproducibly measured.
1.4
Specifications by Methods of Measurements
1.4.1
Measurement of Lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be done rather than clinical examination, unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI Scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint,
since CT is more sensitive than X-ray in identifying new lesions. However, lesions on chest X-ray 
may be considered measurable if they are clearly defined and surrounded by aerated lung.
1.4.2.3
Clinical Lesions 
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 
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photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical examination and imaging, imaging evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor Markers 
Tumor markers alone cannot be used to assess objective tumor response.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’
LESIONS
2.1
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
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 below, 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.
2.1.1
Lymph Nodes
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 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. Nodes 
that have a short axis < 10 mm are considered nonpathological and should not be recorded or 
followed.
2.2
Non-target Lesions
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’. In addition, it is possible to record multiple non-target lesions involving the same 
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organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION 
3.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) 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 1 or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum on study.
3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph Nodes
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 ≥15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. Nodes 
that have a short axis <10 mm are considered nonpathological and should not be recorded or 
followed.
3.1.1.2
Target Lesions That Become ‘Too Small to Measure’
All lesions (nodal and nonnodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
•
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: In case of a lymph node believed to be present and 
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).
3.1.1.3
Target 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.
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•
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’
3.2
Evaluation 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. 
•
CR: Disappearance of all non-target lesions. All lymph nodes must be nonpathological in size 
(< 10 mm short axis).
•
PD: Unequivocal progression of existing non-target lesions. (Note: The appearance of 1 or 
more new lesions is also considered progression).
•
NonCR/NonPD: Persistence of 1 or more non-target lesion(s).
3.2.1
Special Notes on Assessment of Non-target Lesions
The concept of progression of non-target disease requires additional explanation as discussed 
below.
3.2.1.1
When the Subject Also has Measurable Disease
•
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.
•
A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status.
3.2.1.2
When the Subject has Only Non-measurable Disease
•
To achieve unequivocal progression on the basis of the non-target disease, there must be an 
overall level of substantial worsening, such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.
•
A modest increase in the size of 1 or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status.
•
Because worsening in non-target disease cannot be easily quantified (by definition, if all 
lesions are nonmeasurable), a useful test that can be applied when assessing subjects 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 increase in 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 subject should be considered to have had overall PD at 
that point. 
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3.2.1.3
Tumor Markers
Tumor markers will not be used to assess objective tumor responses.
3.3
New Lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, change in 
imaging modality, or findings thought to represent something other than tumor (for example, some 
new bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the subject’s baseline lesions show PR or CR. 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 subject
who has visceral disease at baseline and while on study, has a CT or MRI brain scan ordered that
reveals metastases. The subject’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.
4
RESPONSE CRITERIA
4.1
Time Point Response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline, Table 1 provides a summary of the overall 
response status calculation at each time point.
Table 1:
Subjects with Target (+/– Non-target) Disease
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
NonCR/nonPD
No
PR
CR
Not evaluated
No
PR
PR
NonPD or not all 
evaluated
No
PR
SD
NonPD or not all 
evaluated
No
SD
Not all evaluated
NonPD
No
NE
PD
Any
Yes or No
PD
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = not evaluable.
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4.1.1
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time point 
response.
4.2
Best Overall Response: All Time Points
The best overall response is determined once all the data for the subject is known. It is the best 
response recorded from the start of the study treatment to the date of radiographic progression per 
RECIST 1.1 or the date of subsequent anti-cancer therapy (including tumor-directed radiotherapy 
and tumor-directed surgery), whichever occurs first, taking into account any requirement for 
confirmation. The subject’s best overall response assignment will depend on the findings of both 
target and non-target disease and will also take into consideration the appearance of new lesions.
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point of ≥ 4 weeks later. In this circumstance, the best overall response can be interpreted as 
specified in Table 2. 
When SD is believed to be best response, it must meet the protocol specified minimum time from 
baseline. In this protocol, measurements must have met the SD criteria at least once after study 
entry at a minimum interval of 6 weeks from randomization in order for SD to be the best response.
Table 2:
Best Overall Response When Confirmation of CR and PR is 
Required
Overall Response
Overall Response
Best Overall Response
First Time Point
Subsequent Time Point
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for 
SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for 
SD duration met, otherwise NE
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Table 2:
Best Overall Response When Confirmation of CR and PR is 
Required
Overall Response
Overall Response
Best Overall Response
NE
NE
NE
a Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = not evaluable.
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 subject 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.
4.2.1
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 28 
days after the criteria for response are first met. For this study, the next scheduled tumor assessment 
can meet this requirement.
4.3
Duration of Response
4.3.1
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that progressive disease is objectively 
documented (taking as reference for PD the smallest measurements recorded on study), subsequent 
anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery) is 
initiated, or the participant dies, whichever occurs first.
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented, subsequent anti-
cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery) is initiated, or 
the participant dies, whichever occurs first.
4.3.2
Duration of Stable Disease  
If SD is the best overall response, the duration of SD is measured from the date of randomization
until the criteria for progression are met, taking as reference the smallest sum on study (if the 
baseline sum is the smallest, this is the reference for calculation of PD), subsequent anti-cancer 
therapy (including tumor-directed radiotherapy and tumor-directed surgery) is initiated, or the 
participant dies, whichever occurs first..
 
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APPENDIX 10
SUPPORTIVE CARE GUIDELINES FOR THE MANAGEMENT OF 
HAND FOOT SYNDROME (HFS)
Supportive Care Guidelines for the Management of Hand Foot Syndrome (HFS)
Management of HFS can begin before any symptoms occur. Several prophylactic measures may 
be taken to prevent or reduce the severity of HFS. Before therapy with begins, a full-body skin 
exam should be performed, with a special emphasis on hyperkeratotic areas on palms and soles 
and any deformities. Patients can receive a pedicure, using properly sterilized utensils, to remove 
any preexisting hyperkeratotic areas or calluses that may predispose them to developing HFS
reaction. Patients should be advised to reduce the exposure of their hands and feet to hot water, 
either through dishwashing or hot baths and showers, because this is believed to exacerbate 
symptoms, and patients frequently report symptomatic relief with cold water.
Before initiating treatment:
•
Check condition of hands and feet
•
Suggest a manicure/pedicure, when indicated
•
Recommend pumice stone use for callus or ‘rough spot’ removal
During treatment:
•
Avoid pressure points
•
Avoid items that rub, pinch, or create friction
•
Apply non-urea based skin-hydrating creams liberally
•
Keratolytic creams: Use sparingly and only to affected (hyperkeratotic) areas.
Urea-based creams:
•
Salicylic acid 6%
•
Alpha hydroxy acid (AHA) based creams
•
Concentrations of approximately 5-8% provide gentle chemical exfoliation
•
Apply liberally two times each day
Topical analgesics like lidocaine 2% should be considered for pain control
Topical corticosteroids like clobetasol 0.05% should be considered for patients with grade 2 or 3 
hand-foot skin reaction. Avoid systemic steroids.
Cushions:
•
Protect tender areas
•
Use socks/gloves to cover moisturizing creams
•
Wear well-padded footwear
•
Use insole cushions or inserts (e.g., silicon, gel)
•
Foot soaks with tepid water and Epsom salts
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APPENDIX 11
SUPPORTIVE CARE GUIDELINES FOR THE MANAGEMENT OF 
DIARRHEA FOR CABOZANTINIB
Participants should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Guidelines for the 
evaluation and management of diarrhea are shown in Table 1. 
Administration of antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as 
initial management. Some participants may require concomitant treatment with more than 1 
antidiarrheal agent. When therapy with antidiarrheal agent does not control diarrhea to tolerable 
levels, cabozantinib should be temporarily interrupted or dose reduced. When the diarrhea is 
controlled, retreatment with cabozantinib may be acceptable per investigator decision. 
In addition, general supportive measures should be implemented such as continuous oral isotonic 
hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping 
lactose-containing products, high-fat meals, and alcohol.
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good hygiene should be emphasized. 
Regular examinations of the perianal region should be performed wherever diarrhea has occurred 
during treatment with cabozantinib. Infections of the perianal region should be treated per local 
guidelines.
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Table 1:
Guidelines for Management of Treatment-Emergent Diarrhea for 
Cabozantinib
Status
Management
Tolerable Grade 1-2 
(duration < 48 h)
•
Continue with study treatment and consider dose reduction
•
Initiate treatment with an antidiarrheal agent (e.g., loperamide 4 mg followed by 2 mg 
after each episode of diarrhea [maximum: 16 mg loperamide daily])
•
Dietary modifications (e.g., small lactose-free meals, bananas and rice)
•
Intake of isotonic fluids 1-1.5 L/day)
•
Re-assess after 24 hours:
-
Diarrhea resolving to baseline bowel habits: gradually add solid foods and 
discontinue or decrease antidiarrheal treatment after 12 h diarrhea-free interval
-
Diarrhea not resolving: Continue/resume antidiarrheal treatment
Intolerable Grade 2, 
Grade 2 > 48h, or ≥ 
Grade 3
•
Interrupt study treatment
•
Ask participant to attend clinic
•
Rule out infection (e.g., stool sample for culture)
-
Administer antibiotics as needed, (e.g., if fever or Grade 3-4 neutropenia persists > 
24 h)
•
Administer fluids 1-1.5L/day orally or IV, as appropriate for hydration or to correct 
electrolyte abnormalities
•
For Grade 3-4 or complicated lower grade diarrhea consider hospitalization and IV 
hydration
•
Re-assess after 24 hour
•
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: 
-
Consider restarting study treatment at reduced dose
•
Diarrhea not resolving:
-
Start and or continue antidiarrheal treatment (e.g., loperamide 4 mg followed by 2 
mg after each episode of diarrhea [maximum 16 mg loperamide per day
-
Consider starting second line antidiarrheal or referral to gastroenterologist
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APPENDIX 12
COUNTRY SPECIFIC REQUIREMENTS
COUNTRY SPECIFIC REQUIREMENTS
Country Location
Original language
Country-specific language
Germany, Czech 
Republic, Romania at 
all sites where it is 
mandated by local or 
country regulations
Section 2 Schedule of Activities, 
Table 2-1, Screening Procedural 
Outline,  Laboratory Tests
Add “HIV” to the list of laboratory tests
Germany, Czech 
Republic, Romania at 
all sites where it is 
mandated by local or 
country regulations
Section 6.2 Exclusion
Criteria, Exclusion criterion 1 g)
“Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiencysyndrome (AIDS)”to be replaced
with “Positive test for HIV”.
Czech Republic
Section 8.1:
Discontinuation from Study 
Treatment
Second paragraph modified to read:
“In the case of pregnancy, the investigator must 
immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the 
study treatment will be permanently discontinued in 
an appropriate manner (e.g., dose tapering if 
necessary for participant safety). Please call the 
BMS Medical Monitor within 24 hours of 
awareness of the pregnancy.”
The following statement is deleted:
“If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study 
treatment, a discussion between the investigator and 
the BMS Medical Monitor/designee must occur.”
Czech Republic, 
Romania
Section 9.4.1:
Clinical Safety Laboratory 
Assessments
Serology section modified to read:
Serum for hepatitis C antibody, HCV RNA, 
hepatitis B surface antigen (screening only). HIV 
testing must be performed at sites where mandated 
by local or country regulations, see Appendix 12)
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APPENDIX 13
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section 
Number & 
Title
Description of Change
Dosing Duration 
for Nivolumab
With this revised protocol, the option for 
retreatment on study in subjects who 
progress after completing 2 years of 
nivolumab treatment will be removed 
from the protocol.
Synopsis and 
Section 6.2.1a 
Exclusion 
Criteria
Exclusion criteria 6.2.1a revises criteria 
for CNS metastases that are treated and 
stable, from at least 3 months to at least 1 
month
Section 6.2.1b 
Exclusion 
Criteria
Exclusion criteria 6.2.1b adds ‘celiac 
disease’ as an example external trigger.
Section 6.2.1o 
Exclusion 
Criteria
Exclusion criteria 6.2.1o revises LMWH 
criteria for DVT and PE, from at least 6 
weeks to at least 3 weeks
Section 6.2.2e 
Exclusion 
Criteria
Exclusion criteria 6.2.2e is revised to 
major surgery less than 6 weeks, 
nephrectomy less than 4 weeks, prior to 
randomization,  provided complete 
wound healing and no ongoing post-
operative complications.
Section 6.2.2g 
Exclusion 
Criteria
An exclusion is added regarding 
botanical preparations
Section 6.2.3f 
Exclusion 
Criteria
Exclusion criteria 6.2.3f is clarified
Section 6.2.3i 
Exclusion 
Criteria
Exclusion criteria 6.2.3i adjusts UPCR 
limit to permit UPCR = 1.5, unless 24-
hour urine protein is ≤ 1.5 g
Section 7.1
Treatment
Clarification of a sentence revising 
‘...approximately 30 minutes...’ to read 
‘...at least 30 minutes...’.  For 
consistency, the phrase ‘but may be more 
or less depending on the situation’ is 
deleted.
Section 7.4.1.2 
Dose Delay 
Criteria for 
Cabozantinib
Clarifies that Grade 2 drug-related 
adverse event or laboratory abnormality 
(e.g., AST, ALT, total bilirubin) that 
persists for more than 1 week or worsens 
despite supportive care management, will 
delay cabozantinib dosing
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section 
Number & 
Title
Description of Change
Section 10 
Statistical 
Considerations
Arm B wording is deleted.
Number of Arms is revised from 3 to 2, 
and treatment allocation to 1:1.
The analysis is revised from 
intermediate/poor risk groups to all risk 
groups 
Favorable risk cap is adjusted up to 25%
The sample size is adjusted from N=1014 
to N=580 randomized.
Analysis populations, Efficacy Analysis, 
Safety Analysis and Interim Analysis are 
revised accordingly.
Appendix 2 
Deleted bullets describing records 
maintained by site
Appendix 4
Add a barrier method of contraception 
for patients in Arms A and or B.
Appendix 7
Corrected status definitions of Zubrod-
ECOG-WHO scores
All
Formatting and typographical corrections
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