Clinical trial NCT02409368
Conditions: Non-Small Cell Lung Cancer
Sponsor: Bristol-Myers Squibb
Start date: 2015-04-29; Completion date: 2021-08-27
Enrollment: 812 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to determine the occurrence of high-grade (CTCAE v4.0 Grades 3-4), treatment-related, select adverse events in patients with advanced or metastatic Squamous Cell Non-Small Cell Lung Cancer (SqNSCLC) with progression of disease during or after at least 1 systemic therapy.

Detailed description:

Arms: arm 1: Nivolumab IV infusion
Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
CA209171
IND Number:
NA
EUDRACT Number
2014-001285-10
Date:
18-Apr-2014
Revised Date
10-Sep-2018
Clinical Protocol CA209171
An Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) Monotherapy in 
Subjects with Advanced or Metastatic Squamous Cell (Sq) Non-Small Cell Lung Cancer 
(NSCLC) who Have Received at Least One Prior Systemic Regimen for the Treatment of Stage 
IIIb/IV SqNSCLC
CheckMate 171: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 171
Revised Protocol 05
Medical Monitor
Angelic A. Ranck, MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
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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)
Replaces all version(s) of this 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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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 05
10-Sep-2018
•
OS will be collected for at least 3 years and up to 5 years from 
the first dose of study therapy.
•
Dose delay, criteria to resume treatment, and discontinuation 
updated to align with program standards for safety
•
Study personnel updated 
Revised 
Protocol 04
26-Oct-2016
Incorporates Amendment 04 + Administrative Letters 02 & 03
Amendment 04
26-Oct-2016
Keys changes: 
-
Adjustment to PS 0-1 and PS 2 subgroup sample numbers  
-
Changes to informed consent procedure for treatment beyond 
disease progression 
-
Clarification of SAE reporting to within 100 days of 
discontinuation of drug 
-
 
-
Addition that dose must be recalculated if weight on the day of 
dosing differs by > 10% from the weight used to calculate the 
dose
Administrative 
Letter 03
20-May-2016
Clarification of SAE reporting to within 100 days of discontinuation of 
drug 
Administrative 
Letter 02
14-Aug-2015
The study design and schematics changed to adjust PS 0-1 and PS 
2 subgroup sample numbers  
Clarification of pregnancy testing to serum or urine.
Revised 
Protocol 03
18-Jun-2015
Incorporates Amendment 03
Amendment 03
18-Jun-2015
Three key changes were made to this protocol: the sample size was 
reduced from 1800 to 950 (with 15% screening failure rate, 800 will be 
treated); second-line lung cancer patients will now be allowed to enroll in 
the study; and the randomization at one year into Cohort A and Cohort B 
has been removed.
Revised 
Protocol 02
26-Feb-2015
•
Study Director and Medical Monitor were changed
•
The use of a condom with spermicide was demoted from a highly 
effective to less effective method of contraception
 
•
Table 5.1-3 Pregnancy test had additional language added for
clarification
 
Revised 
Protocol 01
21-Nov-2014
Incorporates Administrative Letter 01 and Amendment 01.
Amendment 01
21-Nov-2014
•
The inclusion criteria have been expanded and the exclusion criteria 
have been minimized in order to expand the subject population.
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Document
Date of Issue
Summary of Change
•
The background section has also been updated to reflect the most 
recently available data. 
•
The options for palliative local therapy have also been expanded to 
meet the needs of the current patient populations. 
•
Randomization after 1 year to subjects who are still benefitting from 
treatment and achieved a partial or complete response to offer insight 
into the optimal treatment duration of nivolumab has been added. 
After 1 year of therapy, subjects will be randomized to continue 
nivolumab monotherapy (Cohort A) or discontinue therapy with the 
option of retreatment disease progression (Cohort B). 
•
The requirement to have a separate assessment plan for the subjects 
in the Performance Status 2 (PS2) subgroup has been eliminated. 
 
 
 
•
Initial tumor assessments have also been changed to occur at Week 8 
instead of Week 6. 
•
The statistical section has been reformatted. 
•
The phrase “rate and frequency” has been changed to the term 
“incidence” throughout the protocol. 
•
The term “Adverse Events of Special Interest” has been changed to 
“Select Adverse Events.” 
•
The Performance Status groups were renamed “Subgroup” (from 
“Cohort”) to avoid confusion with the randomized cohorts. 
•
Treatment discontinuation criteria were moved from Section 3.5 to 
the newly created Section 4.6.5.1 to follow the nivolumab protocol 
structure. 
•
The requirement for electrocardiograms has been removed as these 
tests are not done within the nivolumab clinical development 
program any more.
Administrative 
Letter 01
12-May-2014
The title of this protocol has been modified for consistency with the 
BMS conventions for protocols in the nivolumab program.
Original 
Protocol
18-Apr-2014
Not applicable
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SYNOPSIS
Clinical Protocol CA209171
Protocol Title:  An Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) Monotherapy in Subjects 
with Advanced or Metastatic Squamous Cell (Sq) Non-Small Cell Lung Cancer (NSCLC) who Have Received at 
Least One Prior Systemic Regimen for the Treatment of Stage IIIb/IV SqNSCLC
CheckMate 171: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 171
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nivolumab solution for injection, 3 mg/kg, intravenous (IV) infusion over 60 minutes every 2 weeks,
until disease progression, unacceptable toxicity, withdrawal of informed consent, or end of study. 
Study Phase: II
Research Hypothesis: High-grade (CTCAE v4.0 Grade 3 or higher) treatment-related, select adverse events occur 
with a low frequency in subjects with advanced or metastatic squamous non-small cell lung cancer (SqNSCLC) treated 
with nivolumab monotherapy.
Objectives:  
Primary Objective:
•
To determine the incidence of high-grade (CTCAE v4.0 Grades 3-4), treatment-related, select adverse events in 
subjects with advanced or metastatic SqNSCLC who progressed during or after at least 1 systemic therapy.
Secondary Objectives:
•
To determine the incidence and to characterize the outcome of all high-grade (CTCAE v4.0 Grades 3-4), select 
adverse events in subjects with advanced or metastatic SqNSCLC who have progressed during or after at least 1 
prior systemic therapy
•
To estimate overall survival (OS) in all treated subjects
•
To estimate investigator-assessed objective response rate (ORR) 
 
 
 
Study Design:  The study will include subjects with histologically- or cytologically-documented SqNSCLC who have 
progressed during or after a minimum of 1 prior platinum doublet-based chemotherapy regimen for advanced or 
metastatic disease. Subjects will be treated with 3 mg/kg of nivolumab IV every 2 weeks until disease progression, 
unacceptable toxicity, withdrawal of consent, or end of study. Subjects will undergo screening evaluations to 
determine eligibility within 28 days prior to first dose following signed informed consent. Each 14-day dosing period 
will constitute a cycle.
The Scientific Steering Committee will provide guidance and scientific expertise on the clinical risk/benefit ratio 
closely following a defined Safety Management Plan. 
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Study Schematic:
Study Population: 
Key Inclusion Criteria
a)
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 
i)
PS 0 to 1 (Subgroup1)
ii)
PS 2 (Subgroup 2; minimum of 81 treated subjects. The Scientific Steering Committee will provide 
guidance and scientific expertise on the risk/benefit ratio following a Safety Management Plan).  
b)
Subjects with histologically or cytologically-documented SqNSCLC who presented with stage IIIb/stage IV 
disease or who developed recurrent or progressive disease following prior definitive therapy for localized or 
local advanced disease. A fresh biopsy is not required to take part in the study.
c)
Subjects must have experienced disease recurrence or progression during or after one prior platinum doublet-
based chemotherapy regimen for advanced or metastatic disease.
i)
Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate 
regimen of therapy
ii)
Subjects who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy 
given for locally advanced disease, and developed recurrent (local or metastatic) disease within 6 months 
of completing therapy are eligible.
iii) Subjects with recurrent disease > 6 months after platinum-containing adjuvant, neoadjuvant or definitive 
chemoradiation therapy given for locally advanced disease, who also subsequently progressed during or 
after a platinum doublet-based regimen given to treat the recurrence, are eligible.
d)
Subjects with CNS metastases:
N=approximately
950 subjects enrolled
Study Population
•
Subjects with
advanced or metastatic
squamous cell non-
small cell lung cancer 
(SqNSCLC) who 
received at least 1prior
systemic regimen for lung 
cancer
Intervention:
Assuming a 15% screening failure 
rate, N= ∼800 treated with 
nivolumab 3 mg/kg as a 60-
minute IV infusion every 2 weeks
Study Subgroups
ECOG PS 0-1 (n= ∼719)
ECOG PS 2 (n= ∼81)
Safety assessments every 
2 weeks. First tumor 
assessments at Week 9.
Clinical benefit should be 
balanced by clinical judgment as 
to whether the subject is 
clinically deteriorating and 
unlikely to receive any benefit 
from continued treatment.
A cohort of 81 PS 2 subjects will 
be assessed for safety and 
tolerability.
Treat until progression* or 
unacceptable toxicities
Safety followed 
continuously.
Subjects followed for 
ongoing drug-related AEs 
until: resolution; 
symptoms return to 
baseline; AE deemed 
irreversible; lost to 
follow-up/death; disease 
progression*; withdrawal 
of consent, or end of 
study.
*subject may be treated 
beyond progression under 
protocol-defined 
circumstances
Endpoints:
 ORR. 
OS,
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i)
Subjects are eligible if CNS metastases are treated and subjects are neurologically returned to baseline 
(except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to first 
dose. In addition, subjects must be either off corticosteroids or on a stable or decreasing dose of ≤10 mg 
daily prednisone (or equivalent)
OR
ii)
Subjects are eligible if they have previously untreated CNS metastases that are neurologically 
asymptomatic. In addition, subjects must be either off corticosteroids or on a stable or decreasing dose 
of ≤10 mg daily prednisone (or equivalent)
Key exclusion criteria:
a)
Subjects with untreated, symptomatic CNS metastases are excluded
b)
Subjects with carcinomatous meningitis are excluded. 
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CA209-171
Medication 
Potency 
IP/Non-IP 
Nivolumab Injection
BMS-936558-01 
10 mg/mL; 100 mg/Vial; 10 or 5 
vials per carton
Open-label
IP
Study Assessments: Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a case report form. Additional procedures and assessments may be performed as part of standard of care; 
however, data for these assessments should remain in the subject’s medical record and should not be provided to BMS 
unless specifically requested.
The following assessments should be monitored starting on Cycle 1 Day 1 and will continue as per the schedule in the 
Time and Events Tables at the specified frequency:
•
AEs continuously throughout the study
•
Physical examination and physical measurements including weight, and ECOG PS 
 
 
 
 
Mandatory tumor assessments are to be completed at Weeks 9 and 52 (±5 days). Additional tumor assessments should 
be performed as required by local standards of care or at the investigator’s discretion as discussed in the Time and 
Events Schedule and are recommended every 8-12 weeks until disease progression per RECIST 1.1 criteria (or 
discontinuation of study treatment in subjects receiving nivolumab beyond progression), subject lost to follow up, 
withdrawal of study consent by subject, or end of study. Overall survival will be collected for at least 3 years and up 
to 5 years from the first dose of study therapy, as indicated in the assessment tables.
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Statistical Considerations: 
Sample Size: A total of 950 subjects who are evaluated based on the ECOG PS will be enrolled; Subgroup 1 will 
enroll subjects with PS 0-1 (n ~ 855), and Subgroup 2 will enroll subjects with PS 2 (n ~ 95). The screen failure rate 
is anticipated to be 15%, which results to approximately 719 and 81 treated subjects in Subgroup 1 and Subgroup 2, 
respectively. 
With n=800 subjects, about 4 subjects will experience a rare adverse event with 0.5% true cumulative event rate with 
a rate estimate within a 95% confidence interval (CI) (0.1%-1.3%). Approximately 2 subjects with events and a 95% 
CI of (0.1%-0.9%) for assumed true event rate of 0.25% are projected.
The 95% CI is calculated using the Clopper-Pearson method in PASS12. 
Endpoints: The primary endpoint is the incidence of high-grade (CTCAE v4.0 Grades 3-4), treatment-related, select
adverse events
The secondary endpoints include:
•
Incidence of high grade (Grades 3-4) select adverse events
•
Median time to onset and median time to resolution (Grades 3-4) of select adverse events
•
OS
•
ORR
 
 
Analyses:  The analysis of primary, secondary (excluding objective response rate), and exploratory endpoints will be 
reported for the full safety analysis set and subgroups based on ECOG PS. ORR will be reported for the response 
evaluable analysis set and by PS subgroups and randomized cohorts
Analysis of Primary Endpoints  
The number and percentage of subjects who report high-grade (Grades 3-4), treatment-related, select adverse events 
will be summarized for all treated subjects and by subgroups. Treatment-related, select adverse events will be tabulated 
using worst grade per NCI CTCAE V4.0 criteria by system organ class (SOC) and Medical Dictionary for Regulatory 
Affairs (MedDRA) preferred terms.
Analysis of Secondary Endpoints
Incidence of high grade (Grades 3-4) select adverse events, regardless of relationship to study treatment will be 
analyzed in the same manner as the primary endpoint. 
Descriptive statistics including time to onset and time to resolution of select adverse events and OS will be estimated 
using Kaplan-Meier (KM) product limit method for all treated subjects by subgroups and randomized cohorts.  Median 
time to onset, median time to resolution, and median overall survival, if estimable, will be presented together with 
their 95% confidence interval (CI) using Brookmeyer and Crowley method. If medians are not estimable, estimation 
of other percentiles (eg, 10th or 25th quartile) may be considered.
OS rates at Years 1 and 2, together with their 95% CIs, will also be estimated using KM estimates on the OS curves. 
Associated 2-sided 95% CIs will be calculated using the Greenwood formula. 
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The ORR will be summarized by binomial response rates and their corresponding two-sided 95% exact CIs using the 
Clopper-Pearson method. This analysis will be performed for all response evaluable subjects. This analysis will also 
be performed by subject subgroups.
 
 
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 05: ..................................... 
. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
 
 
 
 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Drug Access to Study ..................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
 
 
 
 
 
3.5 Discontinuation of Subjects Following Any Treatment with Study Drug ........ 
3.6 Post-Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.2 Investigational Product ..................................................................................... 
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4.3 Non-investigational Product ............................................................................. 
4.4 Storage and Dispensing..................................................................................... 
4.5 Method of Assigning Subject Identification ..................................................... 
4.6 Selection and Timing of Dose for Each Subject ............................................... 
4.6.1 Management of Select Adverse Events .................................................... 
4.6.2 Nivolumab Dose Delay Criteria .............................................................. 
4.6.3 Nivolumab Dose Reductions and Escalations ......................................... 
4.6.4 Criteria to Resume Treatment with Nivolumab ....................................... 
4.6.5 Treatment Discontinuation Criteria ........................................................ 
4.6.5.1 Nivolumab Dose Discontinuation ................................................... 
4.6.6 Treatment Beyond Disease Progression .................................................. 
4.6.7 Treatment of Nivolumab-Related Infusion Reactions .............................. 
4.7 Blinding/Unblinding ......................................................................................... 
4.8 Treatment Compliance ...................................................................................... 
4.9 Destruction of Study Drug ................................................................................ 
4.10 Return of Study Drug ...................................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Vital Signs and Physical Examinations ................................................... 
5.3.3 Pregnancy Testing ................................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
 
 
 
 
 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
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8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Safety Analyses......................................................................................... 
8.4.2.1 Primary Analyses ............................................................................ 
8.4.2.2 Secondary Analyses ........................................................................ 
 
8.4.3 Efficacy Analyses ..................................................................................... 
 
 
 
 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
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1.3
Objectives(s)
1.3.1
Primary Objective
•
To determine the incidence of high-grade (CTCAE v4.0 Grades 3-4), treatment-related, select 
adverse events in subjects with advanced or metastatic SqNSCLC who progressed during or 
after at least 1 systemic therapy. 
1.3.2
Secondary Objectives
•
To determine the incidence and to characterize the outcome of all high-grade (CTCAE v4.0 
Grades 3-4), select adverse events in subjects with advanced or metastatic SqNSCLC who have 
progressed during or after at least 1 prior systemic therapy
•
To estimate overall survival in all treated subjects
•
To estimate investigator-assessed ORR
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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 the Declaration of Helisinki.
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information to be provided to subjects and any updates.
The investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives (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 and by the person who conducted the informed consent discussion.
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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 
her informed consent 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 or she 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 
her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by 
the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
The study will include subjects with histologically- or cytologically-documented SqNSCLC who 
have progressed during or after a minimum of 1 prior systemic treatment for advanced or 
metastatic disease. Subjects will be treated with 3 mg/kg of nivolumab IV every 2 weeks until 
disease progression, unacceptable toxicity, withdrawal of consent, or end of study. Subjects will 
undergo screening evaluations to determine eligibility within 28 days prior to first dose following 
signed informed consent (as described in Table 5.1-1). Each 14-day dosing period will constitute 
a cycle. Please refer to Table 5.1-2 for additional procedures to be performed during study 
treatment.
The Scientific Steering Committee (Section 7) will provide guidance and scientific expertise on 
the clinical risk/benefit ratio closely following a defined Safety Management Plan. 
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Subjects will be evaluated in 2 separate subgroups: ECOG PS 0-1 subjects and PS 2 subjects (Table 
3.1-1). 
Enrollment of new subjects on the study will continue until the target recruitment is met. At the 
conclusion of the study, subjects who continue to demonstrate clinical benefit will be eligible to 
receive BMS supplied study treatment. Study treatment will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. After marketing authorization, if permitted 
by the local country, subjects within the study may access locally available drug.  
In this study, overall survival is a key endpoint. 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 drug must continue to be followed for collection of outcome and/or survival follow-up data 
as required and until death or the conclusion of the study. The study will close after the last enrolled 
subject completes at least 3 years of follow-up
The study design schematic is presented in Figure 3.1-1.
Table 3.1-1:
Subject Subgroup
(Subgroup Number) 
Total study population 
n=950
Disease Criteria
Subgroup 1: ECOG PS 01-
(N approximately 855)
•
ECOG Performance Status 0 to 1
•
Failed 1 or more prior systemic therapy
•
Balance enrolling second-line and third-line subjects
Subgroup 2: PS2
(N approximately 95)
•
ECOG Performance Status 2 
•
Failed 1 or more prior systemic therapy
•
Balance enrolling second-line and third-line subjects
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Figure 3.1-1:
Study Design Schematic
3.2
Post Study Drug Access to Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of BMS.
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.
N=approximately
950 subjects enrolled
Study Population
•
Subjects with
advanced or metastatic
squamous cell non-
small cell lung cancer 
(SqNSCLC) who 
received at least 1prior
systemic regimen for lung 
cancer
Intervention:
Assuming a 15% screening failure 
rate, N= ∼800 treated with 
nivolumab 3 mg/kg as a 60-
minute IV infusion every 2 weeks
Study Subgroups
ECOG PS 0-1 (n= ∼719)
ECOG PS 2 (n= ∼81)
Safety assessments every 
2 weeks. First tumor 
assessments at Week 9.
Clinical benefit should be 
balanced by clinical judgment as 
to whether the subject is 
clinically deteriorating and 
unlikely to receive any benefit 
from continued treatment.
A cohort of 81 PS 2 subjects will 
be assessed for safety and 
tolerability.
Treat until progression* or 
unacceptable toxicities
Safety followed 
continuously.
Subjects followed for 
ongoing drug-related AEs 
until: resolution; 
symptoms return to 
baseline; AE deemed 
irreversible; lost to 
follow-up/death; disease 
progression*; withdrawal 
of consent, or end of study
*subject may be treated 
beyond progression under 
protocol-defined 
circumstances
Endpoints: 
, ORR. 
OS, 
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2. Target Population
a) ECOG PS: 
i)
PS 0 to 1 (Subgroup 1)
ii) PS 2 (Subgroup 2; minimum of 95 enrolled (81 treated) subjects. The Scientific
Steering Committee will provide guidance and scientific expertise on the risk/benefit 
ratio following a Safety Management Plan). 
b) Subjects with histologically or cytologically-documented SqNSCLC who presented with 
stage IIIb/stage IV disease or who developed recurrent or progressive disease following 
prior definitive therapy for localized or local advanced disease. NOTE: A fresh biopsy is 
not required to take part in the study.
c) Subjects must have experienced disease recurrence or progression during or after one prior 
platinum doublet-based chemotherapy regimen for advanced or metastatic disease.
i)
Maintenance therapy following platinum doublet-based chemotherapy is not 
considered as a separate regimen of therapy
ii) Subjects who received platinum-containing adjuvant, neoadjuvant or definitive 
chemoradiation therapy given for locally advanced disease, and developed recurrent 
(local or metastatic) disease within 6 months of completing therapy are eligible.
iii) Subjects with recurrent disease > 6 months after platinum-containing adjuvant, 
neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, 
who also subsequently progressed during or after a platinum doublet-based regimen 
given to treat the recurrence, are eligible.
d) Subjects must have evaluable disease by CT or MRI per RECIST 1.1 criteria (radiographic 
tumor assessment performed within 28 days of first dose of study drug) or clinically 
apparent disease that the investigator can follow for response.
e) Subjects with CNS metastases:
i)
Subjects are eligible if CNS metastases are treated and subjects have neurologically 
returned to baseline (except for residual signs or symptoms related to the CNS 
treatment) for at least 2 weeks prior to first dose. In addition, subjects must be either 
off corticosteroids or on a stable or decreasing dose ≤10 mg daily prednisone (or 
equivalent)
OR
ii) Subjects are eligible if they have previously untreated CNS metastases that are 
neurologically asymptomatic. In addition, subjects must be either off corticosteroids or 
on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent).
f)
As of Amendment 01, this criterion is no longer applicable. 
g) Prior palliative radiotherapy must have been completed at least 14 days prior to study drug
administration. See Section 3.4.3.1 for guidance on palliative radiotherapy during study 
treatment.
h) As of Amendment 01, this criterion is no longer applicable. 
i)
As of Amendment 01, this criterion is no longer applicable. 
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j)
Screening laboratory values must meet the following criteria prior to commencement of 
treatment:
i)
WBCs ≥2000/μL
ii) Neutrophils ≥1500/μL
iii) Platelets ≥100 X10³/μL
iv) Hemoglobin ≥9.0 g/dL
v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance (CrCl) > 40 mL/minute (using 
Cockcroft/Gault formula)
(1) Female CrCl= [(140- age in years) X weight in kg X 0.85) ÷ (72 X serum creatinine 
in mg/ dL)]
(2) Male CrCl= [(140- age in years) X weight in kg X 1.00) ÷ (72 X serum creatinine 
in mg/ dL)]
vi) AST ≤3 X ULN
vii)ALT ≤3 X ULN
viii)
Total bilirubin ≤1.5 X ULN (except subjects with Gilbert Syndrome, who must 
have total bilirubin < 3.0 mg/dL)
k) As of Amendment 01, this criterion is no longer applicable. 
l)
Subject Re-enrollment:  This study permits the re-enrollment of a subject who 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.
m) Prior lines of antineoplastic therapy, including chemotherapy, hormonal therapy, 
immunotherapy, surgical resection of lesions, non-palliative radiation therapy, or standard 
or investigational agents for treatment of NSCLC, must be completed 28 days prior to the 
first dose of nivolumab
3. Age and Reproductive Status
a) Males and Females, ages 18 or older
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study drug
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with nivolumab plus approximately 5 half-lives of nivolumab plus 30 days 
(duration of ovulatory cycle) for a total of 5 months post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab plus 
approximately 5 half-lives of the study drug plus 90 days (duration of sperm turnover) for 
a total of 7 months post-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.
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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 WOCBP and 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, WOCBP and male subjects who are sexually active with WOCBP must agree to 
the use of one of the highly effective methods of contraception.
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 
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:
1) Progestogen only hormonal contraception associated with inhibition of ovulation
2) Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants, transdermal, and intrauterine 
hormone releasing systems (IUS).
3) Nonhormonal IUDs, such as ParaGard
4) Bilateral tubal occlusion
5) Vasectomized partner with documented azoospermia 90 days after procedure
a) Vasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomized partner has 
received medical assessment of the surgical success.
6) Intrauterine hormone-releasing system (IUS)
7) Complete abstinence
a) Complete abstinence is defined as the complete avoidance of heterosexual intercourse
b) Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days).
c) It is not necessary to use any other method of contraception when complete abstinence is 
elected.
d) Subjects who choose complete abstinence must continue to have pregnancy tests.
e) Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence.
f)
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
UNACCEPTABLE METHODS OF CONTRACEPTION
1) Vaginal sponge with spermicides
2) Progestin-only pills
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3) Cervical cap with spermicides
4) Diaphragm with spermicides
5) Periodic abstinence (calendar, symptothermal, post-ovulation methods)
6) Withdrawal (coitus interruptus)
7) Spermicide only
8) Lactation amenorrhea method (LAM)
9) Male condoms with or without spermicide for partners of female subjects, as the only method 
of contraception
10) Female condoms
11) A male and a female condom must not be used together
3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) Subjects with untreated, symptomatic CNS metastases are excluded.
b) Subjects with carcinomatous meningitis are excluded. 
2) Medical History and Concurrent Diseases
a) Subjects with active, known or suspected autoimmune disease. Subjects with Type I 
diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
b) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
the first dose of study drug administration. Inhaled or topical steroids and adrenal 
replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the 
absence of active autoimmune disease
c) As of Amendment 01, this criterion is no longer applicable. 
d) Other active malignancy requiring concurrent intervention
e) Subjects with previous malignancies (except non-melanoma skin cancers, and the 
following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, 
melanoma or breast) are excluded unless a complete remission was achieved at least 2 years 
prior to study entry AND no additional therapy is required during the study period
f)
Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the subject to receive protocol therapy
g) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug.
h) Subjects must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days before the first dose of study treatment.
i)
Known alcohol or drug abuse
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j)
Subjects who received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically 
targeting T-cell costimulation or checkpoint pathways) or who have previously taken part 
in a randomized BMS clinical trial for nivolumab or ipilimumab.
3) Physical and Laboratory Test Findings
a) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
b) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection.
4) Allergies and Adverse Drug Reactions
a) History of severe hypersensitivity reactions to other monoclonal antibodies
b) As of Amendment 01, this criterion is not applicable. 
5) Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study 
medication
6) As of Amendment 01, this section was removed. 
a) As of Amendment 01, this criterion was removed.
b) As of Amendment 01, this criterion was removed. 
c) As of Amendment 01, this criterion was removed. 
d) As of Amendment 01, this criterion was removed. 
e) As of Amendment 01, this criterion was removed. 
7) 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
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that 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 woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
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 
> 40 mIU/mL to confirm menopause.
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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 durations 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
Other parenteral products may require washout periods as long as 6 months.
 
 
 
 
 
 
 
 
 
 
 
 
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3.5
Discontinuation of Subjects Following Any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject
•
Pregnancy
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Second malignancy requiring systemic anticancer treatment
In the case of pregnancy, the investigator must immediately notify BMS Medical Monitor/designee 
of this event. In most cases, the study drug will be permanently discontinued in an appropriate 
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manner. If the investigator determines a possible favorable benefit/risk ratio that warrants
continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue investigational product should comply with protocol-specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject withdraws consent for all study procedures including post-treatment study follow-up or 
loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post-Study Drug Study Follow up
Subjects who discontinue study treatment may continue to be followed. In this study, safety and 
survival are key endpoints 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 
drug must continue to be followed for collection of outcome and/or survival follow-up data as 
required and in line with Section 5-Study Assessments and Procedures--until death or the 
conclusion of the study.
The subjects will be followed up for select AEs for a minimum of 100 days from the last dose of 
study therapy and for ongoing drug-related AEs until resolved, return to baseline or deemed
irreversible, or until lost to follow-up or withdrawal of study consent.
One of the endpoints is overall survival, and every attempt will be made to obtain survival status 
every 3 months or until death, lost to follow-up, withdrawal of study consent, or end of study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol-specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by the subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post-treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
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is defined by the inability to reach the subject after a minimum of 3 documented phone calls, faxes, 
or emails as well as lack of response by subject to 1 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.
4
TREATMENTS
4.1
Study Treatments
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
All products, active or placebo, being tested or used as a comparator in a clinical trial
•
Study-required premedication
•
Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, background therapy, rescue medications)
•
Diagnostic agents (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
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4.2
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, the investigational product is nivolumab. 
4.3
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
In this protocol, non-investigational products are not applicable.
4.4
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
 
 
 
 
 
 
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4.6.1
Management of Select Adverse Events 
In some cases, the natural history of AEs associated with immunotherapy can differ from and be 
more severe than AEs caused by agents belonging to other therapeutic classes. Early recognition 
and management may mitigate severe toxicity. Evaluation and management guidelines for the 
following groups of AEs were developed to assist investigators and can be found in the Investigator 
Brochure:
•
Pulmonary toxicity
•
Gastrointestinal toxicity (diarrhea or colitis)
•
Endocrinopathies
•
Hepatotoxicity (including asymptomatic LFT elevations)
•
Renal toxicity
•
Skin toxicity
•
Neurological toxicity
For subjects expected to require more than 4 weeks of corticosteriods or other immunosuppressants 
to manage the AE, consider the recommendations provided in the Investigator Brochure. Tumor 
assessments for all subjects should continue as per local standard of care and guidelines, even if 
dosing is interrupted.
4.6.2
Nivolumab Dose Delay Criteria
Nivolumab administration should be delayed for the following:
•
Grade2 non-skin, drug-related adverse event, with the exception of fatigue 
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
•
Grade 3 drug-related laboratory abnormality, with the following exceptions
•
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
•
Grade ≥3 AST, ALT, total bilirubin will require dose discontinuation 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication
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4.6.3
Nivolumab Dose Reductions and Escalations
Nivolumab dose reductions and escalations are not permitted.
4.6.4
Criteria to Resume Treatment with Nivolumab
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue
•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity
•
Subjects with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may resume 
when laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.
•
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 a 
steroid taper over at least 1 month may be eligible for re-initiation of treatment if discussed 
with and approved by the BMS Medical Monitor.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor (or 
designee). Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
4.6.5
Treatment Discontinuation Criteria
Tumor assessments for all subjects should continue as per protocol even if dosing is discontinued.
4.6.5.1
Nivolumab Dose Discontinuation
•
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-initiation period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:: 
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
hypersensitivity reaction, infusion reactions, and endocrinopathies 
−
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:
o Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
o Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
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* In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
•
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset 
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
•
Any dosing interruption lasting > 6 weeks from the previous dose requires discontinuation, 
with the following exceptions:
−
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the BMS Medical Monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee). 
Any adverse event, laboratory abnormality, or intercurrent illness, which in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing
4.6.6
Treatment Beyond Disease Progression
As described in Section 1.1.4, accumulating evidence indicated a minority of subjects treated with 
immunotherapy may derive clinical benefit despite initial evidence of progressive disease.49
Subjects treated with nivolumab will be permitted to continue treatment beyond initial 
Investigator-assessed RECIST 1.1-defined progressive disease as long as they meet the following 
criteria:
•
Investigator-assessed clinical benefit and do not have rapid disease progression
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Subject provides written informed consent prior to receiving additional nivolumab treatment 
using an ICF describing any reasonably foreseeable risk or discomforts or other alternative 
treatment options
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The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
subject is clinical deteriorating and unlikely to receive any benefit from continued treatment with 
nivolumab.
All decisions to continue treatment beyond initial progression must be discussed with the BMS 
Medical Monitor and documented in the study records. 
Subjects must sign a separate informed consent form to receive treatment beyond progression. 
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional ≥10% increase in tumor burden volume from time of initial progression (including all 
target lesions and new measurable lesions).
Global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at the time should be reported as symptomatic deterioration. Every 
effort should be made to document objective progression (ie, radiographic confirmation) even after
discontinuation of treatment. 
4.6.7
Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthalgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated).
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) 
and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before additional 
nivolumab administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤24 
hours).
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or 
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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 nivolumab will 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 study drug infused must be recorded on the electronic 
case report form (eCRF). The following prophylactic premedications are recommended for future 
infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); these should be administered at least 30 minutes before additional nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]. Grade 4: life-threatening; pressor or ventilatory support indicated).
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and treat 
the subject as follows: recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 solution 
for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Subject should be monitored until the Investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued.
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. Remain 
at bedside and monitor subject until recovery of the symptoms. In case of late-occurring 
hypersensitivity symptoms (eg, appearance of a localized or generalized pruritus within 1 week 
after treatment), symptomatic treatment may be given (eg, oral antihistamine or corticosteroids).
4.7
Blinding/Unblinding
Not applicable
4.8
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as by the subject’s medical 
record and eCRF.
4.9
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site.
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics).
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On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study drug.
4.10
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
Arrangements for the return of study drug will be made by the responsible Study Monitor.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedure Outline (CA209171)
Procedure
Screening Visita
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
Assessed prior to first dose
Medical History
X
Medical history will include smoking history, comorbidities, particularly chronic pulmonary and 
chronic cardiovascular diseases following international established categories (eg, NYHA for 
cardiac insufficiency). Mutation status of EGFR and ALK will be collected and ROS, MET, KRAS, 
and BRAF will be collected, if available. Additional biopsies for mutation status, if not previously 
tested, are not required. 
Safety Assessments
HIV testing (in Germany only)
X
Physical Examination
X
Includes height, weight, and ECOG PS. Focused physical exam may be performed at screening if 
clinically indicated.
ECOG Performance Status
X
Subgroup 1:  PS 0-1
Subgroup 2: PS 2 
Vital Signs and Oxygen Saturation
X
Temperature, BP, HR, RR, O2 saturation by pulse oximetry at rest (also monitor amount of 
supplement oxygen if applicable). Obtain vital signs at screening visit and within 72 hours of first 
dose. 
Assessment of Signs and 
Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days of first dose, prior 
to study treatment initiation.
Serious Adverse Events 
Assessment
X
Adverse Events Assessment
X
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Table 5.1-1:
Screening Procedure Outline (CA209171)
Procedure
Screening Visita
Notes
 
 
 
 
Pregnancy Test 
X
Performed within 24 hours prior to first dose for WOCBP only (serum or urine as required by the 
standard of care at the site)
Additional Assessments
 
Efficacy Assessment
Screening/Baseline Tumor 
Assessment
Chest, abdomen, pelvis, brain, and all other known sites of disease within 28 days prior to first dose 
of study therapy.  Subjects must have evaluable disease by CT or MRI per RECIST 1.1 criteria 
(radiographic tumor assessment performed within 28 days of first dose of study drug) or clinically 
apparent disease that the investigator can follow for response. 
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; HBsAg = 
hepatitis B surface antigen; HCV Ab = hepatitis C antibody; HR = heart rate; LDH = lactate dehydrogenase; O2 = oxygen; PS = Performance Status; RR = 
respiratory rate; TFT = Thyroid Function Test ; TSH, thyroid stimulating hormone; WOCBP = women of child bearing potential.
a
Within 28 days before start of nivolumab
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Table 5.1-2:
CA209171 On-treatment Assessments
Procedure
Each Cycle 
(every 2 weeks)  
Every 2 Cycles 
(every 4 weeks)
Every 3 Cycles 
(every 6 weeks)
Week 9
Week 52
Notes
Safety Assessments
Physical 
Measurements 
(including 
Performance Status)
X
Collect weight and ECOG Performance Status 
within 72 hours prior to dosing. Focused physical 
examination may be performed if clinically 
indicated.
Vital Signs and 
Oxygen Saturation
X
Within 72 hours prior to dosing, tests includes 
temperature, BP, HR, RR, O2 saturation by pulse 
oximetry at rest (also monitor amount of 
supplemental oxygen if applicable) prior to 
dosing and at any time a subject has any new or 
worsening respiratory symptoms.
Serious Adverse 
Event Assessment
X
Assessed using NCI CTCAE v 4.0
Adverse Events 
Assessment
X
Assessed using NCI CTCAE v 4.0
 
 
 
 
 
 
 
Pregnancy Test
X
Completed more frequently if required by local 
standards (serum or urine as required by standard 
of care at the site).
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Table 5.1-2:
CA209171 On-treatment Assessments
Procedure
Each Cycle 
(every 2 weeks)  
Every 2 Cycles 
(every 4 weeks)
Every 3 Cycles 
(every 6 weeks)
Week 9
Week 52
Notes
Assessments
Tumor Scans
X
X
Mandatory tumor assessments are to be done at 
Weeks 9 and 52 (±5 days) according to RECIST 
1.1 criteria. Additional assessments should be 
performed according to local standards of care or 
at the investigator’s discretion and are 
recommended every 8-12 weeks. Assessments 
should include chest, abdomen, and all known or 
suspected sites of disease.  
 
 
 
 
Survival 
X
Clinical Drug Supplies
Administration of 
Study Drug
X
All subjects continue treatment every 2 weeks 
until disease progression, unacceptable toxicity, 
or withdrawal of informed consent. 
Treatment for all subjects can continue beyond 
initial investigator-assessed progression, if the 
subject has investigator-assessed clinical benefit 
and is tolerating the study drug. 
Record Study Drug Infusion start and stop times.
BP = blood pressure; CBC = complete blood count; HR = heart rate; 
 
 NCI CTCAE = National Cancer Institute Common Terminology Criteria for AEs; O2 = oxygen; PS = Performance Status; RR = respiratory rate.
a CBCs with differential includes white blood cell count, lymphocyte count, absolute neutrophil count, hemoglobin, hematocrit, and platelet count. Results to be 
obtained prior to dosing on infusion days.
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Table 5.1-3:
CA209171 Off-Treatment Follow Up Assessments
Procedure
FU1
6 weeks (±2 weeks) 
after last dose
FU2
16 weeks (±2 weeks) 
after last dose
Further Follow-Up 
Every 3 months (±1 
month) after FU2
Notes
Safety Assessments
Physical 
Examinations
X
X
Collect weight and ECOG Performance Status. Focused 
physical examination may be performed if clinically indication.
Vital Signs and 
Oxygen Saturation
X
X
Temperature, BP, HR, RR, O2 saturation by pulse oximetry at 
rest (also monitor amount of supplemental oxygen if 
applicable) prior to dosing and at any time a subject has any 
new or worsening respiratory symptoms.
Serious Adverse 
Event Assessments
X
X
For a minimum of 100 days from the last dose of study 
therapy, subjects followed for ongoing drug-related adverse 
events until resolved, symptoms return to baseline, or are 
deemed irreversible, lost to follow up, or withdrawal of study 
consent. 
Adverse Event 
Assessments
X
X
For a minimum of 100 days from the last dose of study 
therapy, subjects followed for ongoing drug-related adverse 
events until resolved, symptoms return to baseline, or are 
deemed irreversible, lost to follow up, or withdrawal of study 
consent.
 
 
X
X
 
Pregnancy Test
----------See notes-----
Every 4 weeks for 6 months following the end of treatment. 
Completed more frequently if required by local regulations 
(serum or urine as required by standard of care at the site).
Efficacy Assessments
Tumor scans
-------------See notes-----------
Assessments should be performed according to local standards 
of care or at the investigators discretion and are recommended 
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Table 5.1-3:
CA209171 Off-Treatment Follow Up Assessments
Procedure
FU1
6 weeks (±2 weeks) 
after last dose
FU2
16 weeks (±2 weeks) 
after last dose
Further Follow-Up 
Every 3 months (±1 
month) after FU2
Notes
every 8-12 weeks. Assessments should include chest, abdomen, 
and all known or suspected sites of disease.
Survival Follow Up
X
X
Xb
 
b
In-person visit or telephone call
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to first dose) and 
is the value by which study inclusion will be assessed, as it represents the subject’s most current 
clinical state.
5.2
Study Materials
The site will provide all required materials for the tests performed locally (ie, relevant to clinical 
laboratory tests). The site will have available a well-calibrated scale for recording body weight, a 
calibrated sphygmomanometer, and thermometer for temperature. The site will have a validated 
temperature-controlled refrigerator. The site will provide all materials required for accurate source 
documentation of study activities including the Lung Cancer Symptom Scale (LCSS) visual analog 
scale.
BMS will provide a BMS-approved protocol and any amendments or administrative letters (if 
required). Case report forms (electronic or hard copy) will be provided by BMS. Nivolumab will 
be supplied by BMS. BMS will also provide the Investigator Brochure (IB).
5.3
Safety Assessments
Only data for the procedures and assessments specified in this protocol should be submitted to 
BMS on a case report form. Additional procedures and assessments may be performed as part of 
standard of care; however, data for these assessments should remain in the subject’s medical record 
and should not be provided to BMS unless specifically requested.
Subjects will undergo screening evaluations to determine eligibility as mentioned in Table 5.1-1
prior to first nivolumab dose. Safety, including adverse event monitoring and physical 
examination, should be monitored continually, and safety assessments are recommended every 2 
weeks while receiving nivolumab treatment.
The following assessments should be monitored starting on Cycle 1 Day 1 and will continue as 
per the schedule in the Time and Events Tables at the specified frequency:
•
adverse events continuously throughout the study
•
physical examination and physical measurements including weight and ECOG PS 
•
Complete blood count (CBCs) with differential, including white blood cell (WBC), 
lymphocyte count, absolute neutrophil count (ANC), hemoglobin, hematocrit, and platelet 
count. Results to be obtained prior to dosing on infusion days.
•
Serum chemistry tests (blood urea nitrogen [BUN] or serum urea level, serum creatinine, 
sodium, potassium, calcium, chloride, glucose, magnesium, LDH and phosphate). Results to 
be obtained prior to dosing on infusion days.
•
Liver function tests including AST, ALT, total bilirubin, alkaline phosphatase, albumin. 
Results to be obtained prior to dosing on infusion days. 
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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.
5.3.2
Vital Signs and Physical Examinations
Vital signs including temperature, blood pressure, heart rate, respiratory rate, oxygen saturation by 
pulse oximetry at rest (also monitor amount of supplemental oxygen if applicable) within 72 hours 
of dosing. Obtain prior to dosing and at any time a subject has any new or worsening respiratory 
symptoms. If a subject shows changes in oxygen saturation or supplemental oxygen requirement, 
or other pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) consistent 
with possible pulmonary adverse events, the subject should be immediately evaluated to rule out 
pulmonary toxicity, according to the suspected pulmonary toxicity management algorithm 
contained within the Investigator’s Brochure.
5.3.3
Pregnancy Testing
Pregnancy testing must be completed for WOCBP at screening, within 24 hours prior to start of 
study drug (an extension up to 72 hours prior to start of study drug may be permissible in situations 
where results cannot be obtained within a 24 hour window), every 4 weeks while receiving the 
program drugs, and every 4 weeks for 6 months following the end of treatment. Pregnancy testing 
can be completed more frequently if required by local standards. Pregnancy testing may be 
performed at home if an in-office visit is otherwise not required. Telephone contacts are required 
to obtain results for all subjects who perform post-treatment at-home pregnancy testing. Although 
testing may be performed with home pregnancy testing kits, any positive result must be confirmed 
by serum pregnancy testing at the program site.
5.4
Efficacy Assessments
Mandatory tumor assessments are to be done at Weeks 9 and 52 (±5 days), and additional tumor 
assessments should be performed as required by local standards of care or at the investigator’s 
discretion as discussed in Table 5.1-2 and are recommended every 8-12 weeks until:  
•
Disease progression per RECIST 1.1 criteria (or discontinuation of study treatment in subjects 
receiving nivolumab beyond progression)
•
Subject lost to follow-up
•
Withdrawal of study consent by subject
•
End of study
Study evaluations will take place in accordance with Table 5.1-2 and should be performed 
according to RECIST 1.1 criteria. 
High resolution CT with oral or IV contrast or contrast-enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. If a subject has a known allergy to contrast 
material, please use local prophylaxis standards to obtain the assessment with contrast if at all 
possible or use an alternate modality. In cases where contrast is strictly contraindicated, a non-
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contrast scan will suffice. Screening assessments, including chest, abdomen, pelvis, brain, and all 
known or suspected sites of disease, should be performed within 28 days of first dose of study 
drug. Brain MRI is the preferred imaging method for evaluating CNS metastasis. In addition to 
chest and abdomen, all known or suspected sites of disease (including CNS) should be assessed 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 is not adequate for assessment of RECIST 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 the target disease or when progression in bone is suspected. 
Previously treated CNS metastases are not considered measurable lesions for purposes of RECIST 
determined response.
Tumor measurements should be made by the same investigator or radiologist for each assessment 
whenever possible. Changes in tumor measurements and tumor responses to guide ongoing study 
treatment decisions should be assessed by the investigator using RECIST 1.1.
For all subjects, global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’ in the source data and in the case report form. Every effort should be made to 
document objective progression (ie, radiographic confirmation) even after discontinuation of 
treatment.
Survival will be followed after progression either by direct contact (office visits) or via telephone 
contact until death, withdrawal of study consent, lost to follow-up, or end of study.
 
 
 
 
 
 
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6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
•
Related: There is a reasonable causal relationship between study drug administration and the 
AE.
•
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of 1 or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
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hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies:
•
a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).
•
Admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
6.1.1
Serious Adverse Event Collection 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 study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur after written consent and up to 100 
days of discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. All SAEs must be reported from the time 
of informed consent and up to 100 days after discontinuation of dosing (within 30 days of last visit 
for enrollment/screening failures).
An SAE report should be completed for any event where doubt exists regarding its seriousness.
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If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). 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 Contact Information list.
SAE Facsimile Number:  Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic).
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
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6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours and in accordance with SAE reporting procedures described in Section 
6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study 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 should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
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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 Section 6.1.1 for reporting details.)
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs meeting 
the defined criteria must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is 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 worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
The Scientific Steering Committee (SSC) will closely review the safety data throughout the study 
to provide guidance and scientific expertise on the risk/benefit ratio in general and for the separate 
prospective subgroups following a predefined Safety Management Plan respecting the data for rate 
and frequency of Grade 3 and 4 select adverse events (estimated < 25%) and QoL (patient-reported 
outcomes). 
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The total sample size for this study is based on logistical considerations. Nevertheless, certain 
statistical properties of the projected sample size are indicated below.
A total of 950 subjects who are evaluated based on the ECOG PS will be enrolled, and a minimum 
of 11% (95 subjects) should present with PS2. In addition, a minimum of 40% of patients should 
be enrolled as second-line, and a minimum of 40% of patients should be enrolled as third-line. 
With a 15% screen failure rate, a total of approximately 800 subjects will be treated. With n = 800 
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subjects, about 4 subjects will experience a rare adverse event with 0.5% true cumulative event 
rate within 95% confidence interval (CI) (0.1%-1.3%). Approximately 2 subjects with events and 
a 95% CI of 0.1%-0.9% for the assumed true event rate of 0.3% are projected. In addition, with 
800 subjects, the probability of observing at least one rare event (with 0.25% true rate) is 91.0%. 
The 95% CI is calculated using the Clopper-Pearson method in PASS12.
8.2
Populations for Analyses
−
All enrolled subjects: all subjects who signed an informed consent form and were registered 
into the IVRS. 
−
All treated subjects: all subjects who received any nivolumab. This is the primary 
population for safety and efficacy analyses. Subpopulation analyses will be conducted by 
subject PS subgroups.
−
All response evaluable subjects: all treated subjects who have baseline and at least one on-
study evaluable tumor measurement.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint is the incidence of high-grade (CTCAE v4.0 Grades 3-4 or higher),
treatment-related, select adverse events.
Select adverse events are defined in Section 4.6.1.
8.3.2
Secondary Endpoint(s)
The secondary endpoints include:
•
Incidence of high grade (Grade 3-4) select adverse events
•
Median time to onset and  median time to resolution (Grades 3-4) of select adverse events
•
OS is defined as the time from first dosing date 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 treatment and every 3 months via in-person or phone contact after subjects discontinue 
the study drug. 
•
ORR is defined as the number and percentage of subjects with a best overall response (BOR) 
of confirmed CR or PR. ORR as assessed by the investigator will be reported. 
 
 
 
 
 
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8.4
Analyses
The analysis of primary, secondary (excluding ORR), and exploratory endpoints will be reported 
for the full safety analysis set, and by subgroups based on ECOG PS. ORR will be reported for the 
response evaluable analysis set and by PS subgroups. 
8.4.1
Demographics and Baseline Characteristics
The demographic characteristics, medical history, and baseline assessments of subjects will be 
reported as counts and percentages.
Study participation status including completion and discontinuation of treatment will be reported. 
Reasons for discontinuation will be summarized.
8.4.2
Safety Analyses
Safety data will be presented for all treated subjects and by PS subgroups (PS 0-1 and PS2). In 
addition, summaries of safety data for subjects randomized to either continue nivolumab 
monotherapy or discontinue nivolumab monotherapy will also be presented. 
8.4.2.1
Primary Analyses
The number and percentage of subjects who report high-grade (Grades 3-4), treatment-related, 
select adverse events will be summarized for all treated subjects and by subgroups. Treatment-
related, select adverse events will be tabulated using worst grade per NCI CTCAE V4.0 criteria 
by system organ class (SOC) and Medical Dictionary for Regulatory Affairs (MedDRA) preferred 
terms.
In addition to reporting number and percentages of subjects with select adverse events, 95% CIs 
for incidence density rates will be provided based on the Poisson distribution.
8.4.2.2
Secondary Analyses
The number and percentages of subjects who report high-grade (Grades 3-4) select adverse events, 
regardless of relationship to treatment, will be summarized for all treated subjects by subgroups 
and randomized subjects. Select adverse events will be tabulated using worst grade per NCI 
CTCAE V4.0 criteria by SOC and MedDRA preferred terms. In addition to reporting number and 
percentages of subjects with select adverse events, 95% confidence intervals (CIs) for incidence 
density rates will be provide based on the Poisson distribution
In addition, descriptive statistics for time to onset and time to resolution of select adverse events 
will be estimated using Kaplan-Meier (KM) product limit method for all treated subjects and by 
subgroups. Median time to onset and median time to resolution, if estimable, will be presented 
together with their 95% CI using Brookmeyer and Crowley method. If medians are not estimable, 
other percentiles (eg, 10th or 25th) may be reported. 
 
 
 
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8.4.3
Efficacy Analyses
OS is defined as the time between the start of treatment and the date of death due to any cause. A 
subject who has not died will be censored at last known date alive. OS will be followed up while 
subjects are on the study drug and every 3 months via in-person or phone contact after subjects 
discontinue the study drug.
OS will be summarized using Kaplan-Meier (KM) product-limit method and associated statistics
for the treated analysis set. Median values of OS, if estimable, along with 2-sided 95% CI using 
the Brookmeyer and Crowley method will be calculated. If medians are not estimable, other 
percentiles (eg, 10th and 25th) may be reported. OS rates at selected time points, including survival 
rates at Years 1 and 2, together with their 95% CIs will also be estimated using KM estimates on 
the OS curves. Associated 2-sided 95% CIs will be calculated using the Greenwood formula. OS 
summary statistics indicated earlier for the treated analysis set will be reported by subgroups.
The ORR will be summarized by binomial response rates and their corresponding two-sided 95% 
exact CIs using the Clopper-Pearson method. This analysis will be performed for all response 
evaluable subjects. This analysis will also be performed by subject subgroups.
 
 
 
 
 
 
 
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC and Regulatory Authority(ies), if required by local regulations, of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study subjects.
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
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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, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original.
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product. 
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Records or logs must comply with applicable regulations and guidelines and should include the 
following:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted)
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. 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 BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS.
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s)
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs.
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
who is delegated this task on the Delegation of Authority Form .For electronic CRFs, review and 
approval/signature is completed electronically through the BMS electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
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Each individual electronically signing electronic CRFs must meet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report.
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
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 require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If 1 form of contraception is required, Complete Abstinence 
is defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study 
drugs. Female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
If 2 forms of contraception are required, complete abstinence 
is defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study 
drugs. Subjects who choose complete abstinence are not 
required to use a second method of contraception, but female 
subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego 
complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse 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 (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception 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
AEOSI
Adverse events of special interest
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
APC
Antigen-presenting cells
ANC
Absolute neutrophil count
BMS
Bristol-Myers Squibb
BOR
Best overall response
BP
Blood pressure
BUN
Blood urea nitrogen
CBC
Complete blood count
CR
Complete response
CRC
Colorectal carcinoma
CrCl
Creatinine Clearance 
CRPC
Castrate-resistant prostrate carcinoma
CT
Computed tomography
CTCAE
Common Terminology Criteria for AEs
DILI
Drug-induced liver injury
EAP
Expanded access program
ECOG
Easter Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
EGFR-TKI
Epidermal growth factor receptor-tyrosine kinase inhibitor
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
HCV Ab
Hepatitis C antibody
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
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Term
Definition
HRT
Hormone replacement therapy
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IUD
Intrauterine device
IVRS
Interactive voice response system
KM
Kaplan Meier
LCSS
Lung Cancer Symptom Score
LDH
Lactate dehydrogenase
mPFS
Median progression-free survival
LFT
Liver function test
MRI
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose
NCI
National Cancer Institute
O2
Oxygen
ORR
Objective response rate 
OS 
Overall survival
PD-1
Programmed cell death - 1
PR
Partial response
PFS
Progression-free survival
PRO
Patient-reported outcomes
PS
Performance status
QoL
Quality of life
PT
Preferred terms
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RR
Respiratory rate
SSC
Scientific Steering Committee
SqNSCLC
Squamous cell non-small cell lung cancer
TFT
Thyroid function test
TSH
Thyroid stimulating hormone
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Term
Definition
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
women of childbearing potential
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SAP_001.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
AN OPEN-LABEL, MULTICENTER CLINICAL TRIAL WITH NIVOLUMAB 
(BMS-936558) MONOTHERAPY IN SUBJECTS WITH ADVANCED OR METASTATIC 
SQUAMOUS CELL (SQ) NON-SMALL CELL LUNG CANCER (NSCLC) WHO HAVE 
RECEIVED AT LEAST ONE PRIOR SYSTEMIC REGIMEN FOR THE TREATMENT 
OF STAGE IIIB/IV SQNSCLC 
NCT02409368 
29-November-2018 


 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT 
 
AN OPEN-LABEL, MULTICENTER CLINICAL TRIAL WITH NIVOLUMAB 
(BMS-936558) MONOTHERAPY IN SUBJECTS WITH ADVANCED OR METASTATIC 
SQUAMOUS CELL (SQ) NON-SMALL CELL LUNG CANCER (NSCLC) WHO HAVE 
RECEIVED AT LEAST ONE PRIOR SYSTEMIC REGIMEN FOR THE TREATMENT 
OF STAGE IIIB/IV SQNSCLC 
 
CheckMate 171: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 171 
 
VERSION # 2.0 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
TABLE 1: ABBREVIATIONS ......................................................................................................5 
 
 
2 
STUDY DESCRIPTION ..............................................................................................8 
2.1 
Study Design .................................................................................................................8 
2.2 
Treatment Assignment ..................................................................................................9 
2.3 
Blinding and Unblinding ..............................................................................................9 
2.4 
Protocol Amendments ..................................................................................................9 
2.5 
Data Monitoring Committee and Other External Committees ...................................10 
3 
OBJECTIVES .............................................................................................................11 
3.1 
Primary Objective .......................................................................................................11 
3.2 
Secondary Objective ...................................................................................................11 
 
 
4 
ENDPOINTS ..............................................................................................................11 
4.1 
Primary Endpoints ......................................................................................................11 
4.2 
Secondary Endpoints ..................................................................................................11 
 
 
5 
SAMPLE SIZE AND POWER ..................................................................................12 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES .......................................................................................................12 
6.1 
Study Periods ..............................................................................................................12 
6.2 
Treatment Regimens ...................................................................................................12 
6.3 
Populations for Analyses ............................................................................................12 
7 
STATISTICAL ANALYSES .....................................................................................12 
7.1 
General Methods .........................................................................................................12 
7.2 
Study Conduct ............................................................................................................13 
7.2.1 
Accrual ........................................................................................................................13 
7.2.2 
Relevant Protocol Deviations .....................................................................................13 
7.3 
Study Population .........................................................................................................14 
7.3.1 
Subject Disposition .....................................................................................................14 
7.3.2 
Demographic Characteristics .....................................................................................14 
7.3.3 
Medical history – Concurrent diseases ......................................................................15 
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7.3.4 
Baseline Examinations ................................................................................................15 
7.3.5 
Prior Therapy Agent ...................................................................................................15 
7.4 
Extent of Exposure .....................................................................................................15 
7.4.1 
Administration of study therapy..................................................................................15 
7.4.2 
Modifications of Study Therapy ..................................................................................16 
 
 
7.5 
Efficacy .......................................................................................................................17 
7.5.1 
Secondary Analyses ....................................................................................................17 
7.5.1.1 
Overall Survival and Objective Response Rate ..........................................................17 
7.5.1.2 
Subject Follow-up for OS ...........................................................................................17 
7.5.2 
Other Efficacy Analyses ..............................................................................................17 
7.5.2.1 
Follow-up Therapy .....................................................................................................17 
7.6 
Safety ..........................................................................................................................18 
7.6.1 
Primary Analyses ........................................................................................................18 
7.6.1.1 
High Grade Treatment-Related Select Adverse Events ..............................................18 
7.6.1.2 
Select Adverse Events .................................................................................................18 
7.6.2 
Secondary Analyses ....................................................................................................19 
7.6.2.1 
Time-to onset of select AE ..........................................................................................19 
7.6.2.2 
Time-to resolution of select AE...................................................................................19 
 
 
7.6.3.1 
Adverse Events ............................................................................................................20 
7.6.3.2 
Deaths .........................................................................................................................20 
7.6.3.3 
Serious Adverse Events ...............................................................................................20 
7.6.3.4 
Adverse Events Leading to Discontinuation of Study Therapy ..................................21 
7.6.3.5 
Adverse Events Leading to Dose Modification ...........................................................21 
7.6.3.6 
Multiple Events ...........................................................................................................21 
7.6.3.7 
Clinical laboratory evaluations ..................................................................................21 
7.6.3.7.1 
Hematology .................................................................................................................22 
7.6.3.7.2 
Serum Chemistry .........................................................................................................22 
7.6.3.7.3 
Additional Analyses ....................................................................................................22 
7.6.3.8 
Pregnancy ...................................................................................................................23 
7.6.3.9 
Vital Signs ...................................................................................................................23 
7.6.3.10 
Other Observation Related to Safety - Immune Modulating Medication ...................23 
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7.6.4 
Decimal Places ...........................................................................................................24 
7.7 
Interim Analyses .........................................................................................................24 
7.8 
Other Analyses ............................................................................................................24 
8 
CONVENTIONS ........................................................................................................24 
9 
CONTENT OF REPORTS .........................................................................................25 
 
 
DOCUMENT HISTORY...............................................................................................................26 
 
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TABLE 1: ABBREVIATIONS 
AE  
Adverse event 
AEOSI 
Adverse events of special interest 
AIDS 
Acquired immunodeficiency syndrome 
ALT  
Alanine Aminotransferase 
ANC 
Absolute Neutrophil count 
AST  
Aspartate Aminotransferase 
BMS  
Bristol-Myers Squibb 
BOR 
Best overall response 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CR 
Complete response 
CrCl 
Creatinine Clearance 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for AEs 
CRF  
Case Report Form, paper or electronic 
DILI 
Drug-induced liver injury 
EAP 
Expanded access program 
ECOG  
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EGFR-TKI 
Epidermal growth factor receptor-tyrosine kinase inhibitor 
GCP  
Good Clinical Practice 
GI 
Gastrointestinal 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
ICH  
International Conference on Harmonization 
IVRS 
Interactive voice response system 
KM 
Kaplan Meier 
LCSS 
Lung Cancer Symptom Score 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LLN 
Lower limit of normal 
mPFS 
Median progression-free survival 
MRI 
Magnetic Resonance Imaging 
NCI  
National Cancer Institute 
O2  
Oxygen 
ORR  
Objective response rate 
OS  
Overall survival 
PD-1  
Programmed cell death – 1 
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PR  
Partial response 
PFS  
Progression-free survival 
PRO  
Patient-reported outcomes 
PS  
Performance status 
QoL  
Quality of life 
PT  
Preferred terms 
RCC  
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR  
Respiratory rate 
SAE 
Serious adverse event 
SLAE 
Select adverse event 
SSC  
Scientific Steering Committee 
SqNSCLC 
Squamous cell non-small cell lung cancer 
TFT  
Thyroid function test 
TSH  
Thyroid stimulating hormone 
ULN  
Upper limit of normal 
WBC  
White blood cell 
 
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2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is an Open-Label, Multicenter Study. The study will include subjects with histologically- or 
cytologically-documented SqNSCLC who have progressed during or after a minimum of 1 prior platinum 
doublet-based chemotherapy regimen for advanced or metastatic disease. Subjects will be treated with 3 
mg/kg of nivolumab IV every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of 
consent. Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first 
dose following signed informed consent. Each 14-day dosing period will constitute a cycle. 
The Scientific Steering Committee (SSC) will provide guidance and scientific expertise on the clinical 
risk/benefit ratio closely following a defined Safety Management Plan. 
Subjects will be evaluated in 2 separate subgroups: ECOG PS 0-1 subjects and PS 2 subjects. (Table 1.1) 
Table 2.1-1: 
Subject Subgroup 
(Subgroup Number)  
Total study population 
n=950  Patients treated to be mentioned: 800 
Disease Criteria 
Subgroup 1: ECOG PS 0-1 
(N approximately 565) 
x 
ECOG Performance Status 0 to 1 
x 
Failed 1 or more prior systemic therapy 
x 
Balance enrolling second-line and third-line 
subjects 
Subgroup 2: ECOG PS 2 
(N approximately 242) 
x 
ECOG Performance Status 2 
x 
Failed 1 or more prior systemic therapy 
x 
Balance enrolling second-line and third-line 
subjects 
 
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2.2 
Treatment Assignment 
After the subject’s eligibility is established and informed consent has been obtained, the subject will be 
enrolled, and a number will be assigned through an interactive voice response system (IVRS). Specific 
instructions and procedures for using IVRS will be provided to the investigational site in a separate 
document/manual. 
Subjects will be treated with 3 mg/kg of nivolumab as a 60-minute IV infusion (+/-5 min) on Day 1 +/- 2 of 
a treatment cycle every 2 weeks (14 days) until progression, unacceptable toxicity, or withdrawal of 
informed consent. No premedications are recommended for the initiation of dosing. Dosing calculations 
should be based on the body weight assessed at each visit. All doses should be rounded to the nearest 
milligram. The screening body weight may be used for dosing of Cycle 1. There will be no nivolumab dose 
escalations or reductions permitted. Subjects may be dosed no fewer than 12 days from the previous dose.  
Subjects will be monitored continuously for AEs while on the study. Treatment modifications (eg, dose 
delay or discontinuation) will be based on specific laboratory and adverse event criteria. 
2.3 
Blinding and Unblinding 
Not applicable. This is an open-label study. 
2.4 
Protocol Amendments 
The protocol has 3 amendments issued. The table below summarizes the main purposes of these 
amendments. See amendments for further details.  
Amendment # 
Main purpose of the amendment 
Amendment #1 
21-Nov-2014 
x 
The inclusion criteria have been expanded and the exclusion criteria 
have been minimized in order to expand the subject population. 
x 
The background section has also been updated to reflect the most 
recently available data.
x 
The options for palliative local therapy have also been expanded to meet 
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the needs of the current patient populations. 
x 
Randomization after 1 year to subjects who are still benefitting from 
treatment and achieved a partial or complete response to offer insight 
into the optimal treatment duration of nivolumab has been added. After 
1 year of therapy, subjects will be randomized to continue nivolumab 
monotherapy (Cohort A) or discontinue therapy with the option of 
retreatment disease progression (Cohort B). 
x 
The requirement to have a separate assessment plan for the subjects in 
the Performance Status 2 (PS2) subgroup has been eliminated. 
x 
 
x 
The Lung Cancer Symptom Survey has also been eliminated from the 
subject follow up and decreased while on treatment. 
x 
Initial tumor assessments have also been changed to occur at Week 8 
instead of Week 6. 
x 
The statistical section has been reformatted. 
x 
The phrase “rate and frequency” has been changed to the term 
“incidence” throughout the protocol. 
x 
The term “Adverse Events of Special Interest” has been changed to 
“Select Adverse Events.” 
x 
The Performance Status groups were renamed “Subgroup” (from 
“Cohort”) to avoid confusion with the randomized cohorts. 
Amendment #2 
26-Feb-2015 
x 
Study Director and Medical Monitor were changed 
x 
The use of a condom with spermicide was demoted from a highly 
effective to less effective method of contraception 
 
 
 
 
x 
Pregnancy test had additional language added for clarification 
x 
Serum laboratory tests had additional footnote added for clarification 
Amendment #3 
18-Jun-2015 
x 
Three key changes were made to this protocol: the sample size was 
reduced from 1800 to 950 (with 15% screening failure rate, 800 will be 
treated); second-line lung cancer patients will now be allowed to enroll 
in the study; and the randomization at one year into Cohort A and 
Cohort B has been removed. 
 
The SAP is based on the revised protocol 03 incorporating amendment 3 dates 18Jun2015. 
2.5 
Data Monitoring Committee and Other External Committees 
The SSC will closely review the safety data throughout the study to provide guidance and scientific 
expertise on the risk/benefit ratio in general and for the separate prospective subgroups following a 
predefined Safety Management Plan respecting the data for rate and frequency of Grade 3 and 4 select 
adverse events (estimated <25%) and QoL (patient-reported outcomes). 
 
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3 
OBJECTIVES 
3.1 
Primary Objective 
To determine the incidence of high-grade (CTCAE v4.0 Grades 3-4), treatment-related, select adverse 
events in subjects with advanced or metastatic SqNSCLC who progressed during or after at least 1 systemic 
therapy. 
3.2 
Secondary Objective 
x 
To determine the incidence and to characterize the outcome of all high-grade (CTCAE v4.0 Grades 
3-4), select adverse events in subjects with advanced or metastatic SqNSCLC who have progressed 
during or after at least 1 prior systemic therapy 
x 
To estimate overall survival (OS) in all treated subjects 
x 
To estimate investigator-assessed objective response rate (ORR) 
 
 
 
 
 
 
 
 
4 
ENDPOINTS 
4.1 
Primary Endpoints 
The primary endpoint is the incidence of high-grade (CTCAE v4.0 Grades 3-4 or higher), 
treatment-related, select adverse events. 
4.2 
Secondary Endpoints 
The secondary endpoints include: 
x 
Incidence of high grade (Grade 3-4) select adverse events 
x 
Median time to onset and median time to resolution (Grades 3-4) of select adverse events 
x 
OS is defined as the time from first dosing date 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 
treatment and every 3 months via in-person or phone contact after subjects discontinue the study 
drug. 
x 
ORR is defined as the number and percentage of subjects with a best overall response (BOR) of 
confirmed CR or PR with respect to all treated subjects. ORR as assessed by the investigator will 
be reported. 
 
 
 
 
 
 
 
 
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5 
SAMPLE SIZE AND POWER 
The total sample size for this study is based on logistical considerations. Nevertheless, certain statistical 
properties of the projected sample size are indicated below. 
A total of 950 subjects who are evaluated based on the ECOG PS will be enrolled, and a minimum of 30% 
(285 subjects) should present with PS2. In addition, a minimum of 40% of patients should be enrolled as 
second-line, and a minimum of 40% of patients should be enrolled as third-line. With a 15% screen failure 
rate, a total of approximately 800 subjects will be treated. If the true cumulative incidence rate is 0.5 then 
with n = 800 subjects, about 3 subjects will experience a rare adverse event (with a 95% confidence interval 
(CI) of 0.1%-1.3%) for the cumulative incidence rate. If the assumed true event rate is 0.3% then 
approximately 3 subjects will experience events with a 95% CI of 0.1%-0.8% for the assumed true event 
rate. In addition, with 800 subjects, the probability of observing at least one rare event (with 0.3% true rate) 
is 91.0%. 
The 95% CI is calculated using the Clopper-Pearson method. 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES 
6.1 
Study Periods 
See Core Safety SAP. 
6.2 
Treatment Regimens 
Subjects will be treated with 3 mg/kg of nivolumab as a 60-minute IV infusion (+/-5 min) on Day 1 +/- 2 of 
a treatment cycle every 2 weeks (14 days) until progression, unacceptable toxicity, or withdrawal of 
informed consent. No premedications are recommended for the initiation of dosing. Dosing calculations 
should be based on the body weight assessed at each visit. All doses should be rounded to the nearest 
milligram. The screening body weight may be used for dosing of Cycle 1. There will be no nivolumab dose 
escalations or reductions permitted. Subjects may be dosed no fewer than 12 days from the previous dose. 
6.3 
Populations for Analyses 
x 
All enrolled subjects: all subjects who signed an informed consent form and were registered into 
the IVRS. 
x 
All treated subjects: all subjects who received any nivolumab. This is the primary population for 
safety and efficacy analyses.  
x 
All response evaluable subjects: all treated subjects who have baseline and at least one on-study 
tumor measurement. 
 
See section 7.1 for the subpopulation details. 
7 
STATISTICAL ANALYSES 
7.1 
General Methods 
In the analysis described below (except where noted), counts and percentages will be reported for discrete 
variables with inclusion of unknown or missing values as a separate category. The mean, standard 
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deviation, median, range (minimum and maximum), and number of non-missing values will be reported 
for each continuous measure. 
Adverse events and medical history will be coded according to the most recent Medical Dictionary for 
Regulatory Activities (MedDRA). Previous and concomitant medications will be coded using the WHO 
Drug Dictionary.  
The time to event distribution (i.e overall survival and duration of response) will be estimated using 
Kaplan Meier techniques. Median for time to event endpoints along with 95% confidence interval (CI) 
will be constructed based on 95% CI using the Brookmeyer and Crowley method. OS rates at selected 
time points, including survival rates at Years 1 and 2, together with their 95% CIs will also be estimated 
using KM estimates on the OS curves. Associated 2-sided 95% CIs will be calculated using the 
Greenwood formula. 
The analysis of primary, secondary (excluding objective response rate), and exploratory endpoints will be 
reported for the treated population and subgroups based on ECOG PS (PS 0-1 and PS 2). ORR will be 
reported for the response evaluable analysis set and by ECOG PS subgroups. 
SAS® version 9.2 or higher will be used for statistical analyses, tabulations and graphical presentations.  
7.2 
Study Conduct 
7.2.1 Accrual 
The accrual pattern will be summarized per country, investigational site and per month for all enrolled 
subjects. Informed consent date, first dosing date, country, and investigational site will be presented in a 
by subject listing of accrual. 
7.2.2 Relevant Protocol Deviations 
The relevant Protocol Deviations will be summarized for all enrolled subjects. The following 
programmable deviations from inclusion and exclusion criteria will be considered as relevant protocol 
deviations. Non-programmable relevant eligibility and on-treatment protocol deviations, as well as 
significant (both programmable and non-programmable) eligibility and on-treatment protocol deviations 
will be reported through data management listings. 
At entrance: 
- Subjects with any NSCLC histology other than squamous cell. 
- Subjects without measurable disease at baseline. 
- Subjects who did not meet prior therapy restrictions. 
On-study: 
- Subjects receiving concurrent anti-cancer therapy (defined as chemotherapy hormonal immunotherapy, 
radiation therapy, standard or investigational agents for treatment of NSCLC). 
- Subjects treated differently from enrolled (subjects who received the wrong treatment, excluding the 
never treated). 
A subject listing will also be produced. 
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7.3 
Study Population 
7.3.1 Subject Disposition 
The total number of subjects enrolled in the study will be presented. 
Number of subjects enrolled but not treated along with the reason will be tabulated. This analysis will be 
performed on the enrolled population only. 
Number of subjects who discontinued study treatment along with corresponding reason will be tabulated 
using the enrolled population. 
A subject listing for all enrolled subjects will be provided showing the subject’s off study date and reason 
for going off-study. A subject listing for subjects not treated will also be provided, showing the subject’s 
race, sex, age, consent date and reason for not being treated. 
7.3.2 Demographic Characteristics 
Demographic characteristics such as gender, age, race and ethnicity will be listed for all treated 
subjects. Demographic characteristics will also be summarized for all treated subjects.   
The following characteristics will be summarized and listed: 
x 
Age in years 
x 
Age category (< 65, >= 65 to 75, >=75 to < 85, >=85, >=75, >=65 years) 
x 
Gender, Race/Ethnicity 
x 
ECOG PS (0-1, 2) 
x 
Country 
x 
Baseline weight 
x 
Baseline height 
x 
Baseline BMI 
x 
Smoking Status 
x 
Baseline Tumor Assessment 
x 
Lung Cancer Symptom Score 
x 
Baseline HIV result 
x 
Baseline mutation status (EGFR, ALK, ROS, MET, KRAS, BRAF) 
x 
CNS metastasis (Yes, No) 
x 
Current disease stage (IIIB, IV) 
x 
Cardiac insufficiency category by NYHA 
x 
Type of prior cancer regimen (adjuvant, neo-adjuvant, metastatic disease) 
x 
Time from diagnosis to enrollment 
x 
Baseline Vital Sign (Temperature, BP, HR, RR) and Oxygen Saturation. Age will be calculated as 
follows: Age = maximum integer d ([Date of informed consent – Date of Birth +1] / 365.25). 
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7.3.3 
Medical history – Concurrent diseases 
General medical history will be listed by subject and pretreatment events will be tabulated for all treated 
subjects. 
7.3.4 
Baseline Examinations 
Subjects with abnormal baseline physical examination will be tabulated and listed by examination criteria 
using the treated population. 
7.3.5 
Prior Therapy Agent 
Prior therapy will be summarized for all treated subjects. 
The following information will be presented: 
x 
Prior therapy (yes or no). 
x 
Setting of prior systemic therapy regimen received (adjuvant, metastatic disease, neo-adjuvant). 
x 
Best response to most recent prior regimen (CR/PR vs SD vs PD). 
x 
Time from completion of most recent regimen to treatment (<3, 3-6, >6 months). 
x 
Time from completion of prior adjuvant/neo-adjuvant therapy to treatment (subjects who received 
prior adjuvant/neo-adjuvant), (<6 months and >=6 months). 
x 
Prior surgery related to cancer (yes or no) 
x 
Prior radiotherapy (yes or no) 
x 
Prior systemic therapy classified by therapeutic class and generic name 
x 
Prior/current non-study medication classified by anatomic and therapeutic classes. 
Agents and medication will be reported using the generic name. A listing by subject will also be provided 
for prior systemic cancer therapy, prior radiotherapy, prior surgery related to cancer and non-study 
medication. 
7.4 
Extent of Exposure 
Analyses in this section will be performed in all treated subjects. 
7.4.1 
Administration of study therapy 
The analysis of study drug exposure will focus on the on-study period. The first dosing day corresponds 
to the day of first administration of nivolumab. Throughout this analysis plan, nivolumab dose level will 
refer to the actual dose received rather than the planned dose. The dose level will be in mg/kg. 
Subjects will be treated with 3 mg/kg of nivolumab as a 60-minute IV infusion (+/- 5 min) on Day 1+/-2 
of a treatment cycle every 2 weeks (14 days) until progression, unacceptable toxicity, or withdrawal of 
informed consent. 
The following parameters will be summarized (descriptive statistics) for all treated subjects: 
x 
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90 - < 
110%; ı 110%. 
x 
Number of doses received (summary statistics) 
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x 
Cumulative dose 
x 
Duration of treatment: duration of treatment will be presented using a Kaplan-Meier curve whereby 
the last dose date will be the event date for subjects who discontinued study therapy.  Subjects who 
are still on study therapy will be censored on their last dose date. Also, duration of therapy will be 
presented according to the following: >3 months, >6 months, >9 months, and >12 months. 
A by-subject listing of extent of exposure: weight, number of doses, date of first and last dose, duration of 
treatment, dose delay, reason for delay and reason for discontinuation. 
Table 2: 
Administration of study therapy: definition of parameters 
 
nivolumab 
Dosing schedule per protocol 
3 mg/kg every 2 weeks  
Dose 
Dose (mg/kg) is defined as Total Dose administered (mg)/Most recent 
weight (kg). Dose administered in mg at each dosing date and weight is 
collected on the CRF. 
Cumulative Dose 
Cumulative dose (mg/kg) is sum of the doses (mg/kg) administered to a 
subject during the treatment period. 
Relative dose intensity (%) 
[Cumulative dose (mg/kg) /( (Last dose date – Start dose date + 14) x 3/14] 
x 100 
Duration of treatment  
Last dose date – Start dose date +1 
7.4.2 
Modifications of Study Therapy 
A dose will be considered as actually delayed if the delay is exceeding 3 days. It is defined as duration of 
previous cycle in days -14. Dose delays will be divided into the following categories: on-time, 4-7 days, 
8-14 days, 15-42 days, >42 days. Reason for dose delay will be retrieved from CRF dosing pages. 
The nivolumab infusion can be interrupted and/or the IV infusion rate can be reduced. This information 
will be retrieved from CRF dosing pages. 
The following parameters will be summarized: 
x 
Number of subjects with at least one dose delayed 
x 
Number of dose delayed per subject, length of delay, and reason for dose delay. 
x 
Number of subject with at least one dose infusion interrupted along with reason for the 
interruptions and number of infusions interrupted per subject. 
x 
Number of subjects with at least one infusion with IV rate reduced along with the reason of the 
rate reduction and number of IV rate reduced per subject. 
 
 
 
 
 
 
  
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7.5 
Efficacy 
7.5.1 Secondary Analyses 
7.5.1.1 
Overall Survival and Objective Response Rate 
Overall survival is defined as the time between the start of treatment and the date of death due to any 
cause. A subject who has not died will be censored at last known date alive. OS will be followed up while 
subjects are on the study drug and every 3 months via in-person or phone contact after subjects 
discontinue the study drug. 
Overall survival will be summarized using Kaplan-Meier (KM) product limit method for all treated 
subjects by subgroups based on ECOG PS (PS 0-1 and PS 2). Median values of OS, if estimable, along 
with 2-sided 95% CI using the Brookmeyer and Crowley method will be calculated. If medians are not 
estimable, other percentiles (eg, 10th and 25th) may be reported. OS rates at selected time points, including 
survival rates at Years 1 and 2, together with their 95% CIs will also be estimated using KM estimates on 
the OS curves. Minimum follow-up must be longer than the timepoint of interest to generate the OS rate 
for that particular timepoint. For example, if the timepoint of interest is 9 months and the interval of 
enrollment date and last patient last visit is less than 9 months, then, the minimum follow-up is not 
reached and OS rate is not generated. Associated 2-sided 95% CIs will be calculated using the 
Greenwood formula.  
Objective Response Rate is defined as the number and percentage of subjects with a best overall response 
(BOR) of confirmed CR or PR. ORR as assessed by the investigator will be reported. The ORR will be 
summarized by binomial response rates and their corresponding two-sided 95% exact CIs using the 
Clopper-Pearson method. This analysis will be performed for all response evaluable subjects and by 
subject ECOG PS subgroups. In addition, the BOR will also be summarized according to response 
category. A by subject listing will be provided. 
7.5.1.2 
Subject Follow-up for OS 
The extent of follow-up defined as the time between enrollment date and last known date alive (for 
subjects who are alive) or death date ( for subjects who died) will be summarized descriptively (median, 
min, max) for all subjects treated. 
7.5.2 Other Efficacy Analyses 
7.5.2.1 
Follow-up Therapy 
Subsequent therapy will be summarized and listed using the treated population. 
x 
Chemotherapy by drug name 
x 
Immunotherapy by drug name (including anti-PD1 or anti-CTLA4 agents) 
x 
Tyrosine kinase inhibitor by drug name 
x 
Other investigational agent by drug name 
x 
Surgery 
x 
Radiotherapy 
x 
Any combination of the above 
In addition, a by subject listing will also be presented for tumor response and lesion evaluation using the 
treated population. 
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7.6 
Safety 
Safety data will be presented for all treated subjects by ECOG PS subgroups (PS 0-1 and PS2) and worst 
grade per NCI CTCAE (any grade, grade 3-4, and grade 5). Safety and tolerability will be measured by the 
incidence of all adverse events, serious adverse events, deaths, and laboratory abnormalities. Adverse event 
assessments and laboratory tests will be performed at baseline, and continuously throughout the study at the 
beginning of each subsequent cycle. 
7.6.1 
Primary Analyses 
7.6.1.1 
High Grade Treatment-Related Select Adverse Events  
The number and percentage of subjects who report high-grade (CTCAE v4.0 Grade 3 or higher), 
treatment-related, select adverse events (pulmonary, gastrointestinal, will be summarized using the safety 
set by system organ class and Medical Dictionary for Regulatory (MedDRA) preferred term. 
7.6.1.2 
Select Adverse Events 
Categories of “select AEs” have been created to group together the most common and impactful preferred 
terms (PTs) by organ category, providing a better estimate of the frequency of similar kinds of 
organ-related AEs instead of using PTs only. These select adverse events are further defined as follows: 
x 
may differ from or be more severe than AEs caused by non-immunotherapies 
x 
may require unique (non-standard) intervention such as immunosuppressants (or hormone replacement 
therapy) 
x 
early recognition and management may mitigate severe toxicity 
The preferred terms included in the ‘select AEs’ category are those that are expected to be most commonly 
used to describe pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, rash, and endocrinopathies. 
Hypersensitivity/infusion reactions are also considered a select AE category to facilitate the pooling of the 
most relevant preferred terms for analyses of hypersensitivity/infusion reaction events and not because such 
events fit the criteria for select AEs. 
 Select AEs are based on the list provided by BMS every 6 months. 
Unless otherwise specified, analysis will be performed by select AE category and ECOG PS group: Some 
analyses may also be repeated by subcategory of endocrine events. 
x 
Overall summary of any select AEs overall and by worst CTC grade presented by Category or 
Subcategory/PT A presentation of by age category will also be provided. Overall summary of 
drug-related select AEs by worst CTC grade presented by Category or Subcategory / PT  
x 
Overall summary of any serious select AEs by worst CTC grade presented by Category or 
Subcategory /PT  
x 
Overall summary of drug-related serious select AEs by worst CTC grade presented by Category 
or Subcategory /PT. A presentation of by age category will also be provided.  
x 
Overall summary of serious select Endocrine AEs by worst CTC grade presented by Category or 
Subcategory /PT  
x 
Overall summary of drug-related serious select Endocrine AEs by worst CTC grade presented by 
Category or Subcategory /PT  
x 
Overall summary of any select AEs leading to discontinuation overall and by worst CTC grade 
presented by Category or Subcategory /PT  
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x 
Overall summary of drug-related select AEs leading to discontinuation overall and by worst CTC 
grade presented by Category or Subcategory /PT  
The analyses will be conducted using the 30-day safety window and repeated using the 100-day safety 
window. 
By-subject select AE listing will be provided. 
7.6.2 
Secondary Analyses 
7.6.2.1 
Time-to onset of select AE 
Time-to onset of the following specific events will be graphically displayed for each 
category/subcategory of select AEs using the Kaplan-Meier technique: 
x 
Time-to onset of any grade select AE by ECOG PS subgroup 
x 
Time-to onset of grade 3 to 5 select AE by ECOG PS subgroup 
x 
Time-to onset of any grade drug-related select AE by ECOG PS subgroup 
x 
Time-to onset of grade 3 to 5 drug-related select AE by ECOG PS subgroup 
Rates (derived from the graph) by landmark timepoints will be tabulated for these specific events and for 
each subgroup. 
Additional details regarding the time-to onset definition and censoring rules are described in time-to onset 
definition subsection of APPENDIX 1 of the Core SAP. 
The analyses will be conducted using the 30-day safety window and repeated using the 100-day safety 
window. 
Time-to onset of the following specific events will be presented in a table for each category/subcategory 
of select AEs by ECOG PS subgroup: 
x 
Summary of time to onset of select adverse events overall and by worst CTC grade presented by 
Category or Subcategory / PT  
x 
Summary of time to onset of drug-related select adverse events overall and by worst CTC grade 
presented by Category or Subcategory / PT  
7.6.2.2 
Time-to resolution of select AE 
Time to resolution of the following specific events will be summarized separately for each 
category/subcategory. 
x 
Time-to resolution of select AE by ECOG PS subgroup 
x 
Time-to resolution of drug-related select AE by ECOG PS subgroup 
Time-to resolution analyses are restricted to treated subjects who experienced the specific events.  
The following summary statistics will be reported: percentage of subjects who experienced the specific 
events, percentage of subjects with resolution of the longest select AE, median time-to resolution along 
with 95% CI (derived from Kaplan-Meier estimation) and ranges. 
See time-to resolution definition subsection of APPENDIX 1 of the Core SAP for additional details. 
The analyses will be conducted using the 30-day safety window and repeated using the 100-day safety 
window. 
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7.6.4 Decimal Places 
Decimal places should follow GBS General Requirements Statistical Outputs. 
7.7 
Interim Analyses 
Not applicable. 
7.8 
Other Analyses 
Other analyses include the percentage of subjects who received immune-modulating medication or 
hormone replacement therapy. 
Additional exploratory analyses will be performed ad hoc and as necessary to address queries from the 
regulatory authorities.  
8 
CONVENTIONS 
Unless otherwise noted, the following conventions should be understood to apply. Further conventions 
may be detailed in the Data Presentation Plan. 
The duration between two dates will be calculated as [later date] – [earlier date] + 1 day. Study Day 1 or 
first dose date is the date of first study medication. Study day associated with an assessment will be 
calculated as [assessment date] – [first dose date (or randomization date for non-treated subjects)]. If the 
assessment is on or after first dose/randomization then 1 is added to the calculation. 
The following factors will convert days to months or years: 1 month = 30.4375 days, 1 year = 365.25 
days. 
Conventions for Partial/Missing Dates 
Unless specified otherwise the following conventions will be used for imputing partial dates: 
x 
If only the day of the month is missing, the 15th of the month will be used to replace the missing day. 
x 
If both the day and the month are missing, “July 1” will be used to replace the missing information. 
x 
If a date is completely missing, it will be considered as missing. 
For date of death: 
x 
If only the day of the month is missing, the 1st of the month will be used to replace the missing day*.  
x 
If both the day and the month are missing, “Jan 1” will be used to replace the missing information*. 
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x 
If date is missing, death date will be imputed as the last known alive date. 
* 
The imputed death date will be compared with the last known alive date (date of censoring for 
survival). If the death date is not equal to the date of censoring for survival then the maximum of 
the (imputed death date, date of censoring for survival) will be considered as the date of death. 
For date of progression: 
x 
If only the day of the month is missing, the 1st of the month will be used to replace the missing day*.  
x 
If the day and month are missing or a date is completely missing, it will be considered as missing. 
* 
In case, the date of death is present (complete date), the imputed progression date will be 
compared with the date of death. The minimum of the (imputed progression date, date of death) 
will be considered as the date of progression. 
For date of last tumor assessment: 
x 
If only the day of the month is missing, the 1st of the month will be used to replace the missing day*  
x 
If the day and month are missing or a date is completely missing, it will be considered as missing. 
* 
In case, the date of death is present (complete date), the imputed date will be compared with the 
date of death. The minimum of the (imputed date, date of death) will be considered as the date of 
last tumor assessment. 
For adverse events of special interest onset date: 
x 
If only the day of the month is missing, the first of the month will be used to replace the missing day. 
x 
If the day and month are missing or a date is completely missing, it will be considered as missing. 
For adverse events of special interest resolution date: 
x 
If only the day of the month is missing, the last of the month will be used to replace the missing day. 
x 
If the day and month are missing or a date is completely missing, it will be considered as missing. 
Otherwise, missing values will not in general be imputed. 
9 
CONTENT OF REPORTS 
The complete list of analyses contributing to the clinical study report is given in the Data Presentation 
Plan. 
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DOCUMENT HISTORY 
 
Version 
Number 
Date  
Description 
0.1 
4 Sept 2015 
 Initial version 
0.2 
15 Oct 2015 
Revision per BMS comments 
0.3 
20 Dec 2015 
Revisions per BMS comments 
1.0 
15 Feb 2015 
Revisions per client comments 
(version changed for finalization.) 
1.1 
17June2016
Revisions per Core SAP/DPP 
requirement 
2.0 
18July2016
Revisions per BMS comments 
 
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