An Open-Label, Randomized, Phase 2 Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma
Phase: PHASE2
Conditions: Advanced or Metastatic Melanoma
Sponsor: Bristol-Myers Squibb



nivolumab
CA209064
BMS-936558
Clinical Protocol
Revised Protocol No.: 01
2
Date: 28-Mar-2013
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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nivolumab
CA209064
BMS-936558
Clinical Protocol
SYNOPSIS
Clinical Protocol CA209064
Protocol Title: CA209-064: An Open-Label, Randomized, Phase 2 Study of Nivolumab Given Sequentially with 
Ipilimumab in Subjects with Advanced or Metastatic Melanoma (CheckMate 064:  CHECKpoint pathway and 
nivoluMAb clinical Trial Evaluation 064)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nivolumab (BMS-936558) at 3 mg/kg every 2 weeks for up to 6 doses in Induction Period. Ipilimumab 
at 3 mg/kg every 3 weeks for up to 4 doses in Induction Period. Nivolumab at 3 mg/kg every 2 weeks in 
Continuation Period until progression, unacceptable toxicity, or withdrawal of consent, for a maximum duration of 
2 years from first study treatment in Induction Period 1.  
Study Phase: 2
 
 
Objectives:
Primary Objective: 
•
To evaluate the incidence of treatment-related Grade 3 - 5 AEs during the Induction Period in subjects receiving 
sequential induction treatment with either nivolumab followed by ipilimumab or ipiliumuab followed by 
nivolumab
Secondary Objectives:
•
To evaluate the response rate at Week 25 in subjects receiving sequential induction treatment with either 
nivolumab followed by ipilimumab or ipilimumab followed by nivolumab
•
To evaluate progression rates at Week 13 and Week 25 in subjects receiving sequential induction treatment with 
either nivolumab followed by ipilimumab or ipilimumab followed by nivolumab
Study Design:
This is an open-label, randomized, Phase 2 study of two schedules of nivolumab given sequentially with 
ipilimumab, in adult (≥18 years old) male and female subjects with advanced (unresectable Stage III) or metastatic 
(Stage IV) melanoma. Approximately 80 subjects will be randomized (1:1) to receive one of two dosing schedules 
(Cohort A or B). Randomization will stay open until at least 40 subjects in each Cohort have been treated with at 
least one dose of study treatment in Induction Period 1 and 35 subjects in each Cohort have received at least one 
dose of study treatment in Induction Period 2. 
Subjects may be treatment-naive or have experienced disease recurrence or progression after one prior systemic 
therapy (prior immunotherapy with anti-PD1 or anti-CTLA-4 is prohibited). The two dosing schedules to be 
explored are presented in Figure 1.
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Clinical Protocol
•
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
•
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical 
steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the 
absence of active autoimmune disease.
•
Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
•
Subjects who received prior treatment with other immunotherapies (eg, antibodies, vaccines, adoptive T-cell 
transfer), must have experienced disease progression at least 6 weeks prior to first dose of study treatment and, 
with the exception of IL-2 or adjuvant interferon, must be discussed and approved by the Medical Monitor prior 
to signing informed consent
•
Prior therapy with BRAF inhibitor (eg, vemurafenib)
Study Assessments & Endpoints: The primary endpoint of the study is the rate of treatment-related Grade 3-5 AEs 
during the Induction Period (Periods 1 and 2) in subjects receiving sequential induction treatment with either 
nivolumab followed by ipilimumab or ipilimumab followed by nivolumab. 
The treatment-related Grade 3 - 5 AEs rate is defined as number of subjects who experienced at least 1 treatment 
related Grade3 - 5 adverse event (per NCI CTCAE v 4.0 criteria, any PT terms) with an onset date after or on first 
day of the induction period and not later than discontinuation date from the Induction Period, divided by number of 
treated subjects. AEs with an onset date after start of subsequent anti-cancer therapy, or start date of Continuation 
Period treatment will not be included. For subjects who discontinue Induction Period early and enter the Follow-Up 
Period, AEs that occur in Follow-Up, including those before Week 25, will not be included in the primary endpoint. 
For subjects who discontinue treatment before the end of Induction Period 1 or 2 but who are eligible to enter the 
next study period, AEs that occur before end of Induction Period 2 will be included in the primary endpoint, even if
they occur after dosing ends while they are waiting to enter the next study period.
The secondary endpoints are Response Rate at Week 25 and Progression Rates at Weeks 13 and 25. Subjects will be 
assessed for response via tumor assessments (CT or MRI) prior to dosing at Weeks 13, 25, 33, 41, 49 (+/- 1 weeks) 
and then every 12 weeks. Response rate at Week 25 is defined as the number of subjects who have a complete 
response (CR) or partial response (PR) at Week 25 (regardless of the tumor assessment at Week 13), with 
confirmation at scheduled scan at Week 33, divided by the total number of randomized subjects. Progression rates at 
Weeks 13 and 25 are defined as the number of subjects who have Progressive Disease (PD) per RECIST 1.1 at the 
specific timepoint (Week 13 or Week 25) divided by the total number of randomized subjects.
Statistical Considerations:
Sample Size: This trial is an estimation trial. Sample size in this study will be approximately 40 subjects per cohort 
and is not based on power considerations. Tables below provide the 95% confidence intervals computed from 
different observed rates. Those tables indicate what would be the reliability of the AE rate estimates for N=40 
(Table 8.1-1) and N=35 (Table 8.1-2) treated subjects. A threshold of 45% will be applied to the upper limit of the 
confidence interval as an informal guideline for high toxicity 
Thirty-five subjects per cohort will be the minimum number of subjects receiving treatment in Induction Period 2. 
For that purpose, randomization will stay open until at least 40 subjects in each cohort have been treated with at least 
one dose of study treatment in Induction Period 1 and 35 subjects in each cohort have received at least one dose of 
study treatment in Induction Period 2. Assuming a drop-out rate during induction period 1 would be at most 12.5%, 
at least 35 subjects would be treated in induction period 2 if 40 subjects are to be randomized per cohort.
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Analyses:
Primary analysis:
Rate of treatment-related Grade 3-5 AEs during the induction period will be computed by treatment cohort using all 
treated subjects. Corresponding 95% CIs will be calculated using the Clopper-Pearson method. As sensitivity 
analysis, rates and 95% CI will be also computed using the subset of subjects who received at least one dose of 
study treatment in Induction Period 2.
Secondary analyses:
Response rate at Week 25 will be computed by treatment arm using all randomized subjects. Response rate
estimates and corresponding 95% CIs will be calculated using the Clopper-Pearson method. Response rates
including only those subjects who had a tumor assessment at Week 25 will also be computed. Duration of response 
from Week 25 will be assessed for subjects with confirmed response at Week 25. Median DOR estimate and 
corresponding 95% CIs will be provided for each sequential induction regimen using the Kaplan-Meier 
methodology. Progression rate estimates at Week 13 and Week 25 along with corresponding 95% CIs will be 
calculated using the Clopper-Pearson method. 
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10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 2 GUIDANCE ON CONTRACEPTION ................................................. 
91
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101
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Clinical Protocol
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Clinical Protocol
 
 
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
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, subject 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 Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS 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.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate. 
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BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
•
Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
•
Obtain an informed consent signed and personally dated by the subject or the subject'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 subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
•
Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject'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 subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open-label, randomized Phase 2 study of two schedules of nivolumab given 
sequentially with ipilimumab, in adult (≥18 years old) male and female subjects with advanced 
(unresectable Stage III) or metastatic (Stage IV) melanoma. Approximately 80 subjects will be 
randomized (1:1) to receive one of two dosing schedules (Cohort A or B). 
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Induction Period 2 must be reviewed to determine if the subject meets any of the exception 
criteria in Section 3.1.2.3. During the Continuation Period, each tumor assessment must be 
reviewed before the next dose of nivolumab can be given.
In the Continuation Period, subjects will be permitted to continue nivolumab treatment beyond 
initial RECIST 1.1-defined progression if they are assessed by the investigator to be deriving 
clinical benefit, are tolerating study treatment, and provide informed consent (see Section 4.3.5). 
Such subjects should discontinue study treatment upon evidence of further progression.
This study will consist of 3 phases: Screening, Treatment (Induction Period 1, Induction 
Period 2, and Continuation Period), and Follow-Up.
3.1.1
Screening
•
Begins by establishing subject’s initial eligibility and signing of the informed consent.).
•
Subject is enrolled using the Interactive Voice Response System (IVRS). This study permits 
the re-enrollment of a subject that has discontinued the study as a pre-treatment failure 
(ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must 
be re-consented.
•
Subject is assessed for complete study eligibility within 28 days prior to randomization 
(Table 5.1-1).
•
Subjects meeting all eligibility criteria must undergo a fresh tumor biopsy (Section 5.6.1), 
ECG, and whole blood collection for SNP assessment.
3.1.2
Treatment Phase (Induction Period 1, Induction Period 2, Continuation 
Period)
•
Begins with the randomization call to the IVRS. The subject is randomly assigned to either 
Cohort A or Cohort B.
•
Doses of either nivolumab or ipilimumab may be omitted if there is an AE which precludes 
treatment at a scheduled treatment visit (Section 4.3.4.1). Treatment may resume at the next 
scheduled dose if retreatment criteria (specified in Section 4.3.4.2) are met.
•
Dose interruptions will be allowed for infusion reactions, according to guidelines in Section 
4.3.4.3.
•
Tumor biopsies (Section 5.6.1) must be performed at Week 13 and time of disease 
progression, unless the designated lesion(s) have responded during study treatment and are 
no longer accessible for biopsy.
•
Treatment Phase ends when subject completes or discontinues all study dosing.
3.1.2.1
Induction Period 1 
•
Induction Period 1 begins at Week 1, Day 1. Induction Period 1 is the first 12 weeks of study 
treatment (Week 1 to Week 13). Subjects must receive the first dose of study treatment 
within 3 working days following randomization.
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Subjects in Cohort A will receive nivolumab at a dose of 3 mg/kg as a 60 minute IV 
infusion every 2 weeks (14 days) for up to 6 doses. 
-
Subjects in Cohort B will receive ipilimumab at a dose of 3 mg/kg as a 90 minute IV 
infusion every 3 weeks (21 days) for up to 4 doses.
•
Study assessments will be conducted as outlined in Table 5.1-2 and Table 5.1-3. 
•
Tumor biopsies (Section 5.6.1) must be performed prior to dosing at Week 13, unless the 
designated lesion(s) have responded during study treatment and are no longer accessible for 
biopsy.
•
All subjects must have tumor assessment performed at Week 13 (prior to the first dose in 
Induction Period 2). This includes any subject who may have discontinued treatment prior to 
receiving all planned Induction Period 1 doses.
•
Subjects who have clinical or radiographic progressive disease prior to the completion of 
Induction Period 1 are to remain on their current study treatment for the remainder of 
Induction Period 1, provided they are tolerating study treatment and do not have rapid 
clinical deterioration. 
•
Subjects who do not receive all planned doses in Induction Period 1, including those who 
discontinue Induction Period 1 treatment early due to progression or discontinuation criteria 
(Section 4.3.6.2), are to continue their scheduled study assessments (as per Table 5.1-2 and 
Table 5.1-3) and are still eligible to receive the alternative treatment in Induction Period 2, 
starting at Week 13.
•
After completion of Induction Period 1, subjects will proceed to Induction Period 2, 
regardless of the results of the tumor assessment at the end of Induction Period 1.
3.1.2.2
Induction Period 2
•
Induction Period 2 begins at Week 13 and continues to Week 25.
−
Subjects in Cohort A will receive ipilimumab at a dose of 3 mg/kg as a 90 minute IV 
infusion every 3 weeks (21 days) for up to 4 doses. 
−
Subjects in Cohort B will receive nivolumab at a dose of 3 mg/kg as a 60 minute IV 
infusion every 2 weeks (14 days) for up to 6 doses. 
•
Subjects with drug-related AEs after the last dose in Induction Period 1 who fail to meet 
retreatment criteria (Section 4.3.4.2) at Week 13 will still begin Induction Period 2 at Week 
13 and require omission of the initial dose(s) in Induction Period 2 until retreatment criteria 
are met. 
•
Study assessments will be conducted as outlined in Table 5.1-2 and Table 5.1-3. 
•
All subjects, including those who discontinue study treatment prior to receiving all planned 
doses during Induction Period 2, must have a tumor assessment at Week 25 (after the last 
dose of Induction Period 2 and prior to the first dose of the Continuation Period). 
•
Subjects who have clinical or radiographic progressive disease prior to the completion of 
Induction Period 2 are to remain on their current study treatment for the remainder of 
Induction Period 2, provided they are tolerating study treatment and do not have rapid 
clinical deterioration. 
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•
Subjects who do not receive all planned treatment doses in Induction Period 2, including 
those who discontinue Induction Period 2 treatment early due to progression or 
discontinuation criteria in Section 4.3.6.2, are to continue their scheduled study assessments 
(as per Table 5.1-2 and Table 5.1-3) and may still be eligible to receive treatment in the 
Continuation Period, starting at Week 25.
3.1.2.3
Continuation Period
•
Beginning at Week 25, subjects in both cohorts will enter the Continuation Period and 
receive nivolumab at 3 mg/kg every 2 weeks until progression, unacceptable toxicity, or 
withdrawal of consent with the following exceptions below. Note that only the 
protocol-specified tumor assessments at the end of Induction Period 1 and 2 are considered in 
these exceptions.
−
Subjects who met treatment discontinuation criteria during prior nivolumab treatment in 
Induction Period 1 or 2 (see Section 4.3.6.2) may not receive additional nivolumab 
treatment in the Continuation Period.
−
Subjects in both Cohorts A and B who had progression on the tumor assessment at the 
end of Induction Period 1 and have an additional 20% or greater increase in the sum of 
longest diameters, including all target lesions and measurable new lesions, on the tumor 
assessment at the end of Induction Period 2, will be discontinued from study treatment 
and not permitted to proceed to the Continuation Period.
−
Subjects in Cohort A who had progression on the tumor assessment at the end of 
Induction Period 1 but do not have an additional 20% or greater increase in the sum of 
longest diameters (including all target lesions and measurable new lesions) on the tumor 
assessment at the end of Induction Period 2 may, at the discretion of the investigator, 
either proceed to treatment in the Continuation Period or be discontinued from study 
treatment if the investigator feels that the subject is not likely to benefit from nivolumab 
treatment in the Continuation Period. Such Cohort A subjects must also meet the criteria 
for treatment beyond disease progression, as specified in Section 4.3.5.
−
Subjects in Cohort B who did not have progression on the tumor assessment at the end of 
Induction Period 1 but who do have progression on the tumor assessment at the end of 
Induction Period 2 may, at the discretion of the investigator, either be discontinued from 
study treatment or proceed to nivolumab reatment in the Continuation Period, provided 
they meet the criteria for treatment beyond progression, as specified in Section 4.3.5
•
Study assessments will be conducted as outlined in Table 5.1-4. 
•
The maximum duration of treatment to be administered to an individual subject in this study 
is 2 years from the first study treatment in Induction Period 1. 
•
Additional ipilimumab treatment during the Continuation Period is not allowed.
•
In the Continuation Period, nivolumab may be continued beyond initial evidence of 
progression if criteria specified in Section 4.3.5 are met. For subjects who continue 
nivolumab beyond initial progression, a subsequent tumor assessment must be performed 
4 to 8 weeks later. Treatment must be discontinued upon evidence of further progression 
(see Section 4.3.5).
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•
For subjects who begin the Continuation Period with RECIST 1.1-defined progression based 
on their tumor assessment at the end of Induction Period 2 and who receive treatment beyond 
progression in the Continuation Period, the protocol specified tumor assessment at Week 33 
may serve as the subsequent assessment.
•
Tumor assessments will be performed prior to dosing on Weeks 33 and 41, then every 
12 weeks (prior to dosing) starting at Week 49.
3.1.3
Follow-Up Period
•
Begins when the decision is made to discontinue a subject from study treatment or the 
subject has completed 2 years of study therapy from the first study treatment in Induction 
Period 1 (no further treatment with either nivolumab or ipilimumab)
•
For subjects who have NOT progressed, tumor assessments will continue as scheduled at 
Weeks 13, 25, 33, 41 and then starting at Week 49 every 12 weeks until documented 
progression.
•
Subjects will be followed for all toxicities until these toxicities resolve, return to baseline or 
are deemed irreversible. All AEs will be documented for a minimum of 100 days after last 
dose of study treatment.
After completion of the two “X” follow-up visits (Table 5.1-5) subjects will be followed every 
3 months (by clinic visit or telephone contact) for survival and report of any subsequent 
anti-cancer treatments for up to 5 years from the first dose of study treatment in Induction Period 
1 until death, loss to follow-up, or withdrawal of consent.
3.1.4
Study Duration
Accrual duration is expected to be around 1 year; overall study duration will be approximately 
6 years.
Primary and secondary endpoint analysis is expected to be performed approximately at 
20 months from the date of first patient first treatment. This will occur when at least 40 subjects 
per cohort have completed/discontinued Induction Period 1 and at least 35 subjects per cohort
have completed/discontinued Induction Period 2 and all treated subjects with an objective 
response at Week 25 have been followed through study Week 33 in order to confirm disease 
response. This will take place after a maximum of 32 weeks after last patient first treatment date.
An update of OS analysis is expected to be performed at 36 months (12 months accrual + 2 years 
follow-up). This update of OS analysis is planned to occur after 65% of the subjects have died or 
2 years of follow-up time from last subject randomized, whichever comes first. Assuming a 
median OS of 20 months for both cohorts, approximately 65% of the subjects would have died 
after a 12 months accrual period followed by a two years of follow-up time.
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Additional survival follow-up may continue for up to 5 years from the first dose of study 
treatment in Induction Period 1. Additional OS analysis may be conducted periodically until end 
of study. The study will end once survival follow-up has concluded.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive study drug (nivolumab). Study drug 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 study drug if any of the following occur: a) the marketing application is rejected by 
responsible health authority; b) the study is terminated due to safety concerns; c) the subject can 
obtain medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study.
2. Target Population
a) Subjects with histologically confirmed unresectable Stage III or Stage IV melanoma
b) Subjects may be treatment-naive, or have experienced disease recurrence or progression 
during or after one prior systemic regimen for advanced disease
i)
Specific prior immunotherapy regimens, including prior treatment with anti-PD-1 or 
anti-CTLA-4 directed agents, are excluded (see Exclusion criteria for details)
ii) Documented recurrence of Stage III unresectable or Stage IV melanoma after prior 
neo-adjuvant or adjuvant interferon is allowed
iii) Previously treated subjects must have completed their prior regimen > 4 weeks before 
the first dose of study treatment
c) Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria. 
(radiographic tumor assessment must be
performed within 28 days prior to
randomization.)
d) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (refer to 
Appendix 1)
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e) Subjects must have known BRAF V600 mutation status or consent to BRAF V600
mutation testing per local institutional standards during the Screening Period, the results 
of which must be reported within 3 months of randomization.
f)
Subjects must have sufficient tumor tissue accessible for baseline and post-treatment 
biopsies (core needle or excisional). The site of tumor biopsy should not be the only site 
of measurable disease.
i)
Lesions should not have received prior radiation therapy
ii) These sites must be designated for biopsy prior to the first treatment, to avoid 
selection bias that may affect study endpoints.
iii) Pathologic confirmation of viable tumor cells from collected tissue samples is 
strongly recommended to permit consideration of repeat biopsy if deemed of 
acceptable clinical risk.
g) All baseline laboratory requirements will be assessed and should be obtained within 
14 days of randomization. Screening laboratory values must meet the following criteria 
i)
WBCs
≥2000/μL
ii) Neutrophils 
≥1500/μL
iii) Platelets 
≥100 x 10³/μL
iv) Hemoglobin 
≥9.0 g/dL
v) Creatinine Serum creatinine ≤1.5 x ULN or creatinine clearance > 40
mL/minute (using Cockcroft/Gault formula)
vi) AST 
≤3 x ULN 
vii)ALT 
≤3 x ULN 
viii)
Total Bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome who
must have total bilirubin < 3.0 mg/dL)
h) Prior focal radiotherapy to an isolated bony or soft tissue metastasis must be completed at 
least 2 weeks before study drug administration. Target lesions may be located in a 
previously irradiated field if there is documented (radiographic) disease progression in 
that site. No radiopharmaceuticals (eg, strontium, samarium) within 8 weeks before study 
drug administration
i)
Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-consented
3. Age and Reproductive Status
a) Men and women ≥18 years of age
b) Women of childbearing potential (WOCBP) must use method(s) of contraception as 
indicated in Appendix 2. For a teratogenic study drug and/or when there is insufficient 
information to assess teratogenicity (preclinical studies have not been done), a highly 
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Clinical Protocol
effective method(s) of contraception (failure rate of less than 1% per year) is required. 
The individual methods of contraception and duration should be determined in 
consultation with the investigator. WOCBP must follow instructions for birth control 
when the half life of the investigational drug is greater than 24 hours, contraception 
should be continued for a period of 30 days plus the time required for the investigational
drug to undergo five half lives.
There is an insufficient amount of information to assess the teratogenicity for nivolumab.
The half-life of nivolumab is up to 25 days; therefore, WOCBP who received nivolumab
should use an adequate method to avoid pregnancy for 23 weeks after the last dose of 
nivolumab.
There is no data assessing the teratogenicity for ipilimumab. The half-life of ipilimumab 
is 14.7 days; therefore, WOCBP who received ipilumumab should use an adequate 
method to avoid pregnancy for 15 weeks after the last dose of ipilimumab.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational 
product.
d) Women must not be breastfeeding
e) Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year (as indicated on the Informed Consent Form). The 
investigator shall review contraception methods and the time period that contraception 
must be followed. Men that are sexually active with WOCBP must follow instructions for 
birth control when the half life of the investigational drug is greater than 24 hours, 
contraception should be continued for a period of 90 days plus the time required for the 
investigational drug to undergo five half lives.
The half-life of nivolumab is up to 25 days; therefore, men who received nivolumab and 
are sexually active with WOCBP must continue contraception for 31 weeks after the last 
dose of nivolumab.
The half-life of ipilimumab is 14.7 days ; therefore, men who received ipilimumab and 
are sexually active with WOCBP must continue contraception for 24 weeks after the last 
dose of ipilimumab.
f)
Women who are not of childbearing potential (ie, who are postmenopausal or surgically 
sterile; see Section 3.3.3 for the definition of WOCBP) and azoospermic men do not 
require contraception.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Subjects with active CNS metastases are excluded. Subjects are eligible if CNS 
metastases are adequately treated with surgery and/or radiation therapy, and subjects are 
neurologically returned to baseline (except for residual signs or symptoms related to the 
CNS treatment) and neurologically and radiographically stable for at least 6 weeks prior 
to enrollment. In addition, subjects must be either off corticosteroids, or on a stable or 
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decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 14 days prior to 
study treatment.
b) Subjects with carcinomatous meningitis
2. Medical History and Concurrent Diseases
a) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only 
requiring hormone replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
b) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
c) Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways).
d) Subjects who received prior treatment with other immunotherapies (eg, antibodies, 
vaccines, adoptive T-cell transfer), must have experienced disease progression at least 
6 weeks prior to first dose of study treatment and, with the exception of IL-2 or adjuvant 
interferon, must be discussed and approved by the Medical Monitor prior to signing 
informed consent
e) Prior therapy with BRAF inhibitor (eg, vemurafenib)
f)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug.
g) Treatment with any investigational agent within 28 days of first administration of study 
treatment
h) Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder 
cancer, gastric or colon cancers, cervical cancers/dysplasia, or breast carcinoma in situ) 
are excluded unless a complete remission was achieved at least 2 years prior to study 
entry and no additional therapy is required or anticipated to be required during the study 
period.
i)
Known drug or alcohol abuse
j)
Any serious or uncontrolled medical disorder or active infection that, in the opinion of 
the investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the subjet to receive protocol therapy.
3. Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus 
ribonucleic acide (HCV RNA) indicating acute or chronic infection.
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3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject
•
Pregnancy
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Additional protocol specific reasons for discontinuation (see Section 4.3.6)
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5 - Study Assessments and Procedures. The only 
exception to this requirement is when a subject 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 subject’s completion of the study, the reason for 
the discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Treatment Study Follow up
In this study, Overall Survival is an important exploratory endpoint of the study. Post treatment 
study follow-up is of critical importance and is essential to preserving subject safety and the 
integrity of the study. Subjects who discontinue study treatment must continue to be followed for 
collection of outcome and/or survival follow-up data as required and in line with Section 5 -
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Study Assessments and Procedures for up to 5 years from the first dose of study treatment in 
Induction Period 1 until death, lost to follow-up, or withdrawal of consent.
3.6.1
Withdrawal of Consent
Subjects 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
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects 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 drug 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 subject 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.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records.
4
TREATMENTS
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:
•
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
•
Study required premedication, and 
•
Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, backbone therapy, rescue medications)
•
Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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4.1
Study Treatments
Table 4.1-1:
Product Description - Treatment Period
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
BMS-936588-01 
Solution for Injection
100 mg (10 mg/mL)
10 mL vial/ Open-label
10 vials per carton/ 
Open-label
Clear to opalescent, 
colorless to pale yellow 
liquid. May contain 
particles.
2 to 8°C. Protect from 
light and freezing.
Ipilimumab Solution for 
Injection
200 mg (5 mg/mL)
40 mL vial/Open-label
4 vials per
carton/Open-label
Clear, colorless liquid.
May contain particles
2 to 8°C. Protect from 
light and freezing.
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational product(s) is/are: BMS-936558 (nivolumab) and ipilimumab.
4.1.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: Not applicable.
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug 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 drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). Refer to the BMS-936558 (nivolumab)
investigator brochure or ipilimumab package insert for details related to handling and dose 
preparation, as well as any pharmacy instruction sheets.
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
4.2
Method of Assigning Subject Identification
The subject number will be assigned through an interactive voice response system (IVRS) once 
the subject has signed the informed consent form and is registered. Every subject that signs the 
informed consent form must be assigned a subject number in IVRS. Specific instructions for 
using IVRS will be provided to the investigational site in a separate document.
The investigator or designee will register the subject for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
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•
Date that informed consent was obtained
•
Date of birth
•
Gender at birth
Once enrolled in IVRS, enrolled subjects that have signed the informed consent form and met all 
eligibility criteria will be randomized through the IVRS. The following information is required 
for subject randomization:
•
Subject number
•
Date of birth
•
Gender at birth
•
Date of informed consent
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to Cohort A (nivolumab
followed by ipilimumab) or Cohort B (ipilimumab followed by nivolumab).
4.3
Selection and Timing of Dose for Each Subject
Dosing calculations should be based on the body weight assessed at each visit as per Table 5.1-2, 
Table 5.1-3, and Table 5.1-4. All doses should be rounded to the nearest milligram. There will be 
no nivolumab or ipilimumab dose escalations or reductions permitted. 
The first dose of study drug will be administered on Week 1, Day 1. Subsequent doses are to be 
scheduled from the calendar date of the first dose and have a +/- 3 day dosing window. Please 
refer to Table 5.1-2 and Table 5.1-3 for the appropriate timing of doses (in terms of number of 
Weeks/Days from first dose) in the Induction Period.
After each nivolumab dose, the next dose of study treatment may be given no sooner than 
12 days later. After each ipilimumab dose, the next dose of study treatment may be given no 
sooner than 19 days later.
There are no premedications recommended for nivolumab or ipilimumab. Subjects should be 
carefully monitored for infusion reactions during nivolumab and ipilimumab administration. If 
an infusion reaction is noted, subjects should be managed according to Section 4.3.4.3.
There will be no dose delays permitted in this study. Doses of nivolumab or ipilimumab will be 
omitted if omission criteria, described in Section 4.3.4.1, are met. Treatment may resume at the 
next scheduled dose if retreatment criteria (specified in Section 4.3.4.2) are met.
The maximum duration of study treatment to be administered to an invididual subject is 2 years 
from the first study treatment in Induction Period 1.
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4.3.1
Induction Period 1
Induction Period 1 will be the first 12 weeks of study treatment (Weeks 1 to 13). 
•
Subjects in Cohort A will receive nivolumab at a dose of 3 mg/kg as a 60 minute IV infusion 
every 2 weeks (14 days) for up to 6 doses. 
•
Subjects in Cohort B will receive ipilimumab at a dose of 3 mg/kg as a 90 minute IV infusion 
every 3 weeks (21 days) for up to 4 doses. 
4.3.2
Induction Period 2
After completion of Induction Period 1, subjects will proceed to Induction Period 2 (12 weeks 
duration, from Week 13 to 25), regardless of the results of the tumor assessment at the end of 
Induction Period 1. 
•
Subjects in Cohort A will receive ipilimumab at a dose of 3 mg/kg as a 90 minute IV infusion 
every 3 weeks (21 days) for up to 4 doses. 
•
Subjects in Cohort B will receive nivolumab at a dose of 3 mg/kg as a 60 minute IV infusion 
every 2 weeks (14 days) for up to 6 doses. 
4.3.3
Continuation Period
•
Subjects in both Cohorts A and B will receive nivolumab at a dose of 3 mg/kg as a 60 minute 
IV infusion every 2 weeks (14 days), starting at Week 25 until disease progression, 
unacceptable toxicity, or withdrawal of consent, for a maximum duration of up to 2 years 
from the first study treatment in Induction Period 1. 
4.3.4
Dose Modifications for Nivolumab and Ipilimumab
Subjects will be monitored continuously for AEs while on study. Treatment modifications 
(eg, dose omissions) will be based on specific laboratory and AE criteria.
In some cases, the natural history of AEs associated with immunotherapy can differ and be more 
severe than AEs caused by other therapeutic classes. Early recognition and management may 
mitigate severe toxicity. The following Recommended Management Algorithms for nivolumab
were developed to assist investigators and can be found in the BMS-936558 (nivolumab)
Investigator Brochure:
•
Suspected Pulmonary Toxicity
•
Diarrhea and Colitis
•
Suspected Hepatotoxicity (including asymptomatic LFT elevations)
•
Suspected Endocrinopathy 
•
Suspected Nephrotoxicity
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In addition, the ipilimumab Investigator Brochure5 includes Management Algorithms for the 
following adverse reactions:
•
GI Toxicity
•
Hepatotoxicity
•
Skin Toxicity
•
Endocrinopathy
•
Neurological Toxicity
•
Other immune-mediated adverse reactions, including ocular manifestations
It should be noted that beginning with the first dose of Induction Period 2, adverse events may be 
related to the drug given in Induction Period 2, the prior drug given in Induction Period 1, or to 
both drugs. Therefore, it is recommended that the Management Algorithms in both the 
BMS-936558 (nivolumuab) Investigator Brochure and the ipilimumab Investigator Brochure be 
consulted for assistance with managing adverse events after the beginning of Induction Period 2.
4.3.4.1
Dose Omissions for Nivolumab or Ipilimumab
Doses of nivolumab or ipilimumab should be omitted (not delayed) if any of the following 
criteria are met:
•
Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:
−
Grade 2 drug-related fatigue or laboratory abnormalities do not require dose omission
•
Any Grade 3 skin, drug-related adverse event
•
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, or total bilirubin:
−
Grade 3 lymphopenia or leukopenia does not require dose omission
−
If a subject has baseline AST, ALT, or total bilirubin that is within normal limits, omit 
dosing for drug-related Grade ≥2 toxicity
−
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
omit dosing for drug-related Grade ≥3 toxicity
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants omitting the dose of study medication
If the criteria to resume treatment (specified in Section 4.3.4.3) are met within the dosing 
window (Week X ± 3 days), then the dose may be given.
4.3.4.2
Criteria to Resume Treatment with Nivolumab or Ipilimumab
Subjects may resume treatment with nivolumab or ipilimumab when the drug-related AE(s) 
resolve to Grade ≤1 or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue
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•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity
•
Subjects with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who require 
dose omissions for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT or total bilirubin
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment
If dosing is interrupted > 6 weeks, the subject must be permanently discontinued from study 
treatment with that particular drug, except as specified in Section 4.3.6.2.
4.3.4.3
Treatment of Infusion Reactions Related to Nivolumab or Ipilimumab
Infusion reactions related to nivolumab or ipilimumab may occasionally occur, manifested by
fever, chills, rigors, headache, rash, pruritus, arthalgias, hypotension, hypertension, 
bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the study medical monitor and reported as an SAE if it meets the 
criteria. Infusion reactions should be graded according to NCI CTCAE (Version 4.0) 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 subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
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, IV fluids]; prophylactic medications 
indicated for ≤24 hours).
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid 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 subject closely. If symptoms recur, then no further nivolumab or ipilimumab will 
be administered at that visit.
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For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory support 
indicated).
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 
100 mg IV or equivalent), as needed. Subject should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Nivolumab or ipilimumab will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor subject until recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.3.5
Nivolumab Treatment Beyond Disease Progression
As described in Section 1.4.4.4, accumulating evidence indicates a minority of subjects treated
with immunotherapy may derive clinical benefit despite initial evidence of progressive disease 
(PD).
From the beginning of the Continuation Period, subjects will be permitted to continue or resume 
treatment with nivolumab beyond initial RECIST 1.1-defined PD, as long as they meet all of the 
following criteria:
•
Investigator-assessed clinical benefit
•
Subject has tolerated prior nivolumab
•
Stable or improved performance status
•
Treatment beyond progression will not delay an intervention to prevent imminent serious 
complications of disease progression (eg, CNS metastases)
•
Subject provides written informed consent prior to receiving additional nivolumab treatment, 
using an ICF describing any reasonably foreseeable risks or discomforts and other alternative 
treatment options
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued nivolumab treatment.
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Note that subjects with PD on any tumor assessment prior to the end of Induction Period 2 but 
not also on the tumor assessment at the end of Induction Period 2 (when compared to the 
baseline tumor assessment) are not considered to be continuing or resuming treatment beyond 
PD at the time of the beginning the Continuation Period.
All decisions to continue nivolumab treatment beyond initial PD must be discussed with the 
BMS Medical Monitor and documented in the study records.
For subjects who enter the Continuation Period with RECIST 1.1-defined PD on the tumor 
assessment at the end of Induction Period 2, this tumor assessment will be considered as the one 
documenting initial PD (even if PD was also documented on the tumor assessment at the end of 
Induction Period 1 or on any unscheduled tumor assessment prior to the one at the end of 
Induction Period 2). For subjects who enter the Continuation Period without prior evidence of 
PD, the first tumor assessment during the Continuation Period that documents PD will be 
considered the one documenting initial PD.
A radiographic tumor assessment must be performed 4 to 8 weeks after the assessment 
documenting initial PD. (Subjects who begin the Continuation Period with RECIST 1.1-defined 
progression on their tumor assessment at the end of Induction Period 2 may use the protocol 
specified tumor assessment at Week 33 as the subsequent assessment.) Subjects must discontinue 
study treatment upon evidence of further progression, defined as an additional 10% or greater 
increase in tumor burden from the time of initial PD (including all target lesions and new 
measurable lesions). If further progression is not documented on this next tumor assessment, 
then study treatment may continue until there is evidence of further progression on any 
subsequent tumor assessment.
New lesions are considered measurable at the time of initial PD 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 PD may become measurable and 
therefore included in the tumor burden measurement if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes, which must have an increase in short axis to at 
least 15 mm).
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue nivolumab treatment beyond initial investigator-assessed RECIST 1.1-defined 
progression will be considered to have investigator-assessed progressive disease at the time of 
the initial progression event.
The criteria mentioned above, including the requirement for informed consent, do not apply to 
continued nivolumab or ipilimumab treatment in Induction Period 1 or Induction Period 2 
beyond clinical or radiographic progression observed prior to the completion of those periods.
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4.3.6
Nivolumab and/or Ipilimumab Treatment Discontinuation Criteria
4.3.6.1
Permanent Discontinuation Criteria for Both Nivolumab and Ipilimumab
All further study treatment (both nivolumab and ipilimumab) must be permanently 
discontinued if any of the following occurs during treatment with either nivolumab or 
ipilimumab:
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation
•
Grade 4 neutropenia ≤ 7 days
•
Grade 4 lymphopenia or leukopenia
•
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
•
Any drug-related adverse event which requires treatment with any immunosuppressive 
therapy other than corticosteroids (eg, infliximab, mycophenylate)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued dosing of 
nivolumab or ipilimumab
•
Clinical or radiographic progression associated with rapid clinical deterioration which, in the 
judgment of the Investigator, is unlikely to benefit from further study treatment (nivolumab 
or ipilimumab).
4.3.6.2
Permanent Discontinuation Criteria for One Study Treatment 
(Discontinuation of Nivolumab Only or Discontinuation of Ipilimumab 
Only)
If any of the following occurs during treatment with either nivolumab or ipilimumab, treatment 
with that particular drug must be permanently discontinued:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
colitis, diarrhea, hypersensitivity reactions, and infusion reactions:
•
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation
•
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
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•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
−
AST or ALT > 5-10 x ULN for > 2 weeks
−
AST or ALT > 10 x ULN
−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade ≥ 3 motor neuropathy, regardless of causality
•
Any dosing interruption lasting > 6 weeks with the following exceptions:
•
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption
lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted.
•
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS medical monitor. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued dosing of the 
particular drug given at the time of event
Subjects who permanently discontinue nivolumab or ipilimumab during Induction Period 1 may 
still be treated with the alternative agent in Induction Period 2, starting at Week 13, provided the 
criteria for resuming study treatment (Section 4.3.4.3) are met at that time.
Subjects in Cohort A who permanently discontinue ipilimumab during Induction Period 2 may 
still be treated with nivolumab in the Continuation Period, starting at Week 25, provided the 
criteria for resuming study treatment (Section 4.3.4.3) are met at that time and the criteria for 
discontinuation were not also met during prior nivolumab treatment during Induction Period 1.
Subjects who permanently discontinue nivolumab in Induction Period 1 (Cohort A) or Induction 
Period 2 (Cohort B) may not receive retreatment with nivolumab in the Continuation Period.
Subjects in the Continuation Phase will discontinue nivolumab after the completion of 2 years of 
study treatment (from the first dose of study treatment in Induction Period 1).
4.4
Blinding/Unblinding
Not applicable.
4.5
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
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4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are 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.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
4.7
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209064)
Procedure
Screening Visit
Within 28 days prior to 
Randomization
Notes
Eligibility Assessments
Informed Consent
X
Section 2.3.
Inclusion/Exclusion Criteria
X
Section 3.3.
Medical History
X
Section 5.3.1.
ECOG Performance Status
X
Section 5.3.3.
Safety Assessments
Physical Examination
X
Section 5.3.1.
Vital Signs & Oxygen Saturation
X
Section 5.3.2.
Height & Weight
X
Section 5.3.1.
ECG (12-lead)
X
Section 5.3.6. Obtained only for subjects who have met all eligibility criteria.
Assessment of Signs and Symptoms
X
Section 5.3.1. Within 14 days prior to Randomization.
Concomitant Medications
X
Section 3.4. Within 14 days prior to Randomization.
Laboratory Tests
Chemistry & Hematology 
X
Section 5.3.5. Within 14 days prior to Randomization.
Pregnancy Test (WOCBP Only)
X
Section 5.3.4.
Thryoid Function Testing
X
Section 5.3.5.1. Within 14 days prior to Randomization.
Hepatitis B & C
X
Section 5.3.5.2.
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Table 5.1-2:
Cohort A - Induction Period Procedural Outline 
Cohort A Induction Treatment (nivolumab followed by ipilimumab)
+/- 3 Days
Induction Period 1
Induction Period 2
Study Week
W1
W3
W5
W7
W9
W11
W13
W16
W19
W22
Notes
Study Day
D1
D15
D29
D43
D57
D71
D85
D105
D127
D148
PROCEDURE
Exploratory Biomarker Assessments
Peripheral Blood Mononuclear 
Cell Assessments
X
X
X
X
X
X
X
Section 5.6.3.
Peripheral Blood Gene 
Expression Profiling
X
X
X
X
X
Section 5.6.4
Tumor Biopsy (fresh)
X
Section 5.6.1. Collected within 14 days 
prior to dosing.
Efficacy Procedures
Tumor Assessment (CT/MRI)
X
Section 5.4. Chest, abdomen, pelvis, brain 
& all known sites of disease, to be 
performed prior to W13 dosing.
Clinical Drug Supplies
Randomize (IVRS)
X
Section 4.2.
Nivolumab
X
X
X
X
X
X
Section 4.
Ipilimumab
X
X
X
X
Section 4.
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Table 5.1-3:
Cohort B - Induction Period Procedural Outline 
Cohort B Induction Treatment (ipilimumab followed by nivolumab)
+/- 3 Days
Induction Period 1
Induction Period 2
Study Week
W1
W4
W7
W10
W13
W15
W17
W19
W21
W23
Notes
Study Day
D1
D22
D43
D64
D85
D99
D113
D127
D141
D155
PROCEDURE
Peripheral Blood Gene 
Expression Profiling
X
X
X
X
X
Section 5.6.4.
Tumor Biopsy (fresh)
X
Section 5.6.1. Collected within 14 days 
prior to dosing.
Efficacy Procedures
Tumor Assessment (CT/MRI)
X
Section 5.4. Chest, abdomen, pelvis, brain 
& all known sites of disease, to be 
performed prior to W13 dosing.
Clinical Drug Supplies
Randomize (IVRS)
X
Section 4.2.
Nivolumab
X
X
X
X
X
X
Section 4.
Ipilimumab
X
X
X
X
Section 4.
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Table 5.1-4:
Continuation Period Procedural Outline (Cohort A & Cohort B)
Procedure
Continuation Period
Starting at Week 25
Every 2 weeks +/- 3 days
Notes
Efficacy Procedures
Tumor Assessment (CT/MRI)
Week 25, 33, 41 & 49.
After Week 49: every 12 weeks
Section 5.4. To be performed prior to dosing. Scans may be done within 1 week of 
target week. 
At Week 25, Chest, abdomen, pelvis & brain required.
At Week 33 & 41. Chest, abdomen, pelvis required. Brain scans should be done 
with tumor assessments, if there are known brain lesions.
At Week 49, Chest, abdomen, pelvis and brain scan required. Beginning at 
Week 49, if there are no known brain lesions, brain scans required every 24 weeks.
Clinical Drug Supplies
Nivolumab
X
Section 4. Maximum treatment duration is 2 years from first study treatment in 
Induction Period 1.
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Table 5.1-5:
Follow-Up & Survival Period (Cohort A & Cohort B)
Procedure
Initial Follow-Up Phase
Follow-Up Visits 1 (X01) and 2 
(X02)a
Survival (Y) 
Follow-Up Visitsb
Every 3 months
Notes
Subject Status 
X
X
Collection of survival information every 3 months until 
death, lost to follow-up, or withdrawal of study consent.
May be performed by phone contact or office visit.
a X visits occur as follows: X01 = 30 days from last dose +/- 7 days. X02 = 70-84 days from X01.
b Y, survival visits occur every 3 months after X visits.
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5.2
Study Materials
The following materials will be provided at study start:
•
NCI CTCAE version 4.0
•
BMS-936558 (nivolumab) Investigator Brochure
•
Ipilimumab Investigator Brochure
•
Pharmacy Binder
•
Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens
•
Site 
manual 
for 
operation 
of 
interactive 
voice 
response 
system, 
including 
enrollment/randomization worksheets
•
Manual for entry of local laboratory data
•
Serious Adverse Events (or eSAE) case report form pages
•
Pregnancy Surveillance Forms
•
RECIST 1.1 pocket guide
5.3
Safety Assessments
Subjects will be evaluated for safety if they have received any study drug (nivolumab or 
ipilimumab). Adverse events and laboratory values will be graded according to the NCI-CTCAE 
version 4.0. Additionally any occurrence of an SAE from the time of consent until 100 days after 
discontinuation of dosing and any SAE that is believed to be related to study drug or 
protocol-specified procedures after this time period will be documented.
5.3.1
Medical History, Physical Exam, Physical Measurements
At screening/baseline, a medical history will be obtained to capture relevant underlying 
conditions. The screening/baseline physical examination should include physical measurements 
(height, weight, ECOG Performance Status). These evaluations are to be performed at the 
screening visit and within 72 hours prior to the first dose. Baseline signs and symptoms are those 
that are assessed within 14 days prior to randomization. Concomitant medications will be 
collected from within 14 days prior to randomization through the study treatment period and 
follow-up. See Table 5.1-1.
Weight is to be assessed prior to dosing at each dosing visit. Subsequent targeted physical 
examinations will be performed outlined in Table 5.1-1, Table 5.1-2 and Table 5.1-3 and as 
clinically indicated throughout the study. Any physical examination finding that qualifies as an 
AE or SAE must be documented on the appropriate CRF pages.
5.3.2
Vital Signs & Oxygen Saturation
Vital signs are to be assessed at each visit prior to dosing and include blood pressure (BP), heart 
rate, temperature, and oxygen saturation by pulse oximetry at rest and after exertion.
Vital signs are to be taken as per institutional standard of care prior to, during, and after dosing.
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Oxygen saturation by pulse oximetry should be obtained prior to each new dose for subjects on 
both treatment cohorts and at any time a subject has any new or worsening respiratory 
symptoms. A reading at rest and on exertion should be obtained at each time point. The extent of 
the exertion should be based on the judgment of the investigator, but should remain consistent 
for each individual subject throughout the study. If the subject’s status changes, the investigator 
can alter the extent of exertion based on their medical judgment. If a subject shows changes on 
pulse oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, 
cough, fever) consistent with possible pulmonary adverse events, the subject should be 
immediately evaluated to rule out pulmonary toxicity. An algorithm for the management of 
suspected pulmonary toxicity can be found in Appendix 2 of the BMS-936558 (nivolumab)
Investigator Brochure.
5.3.3
ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status will be evaluated and 
documented at Screening and at each dosing visit as outlined in Section 5.1. See Appendix 1 for 
description of ECOG status.
5.3.4
Pregnancy Testing
WOCBP are required to have pregnancy tests performed. WOCBP must exhibit a negative serum 
or urine pregnancy (minimum sensitivity 25 IU/L or equivalent units of HCG within 24 hours 
prior to the start of study drug. Pregnancy testing will be done locally and performed as outlined 
in, Table 5.1-1, Table 5.1-2,Table 5.1-3, Table 5.1-4.
5.3.5
Chemistry & Hematology Tests
Chemistry and Hematology tests will be performed as outlined in the tables in Section 5.1 and 
within 72 hours prior to dosing.
Chemistry tests are to include LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, calcium, magnesium, sodium, potassium, bicarbonate, chloride, 
lactate dehydrogenase (LDH), amylase, lipase and glucose.
Hematology tests are to include a CBC with differential.
Additional measures including non-study required laboratory tests should be performed as 
clinically indicated. Laboratory toxicities (eg, suspected drug inducted liver enzyme elevations) 
will be monitored via on site/local labs until all study drug related toxicities resolve, return to 
baseline or are deemed irreversible. Management algorithms for suspected hepatotoxicity can be 
found in Appendix 4 of the BMS-936558 (nivolumab) Investigator Brochure and in Appendix 7 
of the ipilimumab Investigator Brochure.
5.3.5.1
Thyroid Function Tests
Thyroid function tests will be performed as outlined in Section 5.1.
At Screening, thyroid function testing is to include TSH, free T3, and free T4. At subsequent 
timepoints, thyroid function testing consists of TSH only. However, if TSH is abnormal reflexive 
testing of free T3 and free T4 are to be performed. Management algorithms for suspected 
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endocrinopathy (including abnormal thyroid function) can be found in Appendix 5 of the BMS-
936558 (nivolumab) investigator brochure and in Appendix 9 of the ipilimumab investigator 
brochure.
5.3.5.2
Hepatitis B & C Testing
Hepatitis B (HBV sAG) and Hepatitis C (HCV RNA) testing will be conducted during 
Screening.  
5.3.6
Electrocardiogram (ECG)
All subjects who have met eligibility criteria are required to have a 12-lead ECG performed 
during Screening. If clinically indicated, additional ECGs may be obtained during the study.
5.3.7
Imaging Assessment for the Study
Not applicable.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the tables in Section 5. Screening/baseline 
tumor assessments should be performed within 28 days prior to randomization utilizing 
CTs/MRI. In addition to chest, abdomen, pelvis, the brain and all known sites of disease should 
be assessed at screening/baseline. Subsequent assessments should include chest, abdomen, 
pelvis, and all known sites of disease and should use the same imaging method as was used at 
screening/baseline. 
Change in tumor measurements and tumor responses will be assessed by the investigator using 
the RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. For the secondary 
endpoint of response rate at Week 25, each subject’s response at Week 25 will be evaluated in 
relation to baseline/screening tumor assessment independently of any other tumor assessments 
(including Week 13 or any unscheduled tumor assessments).
In the Induction Period, tumor assessments will be performed after the last dose in Induction 
Period 1 and prior to the first dose in Induction Period 2 (Week 13 +/- 1 week) and after the last 
dose in Induction Period 2 and prior to the first dose in the Continuation Period 
(Week 25 +/- 1 week). Brain scans are required at prior to dosing on Week 13 and Week 25.
In the Continuation Period, tumor assessments will be performed prior to dosing on Weeks 33 
and 41 (+/- 1 week) and then every 12 weeks (prior to dosing) starting on Week 49 (+/- 1 week).
If there are known brain lesions, brain scans should be done with the tumor assessments as 
indicated above. If there are no known brain lesions, brains scans are only required every 
24 weeks beginning at Week 49.
In the Follow-Up Period, tumor assessments are to be performed on subjects that discontinue 
treatment for reasons other than progressive disease. Tumor assessments will be performed prior 
to dosing at Weeks 33 and 41 (+/- 1 week), then every 12 weeks (prior to dosing) starting on 
Week 49 (+/- 1 week) until progressive disease, withdrawal of study consent, subject is lost to 
follow-up, or start of a subsequent anti-cancer therapy. If there are known brain lesions, brain 
scans should be done with the tumor assessments as indicated above. If there are no known brain 
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lesions, brains scans are only required every 24 weeks beginning at Week 49 (brain scan is 
required at Week 49).
Tumor assessments must not be delayed until X01 or X02.
5.4.1
Assessment of Overall Tumor Burden and Measurable Disease
To serially evaluate tumor response to therapy, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable tumor lesion. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows in Sections 5.4.1.1, 5.4.1.2, and 5.4.1.3.
5.4.1.1
Measurable Lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)
•
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
•
20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow up, only the short axis will 
be measured and followed.
5.4.1.2
Non-Measurable Lesions
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥10 to < 15 mm short axis), as well as truly non-measurable lesions.
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.
5.4.1.3
Special Consideration Regarding Lesion Measurability
Bone Lesions
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions.
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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.
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are by definition, 
simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions.
Non-measurable Lesions
Tumor lesions situated in a previously irradiated area, or in an area subjected to loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression 
in the lesion.
5.4.2
Specifications by Methods of Measurements
5.4.2.1
Measurement of Lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should 
be performed as close as possible to the treatment start and never more than 28 days before the 
beginning of treatment.
5.4.2.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
5.4.2.3
CT/MRI Scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
5.4.2.4
Chest X-Ray
Chest CT is preferred over chest x-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than x-ray, particularly in identifying new lesions. However, lesions 
on chest x-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung.
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5.4.2.5
Clinical Lesions
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated both by clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
5.4.2.6
Ultrasound
Ultrasound is not useful in the assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.
5.4.2.7
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
5.4.2.8
Tumor Markers
Tumor markers such as, but not limited to, LDH may be used for clinical management, but will 
not be included in the assessment of BOR.
5.4.3
Baseline Documentation of “Target” and “Non-target Lesions”
5.4.3.1
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.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
5.4.3.2
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
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5.4.3.3
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
5.4.4
Tumor Response Evaluation
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.
5.4.4.1
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
5.4.4.2
Target Lesions that Become “Too Small to Measure”
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). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
5.4.4.3
Target Lesions that Split or Coalesce on Treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum.
As lesions coalesce, a plane between them maybe maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
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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’.
5.4.4.4
Evaluation of Non-target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered progression).
5.4.4.5
When the Subject has Measurable Disease
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy.
A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status.
5.4.5
New Lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of preexisting lesions. This is 
particularly important when the subject’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan reported as a ‘new’ cystic 
lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.
5.4.6
Response Criteria (RECIST 1.1)
For subjects who have measurable disease at baseline, Table 5.4.6-1, provides a summary of the 
overall response status calculation at each time point. 
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Table 5.4.6-1:
Time Point Response - Subjects With Target ( ± Non-target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, NE = Not 
Evaluable
5.4.6.1
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, the case is also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not have changed the 
assigned time-point response.
5.4.6.2
Confirmation of Scans
Verification of Response: Initial observations of response will be confirmed by repeat scans 
which should be performed no earlier than 4 weeks after the original observation to ensure that 
responses identified are not the result of measurement error. After an initial PR or CR is noted, 
the subsequent protocol-specified tumor assessment may serve as the confirmation. For the 
secondary endpoint of response rate at Week 25, any PR or CR at Week 25 may be confirmed by 
the scheduled tumor assessment at Week 33.
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 not 
to have progressive disease per RECIST 1.1.
 
 
 
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5.7
Outcomes Research Assessments
Not applicable.
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5.9
Results of Central Assessments
Not applicable.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following:
•
Related: There is a reasonable causal relationship between study drug administration and the 
AE.
•
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
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•
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
•
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs.
(See Section 6.1.1 for reporting pregnancies).
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).
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 100 days of discontinuation of dosing. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
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If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): See Contact Information 
list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. All nonserious 
adverse events (not only those deemed to be treatment-related) should be collected continuously 
during the treatment period and for a minimum of 100 days following the last dose of study 
treatment.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug 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.
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6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
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 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1. for reporting details).
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Potential drug induced liver injury is defined as: 
•
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND 
•
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND 
•
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This trial is an estimation trial. Sample size in this study will be approximately 40 subjects per 
cohort and is not based on power considerations. Tables below provide the 95% confidence 
intervals computed from different observed rates. Those tables indicate what would be the 
reliability of the AE rate estimates for N=40 (Table 8.1-1) and N=35 (see Table 8.1-2) treated 
subjects. A threshold of 45% will be applied to the upper limit of the confidence interval as an 
informal guideline for high toxicity 
Thirty-five subjects per cohort will be the minimum number of subjects receiving treatment in 
Induction Period 2. For that purpose, randomization will stay open until at least 40 subjects in 
each cohort have been treated with at least one dose of study treatment in Induction Period 1 and
35 subjects in each cohort have received at least one dose of study treatment in Induction 
Period 2. Assuming a drop-out rate during induction period 1 would be at most 12.5%, at least 
35 subjects would be treated in induction period 2 if 40 subjects are to be randomized per cohort.
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Table 8.1-1:
Exact 95% CI width and upper bound for AE rates up to 40% when 
observed in 40 subjects
Nb Subj with Rel Gr3-5 A
Rate of Rel Gr3-5 AE
Exact 95% CI width
Upper limit Exact 95%CI
4
10%
21%
23.7%
8
20%
27%
35.6%
10
25%
29%
41.2%
11
27.5%
29%
43.9%
12
30%
30%
46.5%
13
32.5%
31%
49.1%
14
35%
31%
51.7%
16
40%
32%
57%
Table 8.1-2:
Exact 95% CI width and upper bound for AE rates up to 40% when 
observed in 35 subjects.
Nb Subj with Rel Gr3-5 AE
Rate of Rel Gr3-5 AE
Exact 95% CI Width
Upper Limit Exact 
95%CI
4
11.4%
23.5%
26.7%
7
20%
28.5%
36.9%
9
25.7%
30.8%
43.3%
10
28.6%
31.7%
46.3%
11
31.4%
32.4%
49.3%
14
40%
34%
57.9%
8.2
Populations for Analyses
All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IVRS.
All Randomized Subjects: All subjects who were randomized to any cohort in the study.
All Treated Subjects: All subjects who received at least one dose of study medication. 
 
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8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint of the study is the rate of treatment-related Grade 3-5 AEs during the 
Induction Period (Periods 1 and 2) in subjects receiving sequential induction treatment with 
either nivolumab followed by ipilimumab or ipilimumab followed by nivolumab. 
The treatment-related Grade 3 - 5 AEs rate is defined as number of subjects who experienced at 
least 1 treatment related Grade3 - 5 adverse event (per NCI CTCAE v 4.0 criteria, any PT terms) 
with an onset date after or on first day of the Induction Period and not later than discontinuation 
date from the Induction Period, divided by number of treated subjects. AEs with an onset date 
after start of subsequent anti-cancer therapy, or start date of Continuation Period treatment will 
not be included.
•
For subjects who discontinue Induction Period early and enter the Follow-Up Period, 
AEs that occur in Follow-Up, including those before Week 25, will not be included in the 
primary endpoint.
•
For subjects who discontinue treatment before the end of Induction Period 1 or 2 but who 
are eligible to enter the next study period, AEs that occur before end of Induction Period 
2 will be included in the primary endpoint, even if they occur after dosing ends while 
they are waiting to enter the next study period.
Primary and secondary endpoint analysis will be performed when at least 40 subjects per cohort 
have completed/discontinued Induction Period 1 and at least 35 subjects per cohort have 
completed/discontinued Induction Period 2 and all treated subjects with an objective response at 
Week 25 have been followed through study Week 33 in order to confirm disease response.
8.3.2
Secondary Endpoints
Secondary endpoints will be analyzed at the time of the primary endpoint analysis. Duration of 
response from Week 25 will be re-assessed at time of the OS update analysis. 
8.3.2.1
Response Rate at Week 25
Response rate at Week 25 is defined as the number of subjects who have a complete response 
(CR) or partial response (PR) at Week 25, with confirmation at scheduled scan at Week 33, 
divided by the total number of randomized subjects. Note that the results of the tumor assessment 
at Week 13 will not be considered in the assessment of response rate at Week 25. This means, for 
example, that subjects with progressive disease at Week 13 are not precluded from having an 
assessment of CR or PR at Week 25 for this endpoint if the scan at Week 25 demonstrates such a 
response.
Duration of response (DOR) from Week 25 will also be assessed for subjects with confirmed 
response at Week 25 (see definition above). DOR is defined as the time between the Week 25
assessment date and the date of objectively documented disease progression (taking as reference 
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the smallest sum of diameters of target lesions beginning at Week 25) or death, whichever occurs 
first.
8.3.2.2
Progression Rates at Weeks 13 and 25
Progression rate at a specific timepoint is defined as the number of subjects who have
Progressive Disease (PD) per RECIST 1.1 at that specific timepoint divided by the total number 
of randomized subjects. 
 
 
 
 
 
 
 
 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline laboratory results will be summarized by cohort as randomized using 
descriptive statistics for all randomized subjects.
8.4.2
Primary Endpoint Analysis
Rate of treatment-related Grade 3-5 AEs during the induction period will be computed by 
treatment cohort using all treated subjects. Corresponding 95% CIs will be calculated using the 
Clopper-Pearson method. 
As sensitivity analysis, rates and 95% CI will be also computed using the subset of subjects who 
received at least one dose of study treatment in Induction Period 2.
8.4.3
Efficacy Analyses
8.4.3.1
Response Rate at Week 25
Response rate at Week 25 will be computed by cohort using all randomized subjects. Response 
rate estimates and corresponding 95% CIs will be calculated using the Clopper-Pearson method.
As sensitivity analysis, response rates including only those subjects who were response evaluable 
at Week 25 (ie, those subjects with a tumor assessment at Week 25) will also be calculated.
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8.4.3.2
DOR from Week 25
Duration of response from Week 25 will be assessed for subjects with confirmed response at 
Week 25. Median DOR estimate and corresponding 95% CIs will be provided for cohort using 
the Kaplan-Meier methodology
8.4.3.3
Progression Rates at Weeks 13 and 25
Progression rates at Week 13 and at Week 25 will be computed by cohort using all randomized 
subjects. Progression rate estimates and corresponding 95% CIs will be calculated using the 
Clopper-Pearson method.
 
 
 
 
 
 
8.4.4
Safety Analyses
Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 by cohort. All treatment 
emergent AEs, drug-related AEs, SAEs and drug-related SAEs will be tabulated using worst 
grade per NCI CTCAE v 4.0 criteria by system organ class and preferred term. 
On-study lab parameters including hematology, chemistry, liver function, thyroid function and 
renal function will be summarized using worst grade per NCI CTCAE v 4.0 criteria.
Safety during Induction Period: see primary endpoint definition. 
Safety during Induction Period 1: events considered will be those with an onset date during
Induction Period 1. Rates of treatment related AEs will be computed using subjects treated in the 
induction Period 1. Treatment related AEs will be tabulated using worst CTC grades by system 
organ class and preferred term.
•
For subjects who discontinue Induction Period 1 early and enter the Follow-Up Period, 
AEs that occur in Follow-Up will not be included.
•
For subjects who discontinue treatment before the end of Induction Period 1 but who are 
eligible to enter the Induction period 2, AEs that occur before end of Induction Period 1 
will be included, even if they occur after dosing ends while they are waiting to enter the 
next study period
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•
AEs with an onset date after start of subsequent anti-cancer therapy, or start date of 
Induction Period 2 treatment will not be included.
Safety during Induction Period 2: events considered will be those with an onset date during 
Induction Period 2. Rates of treatment related AEs will be computed using subjects treated in the 
induction Period 2. Treatment related AEs will be tabulated using worst CTC grades by system 
organ class and preferred term.
•
For subjects who discontinue Induction Period 2 early and enter the Follow-Up Period, 
AEs that occur in Follow-Up will not be included.
•
For subjects who discontinue treatment before the end of Induction Period 2 but who are 
eligible to enter Continuation Period, AEs that occur before end of Induction Period 2 
will be included, even if they occur after dosing ends while they are waiting to enter the 
next study period
•
AEs with an onset date after start of subsequent anti-cancer therapy, or start date of 
Continuation Period treatment will not be included. Worst CTC grades by system organ 
class and preferred term during Induction Period 2 will be reported.
The same analysis will be performed excluding AEs persisting from Induction Period 1 that are 
downgraded in Induction Period 2 compared to last grade observed in Induction Period 1. 
Safety during Continuation Period: events considered will be those with an onset date during 
Continuation Period. Rates will be computed using subjects treated in the Continuation Period. 
Overall safety on-treatment: events considered will be those with an onset date after (or on, if 
AE) first day of Induction Period treatment and up to 100 days after the last dose of study drug. 
Rates will be computed using all treated subjects.
 
 
 
 
 
 
 
 
 
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8.4.7
Outcomes Research Analyses
Not Applicable.
8.4.8
Other Analyses 
Not Applicable.
8.5
Interim Analyses
Not Applicable.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, 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 IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
•
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must 
be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (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).
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9.1.2
Monitoring
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 BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator 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, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator 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, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug and the following non-investigational product(s) are inventoried and dispensed. 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 subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
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•
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.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
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. 
For sites using the BMS 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 paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
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, including any paper or electronic 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 .For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
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 considering the following criteria:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
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•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or 
country)
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator or 
BMS as related to the investigational product
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event defined as any untoward medical 
occurrence that at any dose: results in death; is life threatening 
(defined as an event in which the subject 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; results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect; is an 
important medical event (defined as a medical event(s) that 
may not be immediately life threatening or result in death or 
hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require 
intervention [eg, medical, surgical] to prevent one of the other 
serious outcomes listed in the definition above). Examples of 
such events include, but are not limited to, intensive treatment 
in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in 
hospitalization.). For reporting purposes only, BMS also 
considers the occurrence of pregnancy, overdose (regardless of 
association with an AE), and cancer as important medical 
events.
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11
LIST OF ABBREVIATIONS
Term
Definition
μg
microgram
β-HCG
beta-human chorionic gonadotrophin
ADA
Anti-Drug Antibody
AE
adverse event
AIDS
Acquired Immunodeficiency Syndrome
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
C1-
chloride
Ca++
calcium
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CL
Clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CMV
cytomegalovirus
CNS
Central nervous system
CNS
Central Nervous System
CR
Complete Response
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CT
Computed Tomography
CTA
Clinical Trial Agreement
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
D/C
discontinue
D
day
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Term
Definition
DILI
Drug Induced Liver Injury
dL
deciliter
DLT
Dose limiting toxicity
DTIC
Dacarbazine
DNA
Deoxyribonucleic acid
DOR
Duration of response
DTIC
Dacarbazine
ECL
Electrochemiluminescent Immunoassay
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ESR
Expedited Safety Report
Fax
Facsimile
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded
FISH
Fluorescent In Situ Hybridization
FSH
Follicle Stimulating Hormone
g
gram
G
Grade
GCP
Good clinical practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
Gastrointestinal
Gp
glycoprotein
h
hour
HBV
hepatitis B virus
HBVsAg
Hepatitis B surface antigen
HCG
Human chorionic gonadotropin
HCO3
-
bicarbonate
HCV
hepatitis C virus
HCV RNA
Hepatitis C ribonucleic acid
HIPAA
Health information portability and accountability act
HIV
Human Immunodeficiency Virus
HR
heart rate
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Term
Definition
HR
Hazard ratio
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation
ie
id est (that is)
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL
Interleukin
IMP
Investigational Medicinal Product
IND
Investigational New Drug Exemption
Ipi
ipilimumab
irAE
Immune-related adverse event
IRB
Institutional Review Board
ISH
In situ hybridization
IU
International Unit
IV
Intravenous
IVRS
Interactive Voice Response System
K+
potassium
K3EDTA
potassium ethylenediaminetetraacetic acid
kg
kilogram
L
liter
LC
liquid chromatography
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
mAB
Monoclonal antibody
Mg
Milligram
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
MLR
Mixed lymphocyte reaction
Mm
Millimeters
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Term
Definition
MRI
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
N
number of subjects or observations
N/A
not applicable
Na+
sodium
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
NE
Not Evaluable
ng
nanogram
NIMP
Non-Investigational Medicinal Product
NK
Natural Killer
nM
nanometer
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral Blood Mononuclear Cell
PBMC
Peripheral Blood Mononuclear Cell
PCR
Polymerase chain reaction
PD
pharmacodynamics
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PET
Positron Emission Tomography
PFS
Progression free survival
PK
pharmacokinetic
PPK
Population pharmacokinetic
PR
Partial Response
Qty
Quantity
RBC
red blood cell
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
standard deviation
SD
Stable Disease
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Term
Definition
SNP
Single Nucleotide Polymorphism
SOP
Standard Operating Procedures
t
temperature
T
time
T.bilirubin
Total Bilirubin
TA
Tumor Assessment
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
T-HALF
Half life
ULN
Upper Limit of Normal
US
United States
V
version
Vz
Volume of Distribution
W
Week
WBC
white blood cell
WHO
World Health Organization
Wk
Week
WOCBP
women of childbearing potential
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APPENDIX 1
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS
1
Fully active, able to carry on all pre-disease performance without restriction
2
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
 
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APPENDIX 2
GUIDANCE ON CONTRACEPTION
ACCEPTABLE METHODS FOR PROTOCOLS WITH A TERATOGENIC DRUG OR WHEN 
THERE IS INSUFFICIENT INFORMATION TO DETERMINE TERATOGENICITY
(CHOOSE ONE OF THE FOLLOWING 3 OPTIONS)a
OPTION 1: Any TWO of the following methods
•
Hormonal methods of contraceptionb, c, d
•
IUDc, d, e
•
Vasectomyd, f
•
Tubal Ligationd
•
A Barrier method (Female or Male Condom with spermicide, Cervical Cap with spermicide, 
Diaphragm with spermicide)
OPTION 2:  Male condom (with spermicide) and diaphragmg
OPTION 3:  Male condom (with spermicide) and cervical capg
a The theoretical failure rate for any of the options listed is considerably less than 1% per year
b Excludes progestin-only pills
c Hormonal contraceptives may not be used for contraception unless a drug-drug interaction study has 
demonstrated that the pharmacokinetics of the hormone based contraceptive has not been adversely affected by 
the investigational drug in the protocol or there is compelling evidence to substantiate that investigational 
product(s) or con-meds will not adversely affect contraception effectiveness.  The PK scientist and MST chair 
must agree that the use of hormone-based contraception is safe and efficacious for WOCBP. The use of hormone-
based contraceptives is not otherwise restricted
d A highly effective method of birth control with a failure rate less than 1% per year
e IUDS used should have a failure rate less than 1% (highly effective method), such as Mirena and ParaGard
f Must be at least 90 days from date of surgery with a semen analysis documenting azoospermia
g These 2 barrier methods together are acceptable for a teratogenic drug
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UNACCEPTABLE METHODS OF CONTRACEPTION
Abstinence (including periodic abstinence)
No method
Withdrawal
Rhythm
Vaginal Sponge
Any barrier method without spermicide
Spermicide
Progestin only pills
Concomitant use of female and male condom
In countries where spermicide is not available or its use is not considered compatible with male 
condoms, use of a male condom without spermicide in conjunction with a hormonal method, 
IUD, or tubal ligation will be acceptable to fulfill this recommendation. Any barrier method 
when used alone (without spermicide) or the concomitant use of a female and male condom, is 
not considered a sufficient method of contraception, as each carries a failure rate of > 1%.
Women of childbearing potential (WOCBP) receiving BMS-936558 (nivolumab) will be 
instructed to adhere to contraception for a period of 23 weeks after the last dose of 
investigational product. Men receiving nivolumab and who are sexually active with WOCBP 
will be instructed to adhere to contraception for a period of 31 weeks after the last dose of 
investigational product. These durations have been calculated using the upper limit of the 
half-life for BMS-936558 (nivolumab) (25 days) and are based on the protocol requirement that 
WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with 
WOCBP use contraception for 5 half-lives plus 90 days after the last dose of BMS-936558 
(nivolumab).
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