A Phase 2, Single-arm Open-label Study of Combination Nivolumab and Ipilimumab Retreatment in Advanced Renal Cell Carcinoma Patients Progressing on Nivolumab Maintenance Therapy After Nivolumab and Ipilimumab Induction
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 2, Single-arm Open-label Study of Combination Nivolumab and Ipilimumab Retreatment in 
Advanced Renal Cell Carcinoma Patients Progressing on Nivolumab Maintenance Therapy After 
Nivolumab and Ipilimumab Induction 
 
(CheckMate 73M: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 73M) 
 
PROTOCOL(S) CA209-73M 
 
NCT Number: NCT04088500  
  
Document Date (Date in which document was last revised): March 12, 2020 

Page:
1
Protocol Number:
CA20973M
IND Number:
122,840
EX-US
Non-IND
EUDRACT Number:
N/A
Date:
25-Apr-2019
Revised Date
12-Mar-2020
CLINICAL PROTOCOL CA20973M
A Phase 2, Single-arm Open-label Study of Combination Nivolumab and Ipilimumab 
Retreatment in Advanced Renal Cell Carcinoma Patients Progressing on Nivolumab 
Maintenance Therapy After Nivolumab and Ipilimumab Induction
(CheckMate 73M: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 73M)
Short Title:
A Study of Combination Nivolumab and Ipilimumab Retreatment in Patients with Advanced Renal 
Cell Carcinoma  
Revised Protocol: 01
Study Director
Medical Monitor
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
Approved
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v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
Revised Protocol No.: 01
Date: 12-Mar-2020
2
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization.
Approved
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v
Approved
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Clinical Protocol
CA20973M
BMS-936558
nivolumab
Revised Protocol No.: 01
Date: 12-Mar-2020
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 01
12-Mar-2020
The purpose of this revised protocol is to clarify that the sample collection 
at progression post-retreatment is optional and may be collected.  In 
addition, this revised protocol includes updates to study personnel; 
clarification to inclusion criterion for determining progression; 
clarification to exclusion criteria for adverse event of adrenal insufficiency 
and HIV criteria for exclusion; and updated language for additional 
research sample collections.
Original 
Protocol
25-Apr-2019
Not applicable
Approved
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Clinical Protocol
CA20973M
BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 01:
This revised protocol clarifies that the tumor tissue sample collection at the time of progression 
during this study, post-retreatment, is optional. In addition, this revised protocol includes updates 
to study personnel; clarification to inclusion criterion for determining progression; clarification to 
exclusion criteria for adverse event of adrenal insufficiency and HIV criteria for exclusion; and 
updated language for additional research sample collections. Changes are listed below in the table.
Revisions apply to all participants.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Update Medical Monitor contact 
information  
Original test:
Change to:
Update study director contact 
information  
Original text:
Change to:
Update medical monitor name 
and contact information and 
update study director contact 
information.
Revised Protocol No.: 01
Date: 12-Mar-2020
4
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Clinical Protocol
CA20973M
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis, Key 
Inclusion Criteria and 
Section 6.1 Inclusion 
Criteria
Updated inclusion criterion 
synopsis, bullet 3 and Section 6.1, 
2)c) to the following:
Investigator-assessed, per 
RECIST 1.1, disease progression 
on nivolumab maintenance after 
induction with ipilimumab and 
nivolumab and PR/CR or SD ≥6 
months after starting initial 
induction treatment.
Clarify inclusion criterion for 
determining progression.
Synopsis, Key 
Inclusion Criteria 
Key inclusion criteria, bullet 6 
was revised to state “...must be 
submitted to the central vendor 
(block or unstained slides) in 
order to start a participant to 
study treatment...”.
To align key inclusion criteria 
listed in the Synopsis with the 
inclusion criteria listed in Section 
6.1. 
Synopsis, Key 
Exclusion Criteria
To align the exclusion criterion 
for serum creatinine in the 
synopsis with the exclusion 
criterion in the body.
Reconcile discrepancy between 
synopsis and body for the 
exclusion criterion for serum 
creatinine.
Synopsis, Steering 
Committee, Section 
5.1.1 Steering 
Committee and other 
External Committees
Remove the Steering Committee.
Replace with:
No (Synopsis), 
Not applicable (Section 5.1.1)
To clarify that the study will not 
have a Steering Committee.
Section 5.1 Overall 
Design
Add the following statement to 
the second bullet:  with the 
exception of patients with prior 
history of adrenal insufficiency 
that are under control with 
hormone replacement.
Clarify exclusion criterion for 
adverse events of adrenal 
insufficiency that meet criteria for 
treatment discontinuation.
Section 6.2: 
Exclusion Criteria
Exclusion criteria 1) b)
Add the following statement:  
with the exception of patients 
with prior history of adrenal 
insufficiency that are under 
Clarify exclusion criterion for 
adverse events of adrenal 
insufficiency that meet criteria for 
treatment discontinuation. 
Revised Protocol No.: 01
Date: 12-Mar-2020
5
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Clinical Protocol
CA20973M
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & 
Title
Description of Change
Brief Rationale
control with hormone 
replacement.
Exclusion criteria 1) h) marked as 
not applicable.
Delete:
h) 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 (see Appendix 
8).
Change to:
Not applicable per revised 
protocol 01
Exclusion criteria not applicable. 
Section 7, Table 7-1, 
Study Treatments for 
CA20973M
Update the following information 
listed in Table 7-1: Product 
Description /Class and Dosage 
Form, Potency, 
Packaging/Appearance and 
Storage Conditions
To minimize protocol revisions in 
the event of a product packaging 
configuration changes.
Revised Protocol No.: 01
Date: 12-Mar-2020
6
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Clinical Protocol
CA20973M
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.3.2, Safety 
Analyses
Remove coagulation from 
secondary statistical analyses
Correction made to reflect actual 
analysis to be done.
Section 10.3.5 
Interim Analysis,
Remove the assessment by the 
Steering Committee
To remove the assessment of 
interim reports by the Steering 
Committee.
Appendix 5 
Management 
Algorithms
Added Myocarditis algorithm and 
revised date of the other 
algorithms to 2019.
Provided Myocarditis algorithm 
per recent Nivolumab Investigator 
Brochure.
All
Minor formatting and 
typographical corrections
Minor, therefore have not been 
summarized.
Revised Protocol No.: 01
Date: 12-Mar-2020
7
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3.1.1 Research Hypothesis ................................................................................ 
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3.2.1 Cancer Immunotherapy ........................................................................... 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
3.2.3 Ipilimumab Mechanism of Action ............................................................ 
3.2.4 Preclinical Summary of Nivolumab Combined with Ipilimumab ............ 
3.2.5 Summary of Ipilimumab Rechallenge Studies.......................................... 
3.2.6 Indication Background ............................................................................. 
3.2.6.1 Renal Cell Carcinoma: Background and Standard Treatments ..... 
3.2.6.2 Nivolumab in Renal Cell Carcinoma .............................................. 
3.2.6.3 Ipilimumab in Renal Cell Carcinoma ............................................. 
3.2.6.4 Nivolumab Combined with Ipilimumab in Renal Cell Carcinoma . 
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5.1.1 Steering Committee and Other External Committees .............................. 
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5.4.1 Rationale for the Study Population .......................................................... 
5.4.2 Rationale for Choice of DCR as Primary Endpoint ................................ 
5.4.4 Rationale for 2-year Duration of Treatment ............................................ 
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5.5.1 Clinical Pharmacology Summary ............................................................ 
5.5.2 Justification for Combination Nivolumab and Ipilimumab ..................... 
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6.4.1 Retesting During Screening or Lead-in Period ....................................... 
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7.4.1 Dose Modifications .................................................................................. 
7.4.2 Dose Delay Criteria ................................................................................. 
7.4.3 Criteria to Resume Treatment .................................................................. 
7.4.4 Criteria for Treatment Discontinuation ................................................... 
7.4.4.1 Nivolumab Dose Discontinuation ................................................... 
7.4.4.2 Ipilimumab Dose Discontinuation .................................................. 
7.4.5 Treatment of Infusion-related Reactions ................................................. 
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7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
7.7.3 Permitted Therapy ................................................................................... 
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8.1.1 Treatment Beyond Disease Progression .................................................. 
8.1.2 Post Study Treatment Study Follow-up.................................................... 
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9.1.1 Imaging Assessment for the Study............................................................ 
9.1.1.1 Methods of Measurement ................................................................ 
9.1.1.2 Imaging and Clinical Assessment ................................................... 
9.1.2 Patient-reported Outcomes ...................................................................... 
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9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug-induced Liver Injury ....................................................... 
9.2.8 Other Safety Considerations .................................................................... 
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9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital Signs ................................................................................................ 
9.4.3 Electrocardiograms ................................................................................. 
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Approved
1.0
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Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: A Phase 2, Single-arm, Open-label Study of Combination Nivolumab and 
Ipilimumab Retreatment in Advanced Renal Cell Carcinoma Patients Progressing on Nivolumab
Maintenance Therapy After Nivolumab and Ipilimumab Induction
Short Title:
A Study of Combination Nivolumab and Ipilimumab Retreatment in Patients with Advanced Renal 
Cell Carcinoma
Study Phase:
2
Rationale:
Tyrosine kinase inhibitors (TKIs) have been the standard of care for metastatic renal cell carcinoma 
(mRCC) over the past 10 years. In the last few years, immunotherapy has been introduced into the 
treatment algorithm of mRCC. More recently, the combination of ipilimumab and nivolumab has
demonstrated superiority over sunitinib in patients with intermediate and poor risk advanced or
metastatic clear cell renal cell carcinoma (RCC). Treatment consists of an induction phase 
including 4 doses of combination ipilimumab and nivolumab in 3-week intervals followed by a 
maintenance phase with single agent nivolumab given every 4 weeks. If patients progress on 
maintenance nivolumab treatment they are switched to second line treatment. 
No data exist regarding the retreatment of ipilimumab for patients who show signs of progressive 
disease on nivolumab maintenance therapy after nivolumab and ipilimumab induction. Stimulation 
of an immune response by reintroducing ipilimumab and nivolumab could regain tumor control.
Research Hypothesis:
Retreatment with ipilimumab in combination with nivolumab in patients progressing on 
nivolumab maintenance therapy after ipilimumab and nivolumab induction, will result in improved 
clinical benefits based on disease control rate (DCR). 
Study Population:
Adult participants (≥18 years) with histologically confirmed RCC with a clear-cell component
who have progressed on nivolumab maintenance after induction with combination nivolumab and 
ipilimumab.
Key Inclusion Criteria:
•
Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American 
Joint Committee on Cancer Stage IV) RCC
•
Histological confirmation of RCC with a clear-cell component, including participants who may 
have sarcomatoid features
•
Investigator-assessed, per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 
1.1), disease progression on nivolumab maintenance after induction with ipilimumab and 
Revised Protocol No.: 01
Date: 12-Mar-2020
11
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
nivolumab and partial response (PR)/complete response (CR) or stable disease (SD) ≥6 
months after starting initial induction treatment.
•
Measurable disease by computed tomography or magnetic resonance imaging per RECIST 1.1 
criteria
•
Karnofsky Performance Status of at least 70% or higher
•
Tumor tissue (formalin-fixed paraffin-embedded [FFPE] archival prior to the first treatment 
and recently acquired at or after progression on initial nivolumab maintenance) must be 
submitted to the central vendor (block or unstained slides) in order to start a participant to study 
treatment. (Note: Fine needle aspiration and bone metastases samples are not acceptable for 
submission.)
Key Exclusion Criteria:
•
Any prior adverse event that meets the criteria for treatment discontinuation 
•
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 (eg, celiac disease) are permitted to enroll.
•
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of first dose 
of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent are permitted in the absence of active autoimmune disease.
•
Uncontrolled adrenal insufficiency
•
Participants with human immunodeficiency virus (HIV) infections are excluded if any of the 
following applies:
a) CD4+ T-cell count < 350 cells/μL
b) Any acquired immunodeficiency syndrome-defining opportunistic infection occurred in 
the last 12 months
c) HIV viral load is ≥400 copies/mL
d) Antiretroviral therapy has been administered at current doses for less than 4 weeks
e) The participant is not on antiretroviral therapy
•
Participants with a history of chronic hepatitis B or C are excluded if any of the following 
applies:
a) For participants with chronic hepatitis B: The HBV viral load is detectable.
b) For participants with chronic hepatitis C: The HCV viral load is detectable.
•
Known medical, emotional, psychiatric, or logistical condition (eg, a condition associated with 
diarrhea or acute diverticulitis) 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
•
Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study treatment.
Revised Protocol No.: 01
Date: 12-Mar-2020
12
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
•
Presence of any toxicities attributed to prior anticancer therapy, other than alopecia, that have 
not resolved to Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse 
Events version 5.0) or baseline before administration of study treatment
•
Any of the following laboratory test findings:  
a) White blood cells < 2,000/μL
b) Neutrophils < 1,500/μL
c) Platelets < 100,000/μL
d) Serum creatinine > 1.5× upper limit of normal (ULN) unless calculated creatinine 
clearance (CrCl) ≥40 mL/min (measured or calculated by Cockroft-Gault formula).
e) Aspartate aminotransferase or Alanine aminotransferase > 3× ULN [> 5× ULN if liver 
metastases are present])
f)
Total bilirubin (TBili) > 1.5× ULN (except participants with Gilbert syndrome, who must 
have TBili < 3.0× ULN)
Objectives and Endpoints:
Objective
Endpoint
Primary
•
To describe the efficacy in terms of DCR of 
retreatment with ipilimumab in combination with 
nivolumab in patients with mRCC progressing on 
maintenance nivolumab after first-line therapy 
with ipilimumab and nivolumab.
•
DCR is defined as the proportion of participants
who achieve a confirmed best response of CR, PR,
or SD for at least 6 months after first treatment 
dose using the Response Evaluation Criteria In 
Solid Tumors version 1.1 (RECIST 1.1) criteria.
Secondary
•
To describe the overall survival (OS) of 
retreatment with ipilimumab in combination with 
nivolumab in patients with mRCC progressing on 
maintenance nivolumab after first-line therapy 
with ipilimumab and nivolumab.
•
OS is defined as the time from first dose to the 
date of death from any cause. For participants that 
are alive, their survival time will be censored at the 
date of last contact (“last known alive date”). OS 
will be censored for participants at the date of first 
dose if they were treated but had no follow-up.
•
To describe the objective response rate (ORR) of 
retreatment with ipilimumab in combination with 
nivolumab in patients with mRCC progressing on 
maintenance nivolumab after first-line therapy 
with ipilimumab and nivolumab.
•
ORR is defined as the proportion of participants 
who achieve a best response of CR or PR using the 
RECIST 1.1 criteria.
•
To describe the duration of response (DOR) of 
retreatment with ipilimumab in combination with 
nivolumab in patients with mRCC progressing on 
maintenance nivolumab after first-line therapy 
with ipilimumab and nivolumab.
•
DOR is defined as the time between the date of 
first documented response (CR or PR) to the date 
of the first documented progression, per 
RECIST 1.1 criteria, or death due to any cause, 
whichever occurs first.
•
To describe the progression-free survival (PFS) of 
retreatment with ipilimumab in combination with 
nivolumab in patients with mRCC progressing on 
maintenance nivolumab after first-line therapy 
with ipilimumab and nivolumab.
•
PFS is defined as the time between the date of first 
dose and the first date of documented progression, 
as per RECIST 1.1 criteria or death due to any 
cause, whichever occurs first.
Revised Protocol No.: 01
Date: 12-Mar-2020
13
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
Objective
Endpoint
•
To describe the time to objective response (TTR) 
of retreatment with ipilimumab in combination 
with nivolumab in patients with mRCC 
progressing on maintenance nivolumab after first-
line therapy with ipilimumab and nivolumab.
•
TTR is defined as the time between the date of the 
first dose and the first confirmed documented 
response (CR or PR) per RECIST 1.1 criteria.
•
To estimate the incidence of adverse events (AEs)
of retreatment with ipilimumab in combination 
with nivolumab in patients with mRCC 
progressing on maintenance nivolumab after first-
line therapy with ipilimumab and nivolumab.
•
AE incident rate is defined as the proportion of 
participants with any grade AEs. Events reported 
from the first dose and up to and including 
100 days following the last dose of study treatment 
could be included in estimating this incidence rate.
Overall Design:
This is a Phase 2, open-label, single-arm study divided into 2 parts. A Simon 2-stage design will 
be used.
•
In Stage 1, 27 response-evaluable patients will be enrolled and a futility analysis will be 
performed.
•
In Stage 2 (if Stage 1 is positive), 53 more response-evaluable patients will be enrolled.
Number of Participants: 
Approximately 96 participants will be enrolled in order to obtain 80 response-evaluable patients, 
accounting for approximatively 20% of non-evaluable patients or withdrawal. The number of
enrolled participants with SD ≥6 months will be capped at 50%.
A Simon 2-stage design will be used to test whether retreatment with ipilimumab in combination 
with nivolumab in patients with mRCC progressing on maintenance nivolumab after first-line 
therapy with ipilumumab and nivolumab yields a DCR that is of clinical interest. In this study, a 
DCR in excess of 20% will be considered of clinical interest. The Simon design will test the null 
hypothesis that the true DCR is less than or equal to 20% versus the alternative hypothesis that it 
exceeds 20%. The type I error rate will be 5% and the design will have 85% power to reject the 
null hypothesis when the true DCR is 35%.
Treatment Arms and Duration:
Study treatment includes Investigational [Medicinal] Products (IP/IMP) as indicated in Table 1.
Table 1:
Study Treatments for CA20973M
Medication
Potency
IP/Non-IP
Nivolumab
3 mg/kg
480 mg
IP
Ipilimumab
1 mg/kg
IP
Abbreviation: IP = investigational product
Revised Protocol No.: 01
Date: 12-Mar-2020
14
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
The study design schematic is presented in Figure 1 (red rectangle). The duration of the trial is 
expected to be approximately 24 months of treatment (Stage 1 + Stage 2) and 36 months of 
follow-up after the last participant first dosing. A futility analysis will be performed after Stage 1 
and the primary analysis will be conducted upon completion of Stage 2.
Figure 1:
Study Design Schematic
Simon 2-stage Design
Abbreviations: CR = complete response; DCR = disease control rate; mRCC = metastatic renal cell carcinoma; 
PR = partial response; RECIST = Response Evaluation Criteria In Solid Tumors version 1.1; SD = stable disease
Discontinuation of Participants From Treatment:
Participants will be treated until progression, unacceptable toxicity, or maximum 24 months of 
study treatment for nivolumab. Once a patient has discontinued from treatment, he or she will 
continue to be followed for OS for approximately 36 months. All reasonable effort will be made 
to maintain contact with participants during this follow-up period via phone calls, faxes, or emails.
Steering Committee: No
Nivolumab + ipilimumab
induction Q3W
First-Line Treatment
Nivolumab maintenance 
Q2W/Q4W
Progression
Combination Retreatment Therapy
Nivolumab + ipilimumab
retreatment Q3W
Nivolumab
maintenance Q4W
Treat until 
progression, 
unacceptable 
toxicity, withdrawal 
of consent, or 
maximum of 2 years 
duration whichever 
occurs first.
CA20973M
Time
Note: Treatment beyond PD allowed with provisions
Key Inclusion Criteria
• Clear cell mRCC
• Confirmed disease progression 
by RECIST criteria on nivolumab 
maintenance after induction 
with nivolumab + ipilimumab 
and initial PR/CR or SD ≥ 6 
months
Promising DCR:
Continue to Stage 2
Low DCR:
Stop for futility
If promising DCR:
Reject null hypothesis
Stage 1 
Stage 2 Expansion 
Revised Protocol No.: 01
Date: 12-Mar-2020
15
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA20973M)
Procedure
Screening 
Visit
Notes
Eligibility Assessments
Informed Consent
X
Register in IRT system to obtain participant number. The participant must sign the informed consent 
prior to any study-related assessment being performed.
Inclusion/Exclusion Criteria
X
See Section 6.1 and Section 6.2
Medical History
X
Tumor Tissue Samplesa
X
Archival tumor tissue from the original diagnosis (if available) and tumor tissue obtained at or after 
progression on nivolumab maintenance (with an associated pathology report) will be collected. FFPE 
block or 20 unstained slides; a minimum of 15 slides will be acceptable if tumor tissue is limited 
 
.
Safety Assessments
Complete Physical Examination, Vital 
Signs, Performance Status
X
Height, weight, KPS (Appendix 7), BP, RR, heart rate, and temperature within 14 days prior to first 
dose.
Assessment of Signs and Symptoms
X
Concomitant Medication Use
X
AE and SAE Assessment
X
SAEs from time of consent (see Section 9.2).
Laboratory Tests
ECG
X
A single ECG, or triplicate ECGs if abnormal on the first ECG, should be recorded after the 
participant has been supine for at least 15 minutes.
Pregnancy Test (WOCBP only)
X
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 treatment.
Additional Tests
X
See Section 9.4.4 for additional details on tests required. To be completed locally at each site.
CBC with differential, chemistry panel (includes AST, ALT, TBili, ALP, LDH, creatinine, BUN or 
serum urea, glucose, albumin, Na, K, Cl, Ca [also Ca corrected], Phos, and Mg) 
Revised Protocol No.: 01
Date: 12-Mar-2020
16
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA20973M)
Procedure
Screening 
Visit
Notes
Thyroid panel (includes TSH with free T3 and free T4)
Hepatitis B/C (HBVsAg, HCV antibody or HCV RNA)
HIV if mandated locally (see Appendix 8)
Urinalysis
Efficacy Assessment
Body Imaging
X
Contrast-enhanced CT of the chest and CT/MRI of the abdomen, pelvis, and all other known and/or 
suspected sites of disease, within 30 days prior to the date of first dosing (see Section 9.1.1).
Brain Imaging
X
MRI of the brain without and with contrast is required for ALL participants during screening to rule 
out brain metastases. CT of the brain (without and with contrast) can be performed if MRI is 
contraindicated (see Section 9.1.1).
a Tumor tissues will be collected at screening from original diagnostic archival samples (if available) and after progression on nivolumab maintenance. If samples 
within ≤12 months prior to enrollment are not available, please contact the BMS medical monitor.
Abbreviations: ALL = acute lymphoblastic leukemia; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; CT = computed tomography;
ECG = electrocardiogram;
FFPE = Formalin-fixed paraffin-embedded; HBVsAg = hepatitis B virus antigen; HCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; 
 IRT = interactive response technology; KPS = Karnofsky 
Performance Status; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; RNA = ribonucleic acid; RR = respiratory rate; SAE = serious adverse 
event; T3 = thyroxine; T4 = triiodothyronine; TBili = total bilirubin; TSH = thyroid stimulating hormone; WOCBP = women of childbearing potential
Revised Protocol No.: 01
Date: 12-Mar-2020
17
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
Table 2-2:
On-treatment Procedural Outline Cycles 1 through 4 (CA20973M)
Procedurea
Cycle 1 through Cycle 4 (Cycle = 3 weeks)
Dosing Q3W for 4 Doses
Notes
Day 1
Cycle 1
Day 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Safety Assessments
Targeted Physical Examination, 
Vital Signs, Performance Status
X
X
X
X
Within 72 hours prior to dosing, weight, BP, RR, heart rate, 
temperature, and KPS (Appendix 7) to be performed.
Assessment of Signs and 
Symptoms
X
X
X
X
AE and SAE Assessment
Continuously
Record at each visit. Participants will be followed for drug-related 
toxicities until these toxicities resolve, return to baseline, or are 
deemed irreversible. All AEs and SAEs will be documented for a 
minimum of 100 days after last dose (Appendix 3).
Concomitant Medication Use
X
X
X
X
Laboratory Tests
Pregnancy Test (WOCBP only) 
X
X
X
X
Serum or urine test within 24 hours prior to administration of study 
drug. 
Additional Tests
X
X
X
X
See Section 9.4.4 for additional details on tests required.
Laboratory tests do not need to be repeated at C1D1 if performed 
within 14 days prior to the first dose unless repeat of tests for 
eligibility prior to C1D1 dosing is clinically indicated.
After C1D1, within 72 hours prior to re-dosing to include:
•
CBC with differential, chemistry panel at every cycle (includes 
AST, ALT, TBili, ALP, LDH, creatinine, BUN or serum urea, 
glucose, Na, K, Cl, Ca, Phos, and Mg)
•
Thyroid panel (includes TSH with reflexive free T3 and free T4) at 
every cycle
Revised Protocol No.: 01
Date: 12-Mar-2020
18
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
Table 2-2:
On-treatment Procedural Outline Cycles 1 through 4 (CA20973M)
Procedurea
Cycle 1 through Cycle 4 (Cycle = 3 weeks)
Dosing Q3W for 4 Doses
Notes
Day 1
Cycle 1
Day 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Efficacy Assessments
Body Imaging
X
Contrast-enhanced CT of the chest and CT/MRI of the abdomen, 
pelvis, and all other known and/or suspected sites of disease should be 
performed on Week 12 (± 7 days) following date of first dosing. 
See Section 9.1.1 for further details.
Brain Imaging
Participants with a history of brain metastasis or symptoms should 
have a surveillance MRI study per standard of care (approximately 
every 12 weeks), or sooner, if clinically indicated. CT of the brain 
without and with contrast can be performed if MRI is contraindicated. 
See Section 9.1.1 for further details.
Study Treatment
Administer nivolumab and 
ipilimumab
X
X
X
X
Nivolumab is to be administered first (see Section 7.1)
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; 
BUN = blood urea nitrogen; C = cycle; CBC = complete blood count; CT = computed tomography; D = day; KPS = Karnofsky Performance Status; 
LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; Q3W = every 3 weeks; RR = respiratory rate; SAE = serious adverse event; T3 = thyroxine; 
T4 = triiodothyronine; TBili = total bilirubin; TSH = thyroid stimulating hormone; WOCBP = women of childbearing potential
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
Revised Protocol No.: 01
Date: 12-Mar-2020
19
Approved
2.0
v
Approved
1.0
v

Clinical Protocol
CA20973M
BMS-936558
nivolumab
Table 2-3:
On-treatment Procedural Outline Cycle 5 and Beyond (CA20973M)
Procedure a
Cycle 5 and Beyond up to 
24 Months of Treatment
(Cycle = 4 Weeks)
Notes
Day 1
Safety Assessments
Targeted Physical Examination, Vital Signs, 
Performance Status
X
Within 72 hours prior to dosing, weight, BP, heart rate, RR, temperature, KPS 
(Appendix 7), and Performance Status assessment to be performed.
Assessment of Signs and Symptoms
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 AEs and SAEs will be documented for a minimum of 100 days after last 
dose (Appendix 3).
AE and SAE Assessment
Continuously
Record at each visit. Participants will be followed for drug-related toxicities 
until these toxicities resolve, return to baseline, or are deemed irreversible.
All AEs and SAEs will be documented for a minimum of 100 days after last 
dose (Appendix 3).
Concomitant Medication Use
X
Laboratory Tests
Pregnancy Test (WOCBP only) 
X
Serum or urine test within 24 hours prior to administration of study drug.
Additional Tests
X
See Section 9.4.4 for additional details on tests required.
Within 72 hours prior to dosing to include:
•
CBC with differential, chemistrypanel at every cycle (includes AST, ALT, 
TBili, ALP, LDH, creatinine, BUN or serum urea, glucose, Na, K, Cl, Ca, 
P, and Mg)
•
Thyroid panel (includes TSH with reflexive free T3 and free T4) at every 
cycle
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Table 2-3:
On-treatment Procedural Outline Cycle 5 and Beyond (CA20973M)
Procedure a
Cycle 5 and Beyond up to 
24 Months of Treatment
(Cycle = 4 Weeks)
Notes
Day 1
Efficacy Assessments
Body Imaging
Subsequent to Week 12, imaging should occur every 8 weeks (± 7 days) until 
Week 60, then every 12 weeks (± 7 days) until initiation of another anti-
cancer treatment, withdrawal of consent, or death, whichever occurs first.
See Section 9.1.1 for further details.
Brain Imaging
Participants with a history of brain metastasis or symptoms should have a 
surveillance MRI study per standard of care (approximately every 12 weeks), 
or sooner, if clinically indicated. CT of the brain without and with contrast 
can be performed if MRI is contraindicated. See Section 9.1.1 for further 
details.
Study treatment
Administer nivolumab monotherapy
X
Subsequent doses may be administered within 3 days after the scheduled date 
if necessary. See Section 7.
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; 
BUN = blood urea nitrogen; CT = computed tomography; KPS = Karnofsky Performance Status; LDH = lactate dehydrogenase; MRI = magnetic resonance 
imaging; RR = respiratory rate; SAE = serious adverse event; T3 = thyroxine; T4 = triiodothyronine; TBili = total bilirubin; TSH = thyroid stimulating hormone; 
WOCBP = women of childbearing potential
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
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Table 2-4:
Follow-up Procedural Outline (CA20973M)
Procedure
Follow-up Assessments
All Participants
Notes
Follow-Upa
Visits 1 and 2
Survivalb
Follow-up
Safety Assessments
Targeted Physical Examination, 
Vital Signs, Performance Status
X
--
Weight, BP, heart rate, RR, temperature, and KPS (Appendix 7).
Assessment of Signs and 
Symptoms
X
--
AE and SAE Assessment
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 AEs and 
SAEs will be documented for a minimum of 100 days after last dose. (Appendix 3).
Concomitant Medication Use
X
--
Laboratory Tests
Pregnancy Test (WOCBP only) 
X
--
Serum or urine
Additional Tests
X
--
See Section 9.4.4 for additional details on tests required.
CBC with differential, chemistry panel (includes AST, ALT, TBili, ALP, LDH, 
creatinine, BUN, glucose, Na, K, Cl, Ca, Phos, Mg)
Thyroid panel (includes TSH with reflexive free T3 and free T4) 
Efficacy Assessments
Body Imaging
Imaging should occur at every 8 weeks (± 7 days) until Week 60, then every 12 weeks (± 7 days) until initiation of 
another anti-cancer treatment, withdrawal of consent, or death, whichever occurs first (see Section 9.1.1).
Brain Imaging
Participants with a history of brain metastasis or symptoms should have a surveillance MRI study per standard of care 
(approximately every 12 weeks), or sooner, if clinically indicated. CT of the brain without and with contrast can be 
performed if MRI is contraindicated. See Section 9.1.1.
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Table 2-4:
Follow-up Procedural Outline (CA20973M)
Procedure
Follow-up Assessments
All Participants
Notes
Follow-Upa
Visits 1 and 2
Survivalb
Follow-up
Survival Status
Participant Status
X
X
During safety follow-up and every 3 months (clinic visit or by telephone) during 
survival phase. Include documentation of subsequent therapy (see Section 8.1.2).
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; 
BMS = Bristol-Myers Squibb; BUN = blood urea nitrogen; CT = computed tomography; KPS = Karnofsky Performance Status; LDH = lactate dehydrogenase; 
MRI = magnetic resonance imaging; RR = respiratory rate; SAE = serious adverse event; T3 = thyroxine; T4 = triiodothyronine; TBili = total bilirubin; 
TSH = thyroid stimulating hormone; WOCBP = women of childbearing potential
a Follow-up visits occur as follows: Follow-up Visit 1 = 30 days (± 7 days) from the last dose or coincide with the date of discontinuation (± 7 days) if date of 
discontinuation is > 42 days after last dose. Follow-up Visit 2 = 100 days (± 7 days) from last dose of study treatment. Participants must be followed for at least 
100 days after last dose of study treatment. Both follow-up visits should be conducted in person.
b Survival follow-up visits may be conducted in clinic or by phone. Survival visits: first Survival Follow-up Visit 3 months (± 14 Days) after Follow-up Visit 2, 
and subsequent survival follow-up visits every 3 months (± 14 days) for approximately 36 months. 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
3.1
Study Rationale
CA209214 was a Phase 3 study of nivolumab in combination of ipilimumab compared with 
sunitinib in previously untreated patients with locally advanced renal cell carcinoma (RCC) or 
metastatic renal cell carcinoma (mRCC). The study has demonstrated a favorable benefit/risk 
profile for the combination of nivolumab and ipilimumab over current standard of care sunitinib 
in International Metastatic RCC Database Consortium (IMDC) intermediate/poor risk patients as 
shown by the unprecedented overall survival (OS) benefit in this population. It also showed 
superior objective response rate (ORR), higher rate of complete response (CR) as well as a 
clinically meaningful increase in progression-free survival (PFS) compared to sunitinib. While the 
combination has differential toxicities compared to sunitinib due to different mechanism of action, 
it has a manageable safety profile and is well tolerated compared to sunitinib. 
In patients who achieve initial tumor control (whether CR, partial response [PR], or stable disease 
[SD]) on the combination but then progress while on nivolumab maintenance, there is good 
biological rationale for ipilimumab rechallenge (defined as reintroduction of treatment upon 
disease progression). Indeed, an equilibrium between tumor growth and immunological response 
is required in order to prevent disease progression. Selective pressure might drive immunoediting 
and immune escape, resulting in loss of primary tumor response and/or novel antigen repertoire to 
emerge on new legions. By rechallenging with ipilimumab, the T-cell pool will expand and 
reactivate the primed immune system to recognize and respond to any remaining original tumor 
cells or new tumor clones that may have appeared during the tumor escape phase.
In melanoma, clinical data from early studies (MDX010-20, CA184025, CA184243) as well as 
real-world evidence have provided evidence of the activity of ipilimumab rechallenge for patients
who had an initial response or SD with ipilimumab and then progressed, as well as data on the 
combination of ipilimumab and nivolumab for patients who progressed on anti-programmed cell 
death protein 1 (PD-1). In mRCC, while recent retrospective studies suggest that the combination 
nivolumab and ipilimumab can be used as salvage therapy in immuno-oncology (I-O) refractory 
patients1, no data exist regarding the retreatment with ipilimumab for patients who show signs of 
progressive disease on nivolumab maintenance therapy after initial nivolumab and ipilimumab 
induction. 
This study aims to determine if stimulation of an immune response by reintroducing ipilimumab
and nivolumab could regain tumor control, as measured by primary endpoint of disease control 
rate (DCR), with OS, PFS, ORR, and safety as key secondary endpoints. 
 
 
3.1.1
Research Hypothesis
Retreatment with ipilimumab in combination with nivolumab in patients progressing on 
nivolumab maintenance therapy after ipilimumab and nivolumab induction, will result in improved 
clinical benefits based on DCR (defined as the percentage of patients who had SD for at least 
6 months from first treatment dose, CR, or PR) in patients with mRCC.
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3.2
Background
3.2.1
Cancer Immunotherapy
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.2,3,4
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.5 Collectively, these signals govern the 
balance between T-cell activation and tolerance.
3.2.2
Nivolumab Mechanism of Action
PD-1 (cluster of differentiation [CD]279), a 55 kD type I transmembrane protein, is a member of 
the CD28 family of T-cell co-stimulatory receptors that also includes CD28, cytotoxic 
T-lymphocyte-associated antigen 4 (CTLA-4), inducible co-stimulator (ICOS), and B- and 
T-lymphocyte attenuator (BTLA).6
PD-1 contains an intracellular membrane proximal 
immunoreceptor tyrosine inhibitory motif and a membrane distal immunoreceptor tyrosine-based 
switch motif (ITSM). Two ligands specific for PD-1 have been identified: programmed cell death 
protein ligand-1 (PD-L1) (B7-H1/CD274) and programmed cell death protein ligand-2 (PD-L2) 
(B7-DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon 
binding to PD-1 in both murine and human systems. PD-1 delivers a negative signal by the 
recruitment of a protein tyrosine phosphatase SHP-2 to the phosphorylated tyrosine residue in the 
ITSM in its cytoplasmic region. PD-1 is primarily expressed on activated T cells, B cells, and 
myeloid cells.
In vitro, nivolumab (Bristol-Myers Squibb [BMS]-936558), a fully human, immunoglobulin 
(Ig)G4 (kappa [κ]) isotype, monoclonal antibody (mAB) binds to PD-1 with high affinity (EC50 
0.39 nM to 2.62 nM) and inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ±
1 nM). Nivolumab binds specifically to PD-1 and not to related members of the CD28 family such 
as CD28, ICOS, CTLA-4, and BTLA. Blockade of the PD-1 pathway by nivolumab results in a 
reproducible enhancement of both proliferation and interferon gamma (IFN-γ) release in the mixed 
lymphocyte reaction that further increases upon addition of ipilimumab, providing in vitro 
evidence for synergistic activity of the combination.7 Using a cytomegalovirus (CMV) stimulation 
assay with human peripheral blood mononuclear cells, the effect of nivolumab on antigen-specific 
recall response indicates that nivolumab augmented IFN-γ secretion from CMV specific memory 
T cells in a dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by 
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a murine analog of nivolumab enhances the anti-tumor immune response and results in tumor 
rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).8
3.2.3
Ipilimumab Mechanism of Action
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses.9 Ipilimumab is a fully human 
monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human 
and nonhuman primates. The proposed mechanism of action for ipilimumab is interference of the 
interaction of CTLA-4 with B7 molecules on antigen-presenting cells, with subsequent blockade 
of the inhibitory modulation of T-cell activation promoted by the CTLA-4/B7 interaction. 
3.2.4
Preclinical Summary of Nivolumab Combined with Ipilimumab
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve anti-tumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN-γ
production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
anti-tumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer 
models. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies 
increased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor-infiltrating T effector 
cells, and dual blockade increased tumor infiltration of T effector cells and decreased intratumoral 
T regulatory cells, as compared to either agent alone.10
A 4-week toxicity study of nivolumab in combination with ipilimumab conducted in cynomolgus 
monkeys demonstrated that the combination of nivolumab and ipilimumab resulted in 
dose-dependent gastrointestinal (GI) toxicity. Histologic findings included inflammatory changes 
in the large intestine, which increased in incidence and severity in a dose dependent manner. GI 
toxicity/colitis was not observed in cynomolgus monkeys administered nivolumab alone but was 
observed in monkeys receiving ipilimumab. Nivolumab in combination with ipilimumab was also 
associated with lymphoid hypocellularity of the cortex and/or medulla of the thymus and with 
acinar cell degranulation in the pancreas. Additional findings included interstitial mononuclear cell 
infiltrates in the kidneys, portal mononuclear cell infiltrates in the liver, and myeloid 
hypercellularity in the bone marrow. Nivolumab in combination with ipilimumab at the high-dose 
level (ie, 50 mg/kg and 10 mg/kg, respectively) was associated with the death of 1 animal, 
attributed to acute gastric dilatation without histopathological evidence of colitis upon pathology 
evaluation of the GI tract.
3.2.5
Summary of Ipilimumab Rechallenge Studies
Ipilimumab rechallenge in participants progressing after initial immunotherapy treatment has been 
studied in several BMS-led trials. In the Phase 3 advanced melanoma study MDX010-20, optional 
retreatment was planned in the study protocol so patients who initially responded to ipilimumab 
treatment but later progressed were eligible for retreatment with their original randomized 
regimen. A subanalysis was performed on 38 patients retreated at progression with ipilimumab + 
gp100 or ipilimumab + placebo after initial clinical benefit (CR, PR, SD) lasting ≥6 months from 
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baseline and an acceptable safety profile during the initial treatment.11 Best overall response rates 
(CR plus PR) for 31 retreatment-eligible patients in the ipilimumab + gp100 and ipilimumab + 
placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and DCRs were 65.2% and 
75.0%, respectively. Thus, duration of response (DOR) and/or SD were achieved in participants 
who received retreatment upon initial progression of disease (PD), even after up to 2.5 years 
between last dose of ipilimumab and additional retreatment courses. Some patients achieved better 
best overall response (BOR) after retreatment than initial induction. Safety profile of retreatment 
showed no new types of toxicities, with consistent with safety profile of induction, and most events 
were of mild-to-moderate severity. Induction toxicity did not predispose to retreatment toxicity.
Study CA184025 was a Phase 2 rollover study of patients treated on prior Phase 2 studies 
(CA184004, CA184007, CA184008, CA184022, MDX010-08, and MDX010-15) with the 
primary objective of evaluating the safety of extended treatment with ipilimumab in patients with 
metastatic melanoma.12 Of the 122 patients rechallenged with ipilimumab, 7 patients had a CR 
and 21 patients had a PR by modified World Health Organization criteria for a BOR of 23%. An 
additional 31 patients had SD; therefore, the DCR upon retreatment was 48%. In this patient 
population, retreatment with ipilimumab at 10 mg/kg was generally well tolerated and the safety 
profile was similar to that during induction dosing in the parent studies, with no new safety signals 
identified. Tolerability to prior ipilimumab at 10 mg/kg does not preclude the development of 
Grade 3 or 4 immune-related adverse events (irAEs) during retreatment.
Ipilimumab retreatment in patients with pretreated advanced melanoma was also assessed among 
patients participating in an expanded access program in Italy.13 Patients who achieved disease 
control during induction therapy were retreated with ipilimumab upon progression, provided they 
had not experienced toxicity that precluded further dosing. Of 855 patients treated with 
ipilimumab, 51 (6%) patients received retreatment upon disease progression. Data from this study 
showed a retreatment response rate of about 12% and DCR of 55% after ipilimumab rechallenge, 
with 42% of patients alive 2 years after beginning of induction therapy (33% after start of 
retreatment) and median OS of 21 months (12 months after start of retreatment). No new types of 
toxicities occurred during retreatment and most events were of mild-to-moderate severity and 
resolving within a median of 4 days, with 22% of patients having a treatment-related adverse event
(AE) of any grade during retreatment.
In mRCC, no data currently exist on retreatment or rechallenge with ipilimumab. However, a 
recent retrospective study looked at the activity of salvage nivolumab and ipilimumab combination 
in 30 patients who have progressed on a variety of prior immunotherapies.1 The median number 
of prior therapies was 3, and prior I-O therapies included anti-PD-L1 monotherapy (17 patients 
[57%]), I-O/anti-vascular endothelial growth factor (VEGF) combination (5 patients [17%]), and 
nivolumab and ipilimumab combination (1 patient [3%]). The overall ORR on salvage nivolumab 
and ipilimumab was 23%, and DCR was 36%. Eleven patients (37%) developed any grade irAEs 
and 2 patients (6%) developed Grade ≥3 irAEs.
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Indication Background
3.2.6.1
Renal Cell Carcinoma: Background and Standard Treatments
Globally, more than 330,000 cases of RCC are diagnosed annually, with approximately a third of 
the patients succumbing to their disease. RCC accounts for about 3% of all cancers in the United 
States (US) where there are approximately 65,000 new cases and almost 15,000 deaths from RCC 
each year.14 In the European Union, there were approximately 84,000 cases of RCC and 
35,000 deaths in 2012.15 Metastatic disease is found in 30% of participants at diagnosis. Close to 
90% to 95% of metastatic disease has a clear-cell histology. RCC is approximately 50% more 
common in men compared with women.16 RCC occurs predominantly in the sixth to eighth decade 
of life with median age at diagnosis around 64 years of age.
Multiple scoring systems are available to characterize prognosis in treatment-naive RCC. Two of 
the most commonly used are the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic 
scoring system and the IMDC prognostic scoring system.17,18 Each of these systems categorizes 
patients as favorable, intermediate, or poor risk based on how many adverse prognostic factors are 
present (0: favorable risk, 1 to 2: intermediate risk, 3 or more: poor risk). The 6 parameters of 
importance for IMDC prognostic score classification are Karnofsky Performance Status (KPS), 
time from diagnosis to treatment, hemoglobin value, corrected calcium concentration, absolute 
neutrophil count, and platelet count 
. The 5 parameters included in the MSKCC 
prognostic score are KPS, nephrectomy status, hemoglobin value, lactate dehydrogenase (LDH), 
and corrected calcium concentration. Time from diagnosis to treatment is often used in place of 
nephrectomy status. With each system, the total number of adverse prognostic factors present has 
been shown to correlate with OS. Approximately 25% of patients are in the favorable-risk group, 
50% are in the intermediate-risk group, and 25% are in the poor-risk group (median OS: 
~ 9 months). In an analysis of 1,028 patients scored using the IMDC system, median OS for 
favorable-, intermediate-, and poor-risk patients is 43.2 months, 22.5 months, and 7.8 months, 
respectively.19
Until recently, the cytokines interleukin (IL)-2 and interferon were the only active treatments for 
advanced RCC or mRCC. However, due to each of these agents’ limited clinical benefit and 
substantial toxicity profile, newer targeted agents have largely replaced cytokines in the treatment 
of mRCC. There are several agents for the treatment of RCC that target angiogenesis (ie, the VEGF 
receptor tyrosine kinase inhibitors (TKIs), sorafenib, sunitinib, pazopanib, cabozantinib, and 
axitinib; and the VEGF-binding mAB, bevacizumab) and 2 that target the mammalian target of 
rapamycin (mTOR) pathway (ie, everolimus and temsirolimus).
More recently, immunotherapeutic approaches have demonstrated clinical efficacy in RCC with a 
survival advantage. Nivolumab monotherapy has been approved in multiple countries around the 
globe for the treatment of patients with mRCC previously treated with anti-angiogenic agents 
based on the results from CheckMate-025 (CA209025; NCT01668784). Furthermore, 
combination therapy with nivolumab and ipilimumab has demonstrated superior efficacy over 
sunitinib in intermediate- and poor-risk patients with previously untreated advanced RCC leading 
to Food and Drug Administration (FDA) approval of that regimen in the US and other regions.
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3.2.6.2
Nivolumab in Renal Cell Carcinoma
Nivolumab monotherapy has been studied in participants with RCC in several BMS sponsored 
studies, with the largest amount of data coming from 3 studies in participants with mRCC: 
CA209010, CA209009, and CA209025. In CA209010, 168 participants who received at least 
1 prior anti-angiogenic therapy were randomized to receive nivolumab 0.3 mg/kg (n = 60), 
2 mg/kg (n = 54), and 10 mg/kg (n = 54).20 Median PFS was 2.7 months, 4.0 months, and 
4.2 months at 0.3, 2, and 10 mg/kg, respectively. The ORR ranged from 20% to 22% across dose 
levels. Median OS was 18.2 months at 0.3 mg/kg, but was not yet reached at the 2 highest dose 
levels. CA209009 enrolled a similar population to CA209010, but also included 24 participants 
with treatment-naive RCC. Among treatment-naive participants, all of whom received nivolumab 
10 mg/kg every 3 weeks (Q3W), the ORR was 13% (3/23). 
CA209010 includes the largest safety database for nivolumab monotherapy in mRCC. All treated 
participants (n = 167) were included in the safety analyses. Drug-related AEs of any grade occurred 
in 74.6%, 66.7%, and 77.8% of participants treated at 0.3, 2, and 10 mg/kg, respectively. The most 
common (≥10% in any group) drug-related AEs included fatigue, dry skin, rash, pruritus, 
arthralgia, nausea, diarrhea, decreased appetite, dry mouth, and hypersensitivity. Grade 3 
drug-related AEs occurred in 5.1%, 16.7%, and 13% of participants treated at 0.3, 2, and 10 mg/kg, 
respectively. Related Grade 3 events in at least 2 patients across dose levels included nausea, 
aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increased, and anemia. No 
drug-related Grade 4 or Grade 5 events occurred. No dose-toxicity relationship was identified 
except for hypersensitivity/infusion reaction, which occurred most frequently in the 10-mg/kg 
treatment group. 
Based on the clinical activity of nivolumab observed in these Phase 1 and 2 studies, a large Phase 3 
trial (CA209025) was conducted in 821 participants with advanced RCC previously treated with 
1 or 2 anti-angiogenic therapies who were randomized to receive nivolumab 3 mg/kg every 
2 weeks (Q2W) or everolimus 10 mg daily. A planned interim analysis, after a minimum of 
follow-up of 14 months, demonstrated a statistically significant and clinically meaningful 
improvement in OS of nivolumab monotherapy versus everolimus (median OS, 25.0 months 
versus 19.6 months, respectively; hazard ratio [HR] 0.73 [98.5% confidence interval (CI), 0.57 to 
0.93, p-value (P) = 0.002]). ORR was 25% for nivolumab versus 5% for everolimus. Among 
756 participants with quantifiable PD-L1 tumor expression in pretreatment samples, 24% had 
PD-L1 expression ≥1%. Among participants with PD-L1 expression ≥1%, median OS was 
21.8 months in the nivolumab group and 18.8 months in the everolimus group (HR 0.79 [95% CI, 
0.53 to 1.17]). Among participants with PD-L1 expression < 1%, the median OS was 27.4 months 
in the nivolumab group and 21.2 months in the everolimus group (HR, 0.77 [95% CI, 0.60 to 
0.97]). No new safety concerns were identified, and nivolumab monotherapy showed a favorable 
safety profile as compared to everolimus, evidenced by the lower rates of drug related AEs (all 
grades, 79% versus 88%; Grade 3 to Grade 4, 19% versus 37%, respectively) and drug-related 
AEs leading to discontinuation (all grades, 8% versus 13%, respectively) in the nivolumab group. 
These results were the basis for regulatory approval of nivolumab monotherapy in advanced RCC.
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3.2.6.3
Ipilimumab in Renal Cell Carcinoma
Ipilimumab monotherapy for the treatment of mRCC was studied in the Phase 2 clinical trial 
MDX010-11.21 Two sequential cohorts were studied, each with a loading dose of 3 mg/kg 
followed by 3 doses of either 1 mg/kg (group 3-1; n = 21) or 3 mg/kg (group 3-3; n = 40). 
Participants with SD or PR or CR were allowed additional treatment. In group 3-1 (n = 21), 
1 participant (5%) had a PR.22 In group 3-3 (n = 40), 5 participants (12.5%) had a PR. Among 
14 treatment-naive participants in group 3-3, 3 (21%) had a PR.
In the ipilimumab monotherapy Phase 2 clinical trial MDX010-11, the major toxicities were colitis 
(all Grade 3 and 4: 14% in group 3-1, 33% in group 3-3) and hypophysitis (1 Grade 3/4, 
1 Grade 1/2 in group 3-3; none in group 3-1). Most reported AEs were Grade 1/2 (57% in 
group 3-1, 35% in group 3-3), or Grade 3 (38% in group 3-1, 48 % in group 3-3).21 Most reported 
AEs were Grade 1/2 (57% in group 3-1, 35% in group 3-3), or Grade 3 (38% in group 3-1, 48% in 
group 3-3). There were 6 participants (15%) with Grade 4 AEs in group 3-3. The most common 
treatment-related AEs in group 3-1 (total 81%) and group 3-3 (total 93%) were diarrhea (38% and 
40%, respectively) and fatigue (33% and 38%, respectively). Most AEs were manageable with 
appropriate treatment, including high dose corticosteroids and hormone replacement.
3.2.6.4
Nivolumab Combined with Ipilimumab in Renal Cell Carcinoma
The combination of nivolumab with ipilimumab was studied in the Phase 1 study CA209016.23
Participants with mRCC (favorable/intermediate MSKCC score; KPS ≥80%; untreated or any 
number of prior therapies) were randomized to receive nivolumab 3 mg/kg (N3) combined with 
ipilimumab 1 mg/kg (I1 [arm N3 + I1]) or nivolumab 1 mg/kg (N1) combined with ipilimumab 
3 mg/kg (I3 [arm N1 + I3]) intravenously once Q3W for 4 doses followed by nivolumab 3 mg/kg 
Q2W until progression/toxicity. The primary objective was to assess safety/tolerability; the 
secondary objective was to assess anti-tumor activity. Forty-four participants were randomized to 
N3 + I1 (n = 21) and N1 + I3 (n = 23). Most patients (n = 34; 77%) had prior systemic therapy 
(N3 + I1: 16 patients; N1 + I3: 18 patients). The confirmed ORR was 43% (N3 + I1) and 48% 
(N1 + I3). DOR was 4.1+ to 42.1+ weeks (7 of 9 responses ongoing) in N3 + I1, and 12.1+ to 
35.1+ weeks (9 of 11 responses ongoing) in N1 + I3. Best response of disease standard deviation 
was seen in 5 patients (24%; N3 + I1) and 8 patients (35%; N1 + I3). Median PFS was 36.6 weeks 
(N3 + I1) and 38.3 weeks (N1 + I3); these data are still immature, with 11 of 21 events reported 
for N3 + I1 and 10 of 23 events reported for N1 + I3.
The safety of nivolumab combined with ipilimumab was assessed in CA209016. Treatment-related 
AEs were seen in 39 patients (89%), including 16 (76.2%) in N3 + I1 and 23 (100%) in N1 + I3. 
Across the N3 + I1 and N1 + I3 arms, the most common (≥20%) treatment-related AEs of any 
Grade were fatigue (61%), diarrhea (32%), nausea (30%), rash (27%), pruritus (25%), ALT 
increased (23%), AST increased (20%), hypothyroidism (20%), and lipase increased (20%). 
Grade 3 or Grade 4 related AEs occurred in 19 patients (29%), including 6 (29%) at N3 + I1 and 
14 (61%) at N1 + I3. The most common (≥5%) drug-related Grade 3 or Grade 4 events were lipase 
increased (21%), ALT increased (14%), AST increased (7%), diarrhea (9%), fatigue (5%), amylase 
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increased (5%), colitis (5%), and lymphocyte count decreased (5%). No Grade 3 or Grade 4 
pneumonitis was seen. No treatment-related deaths were reported.
In summary, a similar robust level of clinical activity was observed with N3 + I1 and N1 + I3, but 
the N3 + I1 arm exhibited a more favorable safety profile.
Study CA209214 is a Phase 3, randomized, open-label study of nivolumab 3 mg/kg combined with 
ipilimumab 1 mg/kg Q3W for 4 doses followed by nivolumab 3 mg/kg Q2W versus sunitinib 
monotherapy using the approved dose and schedule (50 mg orally once daily for 4 weeks followed 
by 2 weeks off, every cycle) in adult participants with previously untreated advanced RCC. The 
combination therapy with nivolumab and ipilimumab has demonstrated superior efficacy over 
standard of care sunitinib in intermediate- and poor-risk patients with previously untreated 
advanced RCC and is now established as the new standard of care in this setting with regulatory 
approvals in the US, Canada, Japan, and Switzerland. In the Phase 3 trial CheckMate 214, a total 
of 1,096 participants were randomized, including 847 participants with IMDC intermediate and 
poor risks (425 participants in the nivolumab combined with ipilimumab group and 
422 participants in the sunitinib group). The median OS was not reached with nivolumab plus 
ipilimumab versus 26.0 months with sunitinib (HR for death, 0.63; P < 0.0001) (Table 3.2.6.4-1). 
The ORR was 42% versus 27% (P < 0.0001), with a CR rate of 9.4% versus 1.2%. Independent 
Regulatory Review Commission-assessed PFS in intermediate/poor-risk participants also favored 
nivolumab combined with ipilimumab over sunitinib, demonstrating a 3.2-month improvement in 
median PFS (11.56 months versus 8.38 months). The PFS curves separated after a delay of 
approximately 6 months from randomization, resulting in an HR of 0.82 that did not meet the 
prespecified alpha boundary of 0.009 for statistical significance.
Table 3.2.6.4-1:
Summary of Efficacy Results in CA209214
Intermediate/Poor-risk Patients
All Randomized (Any Risk) Patients
Nivolumab + 
Ipilimumab
(N = 425)
Sunitinib
(N = 422)
Nivolumab + 
Ipilimumab
(N = 550)
Sunitinib
(N = 546)
OS
N events (%)
140 (32.9)
188 (44.5)
161 (29.3)
204 (37.4)
Median OS (months)a
NA
25.95 
NA
32.92 
Exact 95% CI
(28.16, NA)
(22.08, NA)
-
(NA, NA)
HR (99.8% CI)b
0.63 (0.44, 0.89)
0.68 (0.49, 0.95)
p-value c
<0.0001
0.0003
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Table 3.2.6.4-1:
Summary of Efficacy Results in CA209214
Intermediate/Poor-risk Patients
All Randomized (Any Risk) Patients
Nivolumab + 
Ipilimumab
(N = 425)
Sunitinib
(N = 422)
Nivolumab + 
Ipilimumab
(N = 550)
Sunitinib
(N = 546)
IRRC-assessed ORR 
(CR+PR)d
Co-primary Objective
Secondary Objective
N responders (%)
177 (41.6)
112 (26.5)
213 (38.7)
176 (32.2)
Exact 95% CI
36.9, 46.5
22.4, 31.0
34.6, 42.9
28.3, 36.3
Difference in ORR 
(95% CI)e,f
16.0 (9.8, 22.2)
7.2 (1.8, 12.7) 
p-valueg
<0.0001
0.0191
BOR
CR
40 (9.4)
5 (1.2)
54 (9.8)
12 (2.2) 
PR
137 (32.2)
107 (25.4)
159 (28.9)
164 (30.0)
SD
133 (31.3)
188 (44.5)
199 (36.2)
232 (42.5)
PD
83 (19.5)
72 (17.1) 
99 (18.0)
78 (14.3)
UTD
31 (7.3)
50 (11.8)
38 (6.9)
59 (10.8)
DOR
Median (95% CI), monthsa
NA 
(21.82, NA)
18.17 
(14.82, NA)
NA 
(21.82, NA) 
20.96 
(18.17, NA)
Min, Maxh
1.4+, 25.5+
1.3+, 23.6+
1.4+, 27.7+ 
1.3+, 26.3+
IRRC-assessed PFS
Co-primary Objective
Secondary Objective
N events (%)
228 (53.6)
228 (54.0)
296 (53.8)
271 (49.6)
Median PFS (months)a
11.56
8.38
12.42
12.32
Exact 95% CI
(8.71, 15.51)
(7.03, 10.81)
(9.89, 16.53)
(9.79, 15.24)
HR (99.1% CI)b
0.82 (0.64, 1.05)
0.98 (0.79, 1.23)
p-valuec
0.0331
0.8498
Source: CA209214 Final CSR24, Table 7.1-1
Abbreviations: CI = confidence interval; CR = complete response; DOR = duration of response; HR = hazard ratio; 
IMDC = International Metastatic RCC Database Consortium; IRRC = Independent Regulatory Review 
Commission; IVRS = interactive voice response system; Max = maximum; Min = minimum; N = number of 
patients; NA = not applicable; ORR = objective response rate; OS = overall survival; PD = progression of disease; 
PFS = progression-free survival; PR = partial response; ROW = rest of the world; SD = stable disease; US = United 
States; UTD = unable to determine
a Median computed using Kaplan-Meier method.
b Stratified Cox proportional hazard model. HR is nivolumab combined with ipilimumab over sunitinib.
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c Log-rank Test stratified by IMDC prognostic risk score (0, 1-2, 3-6) and region (US, Canada/W Europe/N Europe, 
ROW) as entered into the IVRS.
d CI based on the Clopper and Pearson method.
e Strata adjusted difference in ORR (nivolumab + ipilimumab ‒ sunitinib) based on DerSimonian and Laird method.
f Stratified by IMDC prognostic risk score (0, 1-2, 3-6) and region (US, Canada/western Europe/northern Europe, 
Rest of World) as entered into the IVRS.
g Two-sided p-value from DerSimonian and Laird Test.
h Symbol “+” indicates a censored value.
Significant benefit was also observed with nivolumab combined with ipilimumab regardless of 
PD-L1 tumor expression although the benefit was somewhat higher in the PD-L1-positive 
population. In CA209214, the safety of the combination nivolumab combined with ipilimumab is 
acceptable with a tolerable and manageable safety profile (Table 3.2.6.4-2). The majority of select 
AEs and immune-mediated adverse events (IMAEs) were low-grade and manageable using the 
recommended treatment guidelines for early work-up and intervention. The overall safety profile 
observed in the nivolumab combined with ipilimumab group was consistent with the known and 
well-characterized safety profile of nivolumab monotherapy, as well as the nivolumab and 
ipilimumab combination, and was similar to the profile observed across other tumor types in terms 
of type, frequency, and severity of AEs observed. There were no new safety concerns identified.
Table 3.2.6.4-2:
Summary of Safety Results - All Treated Patients in CA209214
Number (%) Patients
Nivolumab + Ipilimumab
(N = 547)
Sunitinib
(N = 535)
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Drug-related AEs
509 (93.1)
250 (45.7)
521 (97.4)
335 (62.6)
Most frequent drug-related AEs (≥15% of any grade in either treatment group)
Fatigue
202 (36.9)
23 (4.2)
264 (49.3)
49 (9.2)
Pruritus
154 (28.2)
3 (0.5)
49 (9.2)
0
Diarrhoea
145 (26.5)
21 (3.8)
278 (52.0)
28 (5.2)
Rash
118 (21.6)
8 (1.5)
67 (12.5)
0
Lipase increased
90 (16.5)
56 (10.2)
58 (10.8)
35 (6.5)
Nausea
109 (19.9)
8 (1.5)
202 (37.8)
6 (1.1)
Hypothyroidism
85 (15.5)
2 (0.4)
134 (25.0)
1 (0.2)
Decreased appetite
75 (13.7)
7 (1.3)
133 (24.9)
5 (0.9)
Asthenia
72 (13.2)
8 (1.5)
91 (17.0)
12 (2.2)
Vomiting
59 (10.8)
4 (0.7)
110 (20.6)
10 (1.9)
Anaemia
34 (6.2)
2 (0.4)
83 (15.5)
24 (4.5)
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Table 3.2.6.4-2:
Summary of Safety Results - All Treated Patients in CA209214
Number (%) Patients
Nivolumab + Ipilimumab
(N = 547)
Sunitinib
(N = 535)
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Dysgeusia
31 (5.7)
0
179 (33.5)
1 (0.2)
Stomatitis
23 (4.2)
0
149 (27.9)
14 (2.6)
Dyspepsia
15 (2.7)
0
96 (17.9)
0
Mucosal inflammation
13 (2.4)
0
152 (28.4)
14 (2.6)
Hypertension
12 (2.2)
4 (0.7)
216 (40.4)
85 (15.9)
Palmar-plantar erythrodysaesthesia syndrome
5 (0.9)
0
231 (43.2)
49 (9.2)
Thrombocytopenia
2 (0.4)
0
95 (17.8)
25 (4.7)
Drug-related Select AEs, by Category
Endocrine
178 (32.5)
38 (6.9)
163 (30.5)
1 (0.2)
Gastrointestinal
154 (28.2
27 (4.9)
278 (52.0)
28 (5.2)
Hepatic
101 (18.5)
45 (8.2)
77 (14.4)
20 (3.7)
Pulmonary
34 (6.2)
6 (1.1)
1 (0.2)
0
Renal
48 (8.8)
7 (1.3)
46 (8.6)
6 (1.1)
Skin
267 (48.8)
20 (3.7)
304 (56.8)
53 (9.9)
Hypersensitivity/infusion reactions
22 (4.0)
0
6 (1.1)
2 (0.4)
Source: CA209214 Final CSR24, Table 8.1-1
Abbreviations: AE = adverse event; CSR = clinical study report; CTC = common terminology criteria; 
MedDRA = Medical Dictionary for Regulatory Activities; N = number of patients.
Notes: MedDRA version 20.0; CTC version 4.0. All events are within 30 days of the last dose of study drug, unless 
otherwise indicated.
3.3
Benefit/Risk Assessment
Extensive details on the safety profile of nivolumab are available in the Investigator’s Brochure 
(IB) and will not be repeated herein.
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no 
maximum tolerated dose reached at any dose tested up to 10 mg/kg. Most AEs were low-grade 
(Grade 1 to Grade 2) with relatively few related high-grade (Grade 3 to Grade 4) AEs. There was 
no pattern in the incidence, severity, or causality of AEs with respect to nivolumab dose level.
A pattern of IMAEs has been defined, for which management algorithms have been developed; 
these are provided in Appendix 5. Most high-grade events were manageable with the use of 
corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms. 
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Patients with mRCC have multiple treatment options available to them (see Section 3.2.6.1), but 
none of the 7 available targeted agents have been able to demonstrate a significant improvement 
in OS when compared to each other. Median OS remains less than 4 years for treatment-naive 
patients with the most favorable prognosis and is substantially shorter for patients who possess 
adverse prognostic factors. Therefore, new therapeutic options with the potential to provide greater 
survival are needed. 
Nivolumab in combination with ipilimumab in the CA209214 study has demonstrated significant 
clinical benefits with reversible and manageable toxicities that are consistent with the known 
IMAE profile of anti-PD-1 immune therapies. The magnitude of OS benefit from the combination 
is unprecedented in studies of mRCC for intermediate- and poor-risk participants. Retreatment
with ipilimumab regimen for patients who had initial clinical benefit but who have progressed on 
nivolumab maintenance is expected to regain tumor control and show a clinical meaningful DCR 
of with a manageable increase in IMAEs.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To describe the efficacy in terms of DCR of 
retreatment with ipilimumab in combination with 
nivolumab in patients with mRCC progressing on 
maintenance nivolumab after first-line therapy 
with ipilimumab and nivolumab
•
DCR is defined as the proportion of participants 
who achieve a confirmed best response of CR, PR,
or SD for at least 6 months after first treatment dose
per RECIST 1.1 criteria.
Secondary
•
To describe the OS of retreatment with ipilimumab 
in combination with nivolumab in patients with 
mRCC progressing on maintenance nivolumab 
after first-line therapy with ipilimumab and 
nivolumab.
•
OS is defined as the time from first dose to the 
date of death from any cause. For participants that
are alive, their survival time will be censored at the 
date of last contact (“last known alive date”). OS 
will be censored for participants at the date of first 
dose if they were treated but had no follow-up.
•
To evaluate additional efficacy measures in all 
participants.
•
ORR is defined as the proportion of participants 
who achieve a best response of CR or PR per 
RECIST 1.1 criteria.
•
DOR is defined as the time between the date of 
first documented response (CR or PR) to the date 
of the first documented progression, per 
RECIST 1.1 criteria, or death due to any cause, 
whichever occurs first.
•
PFS is defined as the time between the date of first 
dose and the first date of documented progression, 
as per RECIST 1.1 criteria, or death due to any 
cause, whichever occurs first.
•
Time to objective response (TTR) is defined as the 
time between the date of the first dose and the first 
confirmed documented response (CR or PR) per 
RECIST 1.1 criteria.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To estimate the incidence of AEs of retreatment
with ipilimumab in combination with nivolumab in 
patients with mRCC progressing on maintenance 
nivolumab after first-line therapy with ipilimumab
and nivolumab.
•
AE incident rate is defined as the proportion of 
participants with any grade AEs. Events reported 
from the first dose and up to and including 
100 days following the last dose of study treatment 
could be included in estimating this incidence rate.
Abbreviations: AE = adverse event; CR = complete response; DCR = disease control rate; DOR = duration of 
response;
 mRCC = metastatic renal cell carcinoma; 
ORR = objective response rate; OS = overall survival; 
PFS = progression-free survival; PR = partial response; RECIST 1.1 = Response Evaluation Criteria In Solid 
Tumors version 1.1; SD = stable disease; TTR = time to objective response
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2, international, multicenter study of rechallenge with ipilimumab 1 mg/kg Q3W 
combined with nivolumab 3 mg/kg for up to 4 doses followed by nivolumab 480 mg every 4 weeks 
(Q4W).
•
The study will enroll participants previously treated with combination regimen ipilimumab and 
nivolumab for advanced RCC and mRCC, who had an initial response of CR, PR, or SD for at 
least 6 months, and who had a confirmed progression on nivolumab maintenance. The number 
of enrolled participants with SD ≥6 months will be capped at 50%. Evaluable tumor tissue, 
recently acquired after confirmed progression, must be obtained prior to treatment initiation.
•
Participants should not have experienced any prior AE that meets the criteria for treatment 
discontinuation as described in Section 7.4.4, with the exception of patients with prior history 
of adrenal insufficiency that are under control with hormone replacement.
•
The study treatment will continue until participants experience disease progression per 
RECIST 1.1, unacceptable toxicity, or a maximum of 24 months of study treatment with 
nivolumab. There is a maximum of 4 doses of ipilimumab.
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•
For drug-related toxicities, dosing of both drugs can be delayed and resumed after resolution 
per protocol-specified criteria (Sections 7.4.2 and 7.4.3, respectively). No dose increases or 
reductions are allowed for either drug. Management algorithms of the drug-related toxicities, 
including the use of corticosteroids and other immunomodulating agents, are provided in 
Appendix 5.
•
During the combination phase (Cycles 1 through 4), participants unable to resume nivolumab 
and ipilimumab for drug-related toxicities will be permitted to proceed to nivolumab 
monotherapy maintenance (Section 7.4.4). 
•
Participants should have baseline computed tomography (CT)/MRI scan results showing
measurable disease lesion(s) per RECIST 1.1 and first postbaseline tumor assessment at 
Week 12 followed by subsequent tumor assessments every 8 weeks in the first 60 weeks, and 
every 12 weeks thereafter (Section 9.1.1 for more details). The tumor assessment schedule 
should continue until initiation of another anti-cancer treatment. Images will be submitted to a 
central imaging vendor and may undergo blinded independent central review (BICR) at any 
time during the study. 
•
AE and serious adverse event (SAE) data should be collected throughout the study until 
100 days after the last dose. Safety laboratory tests, including complete blood count and 
chemistry, will be obtained at each schedule visit and unscheduled visit as indicated. 
 
•
Participants who discontinue the study treatment will be followed for safety at 30 days 
(± 7 days, Follow-up Visit 1) and 100 days (± 7 days, Follow-up Visit 2) of the last dose, 
thereafter for survival. Tumor assessments will continue in follow-up period per schedule until 
initiation of another anti-cancer treatment.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Simon Two-stage Design
Abbreviations: CR = complete response; DCR = disease control rate; mRCC = metastatic renal cell carcinoma; 
PR = partial response; RECIST = Response Evaluation Criteria In Solid Tumors version 1.1; SD = stable disease
This study will consist of 3 phases: screening, treatment, and follow-up.
Screening Stage
Screening begins by establishing the participant’s initial eligibility and signing of the informed 
consent form (ICF). Sufficient, recent tumor tissue (obtained at or after progression on initial 
nivolumab monotherapy) from a metastatic tumor lesion or from a primary tumor lesion that has 
not been previously irradiated (formalin-fixed paraffin-embedded [FFPE] block or 20 unstained 
slides; a minimum of 15 slides, obtained from core biopsy, punch biopsy, excisional biopsy, or 
surgical specimen) will be submitted to the designated laboratory.  Tumor tissue may be obtained 
within ≤12 months prior to enrollment, preferably within 3 months or during the screening period.
Participants will be assessed for complete study eligibility prior to first dose as specified in Table
2-1. The maximum amount of time between confirmation of study eligibility and the date of first 
dose is 7 days.
The Screening stage ends with either confirmation of full eligibility or with the confirmation that 
the participant is a screen failure. This study permits the re-enrollment of a participant who 
discontinued the study as a pre-treatment failure prior to treatment. If re-enrolled, the participant 
Nivolumab + ipilimumab
induction Q3W
First-Line Treatment
Nivolumab maintenance 
Q2W/Q4W
Progression
Combination Retreatment Therapy
Nivolumab + ipilimumab
retreatment Q3W
Nivolumab
maintenance Q4W
Treat until 
progression, 
unacceptable 
toxicity, withdrawal 
of consent, or 
maximum of 2 years 
duration whichever 
occurs first.
CA20973M
Time
Note: Treatment beyond PD allowed with provisions
Key Inclusion Criteria
•
Clear cell mRCC
•
Confirmed disease progression 
by RECIST criteria on nivolumab 
maintenance after induction 
with nivolumab + ipilimumab 
and initial PR/CR or SD ≥ 6 
months
Promising DCR:
Continue to Stage 2
Low DCR:
Stop for futility
If promising DCR:
Reject null hypothesis
Stage 1 
Stage 2 Expansion 
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must be reconsented. A new participant identification number will be assigned by IRT at the time 
of re-enrollment.
Treatment Stage
The treatment stage begins after confirmation of full eligibility and consists of:
•
Nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W for up to 4 doses 
followed by nivolumab 480 mg flat dose IV Q4W
−
Treatment is to be continued until disease progression or unacceptable toxicity. Nivolumab 
treatment may be administered for a maximum of 24 months from the date of the first dose 
in Cycle 1.
•
The duration for the first 4 cycles is 3 weeks each. The duration of Cycle 5 and beyond is 
4 weeks each, with up to 24 months of treatment.
See Table 7.1-1 for the dosing schedule and Section 5.5 for dose and timing justification. Study 
treatments may be delayed for reasons such as toxicity (see Section 7.4.2). Treatment may be 
continued beyond investigator-assessed progression if the investigator confirms that the participant 
meets the criteria specified in Section 8.1.1. A negative pregnancy test should be documented 
within 24 hours prior to the initial dose of the investigational product (IP) and then performed prior 
to administration of study drug or as part of follow-up assessment as described in Section 2. 
On-study laboratory assessments should be drawn within 72 hours prior to dosing and will be 
assessed at the local laboratory.
 AE assessments should be 
documented at each clinic visit. 
The Treatment stage ends when the participant is discontinued from study therapy or completes 
treatment.
Follow-up Stage
The Follow-up stage begins when the decision to discontinue a participant from study therapy is 
made or the participant completes treatment (no further study treatment). Participants must be 
followed for at least 100 days (± 7 days) after the last dose of study treatment. 
•
Follow-up Visit 1 should occur 30 days (± 7 days) from the last dose or can be performed on 
the date of discontinuation if that date is greater than 42 days from the last dose. 
•
Follow-up Visit 2 (FU2) occurs approximately 100 days (± 7 days) from the last dose of study 
treatment. 
•
Both follow-up visits should be conducted in person. 
•
AEs will be followed until the toxicities resolve, return to baseline, or are deemed irreversible. 
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After FU2, all participants will be followed for OS status every 3 months (± 14 days) for 
approximately 36 months. 
•
Survival status can be ascertained in person or by telephone contact. 
•
If new anti-tumor therapy is initiated for either progression or a secondary malignancy at any 
time during this period, this and all other pertinent data obtained should be recorded on the 
appropriate case report form (CRF).
5.1.1
Steering Committee and Other External Committees
Not Applicable
5.2
Number of Participants
Approximately 96 participants will be enrolled in order to obtain 80 response evaluable 
participants, accounting for approximatively 20% of non-evaluable participants or withdrawal. 
The number of enrolled participants with SD ≥6 months will be capped at 50%.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit or scheduled procedure shown in the Schedule of Activities (Section 2) for 
the last participant. Study completion is defined as the final date on which data for the primary 
endpoint (OS) was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for the Study Population
In Study CA209214 with first-line treatment of patients with advanced RCC or mRCC, the clinical 
benefits of nivolumab combined with ipilimumab were highly significant over sunitinib in the 
intermediate- and poor-risk groups, indicating (I-O) therapy is most likely to provide benefits to 
these risk groups. Moreover, data from melanoma studies (see Section 3.2.5) suggests that 
ipilimumab and nivolumab rechallenge is likely to provide clinical benefit to participants who had 
an initial disease control (CR, PR, or SD ≥6 months).
5.4.2
Rationale for Choice of DCR as Primary Endpoint
In clinical studies, DCR is generally a reliable measure of anti-tumor activity that is not 
confounded by subsequent therapies. For the present study, the primary endpoint of DCR defined 
as CR + PR + SD > 6 months was selected based on its clinical relevance in this patient population 
and as such, its potential to inform medical practice. Given the potential for disease control with 
immunotherapy and the response rate observed with combined nivolumab and ipilimumab in 
CA209214, an optimal primary endpoint would capture both objective response and durable SD
that is more meaningful than the clinical benefit expected from second-line targeted therapies in 
this patient population. The DCR as defined for this protocol meets these criteria. Durable SD of 
6 months is clinically meaningful in these patients and discriminate between durable SD and slow 
disease progression. This definition of DCR has been used as primary endpoint to assess the 
clinical benefit of nivolumab and ipilimumab in melanoma metastatic to the brain.25
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5.4.4
Rationale for 2-year Duration of Treatment
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumor types in the nivolumab and ipilimumab development program 
indicate that most of the responses occur early, with a median time to response of 2 to 4 months, 
and emerging data suggest that benefit can be maintained in the absence of continued treatment. 
A recent analysis in a melanoma study suggests the majority of patients who discontinue 
nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of further 
treatment.30 Furthermore, a limited duration of ipilimumab, including only 4 induction doses, 
resulted in long-term survival in patients with metastatic melanoma, with a sustained plateau in 
survival starting around 2 years after the start of treatment.31
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
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and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 participants with non-small cell lung cancer [NSCLC]), specified a maximum 
treatment duration of 2 years. Among 16 participants with NSCLC who discontinued nivolumab 
after completing 2 years of treatment, 12 participants were alive > 5 years and remained 
progression free without any subsequent therapy. In the CA209003 NSCLC cohort, the OS curve 
begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.32 These 
survival outcomes are similar to Phase 3 studies in previously treated NSCLC, in which nivolumab 
treatment was continued until progression or unacceptable toxicity (2-year OS rates of 23% and 
29% and 3-year OS rates of 16% to 18% for squamous and non-squamous NSCLC, respectively).33
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized Phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
Q3W) versus docetaxel in participants with previously treated, PD-L1-positive, advanced NSCLC 
that specified a maximum treatment duration of 2 years for pembrolizumab. OS was significantly 
longer with both pembrolizumab 2 mg/kg (HR 0.72, P = 0.00017) and pembrolizumab 10 mg/kg 
(HR 0.60, P < 0.00001) compared to docetaxel, with an OS plateau developing beyond 2 years in 
both pembrolizumab arms. Among 690 patients who received pembrolizumab, 47 patients 
completed 2 years of pembrolizumab and stopped treatment. Most were able to maintain their 
response, including those with SD, with only 2 patients (4%) having confirmed progression after 
stopping at 2 years.34
Keynote-006 was a randomized Phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2-year duration of pembrolizumab 
treatment. One hundred four (19%) of 556 patients randomized to pembrolizumab completed 
2 years of treatment. With a median follow-up of 9 months after completion of pembrolizumab, 
the estimated risk of progression or death was 9% in these patients.35
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed 
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
PFS compared to those who were randomized to stop treatment, with median PFS 
(post-randomization) not reached versus 10.3 months, respectively; HR = 0.42 (95% CI, 0.25 to 
0.71). With a median follow-up of 14.9 months post randomization, there also was a trend for 
patients on continued treatment to live longer (OS HR = 0.63 [95% CI, 0.33, 1.20]). Of note, the 
PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.36
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Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond 2 years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 24 months from the start of study treatment.
5.5
Justification for Dose
5.5.1
Clinical Pharmacology Summary
Nivolumab pharmacokinetics (PK) was assessed using a population pharmacokinetic (PPK)
approach for both single-agent nivolumab and nivolumab with ipilimumab.
Nivolumab as a single agent: The PK of single-agent nivolumab was studied in patients over a 
dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab as 
a 60-minute IV infusion every 2 or 3 weeks. Nivolumab clearance (CL) decreased over time, with 
a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 24.5% 
(47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) 
in patients with metastatic tumors; the decrease in CLss was not considered clinically relevant. 
Nivolumab CL does not decrease over time in patients with completely resected melanoma, as the 
geometric mean population CL is 24% lower in this patient population compared with patients 
with metastatic melanoma at steady state. The geometric mean volume of distribution at steady 
state (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life is 25 days (77.5%). 
Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 
3 mg/kg Q2W, and systemic accumulation was 3.7-fold. The exposure to nivolumab increases 
dose proportionally over the dose range of 0.1 to 10 mg/kg administered Q2W. The predicted 
exposure (average concentration [Cavg] and maximum observed concentration [Cmax]) of 
nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion.
Nivolumab with ipilimumab: When nivolumab 1 mg/kg was administered in combination with 
ipilimumab 3 mg/kg, the CL of nivolumab was increased by 29%, and the CL of ipilimumab was 
unchanged compared to nivolumab administered alone. When nivolumab 3 mg/kg was 
administered in combination with ipilimumab 1 mg/kg, the CL of nivolumab and ipilimumab were 
unchanged. When nivolumab was administered in combination with ipilimumab, the presence of 
anti-nivolumab antibodies increased the CL of nivolumab by 20% and the CL of ipilimumab was 
unchanged in the presence of anti-ipilimumab antibodies.
Specific Populations: The PPK analysis suggested that the following factors had no clinically 
important effect on the CL of nivolumab: age (29 years to 87 years), weight (35 kg to 160 kg), 
gender, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment, 
and mild hepatic impairment. 
Renal Impairment: The effect of renal impairment on the CL of nivolumab was evaluated by a 
PPK analysis in patients with mild (estimated glomerular filtration rate [eGFR] 
60 mL/min/1.73 m2
to 
89 mL/min/1.73 m2), 
moderate 
(eGFR 
30 mL/min/1.73 m2
to 
59 mL/min/1.73 m2), or severe (eGFR 15 mL/min/1.73 m2
to 29 mL/min/1.73 m2) renal 
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impairment. No clinically important differences in the CL of nivolumab were found between 
patients with renal impairment and patients with normal renal function.
Hepatic Impairment: The effect of hepatic impairment on the CL of nivolumab was evaluated by 
PPK analyses in patients with hepatocellular carcinoma and in patients with other tumors with 
mild hepatic impairment (total bilirubin [TBili] less than or equal to the upper limit of normal 
[ULN] and AST greater than ULN or TBili greater than 1 to 1.5× ULN and any AST) and in
patients with hepatocellular carcinoma with moderate hepatic impairment (TBili greater than 1.5 to 
3× ULN and any AST). No clinically important differences in the CL of nivolumab were found 
between patients with mild/moderate hepatic impairment.
Full details on the clinical pharmacology aspects of nivolumab can be found in the IB.
5.5.2
Justification for Combination Nivolumab and Ipilimumab
In this study, nivolumab 3 mg/kg Q3W will be combined with ipilimumab 1 mg/kg Q3W for up 
to 4 cycles and then switched to nivolumab 480 mg Q4W during the maintenance phase 3 weeks 
after the last combination dose. At the first nivolumab 480 mg Q4W dose, ipilimumab 
concentrations from the combination dose will decline by 2-fold and would approximate 
ipilimumab concentrations to that of a 0.5-mg/kg Q3W ipilimumab dose. A prior study in 
advanced melanoma patients demonstrated acceptable safety and tolerability of a combination 
dosing regimen of nivolumab 6 mg/kg Q4W (body-weight based equivalent of 480 mg Q4W flat 
dose for an 80-kg subject) in combination with ipilimumab 1 mg/kg Q8W dosed continuously.37
This combined with prior exposure-response analysis in RCC, which demonstrated that nivolumab 
exposures when dosed with ipilimumab are not a significant predictor of IMAEs,38 suggest that no 
additional washout is warranted before starting the nivolumab 480 mg Q4W maintenance dose. 
Data in support of the nivolumab 3 mg/kg Q3W combined with ipilimumab 1 mg/kg Q3W regimen 
in RCC come from a Phase 2 clinical study (CA209016) and a Phase 3 clinical study (CA209214). 
Data from CA209016 demonstrated a level of clinical activity, as measured by ORR, for the 
combination of nivolumab combined with ipilimumab that was substantially greater than that of 
either nivolumab or ipilimumab monotherapy in mRCC. The dosing regimen including nivolumab 
3 mg/kg combined with ipilimumab 1 mg/kg was chosen because it exhibited similar clinical 
activity to nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg with a more favorable safety 
profile. 
In the Phase 3 clinical study (CA209214), the clinical benefit of OS was demonstrated in the 
intermediate/poor risk population (HR 0.63 [99.8% CI, 0.44 to 0.89])24 for the N3 Q3W combined 
with I1 Q3W regimen dosed for 4 cycles followed by N3 Q2W maintenance compared to sunitinib 
in first-line RCC.
6
STUDY POPULATION
Participants previously treated with combination regimen ipilimumab and nivolumab for advanced 
RCC and mRCC, who had an initial response of CR, PR or SD for at least 6 months and who had 
a confirmed progression on nivolumab maintenance.
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For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an Institutional Review Board (IRB)/Independent
Ethics Committee (IEC) approved written ICF 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) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American 
Joint Committee on Cancer Stage IV) RCC
b) Histological confirmation of RCC with a clear-cell component, including participants who 
may have sarcomatoid features
c) Investigator-assessed, per RECIST 1.1, disease progression on nivolumab maintenance 
after induction with ipilimumab and nivolumab and PR/CR or SD ≥6 months after starting 
initial induction treatment.
d) Measurable disease by CT or MRI per RECIST 1.1 criteria. Radiated lesions cannot be 
used as measurable lesions, unless there is clear evidence of progression.
e) KPS of at least 70% or higher.
f)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections, obtained at or after progression on initial nivolumab monotherapy maintenance, 
with an associated pathology report, must be submitted. Biopsy should be excisional, 
incisional, or core needle. Fine needle aspiration is unacceptable for submission. Biopsies 
of bone lesions that do not have a soft tissue component are also unacceptable for 
submission 
.
3) Age and Reproductive Status
a) Males and females, ages 18 or older.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding.  
d) WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for 
the duration of treatment with study treatment plus 5 half-lives of study treatment plus 
30 days (duration of ovulatory cycle) for a total of 5 months post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception and fetal protection (Appendix 4) for a total of 7 months
post-treatment completion. In addition, male participants must be willing to refrain from 
sperm donation during this time. 
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f)
Azoospermic males are exempt from contraceptive requirements unless the potential exists 
for fetal toxicity due to study drug being present in seminal fluid, even if the participant 
has undergone a successful vasectomy or if the partner is pregnant.  
g) WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements and must still 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 and, 
when applicable, the potential of fetal toxicity occurring due to transmission of study drug, present 
in seminal fluid, to a developing fetus, even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. Investigators shall advise on the use of highly effective 
methods of contraception, which have a failure rate of < 1% when used consistently and correctly 
(Appendix 4).
6.2
Exclusion Criteria
1) Medical Conditions
a) Any active central nervous system (CNS) metastases 
b) Any prior AE that meets the criteria for treatment discontinuation as described in 
Section 7.4.4, with the exception of patients with prior history of adrenal insufficiency that 
are under control with hormone replacement. 
c) Participants with treated CNS metastases for at least 1 month are eligible as long as they 
meet the following criteria:
i)
Treated CNS metastases are defined as having no ongoing requirement for 
corticosteroids for at least 2 weeks (14 days) prior to first dose and no evidence of 
progression after treatment completed prior to first dose, as ascertained by clinical 
examination and brain imaging (magnetic resonance imaging [MRI] or CT). Stable 
dose of anticonvulsants is allowed. Treatment for CNS metastases may include whole 
brain radiotherapy, radiosurgery (eg, radiosurgery, gamma knife, linear accelerator, or 
equivalent) or a combination as deemed appropriate by the treating physician.
d) Participants with an 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 (eg, celiac disease) 
are permitted to enroll. 
e) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of first dose. Inhaled or topical steroids and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune 
disease.
f)
Uncontrolled adrenal insufficiency
g) Active infection requiring systemic therapy within 14 days prior to the first treatment dose
h) Not applicable per revised protocol 01.
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i)
Participants with HIV infections are excluded if any of the following applies:
i)
CD4+ T-cell count < 350 cells/μL
ii) Any AIDS-defining opportunistic infection occurred in the last 12 months
iii) HIV viral load is ≥400 copies/mL
iv) Antiretroviral therapy has been administered at current doses for less than 4 weeks
v) The participant is not on antiretroviral therapy
j)
Participants with a history of chronic hepatitis B or C are excluded if any of the following 
applies:
i)
For participants with chronic hepatitis B: The HBV viral load is detectable.
ii) For participants with chronic hepatitis C: The HCV viral load is detectable.
k) Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study treatment.
l)
Radiotherapy within 4 weeks except palliative radiation to bone lesions, which requires 
2 weeks washout prior to the first dose of study treatment.
m) Prior malignancy (except for mRCC) active within the previous 3 years from screening 
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.  
n) Presence of any toxicities attributed to prior anticancer therapy, other than alopecia, that 
have not resolved to Grade 1 (National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] version 5.0) or baseline before administration of study 
treatment
o) Any condition including medical, emotional, psychiatric, or logistical that, in the opinion 
of the investigator, would preclude the participant from adhering to the protocol or would 
increase the risk associated with study participation or study drug administration or
interfere with the interpretation of safety results (eg, a condition associated with diarrhea 
or acute diverticulitis)
p) Women who are breastfeeding
2) Prior/Concomitant Therapy
a) Use of an investigational agent or an investigational device within 28 days before 
administration of first dose of study treatment 
b) Prior treatment with a VEGF-targeted agent except when used as a neoadjuvant or adjuvant 
therapy with recurrence > 6 months after the last dose of the therapy 
c) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to treatment. Refer to Section 7.7.1 for prohibited therapies. 
d) Participants who have received a live/attenuated vaccine within 30 days of first treatment.
i)
The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on 
study without restriction.
3) Physical and Laboratory Test Findings
a) White blood cells < 2,000/μL
b) Neutrophils < 1,500/μL
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c) Platelets < 100,000/μL
d) Hemoglobin < 9.0 g/dL 
e) Serum creatinine > 1.5× ULN, unless calculated creatinine clearance (CrCl) ≥40 mL/min 
(using the Cockroft-Gault formula):
Female CrCl = (140 - age in years) × weight in kg × 0.85
72 × serum creatinine in mg/dL
Male CrCl = (140 - age in years) × weight in kg × 1.00
72 × serum creatinine in mg/dL
f)
AST/ALT > 3.0× ULN (> 5× ULN if liver metastases are present)
g) TBili > 1.5× ULN (except participants with Gilbert syndrome, who must have a TBili level 
of < 3.0× ULN)
4) Allergies and Adverse Drug Reaction
a) Known history of allergy or hypersensitivity to study treatment components 
b) Known history of severe hypersensitivity reaction to any mAB
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and BMS 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
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently dosed in the study/included in the analysis population. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, as 
applicable, and to respond to queries from regulatory authorities. Minimal information includes 
date of consent, demography, screen failure details, eligibility criteria, and any SAEs.
6.4.1
Retesting During Screening or Lead-in Period
This study permits the re-enrollment of a participant who discontinued the study as a pre-treatment 
failure (ie, participant has not been treated). If re-enrolled, the participant must re-consent.
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).
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The most current result prior to treatment 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 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 investigational [medicinal] product (IP/IMP) and consists of the 
following (Table 7-1):
•
Nivolumab Solution for Injection
•
Ipilimumab Solution for Injection
An IP, also known as IMP in some regions, is defined as a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical study, including products 
already with a marketing authorization but used or assembled (formulated or packaged) differently 
than the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-IPs.
Table 7-1:
Study Treatments for CA20973M
Product 
Description / Class 
and Dosage Form
Potency
IP/Non-
IP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-936558 
(Nivolumab) 
Solution for 
Injection
10 mg/mL
IP
Open label
Vials
Refer to the label on 
container and/or 
Pharmacy Manual.
BMS-734016
(Ipilimumab)
Solution for 
Injection
5 mg/mL
IP
Open label
Vials
Refer to the label on 
container and/or 
Pharmacy Manual.
Abbreviations: IMP = investigational medicinal product; IP = investigational product.
Note: 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 the investigative sites if available and permitted by local 
regulations.
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7.1
Treatments Administered
Treatments should be administered according to Table 7.1-1.
Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to 
recalculate 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.
When study treatments (nivolumab and ipilimumab) are to be administered on the same day, 
nivolumab is to be administered first. Nivolumab infusion 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 treatment and will start after the infusion line has 
been flushed, the filters have been changed, and the participant has been observed to ensure no 
infusion reaction has occurred. 
There will be no dose increases or reductions of nivolumab allowed. Participants may be dosed no 
less than 19 days from the previous dose during Q3W cycles. For Q4W dosing cycles, participants 
may be dosed within a ± 3-day window. Premedications are not recommended for the first dose of 
nivolumab.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.5.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed. 
Treatment should be continued until disease progression or unacceptable toxicity, with a maximum 
nivolumab treatment of 24 months from the first dose in Cycle 1. 
Nivolumab injection, 100 mg/10 mL (10 mg/mL) is to be administered as a 30-minute IV infusion 
through a 0.2-μm to 1.2-μm pore size, low-protein binding in-line filter at the protocol-specified 
doses.39,40 It is not to be administered as an IV push or bolus injection. For instructions on storage, 
preparation, and administration of nivolumab, please refer to the current IB and/or pharmacy 
manual. Care must be taken to ensure sterility of the prepared solution, as the product does not 
contain any antimicrobial preservative or bacteriostatic agent.
For instructions on storage, preparation, and administration of ipilimumab, please refer to the 
current IB and/or pharmacy manual. 
Ipilimumab is to be administered as a 30-minute IV infusion and may be infused using a volumetric 
pump with a 0.2-μm to 1.2-μm low-protein binding in-line filter at the protocol-specified dose. It 
is not to be administered as an IV push or bolus injections. Care must be taken to ensure sterility 
of the prepared solutions, as the drug product does not contain any antimicrobial preservatives or 
bacteriostatic agents. At the end of the infusion, flush the line with a sufficient quantity of diluent.
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Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Dosage level(s) and 
Formulation
Frequency of 
Administration
Route of Administration
Nivolumab
3 mg/kg
480 mg
Q3W for 4 doses
Q4W (maintenance)
IV
Ipilimumab
1 mg/kg
Q3W for 4 doses
IV
Abbreviations: IV = intravenous; Q3W = every 3 weeks; Q4W = every 4 weeks
Note: After 4 doses of study treatment Q3W, participants receive nivolumab monotherapy. Monotherapy begins 
3 weeks after their last Q3W dose.
7.2
Method of Treatment Assignment
Not applicable.
7.3
Blinding
This is a non-randomized, open-label study; blinding procedures are not applicable.
7.4
Dosage Modification
I-O agents are associated with AEs that can differ in type, severity, and duration than AEs caused 
by other therapeutic classes. Nivolumab and ipilimumab are considered I-O agents in this protocol. 
Early recognition and management of AEs associated with I-O agents may mitigate severe toxicity. 
The safety profile of nivolumab and in combination of ipilimumab is described in the IB. 
Management of drug-related AE includes dose modification and medical interventions, and 
supportive care should be carefully considered. The recommended management algorithms for 
IMAE are outlined in Appendix 5 in the following groups: GI, Renal, Pulmonary, Hepatic, 
Endocrinopathy, Skin, and Neurological. In general, both nivolumab and ipilimumab have similar 
safety profiles and overlapping IMAEs. The management algorithms and criteria for dose delay, 
resumption, or discontinuation should be applicable for both drugs. Both drugs should be delayed, 
resumed, or discontinued when the criteria are met.
7.4.1
Dose Modifications
Dose reductions or dose increases of nivolumab or ipilimumab are not permitted.
7.4.2
Dose Delay Criteria
Nivolumab and ipilimumab administration should be delayed for the following:
•
Grade 2 nonskin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT, and/or TBili abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay.
−
Grade ≥3 AST, ALT, and/or TBili will require dose discontinuation (see Section 7.4.4).
•
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study medication
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During Cycles 1 to 4, both nivolumab and ipilimumab must be delayed at the same time.
Participants who require delay of study treatment should be re-evaluated weekly or more 
frequently if clinically indicated and resume study treatment dosing when retreatment criteria are 
met. Tumor and other assessments should continue as per protocol even if dosing is delayed.
7.4.3
Criteria to Resume Treatment
Delayed doses of study treatment should be administered as soon as the participant meets criteria 
to resume treatment. If a dose has been delayed, the participant should not wait until the next 
scheduled dosing date.
Participants may resume study treatment when the drug-related AEs resolve to Grade ≤1 or 
baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue. 
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
•
For participants with Grade 2 AST, ALT, and/or TBili abnormalities, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, has been 
completed.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS medical monitor or designee.
•
Participants with drug-related endocrinopathies that are adequately controlled with only 
physiologic hormone replacement may resume treatment.
7.4.4
Criteria for Treatment Discontinuation
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is an overlap among the discontinuation 
criteria, if the discontinuation criteria are met for ipilimumab but not for nivolumab, treatment 
with nivolumab may continue if ipilimumab is discontinued.
If a participant meets the criteria for discontinuation and the investigator is unable to determine 
whether the event is related to both or one study drug, the participant should discontinue both 
nivolumab and ipilimumab and be taken off the treatment phase of the study.
For participants who discontinue study treatment without documented disease progression, tumor 
and other assessments per protocol-defined schedule should be followed until initiation of another 
anti-cancer treatment, withdrawal of consent, or death, whichever occurs first. 
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7.4.4.1
Nivolumab Dose Discontinuation
Nivolumab treatment should be permanently discontinued for 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 retreatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, neurologic toxicity, drug-related uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related neurologic toxicity, uveitis, pneumonitis, bronchospasm, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 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
♦Grade ≥3 drug-related AST, ALT, or TBili requires discontinuation*
♦Concurrent AST or ALT > 3× ULN and TBili > 2× ULN
*In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. 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.
•
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or TBili), 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
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy AEs, such as, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (eg, corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS medical monitor.
•
Any event that leads to delay in dosing lasting > 10 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs 
−
Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-related 
reasons, if approved by the BMS medical monitor (or designee)
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Prior to re-initiating treatment in a participant with a dosing delay lasting > 10 weeks, the BMS 
medical monitor (or designee) must be consulted. Tumor and other assessments should continue 
per protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue Q3W during induction, Q4W during maintenance, or more frequently if 
clinically indicated during such dosing delays.
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, 
presents a substantial clinical risk to the participant with continued nivolumab dosing.
7.4.4.2
Ipilimumab Dose Discontinuation
Ipilimumab treatment should be permanently discontinued for 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 retreatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related AE 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.
−
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 abnormality that meets the following criteria 
require discontinuation:
o
Grade ≥3 drug-related AST, ALT, or TBili requires discontinuation*
o
Concurrent AST or ALT > 3× ULN and TBili > 2× ULN
*In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. 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.
•
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, and TBili), 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 AEs, such as hyper- or hypothyroidism or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (eg, corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS medical monitor.
•
Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. 
−
Dosing delays lasting > 8 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 > 8 weeks, the BMS 
medical monitor (or designee) must be consulted. Tumor and other assessments should continue 
per protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue Q3W during induction, Q4W during maintenance, or more frequently if 
clinically indicated during such dosing delays.
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the investigator, 
presents a substantial clinical risk to the participant with continued ipilimumab dosing.
7.4.5
Treatment of Infusion-related Reactions
Because nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they 
are unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other allergic-like reactions. Regardless of 
whether or not the event is attributed to the study drugs, all Grade 3 or 4 infusion reactions should 
be reported within 24 hours to the BMS medical monitor or designee and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to NCI CTCAE [version 5.0] 
guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
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 paracetamol (acetaminophen) 325 mg to 1,000 mg at least 30 minutes 
before additional study drug administrations.
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For Grade 2 symptoms - moderate reaction; requires therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, and 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 paracetamol (acetaminophen) 325 mg 
to 1,000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid 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 drug will be administered at that visit. Administer diphenhydramine 
50 mg IV, and remain at bedside and monitor the participant until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF). 
•
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol (acetaminophen) 325 mg to 
1,000 mg should be administered at least 30 minutes before additional study drug 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 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 mg to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 mg to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. 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 from 
symptoms. In the case of late-occurring hypersensitivity symptoms (eg, appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic treatment may 
be given (eg, oral antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that the IP is dispensed only to study participants. The IP must be 
dispensed only from official study sites by authorized personnel according to local regulations.
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The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed, and BMS should be contacted immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained and should include all 
processes required to ensure drug is accurately administered. This includes documentation of drug 
storage administration, and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents and administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride solution) will not be 
supplied by the Sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current version of the appropriate IB and/or pharmacy manual for complete 
storage, handling, dispensing, and infusion information for nivolumab and ipilimumab.
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
•
Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2 and the pharmacy manual.
7.5.1
Retained Samples for Bioavailability / Bioequivalence / 
Biocomparability
Not applicable.
7.6
Treatment Compliance
Not applicable because treatment is injected and/or infused.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.3)
•
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, nonpalliative radiation therapy, or standard or investigational agents)
•
Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment is permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally. 
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, or rubella) during treatment and until 100 days post last dose
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Antiemetic premedications should not be routinely administered prior to dosing of drugs. See 
Section 7.4.5 for premedication recommendations following a nivolumab- or ipilimumab-related 
infusion reaction.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose
are excluded. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent are permitted in the absence of active autoimmune disease.
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted after at 
least 1 postbaseline tumor assessment if it is clinically indicated.
7.7.2.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, and renal status), the appropriate imaging modality and 
contrast regimen per imaging study. Imaging contraindications and contrast risks are to be 
considered in this assessment. Participants with renal insufficiency are to be assessed as to whether 
or not they should receive contrast and, if so, which contrast agent and dose is appropriate. Specific 
to MRI, participants with severe renal insufficiency (ie, eGFR < 30 mL/min/1.73 m2) are at 
increased risk of nephrogenic systemic fibrosis; therefore, MRI contrast is contraindicated. In 
addition, participants may be excluded from MRI if they have tattoos, metallic implants, 
pacemakers, etc. This will be outlined in the image acquisition manual.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the investigator, and standards set by the local ethics committee.
7.7.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent are permitted. A brief (< 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of nonautoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. The use of 
inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on study without 
restriction.
Supportive care for disease-related symptoms may be offered to all participants on the study.
Concomitant medications are recorded at baseline and throughout the treatment phase of the study 
in the appropriate section of the CRF. All medications (prescriptions or over-the-counter 
medications) continued at the start of the study or started during the study and that are different 
from the study treatment must be documented in the concomitant therapy section of the CRF.
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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 as specified 
in 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 
occurs: a) the study is terminated due to safety concerns; b) the development of nivolumab 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
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a participant meets the criteria for discontinuation and the investigator is unable to determine 
whether the event is related to both or 1 study drug, the participant should discontinue both 
nivolumab and ipilimumab and be taken off the treatment phase of the study.
Participants MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information.
•
Any clinical AE, laboratory abnormality, or intercurrent illness that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, 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 Section 7.4.4.
•
Disease progression of RCC or occurrence of a secondary malignancy that requires systemic 
therapy for treatment
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Refer to the Schedule of Activities (Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS medical monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering, if 
necessary, for participant safety). Refer to Section 9.2.5. 
All participants who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in Section 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 CRF page.
8.1.1
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.10
Participants will be permitted to continue study treatment beyond initial RECIST 1.1-defined 
(Appendix 9) progressive disease, assessed by the investigator up to a maximum of 24 months 
from the date of first dose in Cycle 1, as long as they meet the following criteria:
•
Investigator-assessed clinical benefit
•
Tolerance of study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases).
•
Participant provides additional written informed consent prior to receiving additional study 
treatment. All other elements of the main consent, including description of reasonably 
foreseeable risks or discomforts or other alternative treatment options, will still apply.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the study and continue to receive monitoring according 
to Section 2. Radiographic assessment/scan(s) should continue in accordance with Section 2 and 
should be submitted to the central imaging vendor. 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.
For participants who continue nivolumab 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 diameters of new measurable lesions compared to the time of initial progressive disease. 
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It is recommended that study treatment should be discontinued permanently upon documentation 
of further progression.
New lesions are considered measurable 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 least 
15 mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and is 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 that become measurable, these new lesions must demonstrate an absolute increase of 
at least 5 mm.
8.1.2
Post Study Treatment Study Follow-up
Poststudy 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 (in this study or a rollover study) for collection of outcome and/or survival follow-up 
data as required and in line with Section 5.
Participants who discontinue study treatment may continue to be followed.
BMS may request that survival data be collected on all treated participants outside of the 
protocol-defined window (see Table 2-4). 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.
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8.3
Lost to Follow-up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of 
3 documented phone calls, faxes, or emails as well as lack of response by participant to 
1 registered mail letter. All attempts should be documented in the participant’s medical 
records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain the date and cause of death.
•
If the investigator’s use of a 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
•
Study procedures and timing are summarized in the Schedule of Activities (Section 2). 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before initiation of treatment. 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 laboratories until all study treatment-related toxicities resolve, return to baseline, or 
are deemed irreversible.
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If a participant shows pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, 
cough, fever) consistent with possible pulmonary AEs, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the nivolumab IB.
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 (Section 2).
9.1.1
Imaging Assessment for the Study
Images will be submitted to a central imaging vendor and may undergo BICR at any time during 
the study. Prior to scanning the first participant, sites should be qualified and understand the image 
acquisition guidelines and submission process as outlined in the CA20973M Imaging Manual 
provided by the central imaging vendor. 
Screening and on-study images should be acquired as outlined in the Schedule of Activities
(Section 2). 
Tumor assessments at other time points may be performed if clinically indicated and should be 
submitted to the central imaging vendor as soon as possible. Unscheduled CT/MRI should be 
submitted to central imaging vendor. X-rays and bone scans that clearly demonstrate interval PD, 
for example most commonly as unequivocal lesions that are unmistakably new since the prior 
CT/MRI, should be submitted to the central imaging vendor. Otherwise, they do not need to be 
submitted centrally.
9.1.1.1
Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known and/or suspected sites 
of disease should be performed for tumor assessments. Images should be acquired with slice 
thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
time points. Tumor measurements should be made by the same investigator or radiologist for each 
assessment, whenever possible. Changes in tumor measurements and tumor responses to guide 
ongoing study treatment decisions will be assessed by the same investigator using the RECIST 1.1 
criteria.
If a participant has a contraindication for CT IV contrast, then a non-contrast CT of the chest and 
a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of disease 
should be obtained. 
If a participant has a contraindication for both MRI and CT IV contrasts, then a non-contrast CT 
of the chest and a non-contrast MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. 
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If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT IV contrast, then a non-contrast CT of the chest, abdomen, pelvis, and other 
known/suspected sites of disease is acceptable.
Use of CT component of a PET-CT scanner: Combined modality scanning, such as with 
positron-emission tomography (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 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 1.1 measurements. However, if a site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast), then the CT portion of the PET-CT can be used for RECIST 1.1 measurements. 
Note, however, that the PET portion of the CT introduces additional data that may bias an 
investigator if it is not routinely or serially performed.
Bone scans or PET scans are not adequate for the assessment RECIST 1.1 response in target 
lesions. In selected circumstances where such modalities are the sole method used to assess certain 
non-target organs, those non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when CR is identified in target disease or when progression in 
bone is suspected.
Bone scans may be collected per local standards, as clinically indicated.
MRI of the brain (with and without contrast) should be acquired as outlined in Section 2. CT of 
the brain (without and with contrast) can be performed if MRI is contraindicated.
9.1.1.2
Imaging and Clinical Assessment
Tumor assessments should continue, as described in Section 2, even if dosing is delayed or 
discontinued. Changes in tumor measurements and tumor responses will be assessed by the same 
investigator using the RECIST 1.1 criteria. Investigators will report the number and size of new 
lesions that appear while on study. The time point of tumor assessments will be reported on the 
eCRF based on the investigator’s assessment using the RECIST 1.1 criteria (see Appendix 9) for 
specifics on RECIST 1.1 criteria to be used in this study. Assessments of PR and CR must be 
confirmed by CT/MRI at least 4 weeks apart after initial documentation of response. A best overall 
response (BOR) of SD requires a minimum of 56 days on study from the date of first dose to the 
date of the first imaging assessment.
9.1.2
Patient-reported Outcomes
Not applicable.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or caused the participant to 
discontinue before completing the study. 
IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which noninflammatory etiologies (eg, infection or tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology that were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s CRF.
Contacts for SAE reporting are specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Section 5.6 in the IB represents the Reference Safety Information to determine expectedness of 
SAEs for expedited reporting.
All AEs and SAEs must be collected from the time of signing the consent, including those thought 
to be associated with protocol-specified procedures for a minimum of 100 days after the last dose, 
except in cases where a study participant has started a new antineoplastic therapy. However, any 
SAE occurring after the start of a new treatment that is suspected to be related to study treatment 
by the investigator will be reported. For participants assigned to treatment and never treated with 
study drug, SAEs should be collected for 30 days from the date of first dose.
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 (eg, a follow-up skin biopsy).
•
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 module.
•
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours
of the updated information 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 the causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AEs and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known 
AEs, when appropriate for the program or protocol.
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All nonserious AEs and SAEs (not only those deemed to be treatment related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
after the last dose. 
Every AE must be assessed by the investigator with regard to whether it is considered an IMAE. 
For events that are potentially immune mediated, additional information will be collected on the 
participant’s CRF.
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.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities toward 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 IB and will notify the IRB/IEC, if appropriate according to local requirements.
The Sponsor or designee will report AEs to regulatory authorities and ethics committees according 
to local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
medical monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to the BMS designee within 24 hours of awareness of the event and in accordance with the SAE 
reporting procedures described in Appendix 3.
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If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS medical monitor/designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the
pregnancy
has ended), following approvals of the 
participant/Sponsor/IRB/EC, as applicable.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the Sponsor or designee. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (eg, vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner, the information should be reported to the Sponsor or 
designee, even if the male participant has undergone a successful vasectomy. In order for the 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner must sign an ICF for disclosure of this information. Information on the 
pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (electronic), as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that requires the participant to have the study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that requires the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than the laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug-induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (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).
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Potential DILI is defined as follows: 
1) AT (ALT or AST) elevation > 3× ULN
AND
2) TBili > 2× ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase)
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram 
(ECG), x-ray filming, any other potential safety assessment required or not required by the 
protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
9.3
Overdose
For this study, any accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important will be considered an overdose. All 
occurrences of overdose must be reported as SAEs (see Section 9.2).
In the event of an overdose the investigator should:
1) Contact the Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities.
3) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor, based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
9.4.1
Physical Examinations
Refer to the Schedule of Activities (Section 2).
9.4.2
Vital Signs
Refer to the Schedule of Activities (Section 2).
9.4.3
Electrocardiograms
Details regarding electrocardiograms are described in the Schedule of Activities (Section 2).
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9.4.4
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
Local laboratories will be used for the safety evaluations.
•
A local laboratory will perform the analyses and will provide reference ranges for these tests. 
The clinical laboratory assessments are indicated in Table 9.4.4-1. 
•
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.
•
Results of all laboratory tests required by this protocol must be provided to BMS, recorded 
either on the laboratory pages of the CRF or by another mechanism, as agreed upon between 
the investigator and BMS (eg, provided electronically). If the units of a test result differ from 
those printed on the CRF, the recorded laboratory values must specify the correct units. Any 
abnormal laboratory test result considered clinically significant by the investigator must be 
recorded on the appropriate AE page of the CRF (see Section 9.2.6).
Table 9.4.4-1:
Clinical Safety Laboratory Assessments
Hematology - Complete Blood Count
•
Hemoglobin
•
Hematocrit
•
Total leukocyte count, including differential
•
Platelet count
Urinalysis (screening only)
•
Creatinine
•
Protein
Chemistry
•
Aspartate aminotransferase (AST)
•
Albumin (screening only)
•
Alanine aminotransferase (ALT)
•
Sodium
•
Total bilirubin (TBili)
•
Potassium
•
Alkaline phosphatase (ALP)
•
Chloride
•
Lactate dehydrogenase (LDH)
•
Calcium
•
Creatinine
•
Corrected calcium (screening only)
•
Blood urea nitrogen (BUN) or serum urea
•
Phosphorus
•
Glucose
•
Magnesium
Serology
•
Hepatitis B/C (screening only)
(HBVsAg, HCV antibody or HCV RNA)
•
HIV, if mandated locally (see Appendix 8)
Other Analyses
•
Thyroid stimulating hormone (TSH) with free thyroxine (fT3) and free triiodothyronine (fT4) (screening only) 
•
TSH with reflexive fT3 and fT4
•
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG).
•
Follicle stimulating hormone (FSH) screening - only required to confirm menopause in women < age 55
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9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study investigator per standard 
medical/clinical judgment. 
9.5
Pharmacokinetics
Not applicable.
9.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7
Pharmacogenomics
Not applicable.
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The sample size of the study is based on a Simon 2-stage design that will test whether retreatment
with ipilimumab in combination with nivolumab in patients with mRCC progressing on 
maintenance nivolumab after first-line therapy with ipilimumab and nivolumab yields a DCR that 
is of clinical interest. 
In this study, a DCR in excess of 20% will be considered of clinical interest. The Simon design 
will test the null hypothesis that the true DCR is less than or equal to 20% versus the alternative 
hypothesis that it exceeds 20%. The type I error rate will be 5% for a 1-sided test and the design 
will have 85% power to reject the null hypothesis when the true DCR is 35%.
The Simon design in this study requires 27 response-evaluable patients for the first stage. The 
patients included in the first stage analysis will be followed for at least 2 scans approximately 
4 months after first dose. The enrollment will not be stopped during the first stage analysis so this 
relatively shorter follow-up period will be used in order to mitigate risk to patients being enrolled 
but not included in the first stage analysis. This analysis will quantify patients without progression. 
For example, confirmed responders, patients with unconfirmed response without progression, and 
patients with SD on consecutive scans would all qualify as having disease control. If there are 
exactly 27 patients in the first stage, then 7 or more of these patients, or at least 26%, will warrant 
proceeding to the second stage. Otherwise, enrollment will be stopped. 
The enrollment will stop when either futility is declared at Stage 1 or once approximately 
80 response-evaluable participants have been treated. Approximately 96 participants will be 
enrolled in order to obtain 80 response-evaluable patients, accounting for approximately 20% of 
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non-evaluable patients or withdrawal. The number of enrolled participants with SD ≥6 months 
will be capped at 50%. 
The duration of the trial is expected to be approximately 24 months of treatment (Stage 1 + 
Stage 2) and 36 months of follow-up after the last participant first dosing. A futility analysis will 
be performed after Stage 1 and the primary analysis will be conducted upon completion of Stage 2.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent and were registered into the IRT
Response 
Evaluable
All participants with baseline and at least 1 on-study tumor assessment who received at 
least 1 dose of study treatment. Analysis of demography, protocol deviations, baseline 
characteristics, and efficacy will be performed on this population.
Safety
All participants who take at least 1 dose of study treatment. This is the primary dataset for 
drug exposure and safety analysis.
Abbreviation: IRT = interactive response technology. 
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender, and race.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
DCR is defined as the proportion of participants who achieve a confirmed best response of 
CR, PR, or SD for at least 6 months after first treatment dose using the RECIST 1.1. 
The number and percentage of participants in each category of BOR (CR, PR, SD, PD, or 
UTD) as per RECIST 1.1 criteria will be presented. An estimate of the response rate and an 
associated exact 2-sided 95% CI (Clopper and Pearson) will be presented.
Secondary
OS is defined as the time from first dose date to the date of death from any cause. For 
participants that are alive, their survival time will be censored at the date of last contact (“last 
known alive date”). OS will be censored for participants at the date of first dose if they were 
treated but had no follow-up.
A similar analysis as in PFS will be conducted for OS.
ORR is defined as the proportion of participants who achieve a best response of CR or PR 
using the RECIST1.1 criteria.
DOR is defined as the time between the date of first documented confirmed response (CR or 
PR) to the date of the first documented progression as per RECIST 1.1 or death due to any 
cause, whichever occurs first. For participants who neither progress nor die, the DOR will be 
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Endpoint
Statistical Analysis Methods
censored at the same time they will be censored for the primary definition of PFS. DOR will 
be evaluated for responders (ie, participants with confirmed CR or PR) only.
The primary definition of PFS is specified as the time between the date of first dose and the 
first date of documented progression as per RECIST 1.1 criteria or death due to any cause, 
whichever occurs first. Participants who die without a reported progression will be considered 
to have progressed on the date of their death. The following censoring rules will be applied 
for the primary definition of PFS.
•
Participants who did not progress or die will be censored on the date of their last 
evaluable tumor assessment.
•
Participants who did not have any on-study tumor assessments and did not die will be 
censored on their date of first dose.
•
Participants who receive subsequent systemic anticancer therapy prior to documented 
progression will be censored at the date of the last tumor assessment prior to the 
initiation of the new therapy. 
Median PFS will be estimated via the Kaplan-Meier product limit method. Two-sided 95% 
CI for the median PFS will be computed. Kaplan-Meier plots of PFS will be presented. The 
totality of PFS results will be presented in a single graphical display that includes the 
Kaplan-Meier curve and the median estimate and corresponding CIs.
The secondary definition of PFS is defined as the time between the date of first dose and the 
first date of documented progression as per RECIST 1.1 criteria or death due to any cause, 
whichever occurs first. Participants who die without a reported progression will be considered 
to have progressed on the date of their death. The following censoring rules will be applied 
for the secondary definition of PFS.
•
Participants who did not progress or die will be censored on the date of their last 
evaluable tumor assessment.
•
Participants who did not have any on-study tumor assessments and did not die will be 
censored on their date of first dose.
PFS based on investigator assessments will also be analyzed applying both the primary and 
the secondary definitions.
More detail on PFS will be provided in a separate Statistical Analysis Plan.
TTR is defined as the time from first dose date to the date of the first confirmed documented 
response (CR or PR) per RECIST 1.1 criteria. TTR will be evaluated for responders among 
the population of interest (ie, participants with a BOR of CR or PR).
Abbreviations: BOR = best overall response; CI = confidence interval; CR = complete response; DOR = duration of 
response; OS = overall survival; PFS = progression-free survival; PR = partial response; RECIST 1.1 = Response 
Evaluation Criteria In Solid Tumors version 1.1; SD = stable disease; TTR = time to objective response; 
UTD = unable to determine
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10.3.2
Safety Analyses
All safety analyses for nivolumab will be performed on the Safety Sample.
Endpoint
Statistical Analysis Methods
Secondary
The safety analysis will be performed in all treated participants. Descriptive statistics of safety 
will be presented using the NCI CTCAE version 5.0 by treatment arm. All AEs, drug-related AEs, 
SAEs, and drug-related SAEs will be tabulated using the worst grade per NCI CTCAE version 5.0 
criteria by system organ class and preferred term. On-study laboratory parameters including 
hematology, chemistry, liver function, and renal function will be summarized using worst grade 
per NCI CCAE version 5.0 criteria.
AE incident rate is defined as the proportion of participants with any grade AEs among treated 
participants. Events reported from the first dose and up to and including 100 days following the 
last dose of study treatment could be included in estimating this incidence rate.
Abbreviations: AE = adverse event; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; SAE = serious adverse event
10.3.3
Pharmacokinetic Analysis
Not applicable.
10.3.4
Other Analyses 
10.3.4.1
Immunogenicity
Not applicable.
10.3.4.2
Outcomes Research Analyses
Not applicable.
10.3.5
Interim Analyses 
A futility analysis will be performed after Stage 1 based on a Simon 2-stage design.
•
In Stage 1, 27 response-evaluable patients will be enrolled and a futility analysis will be 
performed.
•
In Stage 2 (if Stage 1 positive), 53 response-evaluable more patients will be enrolled.
If there are exactly 27 patients in the first stage, then 7 or more of these patients, or at least 26%, 
will warrant proceeding to the second stage. Otherwise, enrollment will be stopped. 
The Statistical Analysis Plan will further describe the planned interim analyses.
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REFERENCES
1
Gul A, Shah NJ, Mantia C, Hammers HJ, Ornstein MC, Mcdermott DF, et. al. Ipilimumab plus 
nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory 
metastatic 
renal 
cell 
carcinoma 
(mRCC). 
J 
Clin 
Oncol 
2019;37(7 Suppl):669. 
DOI: 10.1200/JCO.2019.37.7. 
2
Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol 
2003;21:807-39.
3
Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol 2006;6(10):715-27.
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Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol 2002;3(11):991-8.
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
6
Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000;192(7):1027-34. 
7
Selby MJ, Engelhardt JJ, Johnston RJ, et al. Preclinical development of ipilimumab and 
nivolumab combination immunotherapy: mouse tumor models, in vitro functional studies, and 
cynomolgus macaque toxicology. PLoS One 2016;11(9):e0161779.
8
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15(23):7412-20.
9
Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J 2012;18(2):153-9.
10 Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands 
infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. 
Proc Natl Acad Sci U S A 2010;107(9):4275-80.
11 Robert C, Schadendorf D, Messina M, et al. Efficacy and safety of retreatment with ipilimumab 
in patients with pretreated advanced melanoma who progressed after initially achieving disease 
control. Clin Cancer Res 2013;19(8):2232–9.
12 Lebbe C, Weber JS, Maio M, et al. Survival follow-up and ipilimumab retreatment of patients 
with advanced melanoma who received ipilimumab in prior phase II studies. Ann Oncol 
2014;25(11):2277-84.
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13 Chiarion-Sileni V, Pigozzo J, Asciento PA, et al. Ipilimumab retreatment in patients with 
pretreated advanced melanoma: the expanded access programme in Italy. Br J Cancer 
2014;110(7):1721–6.
14 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7-30.
15 Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns 
in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49(6):1374-403.
16 Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating 
socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 
2011;61(4):212-36.
17 Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients 
with advanced renal cell carcinoma. J Clin Oncol 1999;17(8):2530-40.
18 Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with 
metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: 
results from a large, multicenter study. J Clin Oncol 2009;27(34):5794-9.
19 Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of 
the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a 
population-based study. Lancet Oncol 2013;14(2):141-8.
20 BMS-936558: A randomized, blinded, Phase 2 dose-ranging study of nivolumab (MDX-1106, 
BMS-936558) in subjects with progressive advanced/metastatic clear-cell renal cell carcinoma 
(RCC) who have received prior anti-angiogenic therapy; Final Clinical Study Report for 
Study CA209010. Bristol-Myers Squibb Company; 2013. Document Control No.
. 
21 BMS-734016: A Phase 2 open-label study of single agent ipilimumab for the treatment of IL-2 
refractory or IL-2 ineligible patients with stage IV renal cancer; Final Clinical Study Report 
for MDX010-11. Bristol-Myers Squibb Company; 2008. Document Control No.
.
22 Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression 
of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 
2007;30(8):825-30.
23 BMS-936558: A phase 1 study of nivolumab (BMS-936558) plus sunitinib, pazopanib or 
ipilimumab in subjects with metastatic renal cell carcinoma; Final Clinical Study Report for 
Study CA209016. Bristol-Myers Squibb Company; 2016. Document Control No. 
. 
24 BMS-936558: A phase 3, randomized, open-label study of nivolumab combined with 
ipilimumab versus sunitinib monotherapy in subjects with previously untreated, advanced or 
metastatic renal cell carcinoma; Final Clinical Study Report for Study CA209214. 
Bristol-Myers Squibb Company; 2017. Document Control No.
.
25 Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma 
metastatic to the brain. N Engl J Med 2018;379(8):722-30.
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30 Schadendorf D, et al. Efficacy and quality of life outcomes in patients with advanced 
melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) 
due to toxicity in a phase III trial (CheckMate 067). 2016 Annual Meeting of the European 
Association of Dermato-Oncology; August 31-September 3, 2016; Vienna, Austria.
31 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase 
II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 
2015;33(17):1889-94.
32 Brahmer J, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously 
treated advanced non-small cell lung cancer: clinical characteristics of long-term survivors. 
Oral presentation presented at: American Association for Cancer Research (AACR) Annual 
Meeting; April 1-5, 2017; Washington, DC, USA.
33 Felip E, et al. Three-year follow-up from Checkmate 017/057: Nivolumab versus docetaxel in 
patients with previously treated advanced non-small lung cancer (NSCLC). Poster discussion 
presentation at the European Society of Medical Oncology Annual Meeting. 2017 Sep 8-12; 
Madrid, Spain.  Poster 1301PD.
34 Herbst RS, et al. KEYNOTE-010: Durable clinical benefit in patients with previously treated, 
PD-L1-expressing NSCLC who completed pembrolizumab. Poster presentation at the World 
Conference on Lung Cancer 2016 Dec 4-7; Vienna, Austria.
35 Robert C, Long GV, Schachter J, et al. Long-term outcomes in patients with ipilimumab-naive 
advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab 
treatment; J Clin Oncol. 2017;35:15_suppl, 9504-9504.
36 Spigel DR, McLeod M, Hussein MA, et al. Randomized results of fixed-duration (1-yr) vs 
continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC). 
Ann Oncol. 2017;28(suppl 5):v460-v496.
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37 BMS-936558: Phase IIIB/IV, randomized, double blinded study of nivolumab 3 mg/kg in 
combination with ipilimumab 1 mg/kg vs nivolumab 1 mg/kg in combination with ipilimumab 
3 mg/kg in subjects with previously untreated, unresectable or metastatic melanoma; Final 
Clinical Study Report for Study CA209511. Bristol-Myers Squibb Company; 2018. Document 
Control No. 
.
38 BMS-936558: Exposure-response analyses in subjects with renal cell carcinoma (RCC) treated 
with nivolumab as monotherapy or in combination with ipilimumab; Integrated 
Pharmacometric Analysis Report for Nivolumab/Ipilimumab (BMS-936558/BMS-734016). 
Bristol-Myers Squibb Company; 2017. Document Control No.
.
39 Long GV, Tykodi SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical 
safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol 
2018;29(11):2208-13. 
40 Waterhouse D, Horn L, Reynolds C, et al. Safety profile of nivolumab administered as 30-min 
infusion: analysis of data from CheckMate 153. Cancer Chemother Pharmacol 
2018;81(4):679-86.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BICR
blinded independent central review
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BTLA
B- and T-lymphocyte attenuator
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CL
clearance
CLss
steady-state clearance
CMV
cytomegalovirus
CNS
central nervous system
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CT
computed tomography
CTC
common terminology criteria
 
CTLA-4
cytotoxic T-lymphocyte-associated antigen 4
CV%
% coefficient of variation
DILI
drug-induced liver injury
DOR
duration of response
DCR
disease control rate
ECG
electrocardiogram
eCRF
electronic case report form
eg
exempli gratia (for example)
eGRF
estimated glomerular filtration rate
 
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
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Term
Definition
fT3
free thyroxine
fT4
free triiodothyronine
GI
gastrointestinal
HBVsAg
hepatitis B virus antigen
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICOS
inducible co-stimulator
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
IMAE
immune-mediated adverse event
IMDC
International Metastatic RCC Database Consortium
IMP
investigational medicinal product
I-O
immuno-oncology
IP
investigational product
IRB
Institutional Review Board
IRRC
Independent Regulatory Review Commission
IRT
interactive response technology
ITSM
immunoreceptor tyrosine-based switch motif
I1
ipilimumab 1 mg/kg
I3
ipilimumab 3 mg/kg
IV
intravenous
IVRS
interactive voice response system
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase
 
mRCC
metastatic renal cell carcinoma
MRI
magnetic resonance imaging
MSKCC
Memorial Sloan-Kettering Cancer Center 
MTD
maximum tolerated dose
n
number of subjects or observations
N1
nivolumab 1 mg/kg
N3
nivolumab 3 mg/kg
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Term
Definition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
non-small cell lung cancer
OS
overall survival
ORR
objective response rate
PD
progression of disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death protein ligand-1
PD-L2
programmed cell death protein ligand-2
PET
positron-emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PPK
population pharmacokinetic
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
R&D
research and development
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria In Solid Tumors version 1.1
RNA
ribonucleic acid
SAE
serious adverse event
SD
stable disease
TBili
total bilirubin
TSH
thyroid stimulating hormone
TTR
time to objective response
ULN
upper limit of normal
US
United States
UTD
unable to determine
VEGF
vascular endothelial growth factor
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term “Participant” is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term “Subject” used in the eCRF 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 f or 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 Sponsor or designee immediately. A breach of 
the conditions and principles of Good Clinical Practice (GCP) (occurring in any country) in 
connection with that trial or the protocol related to the trial which is likely to affect to a significant 
degree the safety or physical or mental integrity of 1 or more subjects of the trial or the scientific 
value of the trial.
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. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator’s Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor, or designee should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s), the deviation or change will be submitted, as 
soon as possible, to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given by subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
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.
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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 nontechnical 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, 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 must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant 
must also be 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 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 are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are handwritten on paper or entered 
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electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic 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 nivolumab or ipilimumab (whether supplied by BMS, its vendors, or 
the site) must substantiate study treatment integrity and traceability from receipt, preparation, 
administration, and through destruction or return. Records must be made available for review at 
the request of BMS/designee or a Health Authority.
If
Then
Supplied 
by 
BMS 
(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, 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 treatment integrity in 
accordance with requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
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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.
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. 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.
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.
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The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (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. 
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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.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Other criteria (as determined by the study team)
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or results 
from other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator.
Note that abnormal lab tests or other safety 
assessments should only be reported as AEs if the final diagnosis is not available. Once the 
final diagnosis is known, the reported term should be updated to be the diagnosis.
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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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: 
• a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event)
• elective surgery, planned prior to signing consent
• admissions as per protocol for a planned medical/surgical procedure
• routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
• medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases
• admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
• 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
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see Section 9.2.5 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
• The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
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• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
• The investigator will use clinical judgment to determine the relationship.
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
• There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
• The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
• SAEs, whether related or not related to study treatment, and pregnancies must be reported to 
BMS (or designee) immediately within 24 hours of awareness of the event.
• SAEs must be recorded on the SAE Report Form.
−The required method for SAE data reporting is through the eCRF.
−The paper SAE Report Form is only intended as a back-up option when the electronic data 
capture (EDC) system is unavailable/not functioning for transmission of the eCRF to BMS 
(or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
• Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming 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 
• Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−oral 
−injectable 
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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 Methods of Contraception*
• Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
• Diaphragm with spermicide
• Cervical cap with spermicide
• Vaginal Sponge with spermicide
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
• Periodic abstinence (calendar, symptothermal, post-ovulation methods)
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• 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 3, Adverse Events and Serious 
Adverse Events: Definitions and Procedures for Evaluating, Follow-up and Reporting. 
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APPENDIX 5
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 7
PERFORMANCE STATUS SCALES
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-ECOG-
WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal activities Minor 
signs or symptoms of disease
90
0
Symptoms, but fully 
ambulatory
Normal activity with effort
80
1
Cares for self. Unable to carry on normal 
activity or to do active work
70
1
Symptomatic, but in 
bed < 50% of the day.
Requires occasional assistance, but able to 
care for most of his needs
60
2
Requires considerable assistance and 
frequent medical care
50
2
Needs to be in bed 
> 50% of the day, but 
not bedridden
Disabled. Requires special care and 
assistance
40
3
Severely disabled. Hospitalization 
indicated though death non imminent
30
3
Unable to get out of 
bed
Very sick. Hospitalization necessary. 
Active supportive treatment necessary
20
4
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 8
COUNTRY SPECIFIC REQUIREMENTS
Any Countries Where Exclusion of HIV Positive Participants Is Locally Mandated
Country-specific language
Section 2 Flow Chart/Time and Events
Schedule, Table 2-1: Screening
Assessments- LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 1.a
“Known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS)”to be 
replaced with “Positive test for HIV”.
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APPENDIX 9
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline 
.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2× slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
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default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 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 one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
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if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
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FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response;
SD = stable disease 
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; SD = stable disease
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided 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
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR 
(eg, CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of 
a previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47
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