A Randomized, Multicenter, Double-Blind, Phase 3 Study of Nivolumab, Nivolumab in Combination With Ipilimumab, or Placebo as Maintenance Therapy in Subjects With Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) After Completion of Platinum-based First Line Chemotherapy (CheckMate 451: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 451)
Phase: PHASE3
Conditions: Lung Cancer
Sponsor: Bristol-Myers Squibb



Clinical Protocol
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BMS-936558
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Revised Protocol No: 06
Date: 20-Sep-2018
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confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved.References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg,a Contract Research Organization 
(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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Date: 20-Sep-2018
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 06
20-Sep-2018
Moved OS ofnivolumab vs placebo to secondary objectives
The associated power analysis was updated for the primary 
objective to reflect nivolumab in combination with ipilimumab vs 
placebo. Subsequently,number of events required for primary 
analysis of OS was changed from 593 to 386.
Addedprohibited live / attenuated vaccine during treatment and 
until 100 days post last doseto prohibited and/or restricted 
treatments.
Updated study personnel
Revised 
Protocol 05
14-Jul-2018
BICR-assessed PFS was changed as a primary objective to 
secondary objectiveand the associated interim analysis was 
removed
Tumor mutationalburden (TMB) added as a potential predictive 
biomarker secondary objective
The number of events required for primary analysis of OS was 
changed from 576 events to 593events
Study personnel was updated
Revised 
Protocol 04
19-Oct-2017
Details of tissue requirements updated 
Maximum treatment duration added
Contraception language updated to program standards
Exclusion criteria added botanical preparations 
Prohibited/restricted treatments updated
Dose modifications were updated to program standards
Immune-mediated adverse events description added
RECIST 1.1 updated as per BMS standards
Revised 
Protocol 03
31-Aug-2016
Incorporates Amendment 11
Amendment 11
31-Aug-2016
Extended the time to randomization and modified tissue requirements 
for eligibility. The period following last dose of chemotherapy has 
been extended from 7 to 9 weeks (and from 9 to 11 weeks if patients 
undergo PCI). Updates based on nivolumab IB.Changed the 
requirement to collect amylase and lipase to amylase orlipase. Added 
amylase orlipase testing to follow up requirements. Clarified the 
exploratory objective to measure time to symptomdeterioration 
includes the nivolumab monotherapy arm, the timing for PFS analysis 
was specified to be approximately around 6 months after last patient is 
randomized, dose modifications, criteria to resume treatment and 
discontinuation criteria were and safety algorithms were updated. 
Revised 
Protocol 02
11-May-2016
Incorporates Amendment 10
Amendment 10
11-May-2016
Corrected typographical errors and update to match BMS protocol 
model document, provided time for males who are sexually active 
with a WOCBP to use contraception in section 3.3.1 number 3, 
removed language that IP cannot be destroyed from section 4.8, added 
a bullet to OS language in section 8.1 and removed -from section 
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OVERALL RATIONALE FOR REVISED PROTOCOL 06:
After removingthe PFS as co-primary endpoint for the two treatmentarms(vs placebo) in revised 
protocol 05, revised protocol 06 modifiesthe CA209451endpoints in order to have OS of 
nivolumab plus ipilimumab vs placebo as the only primary endpoint. OS for nivolumab vs placebo 
will be tested hierarchically as a secondary endpoint,thus allowing for the use of the full 5% alpha 
on the OS for the nivolumab plus ipilimumab combination vs placebo. 
At the time of study design, there were very limited data about immunotherapy in SCLC, mostly 
with single agent PD-1 inhibitors and less so with immunotherapy combinations of PD-1/CTLA4 
inhibitors. Therefore, the rationale for removing OS from nivolumab monotherapy vs placebo as 
a co-primary endpoint in CA209451 is based on more mature data from the SCLC cohorts in 
CA209032 and from recently published data with immunotherapy in the SCLC maintenance 
setting.
Nivolumab plus ipilimumab showed, in fact, superior efficacy to nivolumab in the randomized 
SCLC cohorts in CA209032, with a statistically significanthigher ORR.1Additionally,in asimilar 
setting to the CA209451 study, pembrolizumab as a maintenance therapy showed a median OS of 
9.6 months in patients with SCLC that did not progress after 1L chemotherapy in a single arm 
study.
2This is not superior to the expected OS with observation only as per current standard of 
care, thus suggesting a potential for a more significant clinical benefit for the combination 
immunotherapy approach as compared to single agent. Additionally, the DMC has monitored the 
CA209451 study every 6 months and has not identified any safetysignal in either the nivolumab 
plus ipilimumab arm or the nivolumab arm.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Synopsis, 
Section 1.3.1 Primary Objectives
Section 1.3.2 Secondary Objectives
Figure 3.1-1 Schema
Section 5.4.2 Primary and 
Secondary Efficacy Assessments
Section 8.3.2 Secondary Endpoints
Section 8.4.2 Efficacy Analyses
OS of nivolumab vs placebo moved to 
secondary objective
Data from the SCLC 
cohorts with 
immunotherapy in the 
SCLC setting supports 
change in study design.
Synopsis 
Section 8.1 Sample Size 
Determination
The associated power analysis was updated for 
the primary objective to reflect nivolumab in 
combination with ipilimumabvs placebo. 
Subsequently, number of events required for 
primary analysis of OS was changed from 593 
to 386.
New power analysis 
implemented for 
updated primary 
objective.
Section 3.4.1 Prohibited and/or 
Restricted Treatments
Addedprohibited live / attenuated vaccine 
during treatment and until 100 days post last 
doseto prohibited and/or restricted treatments.
Align with nivolumab 
program standards for 
safety
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SYNOPSIS
Clinical ProtocolCA209451
Protocol Title:A Randomized, Multicenter, Double-Blind, Phase 3 Study of Nivolumab, Nivolumab in 
Combination with Ipilimumab, or Placebo as Maintenance Therapy in Subjects with Extensive-Stage Disease Small 
Cell Lung Cancer (ED-SCLC) after Completion of Platinum-basedFirst Line Chemotherapy
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):
This is a randomized, double-blind, three-arm, multicenter, Phase 3 study in adult subjects with ED-SCLC, who 
achieve Stable Disease, Partial Response or Complete Response after completion of platinum based first line 
chemotherapy.
Approximately 810 subjects will be randomized in a 1:1:1 ratio to treatment with either nivolumab monotherapy 
(Arm A), nivolumab/ipilimumab combination therapy (Arm B), or placebo (Arm C), and will be stratified according 
to the following factors:
ECOG Performance Status: 0 vs 1 
Gender: Male vs Female 
Prophylactic Cranial Irradiation (PCI) following chemotherapy: Yes vs No
The treatment arms are as follows:
Arm A:
Nivolumab 240 mg administered every 2 weeks as a 30 min IV infusion
Arm B:
Nivolumab 1 mg/kg (30 min IV infusion) and ipilimumab 3 mg/kg (90 minute IV infusion) every 3 weeks for 
fourdoses, followed by nivolumab 240 mg every 2 weeks.
Arm C:
Placebo
In order to maintain a blinded study, the schedule of investigational and placebo treatments is divided into 
two6-week cycles at the start of therapy, followed by ongoing 2-week cycles until discontinuation criteria are met.
On-study tumor assessments will be conducted every 6 weeks (± 5 days) for the first 36weeks. After Week 36, 
tumor assessments will be performed every 12 weeks (± 5 days) until disease progression 
Duration of the study from start of randomization to analysis of the primary endpoint will be approximately 
35months (28 months of accrual + 7months of minimum follow-up, providing an average follow up of 9months).
Additional survival follow-up may continue for up to 5years from the primary analysis of survival. The study will 
end once survival follow-up has concluded.
Study Phase:III
Research Hypothesis:
Maintenance treatment with nivolumab monotherapy, or nivolumab in combination with ipilimumab followed by 
nivolumab monotherapy, will prolong overall survival (OS) as compared with placebo in subjects with ED-SCLC 
who have completed platinum-based first line chemotherapy.
Objectives:
Primary Objectives:
To compare OS of nivolumabin combination with ipilimumabversus placebo in subjects with ED-SCLC after 
completion of platinum-based first line chemotherapy.
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Study Design:  
Study Population:
Key Inclusion Criteria
1) Subjects with SCLC documented by histology or cytology from brushing, washing or needle aspiration of a 
defined lesion, but not from sputum cytology alone.
2) Subjects must have presented at initial diagnosis with extensive stage disease (defined as Stage IV (T any, 
Nany, M1a/b) per NCCN guidelines Version 1.2015, AJCC Cancer Staging Manual, 7th Edition, 2010).
3) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. (See Appendix 1)
4) Subjects must have received 4 cycles of platinum-based first line chemotherapy and must have an ongoing 
response of complete response (CR), partial response (PR), or stable disease (SD) after completion of 
chemotherapy. Acceptable combinations, as recommended per NCCN guidelines, include cisplatin or 
carboplatin combined with either etoposide or irinotecan.
a) As an exception to the above criterion, subjects receiving only 3 cycles of chemotherapy due to toxicity are 
eligible, if they have an ongoing PR or CR after the 3rd cycle.
b) Subjects who have received > 4 cycles of platinum-based first line chemotherapy are not eligible
5) Subjects must be randomized 9 weeks (63 days), from the last dose of platinum-based first line chemotherapy. 
Subjects receiving PCI or brain RTmust be randomized 11 weeks (77 days) of the last dose of platinum-
based first line chemotherapy.
a) Study therapy must notbe administered <3 weeks (21 days) from the last dose of platinum-based first line 
chemotherapy.
b) Blinded study therapy must not be administered < 2 weeks (14 days) from the last dose of radiotherapy.
6) A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (preferred) or 10 unstained slides of tumor 
sample (archival or recent) for biomarker evaluation must be available and submitted to the central lab for 
correlative studies in order for a subject to be randomized.If fewer than 10 slides are available, the BMS 
Medical Monitor or Study Director may approve randomization of subject upon review of the case. Specimens 
must have been submitted to the central laboratory prior to randomization. Excisional, incisional o
r core needle 
biopsies are strongly preferred, however samples collected via endobronchial ultrasound (EBUS) guided biopsy 
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(using a 22g needle or larger) and transbronchial lung biopsy (TBLB) are acceptable. In certain cases, the BMS 
Medical Monitor or Study Director may approve submission of samples collected via other methods. 
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-936558
Medication 
Potency 
IP/Non-IP 
Nivolumab Solution for Injection
100 mg (10 mg/mL)
IP
Ipilimumab Solution for Injection
200 mg (5 mg/mL)
IP
0.9% Sodium Chloride for Injection
N/A
IP
5% Dextrose for Injection
N/A
IP
Study Assessments:
Safety assessments include AEs, physical examinations, vital signs, ECOG performance status, assessment of signs 
and symptoms, laboratory tests, pregnancy tests.
Some of the previously referred to assessments may not be captured as data in the eCRF. They are intended to be 
used as safety monitoring by the treating physician. Additional testing or assessments may be performed as 
clinically necessary or where required by institutional or local regulations
Statistical Considerations:
Sample Size: Approximately 810 subjects will be randomized to three treatment arms in a 1:1:1 ratio. The primary 
objective is to compare OS of nivolumab in combination with ipilimumab versus placebo. 
The analysis of primary endpoint of OS will be conducted when at least 386deaths have been observed pooled 
across the nivolumab in combination with ipilimumab and the placebo treatment groups. It is expected that 208
events will be observed in placebo and 178in theexperimentalarm. With 386events available for comparison of 
OS in nivolumab in combination with ipilimumabtreatmentgroup vs placebo, power of the log-rank test is 
approximately 90% to detect a hazard ratio (HR) of 0.72 with a type I error of 0.05(two-sided). Power calculations 
were performed using EASTSoftware. For nivolumab in combination with ipilimumab, a 3months delay effect
versus placebo and an HR of 0.68post delay was assumed, resulting into an overall HR (experimental vs placebo) of 
0.72at time of the OS analysis. Survival functionfor placeboarm was modeledusing a four hazard pieces to match 
historical data. Median OSderived from the survival functions were8.8 and 11.0months for the placebo and 
experimental arms, respectively.
Given the observed accrual, it is expected that the duration of the study from start of randomization to analysis of 
primary endpoint will be approximately 35months (28 months of accrual + 7months of follow-up, providing an 
average follow up of 9 months).
The independent Data Monitoring Committee (DMC) will have access to periodic interim safety and efficacy reports 
to allow for a risk/benefit assessment.
Analyses:TheOS analyses will be conducted using atwo-sided log-rank test stratified by the stratification factors 
in allrandomized subjects to compare each of the two experimental treatments to the control group.Hierarchical 
procedure will be used to control the overall Type I error rate at 0.05. The secondary endpoint, OS comparing 
nivolumab monotherapy vs placebo, will be tested using 2-sided 5% alpha, if superiority of nivolumab in 
combination with ipilimumab over placebo is demonstrated at the 5% significance level. HRs and corresponding 
two-sided CIs will be estimated using a Coxproportionalhazards model, with treatment group as a single covariate, 
stratified by the above factors. OScurves, OS medians with 95% CIs, and OS rates at 6, 12, and 18 months with 
95% CIs will beestimated using Kaplan-Meier methodology.
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toxicities are typically manageable or reversible with the Management Algorithms provided in 
Appendix 2and the nivolumab IB.
To assure an ongoing favorable benefit-risk assessment forsubjects enrolled onto CA209451, an 
independent Data Monitoring Committee (DMC) will be utilized to monitor the safety and efficacy 
of nivolumab versus nivolumab and ipilimumab versus placebo throughout the conduct of the trial.
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)and applicable local requirements.
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 BMSimmediately. 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 BMSshould also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labelinginformation to be provided to subjects and any updates. 
The investigator or BMSshouldprovide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments,and administrative letters)accordingto 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.
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In situations where consent cannot be given to subjects, their legally acceptable representatives(as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate.
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:
1) 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.
2) Allow time necessary for subject or subject
's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject
's legally 
acceptable representative andby the person who conducted the informed consent discussion.
4) 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.
5) 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 herinformedconsent during the study, consent must additionally be obtained from the 
subject.
6) 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. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her
understanding, and should this subject become capable, he orshe should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
herwritten consent, but who is capable of forming an opinion and assessing information to refuse 
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participation in, or tobe withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a randomized, double-blind, three-arm, multicenter, Phase 3 study in adult subjects with 
ED-SCLC, who achieve Stable Disease, Partial Response or Complete Responseafter completion 
ofplatinum basedfirst line chemotherapy.
Approximately 810 subjects will be randomized in a 1:1:1 ratio to treatment with either nivolumab
monotherapy (Arm A), nivolumab/ipilimumab combination therapy (Arm B), or placebo (Arm C), 
and will be stratified according to the following factors:
ECOG Performance Status: 0 vs 1 
Gender: Male vs Female 
Prophylactic Cranial Irradiation (PCI) following chemotherapy: Yes vs No
The treatment arms are as follows:
Arm A:
Nivolumab 240 mg administered every 2 weeks as a 30 min IV infusion, as described in Table 4.5-
1and Table 4.5-2
Arm B:
Nivolumab 1 mg/kg (30 min IV infusion) and ipilimumab 3 mg/kg (90 minute IV infusion) 
every 3 weeks for four doses, followed by nivolumab 240 mg every 2 weeks, as described 
in Table 4.5-1and Table 4.5-2
Arm C:
Placebo administered as described in Table 4.5-1and Table 4.5-2
In order to maintain a blinded study, the schedule of investigational and placebo treatments is 
divided into two 6-weekcycles at the start of therapy, followed by ongoing 2-week cycles until 
discontinuationcriteria are met (Section 4.5.3.4). This schedule is described in Table 4.5-1and 
Table 4.5-2.
On-study tumor assessments will be conducted every 6 weeks (5 days) for the first 36weeks. 
After Week 36, tumor assessments will be performed every 12 weeks (5 days) until disease 
progression(Section 5.4).
Duration of the study from start of randomization to analysis of the primary endpoint will be 
approximately 37 months (28 months of accrual + 9 months of follow-up).
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Additional survival follow-up may continue for up to 5 years from the primary analysis of survival. 
The study will end once survival follow-up has concluded.
The subjects safety will be monitored on an ongoing basis as described fully in Section 5.3. In 
addition, a BMS Medical Safety Team (MST) routinely reviews safety signals across the 
nivolumab program.
A Data Monitoring Committee (DMC) will be implemented to provide safety and overall 
risk/benefit monitoring of the study (Section 7).
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
The start of the trial is defined as first visit for the first subject screened. The end of trial is 
defined as the last visit for the last subject. Study completion is defined as the final dateon 
which data for the primary endpoint was collected.
3.1.1
Study Phases
The study is divided into the following phases: Screening, Treatment, and Follow-up.
3.1.1.1
Screening
Screening begins after the subject signs the informed consent form (ICF)
The subject is enrolled using the Interactive Voice Response System (IVRS)
Tumor tissue must be available and submitted to the central lab for correlative studies in order 
for a subject to be randomized(except as described in Inclusion Criteria 2f). Subjects must 
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consent to allow the acquisition of tumor tissue by study personnel for performance of the 
correlative studies
Baseline assessments must be performed within the timeframes described in Table 5.1-1:
Prophylactic Cranial Irradiation (PCI) may be offered to subjects following the completion of 
first-line chemotherapy, per local standard of care
For patients with known brain metastases, brain radiotherapy (Whole Brain Radiation Therapy 
(WBRT) orstereotactic radiation)may be offered , per local standard of care
Brain radiotherapy(including PCI)must be completed 2 weeks prior to the start ofblinded
study therapy
Subjects with incidental asymptomatic brain metastasis findings at screening are eligibleonly
if,according to the clinical judgment of the investigator,thesefindings areunlikely to represent 
progression of diseaseafter chemotherapy. 
Randomization must be performed9weeksfrom the last dose of chemotherapy for subjects
not receiving brain radiotherapy(including PCI)and 11 weeks from the last dose of 
chemotherapy for subjects receiving brain radiotherapy(including PCI)
Blinded study therapy must notbe administered <3weeks (21 days) from the last dose of 
platinum-based first line chemotherapy.
The screening phase either ends with confirmation of full eligibility and randomization of the 
subject or with the confirmation that the subject is a screen failure
This study permits the re-enrollment of a subject that has discontinued the study as a 
pre-treatment failure prior to randomization. If re-enrolled, thesubject must be re-consented. 
A new subject identification number will be assigned by IVRS at the time of re-enrollment.
3.1.1.2
Treatment
The treatment phase begins with the randomization call to the IVRS. The subject is randomly 
assigned to one of the 3 treatment arms. Treatment is tobegin within 3 business days of 
randomization
Blinded study therapyis administered as described in Table 4.5-1until disease progression, 
discontinuation due to toxicity,withdrawal of consent, the study ends, orother criteria for 
discontinuationare met as described in Section 3.5and 4.5.3.4.Subjects may be treated beyond 
initial progression as specifiedin Section 5.4
Subjects will be evaluated for response according to RECIST 1.1 criteria. Radiographic 
assessments will be obtained in all treatment arms every 6 weeks for the first 36weeks, and 
subsequently every 12 weeks, or more frequently as clinically indicated,until disease 
progression (or until discontinuation of blinded study drug in patients treated beyond 
progression)or withdrawal of study consent
The Treatmentphase ends when the subject is discontinued from blinded study drug(s)
Study assessments are to be collected as outlined in Table 5.1-2andTable 5.1-3.
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3.1.1.3
Follow-up
Begins when the decision to discontinue a subject from blinded study therapyis made (no 
further treatment with blinded study drug(s))
Subjects who discontinue blinded study therapyfor reasons other than disease progression will 
continue to have radiographic assessments every 6 weeks (5 days) for the first 36weeks after 
randomization, and subsequently every 12 weeks, until disease progression or withdrawal of 
study consent
Follow up visits occur as follows: 
X01 Follow up Visit 1 = 35 days 7days from last dose
XFollow up Visit 2days7 days from X01 Follow Up Visit 1
Survival Follow Up visitsbegin after the X02 Follow Up Visit 2:
For Survival Follow Up Visits, for all subjects, contact will be made (in person or by 
telephone) every 12 weeks upon entry into this phase to evaluate Overall Survival and 
collect data on the initiation of subsequent therapy for the treatment of SCLC
Study assessments are to be collected as outlined inTable 5.1-4.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects assigned to active study drug who continue to demonstrate 
clinical benefit will be eligible to receive BMS supplied study drugfor the maximum of 24 months 
including time on-study treatment. 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 BMS 
supplied 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 and other requirements of the study
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2. Target Population
a) Subjects with SCLC documented by histology or cytology from brushing, washing or 
needle aspiration of a defined lesion, but not from sputum cytology alone
b) Subjects must have presented at initial diagnosis with extensive stage disease (defined as 
Stage IV (T any, N any, M1a/b) per NCCN guidelines Version 1.2015, AJCC Cancer 
Staging Manual, 7th Edition, 2010)
c) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
(SeeAppendix 1)
d) Subjects must have received 4 cycles of platinum-based first line chemotherapy and must 
have an ongoing response of complete response (CR), partial response (PR), or stable 
disease (SD) after completion of chemotherapy. Acceptable combinations, as 
recommended per NCCN guidelines, include cisplatin or carboplatin combined with either 
etoposide or irinotecan
i) As an exception to the above criterion, subjects receiving only 3 cycles of 
chemotherapy due to toxicity are eligible, if they have an ongoing PR or CR after the 
3rd cycle
ii)Subjects who have received > 4 cycles of platinum-based first line chemotherapy are 
not eligible
e) Subjects must be randomized 9weeks (63days), fromthe last dose of platinum-based 
first line chemotherapy. Subjects receiving PCI or Brain RT must be randomized 11 
weeks (77days)fromthe last dose of platinum-based first line chemotherapy
i) Blinded study therapy must notbe administered <3 weeks (21 days) from the last dose 
of platinum-based first line chemotherapy
ii)Blinded study therapymust not be administered < 2 weeks (14 days) from the last dose 
of radiotherapy
f) A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (preferred) or 10 
unstained slides of tumor sample (archival or recent) for biomarker evaluation must be 
available and submitted to the central lab for correlative studies in order for a subject to be 
randomized. If fewer than 10 slides are available, the BMS Medical Monitor or Study 
Directormay still approve randomization of subjects upon review of the case. Specimens 
must have been submitted to the central laboratory prior to randomization. Excisional, 
incisional or core needle biopsies are strongly preferred, however samples collected via 
endobronchial ultrasound (EBUS) guided biopsy (using a 22g needle orlarger) and 
transbronchial lung biopsy (TBLB) are acceptable. In certain cases, the BMS Medical 
Monitor or Study Director may approve submission of samples collected via other 
methods.
g) Subject Re-enrollment: This study permitsthe 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 ageor age of majority inclusive.
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b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24hours 
prior to the start of blinded study drug
c) Women must not be breastfeeding
d) WOCBP mustagree tofollow instructions for method(s) of contraception for the duration 
of treatmentwith blinded study drug (s) plus the time required for the investigational drug 
to undergo approximately five half-lives plus 30 days (duration of ovulatory cycle) for a 
total of 5 monthspost-treatment completion
e) Maleswho are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with blinded study drug (s)plus 
the time required for the investigational drug to undergo approximately five half-lives plus 
90 days (duration of sperm turnover) for a total of 7 monthspost-treatment completion
f) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise on the use of highly effective methods of contraceptionwhich have a 
failure rate of < 1% when used consistently and correctly.
a) Males, ages 18 or age of majority, inclusive
b) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug(s) blinded study 
therapy plus the time required for the investigational drug to undergo approximately five 
half-lives plus 90 days (duration of sperm turnover) for a total of 7 monthspost-treatment 
completion.
c) Azoospermic males are exempt from contraceptive requirements. 
d) Male subjects must be willing to refrain from sperm donation during the entire study and 
for the time required for the investigational drug to undergo approximately7 months after 
the end of study treatment.
Investigators shall counsel male subjects who are sexually active with WOCBP on the importance 
of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall 
advise male subjects who are sexually active with WOCBP on the use of highly effective methods 
of contraception. Highly effective methods of contraception have a failure rate of < 1% when used 
consistently and correctly.
At a minimum, subjects must agree to the use of one highly effective method ofcontraception as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use 
one of the highly effective methods of contraception listed below. Male subjects must inform their 
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female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as follows:
Highly Effective Contraceptive Methods That Are User Dependent 
Combined (estrogen-and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationa
oral 
intravaginal 
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationa 
oral 
injectable 
Highly EffectiveMethods That Are User Independent
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone,vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)b
Intrauterine device (IUD)b
Bilateral tubal occlusion
Vasectomizedpartner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
It is not necessaryto use any other method of contraception when complete abstinence is 
elected. 
WOCBP participantswho choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
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NOTES: 
a Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
b Intrauterine devices and intrauterine hormonereleasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
Diaphragm with spermicide
Cervical cap with spermicide
Vaginal Sponge with spermicide
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal (coitus interruptus).
Spermicide only
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Symptomatic CNS metastasesare excluded. Subjects with previous brainmetastases are 
eligible provided that they are asymptomatic, do not require treatment with radiation
therapy, steroids or anticonvulsants, and have stable disease at the screening tumor 
assessment. In addition, subjects must have been either off corticosteroids, or on a stable 
or decreasing dose of 10 mg daily prednisone (orequivalent).Blinded study 
therapy must 
not be administered < 2 weeks (14 days) from the last dose of radiotherapy 
b) Subjects receiving consolidative chest radiation are excluded. 
c) Carcinomatous meningitis
d) Pleural effusion which cannot be controlledwith appropriate interventions
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e) All toxicities attributed to prior anti-cancer therapy must have been resolved to Grade1 
(NCI CTCAE Version 4) or baseline before administration of blinded study drug(s)other 
than:
i) Subjects with toxicities attributed to prior anti-cancer therapy thateitherare not 
expected to resolve and/orresult in long lasting sequelae, such as neuropathy after 
platinum based therapy, orare not expected to interfere with treatment on study, such 
as fatigueoralopecia, are eligible
ii)Subjects with grade 2 anemia, however hemoglobin level must be 8.0 g/dL
2. Medical History and Concurrent Diseases
a) Women who are pregnantor breastfeeding
b) Active, known or suspected autoimmune disease. Subjects with an autoimmune 
paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded. 
Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll
c) A condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Corticosteroids with minimal systemic absorption (inhaled or topical 
steroids), and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are 
permitted in the absence of active autoimmune disease
d) Prior 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 Tcell 
co-stimulation or checkpoint pathways)
e) Interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected drug-related pulmonary toxicity
f) Previous malignancies (except non-melanoma skin cancers, and the following in situ 
cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) 
unless a complete remission was achieved at least 2 years prior to study entry AND no 
additional therapy is required during the study period
g) Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or blinded study drug(s)administration or interfere with 
the interpretation of safety results
h) Major surgery or significant traumatic injury that is not recovered at least 14 days before 
the first dose of blinded study drug(s)
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3. Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or 
positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV 
antibody test indicating acute or chronic infection
i) Subjects with a positive test for HCV antibody but no detection of HCV RNA 
indicating nocurrent infection are eligible
b) Known medical history of testing positive for human immunodeficiency virus (HIV) or 
known medical history of acquired immunodeficiency syndrome (AIDS). 
c) Inadequate hematologic function defined by:
i) Absolute neutrophil count (ANC) < 1,000/mm3.
ii)Platelet count < 100,000/mm
3, or
iii)Hemoglobin level < 8.0g/dL
d) Inadequate hepatic function as defined by either:
i) Total bilirubin level 1.5 times the ULN(except subjects with Gilbert’s Syndrome, 
who are excluded if total bilirubin 3 times ULN), or
ii)AST and ALT levels 2.5 times the ULN or 5 times the ULN if liver metastases 
are present
e) Inadequate pancreatic function as defined by either:
i) Lipase >1.5 ULN. Subjects with lipase > 1.5 ULN may enroll if there are neither 
clinical nor radiographic signs of a pancreatitis, OR
ii)Amylase > 1.5 ULN. Subjects with amylase > 1.5 ULN may enroll if there are neither 
clinical nor radiographic signs of a pancreatitis
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to any of the study drugs or study drug components
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines derived from plants, minerals, or animals) intended for general health support 
or to treat the disease under study within 2weeks prior to randomization/treatment
Eligibility criteria for this study have been carefully considered to ensure the safety of thestudy 
subjects andthat the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
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oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 
40mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their judgment
in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the 
washout period, the woman can be considered postmenopausal:
1 week minimum for vaginal hormonal products (rings, creams, gels)
4 week minimum for transdermal products
8 week minimum for oral products
Postmenopausal women may continue HRT after FSH testing is completed and postmenopausal 
status is confirmed.
Other parenteral products may require washout periods as long as 6 months.
3.4
ConcomitantTreatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited duringthe study:
Immunosuppressive agents (except to treat a drug-related AE or an autoimmune paraneoplastic 
syndrome). Subjects with an autoimmune paraneoplastic syndrome at enrollment requiring 
concurrent immunosuppressive treatment are not eligible.
Thymosin, thymalfasin, and thymopentinare prohibited
Systemic corticosteroids > 10 mg daily prednisone equivalent, except as stated in Section3.4.3
or to treat a drug-related AE
Any concurrent systemic antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, standard or investigational agents for the treatment of cancer).
Surgical resection of tumor
Any botanical preparations (eg herbal supplements or traditional Chinese medicines derived 
from plants, minerals, or animals) intended to treat the disease under study or provide 
supportive care
Note: thefollowing radiotherapyis permitted
Palliative bone radiotherapy as described in section 3.4.2
Palliative radiotherapy to asingle metastatic site,other than bone,in subjects whodo not 
require immediate initiation of second line systemic anti-cancer therapy. See Section 3.4.2
for additional restrictions.
Any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oralpolio and 
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.
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3.4.2
OtherRestrictions and Precautions
Blinded study therapy must be resumed 6 weeks from the last dose or the subject must be 
permanently discontinued fromblindedstudy therapy.(See exceptionsin Sections 3.5and 4.5.3.4
Discontinuation Criteria)
Non-target bone lesions that do not include lung tissue in the planned radiation field may receive 
palliative radiotherapy at any time while on study treatment. Radiotherapy to non-bone lesions is 
permitted only as described in Section 3.4.1. 
Study treatment must be withheld during radiotherapy 
and for two weeks after completion of radiotherapy. Details of palliative radiotherapy should be 
documented in the source records and case report form (CRF). Details in the source records should 
include: dates of treatment, anatomical site, dose administered and fractionation schedule, and 
AEs.
Subjects requiring palliative radiotherapy should be carefully assessed for disease progression. 
Subjects considered as having progressive disease are required to discontinueblindedstudy 
therapy, unless eligible tocontinue treatmentbeyond progressionper the guidance in Section 5.4
(Treatment Beyond Disease Progression).
3.4.2.1
Imaging Restrictions and Precautions
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg,allergy 
history, diabetic history and renal status), the appropriate imaging modality and contrast regimen 
for each subject. Imaging contraindications and contrast risks should be considered in this 
assessment. Subjects with renal insufficiency should be assessed as to whether or not they should 
receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, subjects 
with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
<30mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this subject population. In addition, subjects are excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
3.4.3
Permitted Therapy
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses including 
doses >10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids 
for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Postmenopausal women may continue HRT after FSH testing is completed and postmenopausal 
status is confirmed.
Concomitant palliative and supportive care for disease-related symptoms (including 
bisphosphonates and RANK-L inhibitors) are allowed. See Section 3.4.2for guidance on 
concomitant palliative radiotherapy
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3.5
Discontinuationof Subjects following anyTreatmentwith Study Drug(s)
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
Disease progression as assessed by RECIST 1.1 criteria (Appendix 3), unless the subject meets 
criteria for treatment beyond progression (Section 5.4)
Subject’s request to stop study treatment
Any clinical adverse event (AE), laboratoryabnormalityor 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
Termination of thestudy by Bristol-Myers Squibb (BMS)
Loss of ability to freely provide consent through imprisonment or involuntarilyincarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
Unblinding a subject for any reason (emergency or non-emergency)
Additional protocol-specified reasons for discontinuation, as described in Section 4.5.3.4
In the case of pregnancy,the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, the blinded study drug(s)will be permanently discontinued in an appropriate 
manner. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of blinded study drug(s), a discussion betweenthe investigator and the Sponsor or 
designee must occur.
All subjects who discontinue blinded study drug(s)should comply with protocol specified follow-
up procedures as outlined in Section 5. Theonly 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).
Subjects must be followed for at least 100 days after the last dose of blinded study therapy. Follow-
up (FU1) occurs approximately 35 days (+/-7 days) after last dose of coinciding with the date of 
discontinuation (+/-7 days) if the date of discontinuation is greater than 35 days after the last dose. 
Follow up visit 2 (FU2) occurs approximately 80 days (+/-7 days) after FU1. Survival visits are 
every 3 monthsfrom FU2 up to 5 yearsand may be conducted during a clinic visit or via the phone. 
The endpoint of this study isOS,and so tracking reporting the subject’s status in the follow up 
setting according to the protocol guidelines for disease progression and survival are critical to the 
final study analysis. The importance of follow up should be clearly communicated to study 
subjects.
If blinded study drug(s)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.
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3.6
Post Study DrugStudy Follow up
In this study,overall survivalis a keyendpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects who 
discontinue study drugmust continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section5until death or the conclusion of the study.
BMS may request that survival data becollected on all randomized subjects outside of the protocol 
defined window (See Table 5.1-4). At the time of this request, each subject will be contacted to 
determine their survival status unless the subject has withdrawn consent for all contact.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue blinded study therapywill remain in the study and must 
continue to be followedfor 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, ifpossible. The 
withdrawal of consent should be explained in detailin the medical records by the investigator, as 
to whether the withdrawal is from further treatment with blinded study therapyonly 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.The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information.If after all attempts, the 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.
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4
STUDY DRUG
Study drugincludesboth Investigational [Medicinal] Product(IP/IMP)andNon-investigational [Medicinal] Product(Non-IP/Non-IMP) 
and can consist of the following:
Table 4-1:
Study Drugs for CA209451
Product Description/ 
Class andDosage Form
Potency
IP/Non-IMP
Blinded or Open Label
Packaging/ 
Appearance
Storage Conditions
(per label)
NivolumabSolution for 
Injection
100 mg (10 mg/mL)
IP
Open Labela
10 mL/vial (5 or 
10vials/carton)
Store at 2°-8°C. Protect 
from light and freezing.
Ipilimumab Solution for 
Injection
200 mg (5 mg/mL)
IP
Open Labela
40 mL/vial 
(4vials/carton)
Store at 2°-8°C. Protect 
from light and freezing.
0.9% Sodium Chloride for 
Injection
N/A
IP
Open Labela
Various (local 
commercial product)
As per as per package 
insert
5% Dextrose for Injection
N/A
IP
Open Labela
Various (local 
commercial product)
As per as per package 
insert
a The term “open label” refers to the medication as it isupon receipt at the pharmacy. The trial will be conducted in a double-blinded fashion.
Pre-medications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations. Solutions used as diluent or placebo (ie, 0.9% Sodium Chloride Injection or 5% Dextrose Injection) 
should also be sourced by investigative sites if available and permitted by local regulations.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in someregions, 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 thanthe 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, the investigational medicinal products are:
Nivolumab 
Ipilimumab
Placebofor nivolumab(0.9% sodium chloride injection or 5% dextrose injection)
Placebo for ipilimumab(0.9% sodium chloride injection or 5% dextrose injection)
4.2
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. Non-investigational products should be sourced by the investigator sites 
if available and permitted by local regulations.
4.3
Storageof Study Drug
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.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Please refer to Section 9.2.2for guidance on IP records and documentation.
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5%dextrose 
injection) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations.
Please refer to the current version of the Investigator Brochure (IB)for complete storage, handling, 
dispensing, and infusion information for nivolumab, ipilimumab, and matching placebo.
The unblinded pharmacist will obtain treatment assignment by IVRS and prepare blinded drug.
The infusion duration of nivolumab/matching placebois 30 minutes and for ipilimumab/matching 
placebois 90 minutes.
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4.4
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:
Date that informed consent was obtained
Date of birth
Gender at birth
Once enrolled in IVRS, subjects that have met all eligibility criteria for whomtumor tissuehas 
been shipped to the central labwill be ready for treatment assignment and drug vial (nivolumab 
versus placebo) assignment through the IVRS. The following information is required for drug vial 
assignment:
Subject number
Date of birth
Tumor tissue must be available and submitted to the central lab
ECOG Performance Status: 0 vs 1
Gender: Male vs Female
Prophylactic Cranial Irradiation (PCI) following chemotherapy: Yes vs No
Subjects meeting all eligibility criteria will be randomized in a 1:1:1 ratioArm A (nivolumab), 
ArmB (nivolumab/ ipilimumab), or Arm C (placebo). Randomization will be achieved using the 
permuted blocks within each stratum.The randomization schedule will allocate subjects among 
the 3 treatment arms in a 1:1:1ratio.
The exact procedures for using the IVRS will be detailed in the IVRS manual.
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4.5
Selection and Timing of Dose for Each Subject
The dosing schedule is detailed in Table 4.5-1and Table 4.5-2.
Table 4.5-1:
Blinded Dosing Schedule (Cycles 1 and 2)
1 Cycle = 42 Days = 6 weeks
C1D1 
C1D8
C1D15
C1D22 
C1D29 
C1D36
ArmA 
(Nivo)
Nivo: 240 mg 
(24mL diluted to 
100 mL)
Ipi pbo: 100mL
N/A
Nivo: 240 mg 
(24mL diluted to 
100mL)
Nivo pbo: 
100mL
Ipi pbo: 100 mL
Nivo: 240 mg 
(24 mL diluted 
to 100 mL)
N/A
Arm B 
(Nivo + 
Ipi)
Nivo: 1 mg/kg 
(diluted to 100mL)
Ipi: 3 mg/kg 
(diluted to 100mL)
N/A
Nivo pbo: 
100mL
Nivo: 1 mg/kg 
(diluted to 
100mL)
Ipi: 3 mg/kg 
(diluted to 
100mL)
Nivo pbo: 
100mL
N/A
Arm C 
(Placebo)
Nivo pbo: 100 mL
Ipi pbo: 100 mL
N/A
Nivo pbo: 
100mL
Nivo pbo: 
100mL
Ipi pbo: 100 mL
Nivo pbo: 
100mL
N/A
Please note instructions below for reduced total volumes for subjects weighing <35 kg.
Table 4.5-2:
Blinded Dosing Schedule (Cycle 3+)
1 Cycle = 14 Days = 2 weeks
C3D1
C3D8
Arm A (Nivo) 
Nivo: 240 mg (24 mL diluted to 100 mL)
N/A
Arm B (Nivo + Ipi)
Nivo: 240 mg (24 mL diluted to 100 mL)
N/A
Arm C (Placebo)
Nivo pbo: 100 mL
N/A
All subjects will be monitored continuously for AEs while on study treatment. Treatment 
modifications (eg, dose delay, or discontinuation) will be based on specific laboratory and 
AEcriteria, as described in Sections 4.5.3and 4.5.4.
When study drugs (ipilimumab or nivolumab) or matched placebos are to be administered on the 
same day, separate infusion bags and filters must be used for each infusion. Nivolumab or 
nivolumab placebo is to be administered first. The second infusion will always be the ipilimumab 
or ipilimumab-placebo study drug, and will start no sooner than 30 minutes after completion of 
the nivolumab or nivolumab-placebo infusion.
Ipilimumab or ipilimumab-placebo must be diluted to 100 mL0.9% Sodium Chloride Solution or 
5%Dextrose solution. Nivolumab or nivolumab-placebo must be diluted to 100 mL 0.9% Sodium 
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Chloride Solutionor 5% Dextrose solution.The dilution volumes required to maintain the blind 
are described in Table 4.5-1and Table 4.5-2.
For weight-based dosing, if the subject’s weight on the day of dosing differs by >10% from the 
weight used to calculate the dose, the dose must be recalculated. All doses should be rounded up 
or to the nearest milligram per institutional standard. There will be no dose modifications allowed.
Subjects weighing <35 kg: For subjects weighing <35 kg, nivolumab and ipilimumab must be 
diluted to 50 mL in 0.9% sodium chloride or 5% dextrose solution. Matching placebo volumes 
must also be 50 mL to maintain the blind.
4.5.1
Dosing Windows
During Cycles 1 and 2:
Subjects may be dosed no less than 12 daysbetween
C1D1 and C1D15
C1D15 and C1D29
C1D29 and C2D1
C2D1and C2D15
C2D15 and C2D29
C2D29 and C3D1
Subjects may be dosed no less than 5 daysbetween
C1D15 and C1D22
C1D22 and C1D29
C2D15 and C2D22
C2D22 and C2D29
DuringCycle 3and beyond:
Subjects may be dosed no less than 12 days from the previous dose of drug
Subjects may be dosed up to 3 business days after the scheduled date if necessary, or longer in the 
event of a toxicity requiring dose delay. Subsequent dosing should be based on the actual date of 
administration of the previous dose of drug.
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.5.2
Study Medications
4.5.2.1
Nivolumab Monotherapy (Arm A)
For subjects randomized to Arm A, nivolumab 240 mg will be administered every 2 weeks as a 30 
min IV infusionuntil progression, unacceptable toxicity, withdrawal of consent, completion of 24 
months of treatment, or the study ends, whichever occurs first.Subjects should begin study 
treatment within 3 business days of randomization. The rationale for this dosage schedule is 
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provided in Section 1.1.6.In order to maintain a blinded study, the schedule of investigational and 
placebo treatments is divided into two 42-day cycles at the start of therapy, followed by ongoing 
2-week cycles. This dosing schedule is described in detail in Table 4.5-1and Table 4.5-2. 
Refer to the Investigator Brochure for more detail. There are no pre-medications recommended on 
the first cycle. If an acute infusion reaction is noted, subjects should be managed according to 
Section 4.5.6.
See Section 4.5.4for information on Management Algorithms for Immuno-Oncology Agents.
4.5.2.2
Nivolumab and Ipilimumab Combination Therapy (Arm B)
For subjects randomized to Arm B, nivolumab/placebo 1 mg/kg (30 min IV infusion) and 
ipilimumab 3mg/kg (90 minute IV infusion) will be administered every 3 weeks for 4 doses, 
followed by nivolumab 240 mg every 2 weeks until progression, unacceptable toxicity, withdrawal 
of consent, completion of 24 months of treatment, or the studyends, whichever occurs first. 
Subjects should begin study treatment within 3 business days of randomization. The rationale for 
this dosage schedule is provided in Section 1.1.7. In order to maintain a blinded study, the schedule 
of investigational and placebo treatments is divided into two 42-day cycles at the start of therapy, 
followed by ongoing 2-week cycles. This dosing schedule is described in detail in Table 4.5-1and 
Table 4.5-2.
Refer to the Investigator Brochure for more detail. There are no pre-medications recommended on 
the first cycle. If an acute infusion reaction is noted, subjects should be managed according to 
Section 4.5.6.
See Section 4.5.4for information on Management Algorithms for Immuno-Oncology Agents.
4.5.2.3
Placebo Therapy (Arm C)
For subjects randomized to Arm C, placebo (0.9% Sodium Chloride Solutionor 5%Dextrose)will 
be administered as described in Table 4.5-1and Table 4.5-2.
4.5.3
Dose Modifications and Delays
4.5.3.1
Dose Modifications
Dose reductions for the management of toxicities of individual subjects or dose escalations are not 
permitted. All dose modification rules apply to all treatment arms given the blinded natureof this 
study.
4.5.3.2
Dose Delays
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the event 
is attributed to nivolumab, ipilimumab, or both). All blinded study drugs must be delayed until 
treatment can resume.
Dose delay criteria also apply for the placebo version of each agent, given the blinded nature of 
this study.
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Blinded study therapyadministration should be delayed for the following:
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
Grade 2 drug related creatinine, AST, ALT and/or Total Bilirubin abnormalities
Any Grade 3 skin, drug-related adverse event
Any Grade 3,drug-related laboratory abnormality, with the following exceptions:
Grade 3 lymphopenia does not require dose delay
Grade 3 drug related amylase or lipase abnormalitythat are not associated with symptoms 
or clinical manifestations of pancreatitis do not require a dose delay
Grade 3drugrelated AST, ALT, or total bilirubin will require dose discontinuation (see 
section 4.5.3.3and section 4.5.3.4)
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of blinded study medication
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently as 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
4.5.3.3
Criteria to Resume Treatment
Subjects may resume treatment with blinded study therapywhen 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
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
Subjects with Grade 2AST/ALT and/or total bilirubinabnormalitiesmay resume treatment 
when laboratory values return to baseline and management with corticosteroids, if needed is 
complete.
Subjects with a combined Grade 2 AST/ALT AND Total Bilirubin values meeting 
discontinuation criteria (section 4.5.3.4) should have treatment permanently discontinued
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of steroid
taper over at least 1 month may be eligible for retreatment if discussed with and approved by 
the BMS Medical Monitor
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacementmay resume treatmentafter consultation with the BMS Medical Monitor.Adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement.
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol.  Doses should not be skipped.In particular, this is to ensure that subjects 
in Arm B will receive 4administrations of combined nivolumab and ipilimumab treatment if 
toxicity allows.
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If treatment is delayed > 6 weeks (42 days) from the last dosedue to blinded study drug-related 
toxicity, the subject must be permanently discontinued from blinded study therapy, except as 
specified in Section 4.5.3.4.In the event treatment is delayed >6 weeks due to reasons other than 
blinded study drug-related toxicity, the case should be discussed with the Medical Monitor before 
proceeding.
4.5.3.4
Discontinuation Criteria
Treatment with blinded study therapy should be permanently discontinued for the following:
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 AE lasting > 7 days, with the following exceptions:
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity,myocarditis, hypersensitivityreaction, or infusion reaction of any duration 
requires discontinuation
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Grade 3 drug-related AST.ALT or Total Bilirubin requires discontinuation 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
*In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ration that warrants continuation of 
study drug(s), a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.
Any Grade 4 drug-related AE 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 72hours 
of their onset
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations, or radiographic signs of pancreatitis. 
For Grade 4 endocrinopathy AEs such as hyper or hypothyroidosis, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone replacement 
(steroids, thyroid hormones) or glucose controlling agents, respectively, retreatment can be 
considered after discussion with the BMS Medical Monitor. 
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Any dosing delayslasting > 6 weeks from the last dose with the following exceptions:
Dosing delaysto allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a subject with a dosing delaylasting > 6 weeks 
from the last dose, the BMS Medical Monitor must be consulted
Dosing delays> 6 weeks from the last dose that occur for non-drug-related reasons may be 
allowed if approved by the BMS Medical Monitor
Any AE, laboratory abnormality, or intercurrentillness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued blinded study 
therapydosing
Tumor assessments for all subjects should continue as per protocol even if blinded study therapy 
dosing is delayed.Periodic study visits to assess safety and laboratory studies should continue at 
least every 6 weeks or more frequently if clinically indicated during such dosing delays.
4.5.4
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology agents are associated with AEs that can differ in severity and duration than AEs 
caused by other therapeutic classes. Nivolumab and ipilimumabare considered an 
immuno-oncology agentsin this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
Gastrointestinal
Renal
Pulmonary
Hepatic
Endocrinopathies
Skin
Neurological
While the ipilimumab investigator brochure contains very similar safety management algorithms 
for theseadverse events, the recommendation is to follow the nivolumab algorithms for 
immune-oncology agents (I-O) in order to standardize the safety management across the three 
blinded treatment arms.
The algorithms are found in the Nivolumab Investigator Brochure and Appendix 2ofthis protocol.
4.5.5
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease (PD).
35The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the subject is clinically deteriorating 
and unlikely to receive any benefit from continued blinded study therapy.
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Subjects will be permitted to continue treatment beyond initial RECIST 1.1 defined PD as long as 
all of the following criteria are met and clearly documented:
Investigator-assessed clinical benefit and no rapid disease progression;
Tolerating blinded study drug(s);
Stable performance status;
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression
Subject provides written informed consent prior to receiving additional blinded study therapy, 
using an ICF describing any reasonably foreseeable risks or discomforts, or other alternative 
treatment options
All decisions to continue treatment beyond initial progression must be discussed with the Medical 
Monitor and documented in the study records. The subject will continue to receive monitoring 
according to the Time and Events Schedules in Table 5.1-2and Table 5.1-3.
A radiographic assessment should be performed within 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD.
For the subjects who continue blindedstudy therapy beyond PD, further progression is defined as 
an additional 10% increase in tumor burden from time of initial PD. This includes an increase in 
the sum of all target lesions and/ or the development of new measurable lesions. For subjects with 
evaluable disease only, further progression is defined as unequivocal disease progression of non-
target lesions or the development of new lesions from time of initial PD. Treatment should be 
discontinued permanently upon documentation of further disease progression.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15mm). Any new lesion considered non-measurable at the time of initial progression 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 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.
For subjects in alltreatment arms, global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
(ie,radiographic confirmation) even after discontinuation of treatment.
4.5.6
Treatment of Nivolumab-or Ipilimumab-Related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic andinduce infusion or hypersensitivity reactions. However, if such a 
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reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo orhypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as a serious 
adverse event (SAE) if criteria are met. 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 50mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30minutes before 
additional blinded study therapyadministrations
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 24 
hours).
Stop the blinded study therapy infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve;if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further blinded study therapywill be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until resolution of 
symptoms. The amount of blinded study drug infused must be recorded on the case report form 
(CRF).
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) 
should be administered at least 30 minutes before additional blinded study therapy
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of
IVhydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae [eg, 
renal impairment, pulmonary infiltrates]). Grade 4: 
(life threatening; pressor or ventilatory support 
indicated).
Immediately discontinue infusion of blinded study therapy. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1mg 
of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
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methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the investigator is comfortable that the symptoms will not recur. Blinded study therapywill be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms.
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg,oral 
antihistamine, or corticosteroids)
4.6
Blinding/Unblinding
The Sponsor, subjects, investigator and site staff will be blinded to the study therapy administered. 
Each investigative site must assign an unblinded pharmacist/designee, and an unblinded site 
monitor will be assigned to provide oversight of drug supply and other unblinded study 
documentation.
Designated staff and associates of the Sponsormay be unblinded prior to database lock to facilitate 
the bioanalytical analysis of pharmacokinetic samples and immunogenicity. A bioanalytical 
scientist in the Bioanalytical Sciences department of Bristol-Myers Squibb Research & 
Development (or a designee in the external central bioanalytical laboratory) maybe unblinded to 
the randomized treatment assignments in order to minimize unnecessary bioanalytical analysis of 
samples.
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject
's management, the blind for that subject may be 
broken by the investigator. The subject’ssafety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject
's treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject
's immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product.It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
Emergency unblinding is available as an option in the IVRS. Consult IVRS Manual for instructions 
on Emergency unblinding).
In cases of accidental unblinding, contact the Medical Moni
tor and ensure every attempt is made 
to preserve the blind.Any request to unblind a subject for non-emergency purposes should be 
discussed with the Medical Monitor.
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4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and CRF.
4.8
Destruction or Return of Investigational Product
For this study, 
IP(those supplied by BMS, 
a vendoror sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site.
If
Then
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be 
destroyed after being inspected and reconciled 
by the responsible Study Monitor unless IP 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(e.g., cytotoxics or biologics).
If IP will be returned, the return will be 
arranged by the responsible Study Monitor.
IP sourced by site, not supplied by BMS (or its 
vendors) (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
It is the investigator’s or designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
On-site disposal practices must not expose humans to risks from the drug
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie,incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
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If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of IP provided by BMS (or its vendors).Destruction of non-IP sourced by the site, not 
supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2for guidance on IP records and documentation.
4.9
Retained Samples for Bioavailability / Bioequivalence
NotApplicable
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209451)
Procedure
Screening
Notes
Eligibility Assessments
Informed Consent
X
Informed Consent may be obtained at any time, provided it is prior to conduct of any study-
related procedures. Note that SAEs are collected from the date of consent.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to 
randomization
Medical History
X
Prior Systemic Therapy
X
Safety Assessments
Physical Examination
X
Physical Measurements
X
Include Height, Weight, and ECOG performance Status. Within 14 days prior to 
randomization
Vital Signs and Oxygen saturation
X
Temperature, BP, HR, and O2 saturation at rest by pulse oximetry. Obtain vital signs at the 
screening visit and within 72 hours prior to randomization.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization
Concomitant Medication Collection
X
Within 14 days prior to randomization
Laboratory Tests
X
CBC with differential, Chemistry panel including LDH, AST, ALT, ALP, T.Bili, BUN or 
serum urea level, uric acid, creatinine, Ca, Mg, Na, K, Cl, P, glucose, bicarbonates(optional),
albumin, amylase orlipase, TSH (reflex to free T3, free T4 for abnormal TSH result), hepatitis 
B surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) within 14 days prior to 
randomization.Screening labs done within 72 hours prior to first dose can also be used for on 
treatment lab purposes at Day 1 dosing.
ECG
X
Within 28 days prior to randomization
Pregnancy Test
X
Performed within 24 hours prior to first dose for WOCBP only (serum or urine -local/site)
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Table 5.1-1:
Screening Procedural Outline (CA209451)
Procedure
Screening
Notes
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment
X
CT/ Chest, CT/MRI Abdomen, Pelvis, and any other known sites of disease; MRI/CTBrain
(refer to section 5.4 for detail on cases where CT of the Brain is acceptable)
Within 21 days prior to randomization.
Additional sites of known or suspected disease (including CNS) should be imaged at the 
screening visit and at subsequent on-study assessments. 
Collection of tumor tissue for biomarker 
evaluation
X
See Section 3.3.1, Inclusion 2f
IVRS/Clinical Drug Supplies
Phone calls to IVRS
Phone calls must be made to IVRS as follows:
Screening phone call to IVRS: For subject number assignment at the time informed consent is 
obtained.
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Table 5.1-2:
On-Treatment Assessments for All Subjects, Cycle 1-2 [Cycle length 42 days]
Procedure
Cycle 1-2 
Day 1
Cycle 1 
Day 8
Cycle 1-2 
Day 15
Cycle 1-2 
Day 22
Cycle 1-2 
Day 29
Notes
Safety Assessments
Targeted 
Physical 
Examination
X
X 
X 
X
Within 72 hours prior to dosing
Vital Signs and 
Oxygen 
Saturation
X
X 
X 
X
Temperature, BP, HR, O2 saturationat restby pulse oximetry at rest (also 
monitor amount of supplemental oxygen if applicable) within 72 hours 
prior to dosing and at any time a subject has any new or worsening 
respiratory symptoms
Physical 
Measurements
X
X 
X 
X
Includes Weight and ECOG performance statuswithin 72 hours prior to 
dosing
Adverse Events 
Assessment
----------Continuously ----------
Assessed using NCI CTCAE v. 4.0. SAEs should be approved in TAO 
within 5 days from entry
Review of 
Concomitant 
Medications
X
X 
X 
X
Extended 
Laboratory Tests
X
X
X
Extended on-study local laboratory assessments should be done within 72 
hours prior to dosing on Days 1, 15, 29 and include: CBC with 
differential, uric acid,BUN or serum urea level, creatinine, Na, K, Ca, 
Mg, phosphorus, chloride, bicarbonate(optional),amylase orlipase, 
glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH.
Limited 
Laboratory Tests
X
Limited on-study local laboratory assessment should be done within 72 
hours prior to dosing on Days 22 and include: CBC with differential, 
AST, ALT, total bilirubin, alkaline phosphataseand creatinine.
Thyroid Function 
Testing
X
TSH (reflex to free T3 and free T4 if abnormal result) to be performed). 
(Day 1 of Cycle1 & 2 or within 72 hours prior to dosing)
Pregnancy Test
X
See Note
Serum or urine within 24 hours prior to first dose and then at least once 
every 4 weeks regardlessof dosing schedule.
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Table 5.1-2:
On-Treatment Assessments for All Subjects, Cycle 1-2 [Cycle length 42 days]
Procedure
Cycle 1-2 
Day 1
Cycle 1 
Day 8
Cycle 1-2 
Day 15
Cycle 1-2 
Day 22
Cycle 1-2 
Day 29
Notes
Efficacy Assessments
Radiographic 
Tumor 
Assessment
See Note
CT chest, CT/MRI abdomen, and any other knownor suspectedsites of 
disease.Repeat CT/MRI of pelvis is required for subjects with pelvic 
metastases at baseline, or if clinically indicatedSubjects with a history of 
brain metastasis should have surveillance MRI/CTof the brain(refer to 
section 5.4 for detail on cases where CT of the Brain is acceptable) every 
6 weeks, or sooner if clinically indicated.
SeeTable 5.4-1for CT and MRI scan schedule.
Additional Exploratory Biomarker Testing
Serum
Whole Blood
Tumor Biopsy
See Note
See Table 5.6-1of Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See Note
See Table 5.5-1of PK and Immunogenicity Sampling
Immunogenicity 
samples
See Note
See Table 5.5-1of PK and Immunogenicity Sampling
Outcomes Research Assessments
Patient Reported 
Outcomes (PRO)
X
X 
X 
X
For on-treatmentvisits: Assessments (Lung Cancer Symptom Scale and 
EQ-5D) will be performedon treatment dayprior to study treatment.
Health Resource 
Utilization
X
X 
X 
X
Except cycle 1. Note that concomitant medication collection will be 
included.
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Table 5.1-2:
On-Treatment Assessments for All Subjects, Cycle 1-2 [Cycle length 42 days]
Procedure
Cycle 1-2 
Day 1
Cycle 1 
Day 8
Cycle 1-2 
Day 15
Cycle 1-2 
Day 22
Cycle 1-2 
Day 29
Notes
Clinical Drug Supplies
Randomization
X
Call IVRS for randomization
Administer 
Blinded Study 
Drug
X
X 
X 
X
IVRS should be called within 1 day prior to blinded study therapy
administration to receive vial assignment. Note: The subject must receive 
the blinded study medicationwithin 3 business daysafter vial assignment. 
See section 4.5.1for minimum dosing intervals between Cycles. A call to 
IVRSis made for every dosing visit.
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Table 5.1-3:
On-Treatment Assessments for All Subjects, Cycle 3 and subsequent cycles [Cycle3+ length 14days] 
(CA209451)
Procedure
Cycle 3 and 
subsequent cycles, 
Day 1
Notes
Safety Assessments
Targeted Physical 
Examination
X
Within 72 hours prior to dosing
Vital Signs and 
Oxygen Saturation
X
Temperature, BP, HR, O2 saturation at rest by pulse oximetry at rest (also monitor amount of supplemental 
oxygen if applicable) within 72 hours prior to dosing and at any time a subject has any new or worsening 
respiratory symptoms
Physical 
Measurements
X
Includes Weight and ECOG performance statuswithin 72 hours prior to dosing
Adverse Events 
Assessment
Continuously
Assessed using NCI CTCAE v. 4.0. SAEs should beapproved in TAO within 5 days from entry
Review of 
Concomitant 
Medications
X
Extended Laboratory 
Tests
X(See note: 
AlternateCycles 3, 
5, 7, 9, etc)
Extended on-study local laboratory assessments should be done within 72 hours prior to dosing for Cycle 3and 
every alternate dose thereafter (Cycles 5, 7, 9, 11 etc.) and include: CBC with differential, uric acid, BUN or 
serum urea level, creatinine, Na, K, Ca, Mg, phosphorus, chloride, bicarbonate(optional), amylase orlipase, 
glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH.
Limited Laboratory 
Tests
X (see note: 
Alternate Cycles 4, 
6, 8, 10, 12,etc)
Limited on-study local laboratory assessment should be done within 72 hours priorto dosing (beginning at 
Cycle 4and every alternate dose thereafter (Cycles 6, 8, 10, 12, etc.) and include: CBC with differential, AST, 
ALT, total bilirubin, alkaline phosphatase and creatinine.
Thyroid Function 
Testing
X
See Note(every 
3Cycles)
TSH (reflex to free T3 and free T4 ifabnormal result) to be performed every3rd cycle within 72 hours prior to 
dosing.(C3D1, C6D1, C9D1, etc)
Pregnancy Test
X
See Note
Serum or urine at least once every 4 weeks regardless of dosing schedule.
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Table 5.1-3:
On-Treatment Assessments for All Subjects, Cycle 3 and subsequent cycles [Cycle3+ length 14days] 
(CA209451)
Procedure
Cycle 3 and 
subsequent cycles, 
Day 1
Notes
Efficacy Assessments
Radiographic Tumor 
Assessment
See Note
CT chest, MRI/CTbrain, abdomen, and any other known or suspected sites of disease,.Repeat CT/MRI of 
pelvis is required for subjects with pelvic metastases at baseline, or if clinically indicated(refer to section 5.4 
for detail on cases where CT of the Brain is acceptable). Tumor assessments will be conducted every 6 weeks 
(± 5 days) for the first 36 weeksthenevery 12 weeks (± 5 days) or sooner if clinically indicated until disease 
progression.SeeTable 5.4-1for CT and MRI scanschedule
Additional Exploratory Biomarker Testing
Serum
Whole Blood
Tumor Biopsy
See Note
See Table 5.6-1of Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See Note
See Table 5.5-1of PK and Immunogenicity Sampling
Immunogenicity 
samples
See Note
See Table 5.5-1of PK and Immunogenicity Sampling
Outcomes Research Assessments
Patient Reported 
Outcomes (PRO)
X
For on-treatmentvisits: Assessments (Lung Cancer Symptom Scale and EQ-5D) will be performedon 
treatment dayprior to study treatment.Assessments will be performed at each cycle on Day 1 for the remainder 
of the first 6 months on study, then every 6 weeks thereafter for the remainder of thetreatment period.
Health Resource 
Utilization
X
Except cycle 1. Note that concomitant medication collection will be included.
Clinical Drug Supplies
AdministerBlinded
Study Drug
X
IVRS should be called within 1 day prior to blinded study drug administration to receive vial assignment. Note:
The subject must receive the blindedstudytherapywithin 3 business days of vial assignment. See Section 4.5.1
for minimum dosing intervals between Cycles. A call to IVRS is made for every dosing visit.
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Table 5.1-4:
Follow-Up Assessments for All Subjects (CA209451)
Procedure
Follow-Upa
Visits 1 and 2
Survival Follow-UpbVisits
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study drug related issues
Adverse Events Assessment
X
X
NSAEs and SAEs must be collected up to 100 days afterblinded
study drug discontinuation. SAEs that relate to any later protocol 
specified procedure must be collected. SAEs should be approved 
in TAO within 5 days from entry.
Review of Concomitant Medication
X
X
Collection of concomitant medications only for treatment-related  
AEs or SAEs until the medication is discontinued.
Extended Laboratory Tests
X
CBC with differential, uric acid, BUN or serum urea level, serum 
creatinine, sodium, potassium, calcium, magnesium, chloride, 
phosphorus, bicarbonate(optional), amylase orlipase, glucose, 
AST, ALT, total bilirubin, alkaline phosphatase, LDH
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result)
Pregnancy Test
X
Serum or urine
Efficacy Assessments
Radiographic Tumor Assessment
CT/MRI 
See Note
See note
See Table 5.4-1for CT/MRI
Outcomes Research Assessments
Patient Reported Outcomes (PRO)
X
EQ-5D only
Both the Lung Cancer Symptom Scale and EQ-5D will be given 
in FU Visits1 &2. In Survival Visits, EQ-5D is collected every 3 
months for the first year of the Follow-up Phase, then every 6 
months thereafter.For Survival Visits these can be collected in 
person or via telephone contact. 
Healthcare resource utilization
X
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Table 5.1-4:
Follow-Up Assessments for All Subjects (CA209451)
Procedure
Follow-Upa
Visits 1 and 2
Survival Follow-UpbVisits
Notes
Exploratory Biomarker Testing
Serum
See Note.
Collection of Biomarker samples at time of progression is 
optional.
See Table 5.6-1of Biomarker Sampling Schedule.
Whole Blood 
Tumor Biopsy 
Subject Status
Survival Status
X
X
Every 3 months after X02; may be accomplished by visit or 
phone contact, to update survival information and assess 
subsequent anti-cancer therapy.
a Follow-up visits occur as follows: X01 = 35 days 7 days from last dose, X02 = 80 days 7 days from X01
b Survival visits continue every 3 months days after Follow-up Visit 2 until death, lost to follow-up, or withdrawal of study consent
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5.1.1
Retesting During Screening
Retesting of laboratory parameters and/or other assessments within theScreening period will be 
permitted (in addition to any parameters that require a confirmatory
 value).
Any new result will override the previous result (ie, the most current result prior to Randomization) 
and is the value by which study inclusion will be assessed, as it represents the subject’s most 
current, clinical state.
Laboratory parametersand/or assessmentsthat are included in Table 5.1-1, Screening Procedural 
Outlinemay be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of anyparticular parameter
is clinically relevant.
5.2
Study Materials
The following materials will be provided to the site by BMS.
NCI CTCAE version 4.0
Nivolumab Investigator Brochure
IpilimumabInvestigator 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 
worksheets
Imaging Manual for image acquisition and submission to central vendor
Manual for entry of local laboratory data
Pregnancy Surveillance Forms
Serious Adverse Events (or eSAE) case report forms
Lung Cancer Symptom Score and EuroPRO Group’s EQ-5D questionnaires
5.3
Safety Assessments
Safety assessments include AEs, physical examinations, vital signs, ECOG performance status, 
assessment of signs and symptoms, laboratory tests, pregnancy tests as outlined in Section 5.1.
Some of the previously referred to assessments may not be captured as data in the eCRF. They are 
intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
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5.3.1
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. 
Contrast-enhanced computed tomography (CT) of the chest and CT or magnetic resonance 
imaging (MRI) of abdomen, and any other known or suspected sites of diseaseare the preferred 
methods of radiographic assessment of tumors. Repeat CT/MRI of pelvis is required for subjects 
with pelvic metastases at baseline, or if clinically indicated.Brain MRI scan is the preferred 
imaging method for evaluating CNS metastasis, and assessment is required at screening, however 
CT of the brain is acceptable if MRI is contraindicated. If a subject has a known allergy to contrast 
material, please use local prophylaxis standards to obtain the assessment with contrast if at all 
possible, or use the alternate modality. In cases where contrast is strictly contraindicated, a non-
contrast scan will suffice.
All known or suspected sites of disease (including CNS) should be assessed at screening and at 
subsequent assessments using the same imaging method and technique. If more than one method 
is used at screening, then the most accurate method according to RECIST 1.1 should be used when 
recording data, and should again be used for all subsequent assessments.
Bone scan, PET scan, or ultrasound are not adequate for assessment of RECIST 1.1 response. In 
selected circumstances where such modalities are the sole modality used to assess certain non 
target organs, those non target organs may be evaluated less frequently. For example, bone scans 
may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
Previously treated CNS metastases are not considered measurable lesions for purposes of RECIST 
1.1 response. Subjects with a history of brain metastasis should have surveillance MRI/CT
approximately every 6 weeksup to 36 weeks and then every 12 weeks, or sooner if clinically 
indicated.
Baseline assessments should be performed within 21 days of randomization.
Subjects will be evaluated for tumor response beginning 6 weeks from the date of randomization 
(5days), then every 6 weeks (5 days) thereafter up to 36weeks. Beyond Week 36,tumor 
assessmentswill be performed every 12weeks (5 days), or more frequently as clinically 
indicated or per local Standard of Care,until disease progression (or until discontinuation of study 
drug in subjects receiving blinded study therapybeyond progression), lost to follow-up, 
withdrawal of study consent, or the study ends. See Table 5.4-1for a schedule of tumor 
assessments. Tumor assessments for all subjects should continue as per protocol even if dosing is 
delayed. Tumor measurements should be made by the same investigator or radiologist for each 
assessment whenever possible.
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Tumor imaging assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST 1.1 criteria; see Appendix 3.
Table 5.4-1:
Schedule of CT/MRI Tumor Assessments
Time On Study
Assessment 
Frequency
Assessment Week
(Day 1 of Week Shown)
Assessment Window
Baseline
Week 0
21days
Between Week 6 and Week 36
Every 6 weeks
6, 12, 18, 24, 30, 36
5 days
Beyond Week 36
Every 12 weeks
48, 60, 72+
5days
5.4.1
Use of CT Component of a PET/CT Scan
Combinedmodality scanning such as with FDG-PET/CT is increasingly used in clinical care, and 
is a modality/technology that is in rapid evolution; therefore, the recommendations outlined here 
may changerather quickly with time. At present, low dose or attenuation correction CT portions 
of a combined FDG-PET/CT are of limited use in anatomically based efficacy assessments and it 
is therefore suggested that they should not be substituted for dedicated diagnostic contrast 
enhanced CT scans for anatomically based RECIST diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the FDG-PET/CT can be usedfor RECIST v1.1 
measurements. Note, however, that the FDG-PET/CT portion ofthe CT introduces additional data 
which may bias an investigator if it is not routinely or serially performed.
5.4.2
Primary and Secondary Efficacy Assessments
The primary endpoint isto compare OS in subjectsrandomized to nivolumab in combination with 
ipilimumab, versus subjects randomized to placebo. The secondary endpointsare to compareOS 
ofnivolumab versus placebo, to compare BICR-assessed PFS ofnivolumab and nivolumab 
combined with ipilimumab versusplacebo, and to evaluate (descriptively) OS and BICR-assessed 
PFS ofnivolumab combined with ipilimumab versusnivolumab monotherapy. See Section 8.3for 
the definition of OSand PFS.
Every effort will be made to collect survival and imagingdata on all subjects,including subjects 
withdrawn from treatment for any reason, who are eligible to participate in the study and who have 
not withdrawn consent for additionaldata collection. If the death of a subject is not reported, all 
dates in this study representing a date of subject contact will be used in determination of the 
subject’s last known date alive.
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5.5
Pharmacokinetic Assessments
Table 5.5-1: 
Pharmacokinetic (PK) and Immunogenicity Sample Collections
Parta
Study Day
1 Cycle = 6 Weeks 
(Part A)
1Cycle=2 Weeks
(Part B)
Time 
(Relative to 
Dosing)
Hour
Time 
(Relative to 
Dosing)
Hour: Min
Pharmacokinetic 
Blood Samples 
for Nivolumab
Immunogenicity
Blood Samples 
for Nivolumab
Pharmacokinetic 
Blood Samples 
for Ipilimumab
Immunogenicity
Blood Samples 
for Ipilimumab
A
C1D1
0 (predose)b
00:00
X
X
X
X
A
C1D22
0 (predose)b
00:00
X
X
X
X
A
C2D22
0 (predose)b
00:00
X
X
X
X
B
C9D1
0 (predose)b
00:00
X
X
X
X
B
C17D1
0 (predose)b
00:00
X
X
X
X
B
C25D1
0 (predose)b
00:00
X
X
X
X
B
D1 of every 12th
cycle after 
C25D1until end of 
studytreatmentor 
up to 2 years of 
treatment
0 (predose)b
00:00
X
X
X
X
a
Part A indicates first 12 weeks of treatment (nivolumab + ipilimumab dosing). Part B indicates nivolumab monotherapy period starting from Week 13.
b
Predose (0 Hour) samples may be collected up to 4 days prior to dosing. However, if a predose sample is collected, and the dose is subsequently delayed, 
an additional predose sample should not be collected.
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5.7
Outcomes Research Assessments
The evaluation of health related quality of life is an increasingly important aspect of a clinical 
efficacy. Such data provides an understanding ofthe impact of treatment from the subjects’ 
perspective and offers insights into the patient experience that may not be captured through 
physician reporting. Generic health related quality of life scales additionally provide data 
necessary in calculating utility values for health economic models. The EQ-5D will be collected 
in order to assess the impact of study treatment on generic health related quality of life, which will 
also be used in populating health economic models most notably, cost effectiveness analysis.
The Lung Cancer Symptom Scale (LCSS) will be collected to assess the impact of study treatment 
on patient reported disease related symptoms(See Appendix 4). The Lung Cancer Symptom Scale 
is a validated instrument designed to assess the impact oftreatment on disease-related symptoms. 
It consists of 6 symptom specific questions related to dyspnea, cough, fatigue, pain, hemoptysis 
and anorexia plus 3 summary items: symptom distress, interference with activity, and global health 
related quality of life (HRQoL). The degree of impairment is recorded on a 100 mm visual 
analogue scale with scores from 0 to 100 with zero representing the best score.
General health status will be measured using the EQ-5D(EQ-5D-3L See Appendix 5). The EQ-5D 
is a standardized instrument for use as a measure of self-reported health status. The EQ-5D 
comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety) and a 
visual analog rating scale (VAS). The utility data generated from the EQ-5D is recommended for 
and commonly used in cost effectiveness analysis.
Healthcare resource utilization data (eg, hospitalizations, non-protocol specified medical visits,
diagnostics,etc) will be collected for all randomized subjects. The resource utilization capture is 
specific to hospital admission utilization data and non-protocol specified visits related to study 
therapy.
5.8
Other Assessments 
5.8.1
 
 
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5.8.2
Blinded IndependentCentralReview (BICR)
A Blinded Independent Central Review will be performed for randomized subjects to determine 
RECIST 1.1 response for the analysis of PFSand ORR. Details of the Imagingresponsibilities and 
procedures will be specified in the Imagingcharter.Tumor assessments should be submitted to the 
third-party BICR vendor as they are performed on an ongoing basis.
Siteswill be informed of quality issues or the needfor repeat scanning via queries from the central 
imaging vendor. Results of Central Imaging analysis will not be returned to the site.
6
ADVERSE EVENTS
An Adverse Event(AE)is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition inaclinical investigation subject administered blinded study drug
and that does notnecessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (such asan abnormallaboratory finding), symptom, or
disease temporally associated with the use of blinded study drug, whether or not considered related 
to theblindedstudy drug.
The causal relationship to blinded study drug is determined by a physician and should be used to 
assess all adverse events (AE).The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between blinded study drug 
administration and the AE.
Not related: There is not a reasonable causal relationship betweenblindedstudy drug 
administration and the AE.
The term “reasonable causal relationship”means there is evidence to suggest a causal relationship.
Adverse eventscan 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.)
BMSwill be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320.
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6.1
Serious Adverse Events
A SeriousAdverse Event(SAE)is any untoward medical occurrence that at any dose: 
results in death
is life-threatening (defined as an event inwhich the subject was at risk ofdeath 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 
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in deathor 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 6.6for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via theblinded
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 Section6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to blinded study therapy (eg,death 
is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be 
reported as SAE (see Section 6.1.1for reporting details).
NOTE:
The following hospitalizationsarenot 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 thanto remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
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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, 
caregiverrespite, family circumstances, administrativereason).
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse EventCollection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not 
related to blinded 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 discontinuationof dosing.  For subjects who are randomized but never 
treated with study drug, SAEs should be collected for 30 days from the date of randomization. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up skin biopsy).
The investigator mustreportany SAE that occurs after these time periods and that is believed to 
be related toblindedstudy drug or protocol-specified procedure.
An SAE report mustbe completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related toblindedstudy 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 mustbe specified in the narrative section of the SAE Report 
Form.
SAEs, whether related or not related toblindedstudy drug, and pregnancies must be reported to 
BMS(or designee)within 24 hoursof awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms).The 
preferred method for SAE data reporting collection is through the eCRF. The paper 
SAE/pregnancy surveillance forms are only intended as a back-up option when the eCRF system 
is not functioning. In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address:Refer to ContactInformation list.
SAEFacsimile Number:Refer to ContactInformation list.
For studiescapturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required forSAE andpregnancy reporting):Refer to Contact
Information list.
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If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports mustinclude the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to blinded study drug or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours to 
Sponsor or designee using the same procedure used for transmitting the initial SAE report.
All SAEs mustbe followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
regulations 21 CFR Parts 312 and 320. A Suspected Unexpected Serious Adverse Reaction 
(SUSAR) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonseriousAE information should begin at initiation of blinded study drug. 
Nonserious AEinformation should also be collected from the start of a placebo lead-in period or 
other observational period intended to establish a baseline status for the subjects.
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 ofblindedstudy drug andfor 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). 
All nonserious AEs (not only those deemed to be treatment-related) shouldbe collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.2.2
Immune-Mediated Adverse Events
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
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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 laboratorytest resultabnormality that required the subject to haveblindedstudy drug 
discontinued or interrupted
Any laboratorytest resultabnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinicalrather than laboratory term would be used by the
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the blinded study drug, it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of studyexposure, including during at least 5
half lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
In most cases, theblindedstudy drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy.
In the rare event that the benefit of continuingblindedstudy drug is thought to outweigh the risk, 
after consultation with BMS, the pregnant subject may continueblindedstudy drug after a 
thorough discussion of benefits and risk with the subject
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 must be performed on the subject.
The investigator must immediately notify the BMS(or designee) Medical monitorof this event 
and complete and forward a Pregnancy Surveillance Form to BMS(or designee)within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section6.1.1. 
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 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from the 
female partner, the female partner must signan informed consent form for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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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 Section6.1.1for 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 Section6.1.1for reporting details).
Potential drug induced liver injuryis defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
6.7
Other Safety Considerations
Any significant worseningnoted 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
A Data Monitoring Committee (DMC) will be utilized to provide general oversight and safety
considerations for this study. The DMC will provide advice to the Sponsor regarding actions the 
committee deems necessary for the continuing protection of subjects enrolled in this study. The 
DMC will be charged with assessing such actions in light of an acceptable risk/benefit profile for 
nivolumabmonotherapy and nivolumab in combination with ipilimumab. The DMC will act in an 
advisory capacity to BMS and will monitor subject safety data for the studyapproximately every 
6 months for the duration of the trial.
The DMC will be advisory to the clinical study leadership team. The clinical study leadership will 
have responsibility for overall conduct of the study including managing the communication of 
study data. The group will be responsible for promptly reviewing the DMC recommendations, for 
providing guidance regarding the continuation or termination of the study, and for determining 
whether amendments to the protocol or changes to the study conduct are required.
Details of the DMC responsibilities and procedures will be specified in the DMC charter.
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When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Per original protocol, approximately 810 subjects were to be randomized to the three treatment 
arms in a 1:1:1 ratio.
The primary objective is to compare Overall Survival (OS)of nivolumab in combination with 
ipilimumab versus placebo.The analysis of primary endpoint of OS will be conducted when at 
least 386deaths have been observed pooled across the twotreatment groups. Using accrual and 
treatment effect assumptions described below, it is expected that 208 events will be observed in 
placebo and 178 in nivolumab in combination with ipilimumabtreatment groups. With 386events
available for comparison of OS in nivolumab in combination with ipilimumabvs placebogroups, 
power of the log-rank test is approximately 90% to detect a hazard ratio (HR) of 0.72 with a typeI 
error of 0.05 (two-sided).The critical hazard ratiofor determining whether nivolumab in 
combination with ipilimumabis superior to placebois 0.82.
Power calculations were performed using EASTSoftware (version 6.4.1). Results were 
generated by 10000 simulations. Model assumptions were as follows: 
Survival functionfor placeboarm was modeledusinga four hazard pieces: OS rates at 3, 9, 18 
and 26 months were assumed to be 90%, 47%, 15% and 9%, respectively,based on published 
survival curve for placebo maintenance in Extensive-Stage SCLC, adjusted for induction phase 36. 
Median OSfor placebo was 8.8 months.
For nivolumab in combination with ipilimumab, a delayed effect versus placebo with a hazard 
ratio (HR) of 1 for the first 3months 37and an HR of 0.68thereafter was assumed, resulting into 
overall HR (experim vs placebo) of0.72at time of the OS analysis. Median OS for the 
experimental armwas 11.0months. 
Accrual information used in the simulations had the same pattern as the actual data at time of the 
protocolamendment (832 subjectswere accrued in 28 monthsand randomized to the three 
treatment groups). A 5% probability of dropout by month 6 was taken into account. Given the 
observed accrual and dropout and survival assumptions it is expected that 
the duration of the study 
from start of randomization to final analysis will be approximately 35months (28 months of 
accrual + 7months of minimum follow-up, providing an average follow up of9 months).
This study includes a sub-study to allow enrollment of patients from China (site-specific protocol 
amendment 12). Data from these additional subjects will be reported separately. Subjects from 
China randomized on or before end of global study accrual will be included in the population used 
for the primary analysis clinical study report. The required numberof deathsfor the primary OS 
analysis is based on the global study population. 
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Theindependent Data Monitoring Committee (DMC) will have access to periodic interim safety 
and efficacy reports to allow for arisk/benefit assessment.
8.2
Populations for Analyses-Data set descriptions
Global study population: all subjects enrolled during the global accrual window (from first 
patient first consent date to last patient outside of China‘s consent date). Any patientfrom 
China enrolled during the global accrual window will be included
All Enrolled Subjects: All subjects who signed an informed consent form and wereregistered 
into the IVRS
All Randomized Subjects: All subjects who were randomized to any treatment group
All Treated Subjects: All subjects who received at least one dose of any studymedication
PK Subjects: All randomized subjects with available serum time-concentration data
Immunogenicity Subjects: All randomized subjects with available ADA data
BiomarkerSubjects: All randomized subjects with available biomarker data
8.3
Endpoints
8.3.1
Primary Endpoint(s)
OS is defined as the time from randomization to the date of death. A subject who has not died will 
be censored at last known date alive. OS will be followed continuously while subjects are on the
blindedstudy drug and every 3 months via in-person or phone contact after subjects discontinue 
theblindedstudy drug.
8.3.2
Secondary Endpoint(s)
Secondary endpoint of OS comparing nivolumabmonotherapyversus placebo is defined similarly 
to the primary endpoint. 
PFS is defined as the time from randomization to the date of the first documented tumor 
progression (per RECIST 1.1) or death due to any cause. Subjects who die without a reported prior 
progression will be consideredto have progressed on the date of their death. Subjects who did not 
progress or die will be censored on the date of their last evaluable tumor assessment. Subjects who 
did not have any on study tumor assessments and did not die will be censored on the date they 
were randomized. Subjects who started any subsequent anti-cancer therapy without a prior 
reported progression will be censored at the last evaluable tumor assessment prior to initiation of 
the subsequent anti-cancer therapy. Progression will be assessed every 6 weeks (from the first on-
study radiographic assessment) until disease progression is noted.
An OS descriptive analysis will be performed to evaluate nivolumab monotherapyto nivolumab 
with ipilimumab treatment regimen.
Tumor mutationalburden (TMB) is measured using FoundationOne CDxTM(F1CDx) assay, a 
comprehensive genomic profile (CGP) assay based on baseline tumor tissue. TMB is defined as 
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the number of somatic, coding, base substitution, and indel mutations per megabase of genome 
examined.
8.3.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline laboratory results will be summarized by treatment arm as randomized 
using descriptive statistics for all randomized subjects.
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8.4.2
EfficacyAnalyses
OS for each of the two experimental arms will be compared to the control group usinga two-sided 
log-rank test stratified by ECOG Performance Status (0 vs 1), Gender (male vs female) and 
Prophylactic Cranial Irradiation (PCI) following chemotherapy (Yes vs No)(IVRS source) in all 
randomized subjects. HRs and corresponding two-sided CIs will be estimated using a Cox 
proportional hazards model, with treatment group as a single covariate, stratified by the above 
factors. OScurves, OS medians with 95% CIs, and OS rates at 6, 12 and 18 months with 95% CIs 
will be estimated using Kaplan-Meier methodology.
BICR-assessed PFSfor each of the two experimental arms will be compared to the control group 
using a two-sided log-rank test stratified by the same stratificationfactors as in the OS primary 
analysis.HRs and corresponding two-sided CIs will be estimated using a Cox proportional hazards 
model, with treatment group as a single covariate, stratified by the same stratification factors as 
above. PFS curves, PFS medians with 95% CIs, and PFS rates at 6, 12 and 18 months with 95% 
CIs will be estimated for each of the three treatment groups using Kaplan-Meier methodology.
Hierarchicalprocedure will be used to control the overall Type I error rate at 0.05. 
The secondary endpoint,OS comparing nivolumab monotherapy vs placebo, will be testedusing 
2-sided 5% alpha, if superiority of nivolumab in combination with ipilimumab over placebo is 
demonstratedat the 5% significance level. If superiority in OS of nivolumab monotherapy over 
placebo is demonstrated, the 5% alpha is passed to test the secondary endpointsof PFS. PFSwill 
be tested hierarchically, starting with comparison of PFS of nivolumab plus ipilimumab with
placebo, followed bycomparison of PFS of nivolumab monotherapy withplacebo.The 
exploratoryendpoint of ORR will be calculated for each treatmentgroup. Exact two-sided 95% 
CIs for the rates will be computed using the method of Clopper and Pearsonfor each of the three 
treatment groups. 
Descriptive analyses of OS, PFS, and ORR will be performed toevaluate differences between the 
two experimental arms, nivolumab combined with ipilimumab and nivolumab monotherapy. 
These include HRs and medians with corresponding two-sided 95% CIs for OS and PFS, as well 
as an ORR odds ratio with corresponding 95% CI.
Descriptive analyses will be performed to evaluate the potential of PD-L1 expressionand TMBas 
a predictive biomarker for PFS and OS.
8.4.3 
Safety Analyses
Safety analyses will be performed for all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. All on-study AEs, drug-related, AEs, SAEs and drug-related SAEs 
will be tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ class and 
MedDRA preferred term. The listings by subject will be produced for all deaths, all SAEs, and all 
AEs leading to discontinuation ofblindedstudy drug. On-study lab parameters including 
hematology, chemistry, liver function, thyroid function, and renal function will be summarized 
using worst grade per NCI CTCAE v4.0 criteria.
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8.4.4
Pharmacokinetic Analyses
The concentration vs time data obtained inthis study may be combined with data from other studies 
in the clinical development program to develop a population PK model. This model may be used 
to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab and to determine 
measures of individual exposure (such as steady-state peak, trough, and time-averaged 
concentration). Model determined exposures may be used for exposure-response analyses of 
selected efficacy and safety end points. Results of population PK and exposure-response analyses 
will be reported separately.
8.4.5
8.4.5.1
Pharmacodynamic Analyses
To assess pharmacodynamic effects in serum obtained from subjects on each treatment arm, 
summary statistics for biomarkers and their corresponding changes (or percent changes) from 
baseline will be tabulated by planned study day and in each arm. The time course of biomarker 
measures will be investigated graphically, if there is indication of meaningful pattern over time, 
further analysis (eg, by linear mixed model) may be performed to characterize the relationship.
8.4.5.2
Pharmacogenomic Analyses
Pharmacogenomic and Exploratory Analyses
Potential relationships between biomarker data and efficacy or safety endpoints will be 
investigated as part of an analysis plan aimed at identifying baseline biomarkers that may be used 
to prospectively identify subjects likely (or not likely) to respond to nivolumab and to identify 
subjects who may be predisposed to having adverse reactions to treatment. These exploratory 
predictive biomarker analyses will be completed with biomarkers measured in blood and in tumor 
samples and will focus primarilyas outlined in the exploratory objectiveson NPs in select genes 
associated with immunity or on the expression of PD-1, PD-L1, and PD-L2 proteins in tumor
specimens. Similar analyses will be completed with data regarding serum-soluble factors, serum 
mRNAcontent, and putative additional analyses to be completed using FFPE tissue.
Associations between biomarkers and efficacy measures will be analyzed on all randomized 
subjects with available biomarker data. Efficacy measures will include response, PFS, and OS. 
Demographic and case-history factors will be examined to determine whether stratification or 
adjustments should be made within the subsequent statistical analyses, and if necessary, the 
appropriate stratification or adjustment will be made. 
Biomarkers will be summarized graphically as they relate to efficacy and safety endpoints, as 
applicable. Summary statistics will be tabulated. SNP allele frequencies will be summarized. The 
relationships between binary measures (eg, response) and candidate biomarkers will be 
investigated using logistic regression. Associations will be summarized in terms of point and 
interval estimates of hazard ratios, odds ratios, or other statistics, as appropriate for the analyses 
completed. Models to predict clinical activity based on combinations of biomarkers may also be 
investigated.
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Additional post hoc statistical analyses not specified in the protocol, such as alternative modeling 
approaches may be completed. All analyses described in this sectionare based on the availability 
of the data.
8.4.6
Outcomes Research Analyses
LCSS questionnaire complete rate, defined as the proportion of questionnaires actually received 
out of the expected number (ie, the number of subjects still on treatment and in follow-up), will be 
calculated and summarized at each assessment point. 
Baseline and change from baseline of the average symptom burden index score at each assessment 
point will be summarized using descriptive statistics. Subject’s overall health state on a visual 
analog scale (EQ-VAS) at each assessment time point and the difference from baseline will be 
summarized using descriptive statistics Proportion of subjects reporting problems for the 5 EQ-5D 
dimensions at each assessment time point will be summarized by level of problem. Summary
statistics will be calculated for the population preference-based health state utilityscore (EQ-5D 
Index).
8.4.7
Other Analyses 
Methodology for exploratory analyses including immunogenicity, other HRQoL assessments 
(PRO), and healthcare resource utilization is described in the statistical analysis plan.
8.5
Interim Analyses
Not applicable
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority)except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) priorto 
obtaining relevantapproval/favorable opinion(s), 
the deviation or change will be submitted as soon 
as possible to:
IRB/IEC 
Regulatory Authority(ies), if applicableby local regulationsper national requirements
Documentation of approval/favorable opinionsigned by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, must be sent to BMS.
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If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consentform 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).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
In addition, the study may be evaluated by 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. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, suchsystems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.2
Records
9.2.1
Records Retention
The investigator (or head of the study site in Japan)must retain all study recordsand source 
documents for the maximum period required by applicable regulations and guidelines, or 
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institution procedures, or for the period specified by BMSor designee, whichever is longer. The 
investigator must contact BMS or designee prior to destroying any records associated with the 
study.
BMS will notify the investigator (or head of the study site in Japan) when thestudy records are no 
longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator,study site,IRB). Notice 
of such transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, orthe site) must substantiate IP integrity 
and traceability from receipt, preparation, administration, and through destruction or return. 
Records must be made available for review at the request of BMS/designee or a Health Authority.
If...
Then...
Suppliedby BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
amount received and placed in storage 
area
amount currently in storage area
label identification number or batch 
number
amount dispensed toand returned by each 
subject, including unique subject 
identifiers
amount transferred to another area/site for 
dispensing or storage
nonstudy disposition (e.g., lost, wasted) 
amount destroyed at study site, if 
applicable
amount returned to BMS
retain samples for 
bioavailability/bioequivalence, if 
applicable 
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
The investigator or designee accepts 
responsibility for documenting traceability and 
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If...
Then...
the sites stock or commercial supply, or a 
specialty pharmacy)
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy. 
BMS or designee will provide forms to facilitate inventory control ifthe 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. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMSelectronic 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/pregnancyCRFs,must be promptly 
reviewed, signed, and dated by the investigator or qualifiedphysician who is a subinvestigatorand 
who is delegated this task on the Delegation of Authority Form. Subinvestigators in Japan may not 
be delegated the CRF approval task. For electronic CRFs, review and approval/signature is 
completed electronically through the BMS electronic data capture tool.Theinvestigator must 
retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMStraining requirements and 
must only access theBMS electronic data capture tool using the unique useraccount 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 as appropriate based onthe following 
criteria:
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External Principal Investigator designated at protocol development
National Coordinating Investigator 
Study Steering Committee chair or their designee
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 must 
adhere to the publication requirements set forth in the clinical 
trial agreement (CTA) governing [Study site or Investigator] participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to BMS at the 
earliest practicable time prior to submission or presentation and otherwise within the time period 
set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
This also means that abstinence is the preferred and usual lifestyle of the 
patient. This does not mean periodic abstinence (eg, calendar, ovulation, 
symptothermal, profession of abstinence for entry into a clinical trial, 
post-ovulation methods) and withdrawal, which are not acceptable 
methods of contraception. Women must continue to have pregnancy tests. 
Acceptable alternate methods of highly or less effective contraception’s 
must be discussed in the event that the subject chooses to forego complete 
abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AIDS
Acquired immunodeficiency syndrome
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
-HCG
beta-human chorionic gonadotrophin
BID, bid
bis in die, twice daily
BICR
Blinded independent central review
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
Calcium
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
Chloride
CLcr
creatinine clearance
cm
Centimeter
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CTLA-4
Cytotoxic t lymphocyte-associated antigen 4
CYP
cytochrome p-450
D/C
Discontinue
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Term
Definition
dL
Deciliter
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
Eg
exempli gratia (for example)
ESR
Expedited Safety Report
FDA
Food and Drug Administration
FISH
Fluorescent in situ hybridization
FSH
follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRQoL
Health Related Quality of Life
HRT
hormone replacement therapy
ICD
International Classification of Diseases
ICH
International Conference on Harmonization
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IMAE
Immune-mediated adverse events
IND
Investigational New Drug Exemption
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Term
Definition
IRB
Institutional Review Board
IU
International Unit
IU/L
International unit per liter
IU/mL
International unit per milliliter
IVRS
Interactive voice response system
IV
intravenous
K+
potassium
kg
Kilogram
KM
Kaplan-meier
L
Liter
LAM
Lactation amenorrhea method
LCSS
Lung cancer symptom scale
LDH
lactate dehydrogenase
mAB
Monoclonal antibody
mg
Milligram
Mg++
magnesium
Min
Minute
mL
Milliliter
mmHg
millimeters of mercury
MTD
maximum tolerated dose
g
Microgram
N
number of subjects or observations
Na+
Sodium
N/A
not applicable
NE
Not evaluable
Ng
Nanogram
NCCN
National Comprehensive Cancer Network
NIMP
non-investigational medicinal products 
ORR
Overall response rate
OS
Overall survival
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Term
Definition
PD
Progressive disease
PD
Pharmacodynamics
PD-1
Programmed Death-1
PD-L1
Programmed death-ligand 1
PD-L2
Programmed death-ligand 2
PFS 
progression-free survival
PR
Partial response
PK
Pharmacokinetics
PT
prothrombin time
RCC
Renal cell carcinoma
RECIST 1.1
Resonse evaluation criteria in solid tumors version 1.1
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SD
Stable disease
SOP
Standard Operating Procedures
t
Temperature
T
Time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
TID, tid
ter in die, three times a day
TILs
Tumor infiltrating lymphocytes
TSH
Thyroid stimulating hormone
Tmax, TMAX
time of maximum observed concentration
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 3
RESPONSEEVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES(VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria InSolid Tumors version 1.1 
(RECIST1.1)guideline with BMS modifications.(Eisenhauer EA et al. EurJ Cancer 2009; 45: 
228-47)
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions:Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurementis to be recorded) with a minimum size of:
10 mm by CT/MRIscan (scan slice thickness no greater than 5 mm), or 2x slice thickness if 
greater than 5mm.
Malignant lymph nodes:To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT/MRIscan (scan slice thickness 
recommended to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15mm by CT/MRIscan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the planeof 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis 10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
<10mm or pathological lymph nodes with 10 to< 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identifiedby physical exam that is not measurable by 
reproducible imaging techniques.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
Bone scan, PET scan and plain films are notconsidered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiablesofttissuecomponents, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the softtissuecomponentmeets the definition of measurability 
described above.
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).
Note: A maximum of two lesions canbe selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum 
of two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
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2.
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
Complete Response (CR):Disappearance of all target lesions. Any pathological lymph 
nodes (whethertarget 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% increasein the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression).
Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Not Evaluable (NE):If one or more target lesions cannot be measured or adequately 
assessed as either fully resolved or too small to measure (due to missing or poor quality 
images), and the sum of diameters of the remaining measured target lesions (if any) has not 
increased sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a 
normal lymph node is defined as having a short axis of < 10 mm. Case report forms or other data 
collection methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR,each node must achieve a short axis < 10 mm. For PR, 
SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg,2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assignedas the reference diameter.(Note:It is less likely that this rule will be used for 
lymph nodes since they usually have a definable size when normal and are frequently surrounded 
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by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.
Complete Response (CR):Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10mm short axis). 
Non-CR/Non-PD:Persistence of one or more non-target lesion(s)
Progressive Disease (PD):Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to qualifyfor unequivocal progression status. Pleural effusions, 
pericardial effusions and ascites will not be followed as target or non-target lesions and will not 
contribute to response or progression. The designation of overall progression solely on the basis 
ofchange in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare.
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2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include, an increase in lymphangitic disease 
from localized to widespread, or may be described as ‘sufficient to require a change in therapy’. 
If ‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at 
that point. While it would be ideal to have objective criteria to apply to non-measurable disease, 
the very nature of that disease makes it impossible to do so; therefore the increase must be 
substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new 
fluid collection is seen on a post-baseline imaging exam, a comment may be made, but the 
appearance of a new fluid collection alone should not result in an assessment of Progressive 
Disease (PD). A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression. An example 
of this is the patient who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. A lesion identified on 
Chest X-Ray that was not present in prior CT can be considered a new lesion and will result in 
Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. While FDG-
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PET response assessments need additional study, it is sometimes reasonable to incorporate the 
use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is thebest response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmationand censoring rules regarding subsequent therapy. The patient’s best overall 
response assignment will depend on the findings of both target and non-target disease and will 
also take into consideration the appearance of new lesions. Furthermore, depending on the nature 
of the study and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) 
disease only, Table 2.3.2-2is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (±Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
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Table 2.3.2-1:
Time Point Response: Patients With Target (±Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point 
of 4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as 
in Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (±7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment:When nodal disease is included in the sum of target
lesions and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement 
reported on scans. This measurement should be recorded even though the nodes are normal in 
order not to overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the case report 
form (CRF).
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Table 2.3.3-1:
Best Overall Response (Confirmation of CRand PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BestOverall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD durationmet, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE=inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). 
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
2.3.4
Confirmation Scans
Verification of Response:To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequentrepeat assessments that should be performed no 
less than 28days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of apreviously identified CR even with an intervening NEor PR(eg, 
CR NE CRor CR PR CR).Subsequent documentation of a PR may provide confirmation of a
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRsfor confirmation.
Verification of Progression:Progression of disease should be verified in cases where 
progression is equivocal. If repeat scans confirm PD, then progression should be declared using 
the date of the initial scan. If repeat scans do not confirm PD, then the subject is considered to 
not have progressive disease.
Revised Protocol No: 06
Date: 20-Sep-2018
118
7.0
Approved
930091505
7.0
v