Clinical trial NCT02038946
Conditions: Lymphoma
Sponsor: Bristol-Myers Squibb
Start date: 2014-03-26; Completion date: 2020-12-28
Enrollment: 116 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the clinical benefit of Nivolumab, as measured by independent radiologic review committee (IRRC)-assessed objective response rate (ORR) in subjects with FL lymphoma who have failed therapy with both CD20 antibody and an alkylating agent.

Detailed description:

Arms: arm 1: Nivolumab 3 mg/kg injection by Intravenous for every 2 weeks until disease progression or discontinuation due to toxicity
Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_002.pdf: 
Page:
1
Protocol Number:
CA209140
IND Number:
119,380
Ex-US
Non-IND
EUDRACT Number
2013-003645-42
Date:
04-Oct-2013
Revised Date
21-Jul-2016
Clinical Protocol CA209140
A Single-Arm, Open-Label Phase 2 Study of Nivolumab (BMS-936558) in Subjects with 
Relapsed or Refractory Follicular Lymphoma (FL) 
(CheckMate 140: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 140)
Revised Protocol Number: 03
Incorporates amendment(s) 04
Medical Monitor
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
5 Research Parkway
Wallingford, CT 06492
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 
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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 confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No: 03
Date: 21-Jul-2016
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 03
21-Jul-2016
Incorporates Amendment 04 and Administrative Letter 02.
Amendment 04
21-Jul-2016
Safety management algorithms were updated in the Investigator 
Brochure, requiring revision of the Appendix 1 algorithms. This revision 
applies to all subjects receiving study drug, or who have discontinued 
study drug and are being treated for suspected pulmonary toxicity, skin 
toxicity and nephrotoxicity.
Administrative 
Letter 02
06-Oct-2014
Updates Medical Monitor contact information
Revised 
Protocol 02
23-Jul-2014
Incorporates Amendment(s) 03
Amendment 03
23-Jul-2014
Removes the interim analyses and extends the duration of follow-up 
required for all subjects prior to performing the final analysis of the 
primary endpoint. 
Modifies a few eligibility criteria to facilitate subject enrollment.
Allows for continued treatment of subjects in certain instances where 
protocol-defined progression criteria have been met.
The amendment also serves to clarify various protocol requirements to 
ensure consistency in the execution of the study including secondary and 
exploratory objectives, submission of bone marrow aspirate and tumor 
biopsy samples for biomarker analyses, and assessments to be performed 
on subjects that discontinue study treatment to receive an allogeneic SCT 
or ASCT. 
Revised 
Protocol 01
06-Dec-2013
Incorporates Amendment(s) 02 and Administrative Letter 01
Amendment 02
06-Dec-2013
The main objective of this amendment is to implement a mandatory 
recommendation received from the U.S. Food and Drug Administration 
(FDA) as follows:

The exclusion criterion has been added to exclude the subjects 
who received chest radiation 24 weeks prior to first dose of 
the study drug.
Justification for this exclusion criterion is that pneumonitis has been 
noted in the current Investigator Brochure as a treatment-related serious 
adverse event (SAE). The FDA notes that “Radiation pneumonitis can 
occur in patients who have received chest radiation up to 24 weeks after 
radiation therapy.” Chest radiation is not commonly used in the subjects 
eligible for this protocol, and this amendment will comply with the FDA 
recommendation without altering the basic study population or trial 
design.
Additional updates were also made to the protocol including items such 
as clarifying the schedule of tumor assessment, correcting typographical 
and formatting errors,
 
.
Administrative 
15-Nov-2013
Bullet “Admission for administration of anti-cancer therapy in the 
absence of any other SAEs” related to the hospitalizations was 
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Document
Date of Issue
Summary of Change
Letter 01
erroneously added to the list of Serious Adverse Events (SAE) 
definitions.
Original 
Protocol
04-Oct-2013
Not applicable
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SYNOPSIS
Clinical Protocol CA209140
Protocol Title: A Single-Arm, Open-Label Phase 2 Study of Nivolumab (BMS-936558) in Subjects with Relapsed 
or Refractory Follicular Lymphoma (FL)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nivolumab (BMS-936558) administered IV over 60 minutes at 3 mg/kg every 2 weeks until 
progression or unacceptable toxicity
Study Phase: 2b
Research Hypothesis: Treatment with nivolumab will lead to clinical benefit, as demonstrated by an improved 
clinically meaningful objective response rate, including durable responses with substantial magnitude of tumor 
reduction in subjects with refractory FL who have failed therapy with both rituximab and an alkylating agent.
Primary Objective: To assess the clinical benefit of nivolumab, as measured by independent radiologic review 
committee (IRRC) assessed objective response rate (ORR) in subjects with FL who have failed therapy with both 
rituximab and an alkylating agent.
Secondary Objectives:

To assess the duration of response (DOR) based on IRRC assessments

To assess the complete remission rate (CRR) and the duration of CR based on IRRC assessment

To assess the PR rate and the duration of PR based on IRRC assessment

To assess the progression free survival (PFS) based on IRRC assessment

To assess the ORR, based on investigator assessments.
Exploratory Objectives:
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Study Design: This is a single arm phase 2 study in subjects 18 years old with relapsed or refractory follicular 
lymphoma after failure of at least two prior lines of therapy. Approximately 90 subjects will be treated with 
nivolumab 3 mg/kg IV every 2 weeks. Subjects will undergo screening evaluations to determine eligibility within 
28 days prior to first dose. Each 14-day dosing period will constitute a cycle. Tumor assessments will begin 8 weeks 
after the start of therapy and follow the schedule shown in Table 5.4.1-1. An independent radiology review 
committee (IRRC) will also be utilized. The primary endpoint of this study is IRRC-assessed ORR, using 
2007 International Working Group (IWG) Response Criteria for Malignant Lymphoma. Secondary endpoints 
include IRRC-assessed DOR, as well as CRR, duration of CR, PR rate, duration of PR, and PFS as determined by 
IRRC and ORR based on investigator assessment. Collection of fresh tumor tissue (FFPE tumor tissue block or 
10 unstained slides from a biopsy performed during the screening phase or collected as a standard of care procedure 
within 90 days prior to obtaining informed consent for determination of PD-L1 expression status) is mandatory. 
Archival tissue should be submitted for all subjects if available.
FL who have failed 
2 prior lines of 
therapy
S
c
r
e
e
n
BMS-936558
3 mg/kg every 
2 wks until 
treatment 
discontinuation
Primary endpoint: 
ORR by IRRC
Secondary endpoints 
include:
Duration of Response , 
CR Rate and PFS based 
on IRRC assessment
ORR based on 
investigator assessment
Follow-up Phase
It is anticipated that accrual will last 18 months, with approximately 115 subjects enrolled.
Study Population: Male and female, ages 18 and above, with relapsed or refractory follicular lymphoma after 
failure of at least two prior lines of therapies (each containing CD20 antibody and/or an alkylating agent) will be 
eligible to participate in the study. Other key inclusion criteria include ECOG PS 0-1, at least one measurable lesion 
15 mm (1.5 cm) in the longest diameter. (See protocol Sections 3.3.1 and 3.3.2 for full list of criteria.)
Study Assessments: The primary endpoint is ORR as determined by an IRRC according to the 2007 IWG criteria. 
Subjects will be assessed for response by imaging (spiral CT/MRI) beginning at Week 8 and follow the schedule 
shown in Table 5.4.1-1. A PET scan is required to confirm CR.
Subjects that discontinue study treatment to receive an allogeneic SCT or ASCT will have tumor assessment and 
GVHD evaluations performed as described in Sections 5.3 and 5.4.
Statistical Considerations:
Sample Size: The planned sample size for this study will be approximately 90 treated subjects.
The sample size was determined based on two considerations: the ability to produce a CI which would exclude an 
ORR of 20%, which is not considered clinically relevant and provide sufficient information for a reliable 
understanding of the safety profile.
Assuming the true ORR is 35%, the study has approximately 87% power to reject the null hypothesis that the true 
ORR is ≤20%, considering a 2-sided alpha of 5%. In addition, Table xx summarizes the 95% exact CI for the target 
ORRs ranging from 30% to 44% with sample size of 90. At observed ORR ≥30%, the lower bound of the 95% CI 
excludes 20%.
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Endpoints: The primary endpoint is IRRC-assessed ORR. The secondary endpoints are duration of ORR 
(DOR) based on IRRC assessments, IRRC-assessed complete remission rate and duration of CR, IRRC-assessed PR 
rate and duration of PR, IRRC-assessed progression free survival (PFS), and investigator-assessed ORR.
Analyses: The IRRC-assessed ORR will be summarized by binomial response rates and their 
corresponding two-sided 95% exact CIs using the Clopper-Pearson method. The null hypothesis will be rejected if 
the 2-sided 95% CI lower bound is greater than 20%.
The IRRC-assessed DOR will be summarized for subjects who achieve PR or CR using the Kaplan-Meier (KM) 
product-limit method. Median values of DOR, along with the two-sided 95% CIs using a method based on the log-
log transformation, will also be calculated.
IRRC-assessed CR and PR rates and investigator-assessed ORR will be summarized similarly to the primary 
endpoint. Duration of CR and PR will be summarized similarly to DOR. IRRC-assessed PFS will be summarized 
descriptively using the Kaplan-Meier (KM) product-limit method. Median values of PFS, along with the two-sided 
95% CIs using a method based on the log-log transformation, will also be calculated.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION 
 ..................................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory 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 Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.2.1 Permitted Therapy .......................................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.6 Post Treatment Study Follow up....................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 TREATMENTS ......................................................................................................... 
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4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Non-investigational Product .................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Antiemetic Premedications ...................................................................... 
4.3.2 Dose Delay Criteria ................................................................................. 
4.3.2.1 Management Algorithms for Immuno-Oncology Agents ................ 
4.3.3 Doses Reductions and Escalations .......................................................... 
4.3.4 Criteria to Resume Nivolumab Dosing .................................................... 
4.3.5 Treatment Discontinuation Criteria ........................................................ 
4.3.6 Treatment of Nivolumab Related Infusion Reactions .............................. 
4.3.7 Guidelines for Assessment and Management of Tumor Lysis Syndrome  
4.3.8 Treatment Beyond Disease Progression .................................................. 
4.3.8.1 Circumstances in which Post-progression Treatment is Permitted 
4.3.8.2 Assessment schedule for the subjects with post-progression 
treatment ............................................................................................... 
4.3.8.3 Discontinuation due to Further Progression .................................. 
4.3.8.4 Radiographic Assessment for Subjects who Discontinue Study Drug 
during Post-progression Treatment ...................................................... 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Radiographic Assessments ....................................................................... 
5.4.2 Assessment of Overall Tumor Burden and Measurable Disease ............. 
5.4.2.1 Measurable Lesions ........................................................................ 
5.4.2.2 Non-Measurable Lesions ................................................................ 
5.4.3 Specifications by Method of Assessment .................................................. 
5.4.3.1 Measurement of Lesions ................................................................. 
5.4.3.2 Method of Assessment ..................................................................... 
5.4.3.3 Spiral CT/MRI Scan ........................................................................ 
5.4.3.4 Clinical Lesions .............................................................................. 
5.4.3.5 PET scan ......................................................................................... 
5.4.4 Baseline Documentation of “Target” and “Non-Target” Lesions.......... 
5.4.4.1 Target Lesions ................................................................................. 
5.4.4.2 Non-Target Lesions ......................................................................... 
5.4.5 Bone Marrow Assessments ...................................................................... 
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5.4.6 Disease Response Evaluation .................................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetic Sample Analysis ........................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
5.8.1 Immunogenicity Assessments ................................................................... 
5.9 Results of Central 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 .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Endpoint Methods ............................................................. 
8.4.2.2 Secondary Endpoint Methods ......................................................... 
8.4.2.3 Exploratory Endpoint Methods ....................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.4.7.1 Immunogenicity 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 ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
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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 .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ................................................................................................................. 
APPENDIX 2 2007 INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR MALIGNANT LYMPHOMA .................................................... 
APPENDIX 3 FLIPI SCALE........................................................................................ 
APPENDIX 4 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 5 ACUTE GVHD GRADING AND STAGING ..................................... 
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1
INTRODUCTION 
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1.2
Research Hypothesis 
Treatment with nivolumab will lead to clinical benefit, as demonstrated by an improved 
clinically meaningful objective response rate, including durable responses with substantial 
magnitude of tumor reduction in subjects with refractory FL who have failed therapy with both 
rituximab and an alkylating agent.
1.3
Objectives(s)
1.3.1
Primary Objectives
To assess the clinical benefit of nivolumab, as measured by independent radiologic review 
committee (IRRC) assessed objective response rate (ORR) in subjects with FL who have failed 
therapy with both rituximab and an alkylating agent.
1.3.2
Secondary Objectives

To assess the duration of response (DOR) based on IRRC assessments

To assess the complete remission rate (CRR) and the duration of CR based on IRRC 
assessment

To assess the PR rate and the duration of PR based on IRRC assessment

To assess the PFS based on IRRC assessment

To assess the ORR, based on investigator assessments
1.3.3
Exploratory Objectives
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Clinical Protocol
CA209140
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Clinical Protocol
CA209140
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CA209140
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Clinical Protocol
CA209140
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CA209140
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CA209140
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Clinical Protocol
CA209140
BMS-936558
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Clinical Protocol
CA209140
BMS-936558
nivolumab
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate. 
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BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
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. 
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.
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The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a single-arm Phase 2 study in subjects 18 years old with relapsed FL after failure of at 
least two prior lines of therapy, (each containing rituximab and/or an alkylating agent). 
Approximately 90 subjects will be treated with nivolumab 3 mg/kg IV every 2 weeks. 
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first
dose. Each 14-day dosing period will constitute a cycle. Tumor assessments by spiral CT/MRI 
will begin 8 weeks after the start of therapy and will continue every 8 weeks through the first 
8 months, every 12 weeks Months 9 - 24, and then every 6 months thereafter until disease 
progression. An IRRC will also be utilized. The primary endpoint of this study is IRRC-assessed 
objective response rate, using 2007 International Working Group (IWG) Response Criteria for 
Malignant Lymphoma criteria (Appendix 2). Secondary endpoints include IRRC-assessed 
duration of objective response, as well as complete remission rate, duration of CR, PR rate, 
duration of PR and PFS as determined by IRRC assessment and ORR based on investigator 
assessment.
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
FL who have failed 
2 prior lines of 
therapy
S
c
r
e
e
n
BMS-936558
3 mg/kg every 
2 wks until 
treatment 
discontinuation
Primary endpoint: 
ORR by IRRC
Secondary endpoints 
include:
Duration of Response , 
CR Rate and PFS based 
on IRRC assessment
ORR based on 
investigator assessment
Follow-up Phase
Study Duration
It is anticipated that accrual will last 18 months, with approximately 115 subjects enrolled. It is 
anticipated that the analysis of the primary endpoint will take place approximately 30 months 
from FPFV.
Additional survival analysis will be conducted for up to 5 years beyond analysis of the primary 
endpoint.
This study will consist of 3 phases: screening, treatment, and follow-up.
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Screening:

Begins by establishing subject’s initial eligibility and signing of the informed consent form 
(ICF)

Subject is enrolled using the Interactive Voice Response System (IVRS) to obtain a subject 
ID

Confirm that documentation of relapsed or refractory FL is present in the subject’s medical 
record;

Submission of tumor tissue (FFPE tumor tissue block or 10 unstained slides) from a 
biopsy performed within 90 days prior to obtaining informed consent is mandatory for 
determination of PD-L1 expression status. If tissue taken as part of a standard of care 
procedure within 90 days prior to obtaining informed consent is not available, then a 
biopsy must be performed during the screening period and submitted accordingly.

Biopsy samples should be excisional, incisional or core needle.

Subjects may initiate the study drug before the outcome of PD-L1 expression status 
become available.
NOTE: In rare cases where tumor tissue, obtained during screening or within 90 days prior to 
obtaining informed consent, cannot be provided, the reason must be clearly documented in the 
medical record AND the BMS Medical Monitor must be contacted. Archival tissue, if available, 
should be submitted for these subjects. Submission of archival tissue is also encouraged for all 
subjects, irrespective of whether tumor biopsy tissue is available as specified.

Confirm that a bone marrow biopsy/aspirate was performed within 90 days prior to obtaining 
informed consent in the subject’s medical record;

If a bone marrow biopsy/aspirate was not performed within 90 days prior to obtaining 
informed consent, a bone marrow biopsy/aspirate must be performed during the screening 
period.

If a bone marrow biopsy/aspirate needs to be performed during the screening period, 
submission of an aspirate sample for biomarker analyses is optional as per Table 5.1-1

Subjects can start the study drug before bone marrow biopsy results become available; 
results need to be documented in the subject’s medical record later

The Follicular Lymphoma International Prognostic Index (FLIPI) as determined at the time 
of initial disease diagnosis must be reported in the eCRF. (See Appendix 3)

Baseline disease or tumor assessments should be performed within 28 days of first dose of 
study drug, according to Table 5.1-1

Subject is assessed for study eligibility within the required timeframe found in Table 5.1-1

The screening phase either ends with confirmation of full eligibility and treatment of the 
subject or with the confirmation that the subject is a screen failure.
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Treatment:

Treatment begins with the call to the IVRS to obtain vial assignments. A negative pregnancy 
test should be documented within 24 hours prior to the start of investigational product.
Subsequently, women of childbearing potential (WOCBP) must have a pregnancy test every 
4 weeks (± 7 days) regardless of dosing schedule.

The subject should receive the dose of study medication within 1 day of vial assignment.

Subjects may be dosed no less than 12 days between doses and no more than 3 days after the 
scheduled dosing date. Dose given after the 3-day window is considered a dose delay. 
A maximum delay of 42 days between doses is allowed.

All of the vital signs starting after Cycle 1 will be collected within 72 hours prior to dosing. 

Adverse event assessments should be documented at each clinic visit. 

Biomarker, PK and immunogenicity samples will be done according to the schedules in 
Sections 5.5, 5.6, and 5.8.1.

Study drug is administered as an IV infusion over 60 minutes on Treatment Day 1 of each 
cycle until disease progression or discontinuation due to toxicity, withdrawal of study 
consent, or the study ends. Treatment beyond progression is allowed in certain instances as 
described in Section 4.3.8

Study drug dosing may be delayed for toxicity. See Section 4.3.2.

Subjects will be evaluated for response according to revised International Working Group 
Criteria beginning at Week 9 and continuing every 8 weeks (1 week) for the first eight 
months of treatment, then every 12 weeks (2 weeks) up to 2 years of treatment, continuing 
every 6 months (3 weeks) beyond 2 years of treatment, until disease progression is 
documented or until the subject initiates a preparative regimen for allogeneic SCT or ASCT, 
whichever occurs earlier. If the subject discontinues treatment prior to disease progression, 
tumor assessment will continue in the follow-up phase.

Screening/Baseline and all subsequent scans will be submitted to an IRRC, once the subject 
has been enrolled and throughout the study period.

Quality of Life (QoL) tools must be completed at Treatment Day 1 prior to the first dose of 
study drug. Following that, QoL tools will be completed according to the schedule in Table 
5.1-2 and Table 5.1-3.

This phase ends when the subject is discontinued from study therapy. For a complete list of 
reasons for treatment discontinuation, refer to Sections 3.5 and 4.3.5.
Follow-up:

Begins when the decision to discontinue a subject from study therapy is made (no further 
treatment with study therapy).

Subjects will have two follow-up visits for safety. Follow-up visit 1(X01), 35 days (± 7 days) 
from the last dose of study therapy and Follow-up visit 2 (X02), 80 days (± 7 days) from 
X01. After X02, subjects will be followed every 3 months for ongoing drug-related AEs until
resolved, return to baseline or deemed irreversible, or until lost to follow-up or withdrawal of 
study consent.
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
PK and immunogenicity samples will be collected at the first two follow-up visits. 

Subjects who discontinue study therapy for reasons other than disease progression or 
allogeneic SCT or ASCT will continue to have radiographic assessments at the intervals 
described in the Treatment Phase until disease progression, lost to follow-up, or withdrawal 
of study consent.

For subjects who discontinue study therapy by proceeding to allogeneic SCT or ASCT, 
tumor assessment by the investigator will be required after allogeneic SCT or ASCT 
(see Section 3.6). For the subjects who discontinue study therapy by proceeding to allogeneic 
SCT, acute and chronic Graft-Versus-Host Disease (GVHD) documentation will also be 
simultaneously collected (see Section 5.3).

After completion of the two follow-up visits for safety, subjects will be followed every 
3 months for survival, until death, lost to follow-up or withdrawal of study consent.

QoL tools will be completed according to the schedule in Table 5.1-2 and Table 5.1-3.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive study drug. Study drug will be provided via an extension of the study, a 
rollover study requiring approval by responsible health authority and ethics committee or 
through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to study drug if any of the following occur: a) the marketing application is rejected by 
responsible health authority; b) the study is terminated due to safety concerns; c) the subject can 
obtain medication from a government sponsored or private health program; or d) therapeutic 
alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study.
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2. Target Population
a) Tumor biopsy confirmation of relapsed or refractory FL must be obtained prior to the 
initiation of study drug.
i.
Grade 1, 2, or 3a FL without pathologic evidence of transformation.
ii.
FL should be pathologically confirmed by standard immunohistochemical or flow 
cytometric techniques. 
iii.
Documentation of the above should be present in the subject’s medical record.
b) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 4).
c) Measurable Disease: Subjects must have at least one lesion that is 15 mm (1.5 cm) in 
the longest diameter on cross-sectional imaging and measureable in two perpendicular 
dimensions per computed tomography (spiral CT) or MRI
d) Treatment of FL consisting of 2 prior treatment lines; each of the two prior treatment 
lines must include CD20 antibody and/or an alkylating agent (eg, bendamustine, 
cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, nitrosoureas). At least 
one of the prior treatment lines must include rituximab.
NOTE: Separate lines of therapy are defined as two regimens separated by disease 
progression, relapsed disease, or refractory disease.
Definition of Relapsed FL

The appearance of new lesions > 6 months after obtaining a CR 

An increase 50% in the size of previously involved sites > 6 months after 
completing planned therapy. 
Definition of Refractory FL

< 50% decrease in lesion size after planned therapy, 

The appearance of new lesions during therapy or < 6 months after completion of 
planned therapy

An increase of 50% in the size of previously involved sites during therapy or 
< 6 months after completion of planned therapy.
e) Subject Re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been treated). If 
re-enrolled, the subject must be re-consented.
3. Physical and Laboratory Test Finding
a) Screening laboratory values must meet the following criteria and should be obtained 
within 14 days prior to first dose:
i)
Absolute neutrophil Count 750/L (no WBC growth factors for prior 14 days)
ii) Platelets 50 x103/L (no platelet transfusions for prior 14 days)
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iii) Hemoglobin 8.5 g/dL (no RBC transfusions for prior 7 days)
iv) Serum creatinine 1.5 x ULN or creatinine clearance (CrCl) 40 mL/min (measured 
using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
v) AST/ALT 3 x ULN
vi) Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL).
4. Age and Reproductive Status
a) Men and women 18 years of age
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 from the time 
of enrollment for the duration of treatment with study drug plus 5 half-lives of study drug 
plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment 
completion
e) Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug plus 5 half-lives 
of study drug plus 90 days (duration of sperm turnover) for a total of 31 weeks 
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 these sections
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% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one 
method being highly effective and the other method being either highly effective or less 
effective as listed below:
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HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner.

Nonhormonal IUDs, such as ParaGard

Tubal ligation 

Vasectomy.

Complete Abstinence*
*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.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Male Condom without spermicide*

Progestin only pills by WOCBP subject or male subject’s WOCBP partner

Female Condom* 
*A male and female condom must not be used together 
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Known central nervous system lymphoma.
2. Medical History and Concurrent Diseases
a) History of interstitial lung disease
b) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
c) Prior malignancy active within the previous 3 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial 
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
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d) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
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.
e) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease.
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection
b) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody with the 
following exception:
Subjects who experienced Grade 3 or 4 infusion-related reaction with the first dose of 
rituximab, but who were able to receive subsequent rituximab without recurrence of 
Grade 3 or 4 infusion-related reaction are eligible
5. Prohibited Treatments and/or Therapies
a) Prior chemotherapy within 2 weeks, nitrosureas within 6 weeks, therapeutic anticancer 
antibodies within 4 weeks, radio- or toxin immunoconjugates within 10 weeks, radiation 
therapy within 3 weeks, or major surgery within 2 weeks of first dose of study drug
b) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell costimulation or immune 
checkpoint pathways
c) Prior allogeneic SCT
d) Autologous SCT 12 weeks prior to first dose of study drug
e) Chest radiation 24 weeks prior to first dose of the study drug
f)
Carmustine (BCNU) 1000 mg received as part of pre-transplant conditioning regimen
6. 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.
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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, women under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.*
*Women treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is >40 mIU/mL at any time 
during the washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products.
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:

Immunosuppressive agents (except to treat a drug-related adverse event)

Systemic corticosteroids > 10 mg daily prednisone equivalent (except as stated in 
Section 3.3.2 or to treat a drug-related adverse event). 

Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy, or standard or investigational agents 
for treatment of cancer).
Supportive care for disease-related symptoms may be offered to all subjects on the trial.
3.4.2
Other Restrictions and Precautions
3.4.2.1
Permitted Therapy
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of 
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corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
Concomitant medications are recorded at baseline and throughout the treatment phase of the 
study in the appropriate section of the case report form (CRF). All medications (prescriptions or 
over the counter medications) continued at the start of the study or started during the study and 
different from the study drug must be documented in the concomitant therapy section of the 
CRF.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Disease progression as determined by investigator assessment following the guidelines 
given in Section 5.4 except as outlined in Section 4.3.8 Treatment Beyond Disease 
Progression.

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

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness

Additional protocol-specific reasons for discontinuation (See Section 4.3.5).
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate 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 CRF page.
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3.6
Post Treatment Study Follow up
In this study, ORR and DOR are key endpoints of the study. Post treatment study follow-up is of 
critical importance and is essential to preserving subject safety and the integrity of the study. 
Subjects who discontinue study treatment must continue to be followed for collection of outcome 
and/or survival follow-up data as required and in line with Section 5 until death or the conclusion 
of the study.
In addition, subjects who discontinue study therapy by proceeding to allogeneic SCT or ASCT 
will require tumor assessment (CR or non-CR) by the investigators according to the 2007 IWG 
criteria on Day 100, at 6 months, 1 year and every year thereafter from the date of stem cell 
infusion until the first non-CR after SCT is documented (see Section 5.4). For the subjects who 
discontinue study therapy by proceeding to allogeneic SCT, documentation of acute and chronic 
GVHD will be simultaneously collected (see Section 5.3).
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor-
retained third-party representative to assist site staff with obtaining subject’s contact information 
or other public vital status data necessary to complete the follow-up portion of the study. The site 
staff and representative will consult publicly available sources, such as public health registries 
and databases, in order to obtain updated contact information. If after all attempts, the subject 
remains lost to follow-up, then the last known alive date as determined by the investigator should 
be reported and documented in the subject’s medical records.
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4
TREATMENTS
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, 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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4.1
Study Treatments
Table 4.1-1:
Product Description: Treatment Period
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
BMS-936558-01 
Solution for Injectiona
100 mg
(10 mg/mL)
10 mL per vial/Open-
label
10 vials per 
carton/Open-label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles
2° to 8°C. Protect from 
light and freezing.
a Nivolumab is labeled as BMS-936558-01 Solution for Injection.
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations.
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: BMS-936558 (nivolumab).
BMS-936558 100 mg (10 mg/mL) will be packaged in an open-label fashion.
Ten BMS-936558, 10 mL vials will be packaged within a carton (see Table 4.1-1), and are not 
subject or treatment arm specific. Vial assignments by subjects will be made through the IVRS to 
track usage and resupply. 
4.1.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, non-investigational product(s) is/are: Not applicable for this study. 
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by 
the sponsor and should be purchased locally if permitted by local regulations.
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.
For details on prepared drug storage and use time of nivolumab under room temperature/light 
and refrigeration, please refer to the Investigator Brochure section for “Recommended Storage 
and Use Conditions” and/or pharmacy reference sheets.
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Nivolumab is to be administered as a 60-minute IV infusion, using a volumetric pump with a 
0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be diluted with 
0.9% normal saline for delivery but the total drug concentration of the solution cannot be below 
0.35 mg/mL. It is not to be administered as an IV push or bolus injection. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline.
4.2
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an IVRS to obtain the subject number. Every 
subject that signs the informed consent form must be assigned a subject number in IVRS. 
Specific instructions for using IVRS will be provided to the investigational site in a separate 
document. 
The investigator (or designee) will register the subject for enrollment by following the 
enrollment procedures established by BMS. The following information is required for 
enrollment:

Date of informed consent

Date of birth

Gender at birth.
4.3
Selection and Timing of Dose for Each Subject
Eligible subjects will receive treatment with nivolumab at a dose of 3 mg/kg, as a 60-minute 
IV infusion, on Day 1 of a treatment cycle every 2 weeks. Subjects must be treated within one 
day after study drug vial assignment. Dosing calculations should be based on the body weight 
assessed as per Table 5.1-2. If the subject’s weight on the day of dosing differs by > 10% from 
the weight used to calculate the dose, the dose must be recalculated. All doses should be rounded 
to the nearest milligram. There will be no dose escalations or reductions of nivolumab allowed. 
Subjects may be dosed no less than 12 days between doses and no more than 3 days after the 
scheduled dosing date. There are no premedications recommended for nivolumab on the first 
cycle. If an acute infusion reaction is noted, subjects should be managed according to 
Section 4.3.6.
Treatment may be delayed for up to a maximum of 6 weeks from the previous dose 
(See Sections 4.3.2 and 4.3.4).
Tumor assessments by spiral CT/MRI for all subjects should continue as per protocol even if 
dosing is delayed.
Subjects will be monitored continuously for AEs while on study. Treatment modifications 
(eg, dose delay or discontinuation) will be based on specific laboratory and adverse event 
criteria.
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4.3.1
Antiemetic Premedications
Antiemetic premedications should not be routinely administered prior to dosing of drugs.
4.3.2
Dose Delay Criteria
Dose delay criteria apply for all drug-related adverse events. Nivolumab must be delayed until 
treatment can resume (see Section 4.3.4).
Nivolumab administration should be delayed for the following:

Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay

Any Grade 3 skin, drug-related adverse event

Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, or total bilirubin:

Grade 3 lymphopenia or leukopenia does not require dose delay

If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity

If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade 3 toxicity

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
4.3.2.1
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of adverse events 
associated with immuno-oncology agents may mitigate severe toxicity. Management algorithms 
have been developed to assist investigators in assessing and managing the following groups of 
adverse events:
Gastrointestinal
Renal
Pulmonary
Hepatic
Endocrinopathies
Skin
Neurological
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For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider recommendations provided in the 
algorithms. These algorithms are found in the Nivolumab IB and in Appendix 1 of this protocol. 
Discussions with the BMS Medical Monitor on how to apply these algorithms are strongly 
encouraged. The guidance provided in these algorithms should not replace the Investigator’s 
medical judgment but should complement it.
4.3.3
Doses Reductions and Escalations
Doses reductions and escalations of nivolumab are not permitted.
4.3.4
Criteria to Resume Nivolumab Dosing
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 baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who require 
dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin

Subjects with combined Grade 2 AST/ALT AND
total bilirubin values meeting 
discontinuation parameters (Section 4.3.5) should have treatment permanently discontinued

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
If the criterion to resume treatment is met, the subject should restart treatment at the next 
scheduled timepoint per protocol.
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.3.5.
4.3.5
Treatment Discontinuation Criteria
Nivolumab treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment 

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, drug-related uveitis, pneumonitis, 
bronchospasm, hypersensitivity reactions, infusion reactions and endocrinopathies:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation
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
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 

AST or ALT > 5 - 10 x ULN for > 2 weeks

AST or ALT > 10 x ULN

Total bilirubin > 5 x ULN

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:

Grade 4 neutropenia 7 days

Grade 4 lymphopenia or leukopenia

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset

Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations, or radiographic signs of pancreatitis. It is recommended to consult with 
the BMS Medical Monitor for Grade 4 amylase or lipase abnormalities

Grade 3 or 4 drug-related endocrinopathy AEs such as adrenal insufficiency, ACTH 
(Adrenocorticotropic Hormone) deficiency, hyper- or hypothyroidosis, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (steroids, 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 with the following 
exceptions:

Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor assessments 
should continue as per protocol even if dosing is interrupted. 

Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS medical monitor. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the BMS medical monitor must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted.

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
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nivolumab

Disease progression (as determined by investigator assessment following the guidelines 
given in Section 5.4). Treatment beyond progression is allowed in certain instances as 
described in Section 4.3.8.

Subject who initiated the preparative regimen for allogeneic SCT or ASCT after the first dose 
of nivolumab treatment.
4.3.6
Treatment of Nivolumab Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce an infusion or hypersensitivity reaction. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, 
hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions 
should be reported within 24 hours to the BMS Medical Monitor and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (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 paracetamol 325 to 1000 mg (acetaminophen) 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 
bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, 
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) should be administered at least 30 minutes before 
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additional nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 
25 mg of IV hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or ventilatory 
support indicated).
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat 
the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected 
slowly 
for 
IV 
administration, 
and/or 
diphenhydramine 
50 mg 
IV 
with 
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 from symptoms. In the case 
of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritis 
within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or 
corticosteroids).
4.3.7
Guidelines for Assessment and Management of Tumor Lysis Syndrome
The possibility of tumor lysis syndrome cannot be ruled out for the subjects with lymphoma. 
Therefore, adequate management such as hydration and/or the use of allopurinol is 
recommended in the subjects who have risk factor of potential tumor lysis syndrome, for 
example the subjects with high tumor burden, reflected by high serum LDH levels, or bulky 
disease, or those with preexisting renal failure.
4.3.8
Treatment Beyond Disease Progression
4.3.8.1
Circumstances in which Post-progression Treatment is Permitted
Subjects meeting progression defined by relapsed disease (after CR) or progressive disease (after 
PR, SD) per 2007 IWG criteria may continue receiving study medication beyond 
investigator-assessed progression as long as they meet the following criteria:

Continue to meet all other study protocol eligibility criteria

Investigator-assessed clinical benefit, and do not have rapid disease progression 

Stable performance status 

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression 

Patients will be re-consented with an informed consent document describing any reasonably 
foreseeable risks or discomfort and other alternative treatment options 

Tolerance of study drug 
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The decision to continue treatment beyond investigator-assessed progression should be discussed 
with the BMS Medical Monitor and documented in the study records. The assessment of clinical 
benefit should take into account whether the subject is clinically deteriorating and unlikely to 
receive further benefit from continued treatment.
4.3.8.2
Assessment schedule for the subjects with post-progression treatment
The subject should continue to receive monitoring according to the On-Treatment Assessments 
on Table 5.1-2 except for FDG-PET scans. Radiographic assessment by CT (preferred) or MRI 
described in the section 5.4.1 and Table 5.4.1-1 are required when subjects continue post-
progression treatment. FDG-PET scans are not mandated after investigator-assessed progression
4.3.8.3
Discontinuation due to Further Progression
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). 

Further progression is evaluated by a subsequent CT or MRI which is performed at least 
8 weeks from previous CT or MRI.

The tumor burden volume from time of initial progression should be used as the reference 
baseline for comparison with the post-progression assessment.

New lesions are considered measurable at the time of initial progression if the long axis is 
more than 15 mm regardless of the short axis. If a lymph node has a long axis of 11 to 
15 mm, it should only be considered measurable if its short axis is more than 10 mm.

Any new lesion considered non-measurable at the time of or after initial progression may 
become measurable and therefore included in the tumor burden determination.
4.3.8.4
Radiographic Assessment for Subjects who Discontinue Study Drug 
during Post-progression Treatment
For subjects that discontinue post-progression treatment, no additional radiographic assessments 
will be required. Upon treatment discontinuation, these subjects will continue in the follow-up 
phase of the study (see Section 5.1). Subjects who proceed to allogeneic SCT or ASCT will be 
followed as described in Section 5.4.
4.4
Blinding/Unblinding
Not applicable.
4.5
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and CRF.
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BMS-936558
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4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
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BMS-936558
nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209140)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed 
prior to first dose
Medical History
X
Prior Systemic Therapy
X
Safety Assessments
Physical Examination
X
Physical Measurements
X
Include Height, Weight, and ECOG performance Status
Follicular Lymphoma International 
Prognostic Index (FLIPI) at time of initial 
diagnosis
X
Refer to Appendix 3
Vital Signs and Oxygen saturation
X
Temperature, BP, HR, and O2 saturation by pulse oximetry (at rest and after 
exertion). 
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 
14 days prior to first dose.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Laboratory Tests
X
CBC with differential, Chemistry panel including LDH, AST, ALT, ALP, 
T.Bili, BUN or serum urea level, uric acid, creatinine, Ca, Mg, Na, K, Cl, P, 
glucose, amylase, lipase, TSH (reflex to free T3, free T4 for abnormal TSH 
result), hepatitis B surface antigen (HBV sAg), and hepatitis C antibody 
(HCV Ab) or HCV ribonucleic acid (RNA) within 14 days prior to first dose.
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Table 5.1-1:
Screening Procedural Outline (CA209140)
Procedure
Screening
Visita
Notes
Urinalysis
X
Total protein, glucose, blood, leukocyte esterase, specific gravity, and pH, 
within 14 days prior to first dose.
Pregnancy Test
X
For WOCBP only (serum or urine - local/site)
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment

Spiral CT/MRI of Chest, Abdomen, 
Pelvis, and any other known sites of 
disease 

PET scan
X
Should be performed within 28 days prior to first dose.
Additional sites of known or suspected disease (including CNS) should be 
imaged at the screening visit and at subsequent on-study assessments. 
PET scan required at screening.
Bone Marrow Biopsy/Aspirate 
See Note
If results of a bone marrow biopsy/aspirate performed within 90days prior to 
obtaining consent are not in the subject’s medical record then one must be 
performed during screening. If a biopsy/aspirate is performed, submission of 
aspirate for biomarker analyses is optional 
.
Collection of tumor tissue 
X
Collection of tumor tissue (FFPE tumor tissue block or 10 unstained slides) 
for determination of PD-L1 expression status: Submission of tumor tissue 
(obtained during the screening phase or collected as a standard of care 
procedure within 90 days prior to obtaining informed consent) is mandatory.
Tumor biopsies in formalin for IHC of tumor and TIL. Biopsy samples should 
be excisional, incisional or core needle.
IVRS/Clinical Drug Supplies
Phone calls to IVRS
Phone calls must be made to IVRS as follows:

For subject number assignment at the time informed consent is 
obtained.

Prior to dosing for study drug vial assignment (call should be made 
within 1 day prior to dosing).
a Within 28 days prior to first dose
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Table 5.1-2:
Short-term Procedural Outline (CA209140)
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Each Cycle 
within 3 Days 
prior to 
Dosing
Notes
Safety Assessments
Targeted Physical Examination
X
X
Lymph node areas (eg, submandibular, cervical, 
supraclavicular, axillary, or inguinal lymph node), and 
abdominal organs (eg, spleen)
Vital Signs and Oxygen Saturation
X
X
X
Temperature, BP, HR, O2 saturation by pulse oximetry at 
rest and after exertion (also monitor amount of 
supplemental oxygen if applicable) prior to dosing and at 
any time a subject has any new or worsening respiratory 
symptoms
Physical Measurements
X
X
X
Includes Weight and ECOG performance status
Adverse Events Assessment
---------- Continuously ----------
Assessed using NCI CTCAE v. 4.0.
Review of Concomitant Medications
X
X
X
Laboratory Tests
X
X
X
Extended on-study local laboratory assessments should be 
done within 72 hours prior to dosing for Cycle 1 through 
Cycle 5 and every alternate dose thereafter (Cycles 7, 9, 11, 
13, etc) and include: CBC with differential, uric acid, 
serum urea level, serum creatinine, sodium, potassium, 
calcium, magnesium, phosphorus, chloride, amylase, lipase,
glucose, AST, ALT, total bilirubin, alkaline phosphatase, 
LDH.
Limited on-study local laboratory assessment should be 
done within 72 hours prior to dosing (beginning at Cycle 6
and every alternate dose thereafter (Cycles 8, 10, 12, 14,
etc) and include: CBC with differential, LFTs (ALT, AST, 
total bilirubin, alkaline phosphatase) and creatinine.
Thyroid Function Testing
See Note
TSH (reflex to free T3 and free T4 if abnormal result) to be
performed every 6 weeks (7 days) regardless of dosing 
schedule.
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Table 5.1-2:
Short-term Procedural Outline (CA209140)
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Each Cycle 
within 3 Days 
prior to 
Dosing
Notes
Pregnancy Test for WOCBP
X
See Note
Serum or urine - local/site test to be performed within 
24 hours prior to first dose and then at least once every 
4 weeks (± 7 days) regardless of dosing schedule
Efficacy Assessments
Radiographic Tumor Assessment

Spiral CT/MRI of Chest, Abdomen, 
Pelvis, and any other known sites of 
disease

PET Scan
See Note
See Section 5.4.1 and Table 5.4.1-1 for spiral CT/MRI 
assessment schedule
PET scan required to confirm CR.
Bone Marrow Aspirate and Biopsy
See 
Note 
See Note
Required to confirm any CR in subjects with bone marrow 
disease at screening
 
Additional Exploratory Biomarker 
Testing
PK and Immunogenicity Assessments
PK samples
See Note
See separate Table 5.5-1 for sampling details
Immunogenicity samples
See Note
See separate Table 5.5-1 for sampling details
Outcomes Research Assessments
EORTC QLQ-C30
X
See Note
Assessments to be collected every 8 weeks for the first 
8 months;
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Table 5.1-2:
Short-term Procedural Outline (CA209140)
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Each Cycle 
within 3 Days 
prior to 
Dosing
Notes
EQ-5D
X
See Note

Day 1 (prior to dosing) of Cycles 5, 9, 13, 17
every 12 weeks thereafter;

Day 1 (prior to dosing) of Cycles 23, 29, 35+.
Clinical Drug Supplies
Administer Study Drug
X
X
IVRS should be called within 1 day prior to study drug 
administration to receive vial assignment
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Table 5.1-3:
Follow-Up Assessments (CA209140)
Procedure
X, Follow Up,a
Visits 1 and 2
S, Survival Follow-Upb
Visits
Notes
Safety Assessments
Targeted Physical Examination
X
Lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), and abdominal organs (eg,
spleen)
To assess for potential late emergent study drug related issues
Adverse Events Assessment
X
X
In survival follow-up period, only to include toxicities from 
study therapy
Laboratory Tests
X
CBC with differential, uric acid, serum urea level, serum 
creatinine, sodium, potassium, calcium, magnesium, chloride, 
glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result)
Pregnancy Test (WOCBP only)
X
Serum or urine
GVHD Assessments
See note
See note
Only for subjects who discontinued study therapy by proceeding 
to allogeneic SCT. To be assessed on Day 100, at 6 months, at 
1 year and every one year thereafter from the date of stem cell 
infusion until the first non-CR after SCT is documented.
See Section 5.3.
Efficacy Assessments
Radiographic Tumor Assessment

Spiral CT/MRI 

PET Scan
X
(See Note)
X
Only for subjects without progression on study therapy.

Tumor assessments should occur at the same intervals 
described in the Treatment Phase until disease 
progression, lost to follow-up, or withdrawal of study 
consent.

Spiral CT/MRI of chest, abdomen, pelvis and all known 
sites of disease. Use same imaging method as was used 
at screening/baseline. 
PET scan required to confirm CR.
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Table 5.1-3:
Follow-Up Assessments (CA209140)
Procedure
X, Follow Up,a
Visits 1 and 2
S, Survival Follow-Upb
Visits
Notes
Tumor Assessment by the Investigator 
(CR or non-CR)
See note
See note
Only for subjects who discontinued study therapy by proceeding 
to allogeneic SCT or ASCT. To be assessed on Day 100, at 
6 months, at 1 year and every one year thereafter from the date of 
stem cell infusion until the first non-CR after SCT is 
documented.  See Section 5.4.
Outcomes Research Assessments
EORTC QLQ-C30
X
EQ-5D
X
X
EQ-5D during the survival follow-up will be assessed during a 
clinic visit or via a phone contact
Pharmacokinetic/ImmunogenicityAssessments
PK Samples
X
See separate Table 5.5-1 for Sampling Schedule details
Immunogenicity samples
X
See separate Table 5.5-1 for Sampling Schedule details
Exploratory Biomarker Testing
Subject Status
Survival Status
X
X
Every 3 months after X02; may be accomplished by visit or 
phone contact , to update survival information and assess 
subsequent anti-cancer therapy
a X visits occur as follows: X01 = 35 days 7 days from last dose, X02 = 80 days 7 days from X01
b S, Survival visits continue every 3 months after X visits
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5.2
Study Materials
The following materials will be provided at study start:

NCI CTCAE version 4.0

Nivolumab Investigator Brochure

Pharmacy Binder

Laboratory manuals for collection and handling of blood (including PKs, biomarker and 
immunogenicity) and tissue specimens

Site manual for operation of IVRS, including enrollment worksheet

Manual for entry of local laboratory data

Serious Adverse Events (or eSAE) case report forms

EORTC QLQ-C30 and EQ-5D questionnaires

Pregnancy Surveillance Forms

IRRC manual.
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, BP, HR, 
temperature and oxygen saturation by pulse oximetry at rest and after exertion and should be 
performed within 28 days prior to first dose as described in Table 5.1-1 Notes. Baseline signs 
and symptoms are those that are assessed within 14 days prior to first dose. Concomitant 
medications will be collected from within 14 days prior to first dose through the study treatment 
period.
Baseline local laboratory assessments should be done within 14 days prior to first dose to 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), uric acid, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, P, LDH, glucose, urinalysis, TSH, and 
Hep B and C testing (HBV sAg, HCV Ab or HCV RNA) (see Table 5.1-1). Pregnancy testing for 
WOCBP (done locally) must be performed at baseline (within 28 days prior to first dose) and 
repeated within 24 hours prior to the initial administration of study drug, then every 4 weeks 
(± 7 days) regardless of dosing schedule.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase (Follow-up 
visits X01 and X02, Table 5.1-3) toxicity assessments should be done in person. Once subjects 
reach the survival follow-up phase either in person or documented telephone calls/emails to 
assess the subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
Performance status and body weight should be assessed at each on study visit prior to nivolumab 
dosing and at Cycle 1 Day 8. Vital signs should also be taken as per institutional standard of care 
prior to, during, and after dosing. Oxygen saturation by pulse oximetry at rest and after exertion 
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should be assessed at each on-study visit prior to nivolumab dosing. The start and stop time of 
the nivolumab infusion should be documented. Physical examinations are to be performed as 
clinically indicated. If there are any new or worsening clinically significant changes since the last 
exam, report changes on the appropriate non-serious or serious adverse event page.
On treatments local laboratory assessments should be done within 72 hours prior to dosing;

Extended on-treatment local laboratory assessments: Cycle 1 through Cycle 5 and every 
alternate dose thereafter (Cycle 7, 9, 11, 13, etc) and include: CBC with differential, uric 
acid, serum urea level, serum creatinine, sodium, potassium, calcium, magnesium, 
phosphorus, chloride, amylase, lipase, glucose, AST, ALT, total bilirubin, alkaline 
phosphatase, LDH.

Limited on-study treatment laboratory assessment: beginning at Cycle 6 and every 
alternate dose thereafter (Cycle 8, 10, 12, 14, etc) and include: CBC, LFTs (ALT, AST, total 
bilirubin, alkaline phosphatase) and creatinine.
In addition, TSH (with reflexive Free T4 and Free T3) should be performed every 6 weeks 
(± 7 days) regardless of dosing schedule.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline or are deemed irreversible.
Oxygen saturation by pulse oximetry should be obtained prior to each dose of nivolumab and at 
any time a subject has any new or worsening respiratory symptoms. A reading at rest and on 
exertion should be obtained at each time point. The extent of the exertion should be based on the 
judgment of the investigator, but should remain consistent for each individual subject throughout 
the study. If the patient’s subject’s status changes, the investigator can alter the extent of exertion 
based on their medical judgment. If a subject shows changes on pulse oximetry or other 
pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) consistent with 
possible pulmonary adverse events, the patient subject should be immediately evaluated to rule 
out pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity can 
be found in the BMS-936558 (nivolumab) Investigator Brochure.
Some of the previously referred to assessments may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
For subjects who discontinue study therapy by proceeding to allogeneic SCT, documentation of 
acute and chronic GVHD will be captured on Day 100, at 6 months, 1 year and every year 
thereafter from the date of stem cell infusion until the first non-CR after SCT is documented 
Appendix 
5. 
Investigators 
will 
make 
telephone 
contact 
with 
the 
subject’s 
hematologist /oncologist /transplant physician to obtain this information if the subject is being 
followed by another physician.
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5.3.1
Imaging Assessment for the Study
Images will be submitted to an imaging corelab for central review. Sites will be trained prior to 
scanning the first study subject. Image acquisition guidelines and submission process will be 
outlined in the CA209140 Imaging Manual to be provided by the corelab.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
5.4
Efficacy Assessments
The primary efficacy assessment is ORR, defined as a subject achieving either a PR or CR 
according to the 2007 IWG criteria (Appendix 2). The primary efficacy assessment, along with 
the secondary endpoints of DOR, CRR, CR duration, PRR, PR duration and PFS will be based 
on IRRC assessments. Assessment of ORR, based on investigator assessments, will be examined 
as a secondary endpoint. Sites are required to send all on-study disease assessments to the IRRC 
for review.
Once subjects discontinue study therapy by proceeding to allogeneic SCT or ASCT, they will not 
undergo IRRC- radiographic assessments as described in Section 5.4.1. Instead, they will be 
evaluated using the following schedule. Tumor assessment (CR or non-CR) will be assessed 
by the investigator according to the 2007 IWG criteria and will be required on Day 100, at 
6 months, 1 year and every year thereafter from the date of stem cell infusion until the first 
non-CR after SCT is documented. Investigators will make telephone contacts with the subject’s 
referring hematologist/oncologist/transplant physician to obtain CR or non-CR status and 
document the status if subject is being followed by another physician.
5.4.1
Radiographic Assessments
Radiographic study evaluations will take place in accordance with the flow charts in 
Section 5.1 and Table 5.4.1-1. Baseline assessments should be performed within 28 days prior to 
the first dose, utilizing spiral CT or MRI. In addition to chest, abdomen, and pelvis, all known 
sites of disease (including CNS) should be assessed at baseline. A PET scan is required at 
baseline for all subjects, and to confirm a complete response (CR).
On-study assessments should include chest, abdomen, and pelvis, and all known sites of disease 
(including CNS) and should use the same imaging method as was used at baseline. 
Subjects will be evaluated for tumor response by spiral CT/MRI beginning at Week 9 and 
continuing every 8 weeks (1 week) through the first 8 months, every 12 weeks (2 weeks) 
Months 9 - 24, and then every 6 months (3 weeks) thereafter until disease progression is 
documented or until the subject initiates a preparative regimen for allogeneic SCT or ASCT, 
whichever occurs earlier. 
Tumor assessments for ongoing study treatment decisions will be completed by the investigator 
using 2007 IWG criteria (Appendix 2).
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Table 5.4.1-1:
Schedule of Spiral CT/MRI Tumor Assessments
Time On Study
Assessment 
Frequency
Assessment Week
(Day 1 of Week Shown)
Assessment Window
Dose 1 to 8 Months
Every 8 weeks
9, 17, 25, 33
1 week
Month 9 to 2 Years
Every 12 weeks
45, 57, 69, 81, 93
2 weeks
> 2 Years
Every 6 months
119, 145, 171+
3 weeks
Note: Once subjects discontinue study therapy by proceeding to allogeneic SCT or ASCT, they will not undergo 
radiographic assessments as per the frequency described here, but will be followed with specific schedule 
(see Section 5.4).
5.4.2
Assessment of Overall Tumor Burden and Measurable Disease
To serially evaluate tumor response to therapy, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable tumor lesion. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows in Sections 5.4.2.1 and 5.4.2.2.
5.4.2.1
Measurable Lesions
Measurable lesions must be accurately measured in at least two perpendicular dimensions based 
on Cheson 2007 criteria.95 In order to meet eligibility criteria, subjects must have at least 
one lymph node or extra-nodal node with long axis measurement > 15 mm, regardless of 
the short axis measurement. Additional lymph nodes are considered to be measurable for 
purposes of efficacy assessments if the longest axis is 11 to 15 mm AND the short axis is 
> 10 mm. Lymph nodes 10 mm x 10 mm will not be considered as measurable
If possible, nodes or masses should be from disparate regions of the body and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
5.4.2.2
Non-Measurable Lesions
All other lesions, including small lymph nodes (longest diameter < 10 mm) as well as truly 
non-measurable lesions.
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.
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5.4.3
Specifications by Method of Assessment
5.4.3.1
Measurement of Lesions
All measurements should be recorded in metric notation (cm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 28 days before the 
beginning of treatment.
5.4.3.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical 
5.4.3.3
Spiral CT/MRI Scan
Spiral CT/MRI is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on Spiral CT/MRI scan is based on 
the assumption that CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
NOTE: PET/CT hybrid scanners may be used for the acquisition of required CT images only if 
the CT is of diagnostic quality and adheres to protocol-specified scan parameters. Also, the CT 
images must be separated from the PET data prior to submitting the data, and cannot be 
transmitted as fused CT/PET images.
Note on PET/CT scans: Combined modality scanning such as with PET/CT is increasingly used 
in clinical care. Low dose or attenuation correction CT portions of a combined PET/CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for anatomically 
based measurements. However, if a site can document that the CT performed as part of a 
PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the 
CT portion of the PET/CT can be used for measurements.
5.4.3.4
Clinical Lesions
Clinical lesions will only be considered measurable when they are superficial and 10 mm 
diameter as assessed using calipers. As previously noted, when lesions can be evaluated both by 
clinical exam and imaging, imaging evaluation should be undertaken since it is more objective 
and may also be reviewed by the IRRC.
5.4.3.5
PET scan
A baseline PET scan is required for each treated subject. An additional PET scan is required to 
confirm a CR.
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5.4.4
Baseline Documentation of “Target” and “Non-Target” Lesions
5.4.4.1
Target Lesions
At baseline, up to 6 of the largest dominant nodes or nodal masses meeting the criteria for 
measurable lesions given in Section 5.4.2.1 should be identified as target lesions and their 
measurements recorded. Other measurable lesions will be designated as non-target lesions.
A sum of the product of the diameters (SPD) will be calculated for all target lesions and recorded 
as the baseline SPD. The baseline SPD will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.
5.4.4.2
Non-Target Lesions
All other lesions (or sites of disease) including non-measurable lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
multiple liver nodules’).
5.4.5
Bone Marrow Assessments
To determine the extent of disease involvement in the bone marrow, biopsy/aspirate performed 
within 90 days prior to obtaining informed consent must be documented at screening or a bone 
marrow biopsy/aspirate must be performed during the screening period. If a bone marrow 
biopsy/aspirate is performed during the screening period, consider submitting a bone marrow 
aspirate sample for biomarker analyses.
For subjects with marrow involvement at screening, a bone marrow biopsy and aspirate will be 
required to confirm a CR, 
 
.
5.4.6
Disease Response Evaluation
The determination of disease response to study treatment will be made using 2007 IWG criteria 
(Appendix 2).
Note: 2007 IWG criteria define relapsed disease or progressive disease based largely on the 
evaluation of nodal masses, spleen/liver, and bone marrow (Appendix 2). The criteria also 
stipulate that disease that is only assessable but not measureable (eg, pleural effusion or bone 
lesion) will be recorded as “present” or “absent”, unless such an assessable abnormality, noted 
by imaging studies or physical examination, is confirmed to be histologically negative. For 
purposes of protocol-defined disease progression, the appearance of new sites of assessable but 
not measureable disease while on treatment meets protocol criteria for progression if histological 
results are documented (eg, the presence of lymphoma cells in a pleural effusion or spinal fluid).
5.5
Pharmacokinetic Assessments
Samples for pharmacokinetic and immunogenicity assessment will be collected for all subjects 
receiving nivolumab. Table 5.5-1
lists the sampling schedule to be followed for 
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pharmacokinetics and immunogenicity. All timepoints are relative to the start of study drug 
administration. All on treatment PK timepoints are intended to align with days on which study 
drug is administered. If it is known that a dose is going to be delayed, then the predose sample 
should be collected just prior to the delayed dose. However, if a predose sample is collected, but 
the dose is subsequently delayed, an additional predose sample should not be collected. Further 
details of blood collection and processing will be provided in the procedure manual.
Table 5.5-1:
Sampling Schedule
Study Day
Time 
(Relative to 
Dosing)
Hour
Time 
(Relative to 
Dosing)
Hour:Min
Nivolumab PK 
Sample
Nivolumab 
Immunogenicity 
Sample
Cycle 1 Day 1
predosea
00:00
X
X
Cycle 1 Day 1
EOIb
01:00
X
Cycle 3 Day 1
predosea
00:00
X
X
Cycle 7 Day 1
predosea
00:00
X
X
Cycle 7 Day 1
EOIb
01:00
X
Day 1 of every 8th 
cycle until 
discontinuation of 
study treatment
predosea
00:00
X
X
First 2 Follow-up 
visits- FU1 & FU2
X
X
a Predose samples should be taken just prior to the administration (preferably within 30 minutes, however predose 
collection up to 4 hours before study drug administration would be acceptable).If the infusion is delayed and a 
predose sample was already collected, there is no need to collect an additional predose sample.
b EOI = end of infusion. This sample should be taken immediately prior to stopping the infusion of nivolumab 
(preferably within 2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal 
infusion duration, the collection of this sample should also be delayed accordingly. EOI samples may not be 
collected from the same IV access as drug was administered; refer to the lab manual for additional restrictions.
5.5.1
Pharmacokinetic Sample Analysis
Serum samples will be analyzed for nivolumab by a validated method. In addition, selected 
serum samples may be analyzed by an exploratory analytical method that measures nivolumab 
for technology exploration purposes; exploratory results will not be reported.
5.6
Biomarker Assessments
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Tumor Biopsy:
Minimum of 1 FFPE tumor tissue block (preferred) OR minimum of 10 FFPE unstained sections 
are required for assessment of PD-L1 status and other biomarker evaluations.
Tumor samples obtained from bone metastases are not considered acceptable for PD-L1 testing 
because the PD-L1 assay does not include a decalcification step. For any cases where the only 
tumor tissue available is from a bone metastasis lesion, please discuss further with the study 
Medical Monitor.
Bone Marrow Aspirates
Submission of samples from bone marrow aspirates that may be performed at screening and 
during CR evaluation (only for subjects who had marrow involvement at study entry) is optional 
but strongly encouraged for biomarker assessment. These will be utilized to assess the 
phenotypic and functional status of immune cells and tumor cells.
All subjects may volunteer to undergo bone marrow biopsy and aspirate at any time during 
therapy if clinically indicated. When bone marrow biopsy is done, submission of bone marrow 
aspirate is strongly encouraged
Bone marrow aspirates will be obtained using institutional standards for these procedures.
 
 
 
 
 
 
 
 
 
 
 
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5.7
Outcomes Research Assessments
Outcomes research data including health related quality of life and patient reported symptom 
burden provide a more complete understanding of the impact of treatment by incorporating the 
patients’ perspective. These data offer insights into the patient experience that may not be 
captured through physician reporting. Generic health related quality of life scales provide data 
necessary in calculating utility values for health economic models. The EQ-5D will be collected 
in order to assess the impact of nivolumab on generic health related quality of life and the data 
will be used for populating health economic models most notably, cost effectiveness analysis. 
The EORTC-QLQ C-30 will be collected in order to assess cancer specific health related quality 
of life. The combination of the generic scale for general health status and economic evaluation 
and the cancer specific scale will provide a robust outcomes research package. 
The EORTC QLQ-C30 is one the most commonly used QoL instrument in oncology studies. The 
EORTC 
QLQ-C30 
is 
a 
30-item 
instrument 
comprising 
six 
functional 
scales 
(physical functioning, cognitive functioning, emotional functioning, role functioning, social 
functioning 
and 
global 
quality 
of 
life) 
as 
well 
as 
nine 
symptom 
scales 
(fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties). Except for the overall health status and global quality of life items, 
responses for all items are 4-point categorical scales ranging from 1 (Not at all) to 
4 (Very much). The overall health status/quality of life responses are 7-point Likert scales. 
General health status will be measured using the EQ-5D. The EQ-5D is a standardized 
instrument for use as a measure of self-reported general health status. The EQ-5D comprises 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety) and a visual 
analog rating scale (VAS). The utility data generated from the EQ-5D is recommended for and 
commonly used in cost effectiveness analysis.
All QoL assessments will be administered as outlined in Table 5.1-2 and Table 5.1-3.
5.8
Other Assessments 
5.8.1
Immunogenicity Assessments
Serum samples collected at timepoints identified in Table 5.5-1 will be analyzed by a validated 
immunogenicity assay. All on-treatment timepoints are intended to align with days on which 
study drug is administered, if dosing occurs on a different day, the immunogenicity sampling 
should be adjusted accordingly. 
 
 
In addition, serum samples designated for PK or biomarker assessments may also be used for 
immunogenicity analysis if required (eg, insufficient volume for complete immunogenicity 
assessment or to follow up on suspected immunogenicity related AE).
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5.9
Results of Central Assessments
The primary endpoint is ORR, as determined by the IRRC. 
Site will be informed of quality issues or needs for repeat scanning via queries from the corelab. 
Results of central Imaging analysis will not be returned to the site.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

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.) 
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Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. 
(See Section 6.1.1 for reporting pregnancies).
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 anti-cancer therapy in the absence of any other SAEs
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 100 days of discontinuation of dosing. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
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If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: 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. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
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). 
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.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
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6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half lives after product administration, 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 the 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.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and where applicable, offspring information must be reported on the Pregnancy 
Surveillance form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
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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
An IRRC will be utilized in this study for determination of IRRC-assessed primary (ORR) and 
secondary (DOR, CRR, PFS) endpoints. The IRRC will review all available tumor assessment 
scans for all treated subjects. Details of IRRC responsibilities and procedures will be specified in 
the IRRC charter.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The planned sample size for this study will be approximately 90 treated subjects.
The sample size was determined based on two considerations: the ability to produce a CI which 
would exclude an ORR of 20%, which is not considered clinically relevant and provide sufficient 
information for a reliable understanding of the safety profile.
Assuming the true ORR is 35%, the study has approximately 87% power to reject the null 
hypothesis that the true ORR is 20%, considering a 2-sided alpha of 5%. In addition, Table 
8.1-1 summarizes the 95% exact CI for the target ORRs ranging from 30% to 44% with sample 
size of 90. At observed ORR 30%, the lower bound of the 95% CI excludes 20%.
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Table 8.1-1:
Observed ORR with Exact 95% CI
True ORR
95% Exact CI
30%
[20.8%-40.6%]
34%
[24.7%-45.2%]
40%
[29.8%-50.9%]
44%
[34.0%-55.3%]
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 at least one dose of nivolumab. This is 
the primary population for safety and efficacy analyses

All response evaluable subjects: All treated subjects who have baseline and at least one 
on-study evaluable tumor measurement

PK subjects: All subjects with available serum time-concentration data from subjects 
dosed with nivolumab

Immunogenicity evaluable subjects: all treated subjects with baseline and at least one 
post baseline immunogenicity assessment.

All PD-L1 evaluable subjects: All treated PD-L1 subjects with quantifiable baseline 
PD-L1 expression

Biomarker subjects: All treated subjects with available biomarker data

Outcomes Research subjects: all treated subjects who have an assessment at baseline 
(Visit 1 assessment prior to administration of drug) and at least 1 subsequent assessment 
(for EORTC QLQ-C30 and EQ-5D separately).
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective will be measured by the primary endpoint of IRRC-assessed ORR. It is 
defined as the number of subjects with a best overall response (BOR) of CR or PR, according to 
the 2007 IWG criteria, divided by the number of treated subjects. The final analysis of the 
primary endpoint will occur at least 12 months after the last enrolled subject’s first dose of study 
therapy. The BOR is defined as the best response designation recorded between the date of first 
dose and the date of initial objectively documented progression per the 2007 IWG criteria or the 
date of subsequent therapy, whichever occurs first. Stem Cell Transplant will be considered as 
subsequent therapy. For subjects without documented progression or subsequent therapy, all 
available response designations will contribute to the BOR determination. For purposes of 
analysis, if a subject receives one dose and discontinues the study without assessment or receives 
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subsequent therapy prior to assessment, this subject will be counted in the denominator (as non-
responder).
8.3.2
Secondary Endpoint(s)
The first secondary objective will be measured by the DOR based on IRRC assessment. DOR is 
defined as the time from first remission (CR or PR) to the date of initial objectively documented 
progression as determined using the 2007 IWG criteria or death due to any cause, whichever 
occurs first. For subjects who neither progress nor die, the DOR will be censored on the date of 
their last evaluable tumor assessment. Subjects who start subsequent therapy without a prior 
reported progression will be censored at the last evaluable tumor assessments prior to initiation 
of the subsequent anticancer therapy. This endpoint will only be evaluated in subjects with 
objective response of CR or PR. 
The second secondary objective will be measured by the CRR based on IRRC assessment. The 
CRR is defined as the number of subjects with a BOR of CR according to the 2007 IWG criteria, 
divided by the number of treated subjects. The BOR is defined similarly as above. The duration 
of CR will only be evaluated in subjects with BOR of CR and is defined as the time from first 
documentation of CR (the date of first negative FDG-PET scan or the date of first documentation 
of no disease involvement in the bone marrow (if required), whichever occurs later) to the date 
of initial objectively documented progression as determined using the revised 2007 IWG criteria 
for malignant lymphoma or death due to any cause, whichever occurs first. Censoring will be 
applied as per DOR definition.
The third secondary objective will be measured by PR rate based on IRRC assessment. It is 
defined as the number of subjects with a BOR of PR according to the 2007 IWG criteria, based 
on IRRC assessment, divided by the number of treated subjects. The duration of PR will only be 
evaluated in subjects with BOR of PR and is defined as the time from first documentation of PR 
to the date of initial objectively documented progression as determined using the 2007 IWG 
criteria or death due to any cause, whichever occurs first. Censoring will be applied as per DOR 
definition.
The fourth secondary objective will be measured by IRRC-assessed PFS. It is defined as the time 
from first dosing date to the date of the first documented progression, as determined by an IRRC, 
or death due to any cause, whichever occurs first. Subjects who die without a reported 
progression will be considered to have progressed on the date of their death. Subjects who did 
not progress or die will be censored on the date of their last evaluable assessment. Subjects who 
did not have any on study assessments and did not die will be censored on the first dosing date. 
Subjects who started any subsequent anti-cancer therapy without a prior reported progression 
will be censored at the last evaluable assessment prior to initiation of the subsequent anti-cancer 
therapy.
The fifth secondary objective will be measured by investigator-assessed ORR. Investigator-
assessed ORR is defined similarly as described for the primary endpoint above.
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8.3.3
Exploratory Endpoint(s) 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline laboratory results will be summarized using descriptive statistics for 
all treated subjects
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods
The IRRC-assessed ORR will be summarized by a binomial response rate and its corresponding 
two-sided 95% exact CI using the Clopper-Pearson method.97 The null hypothesis will be 
rejected if the 2-sided 95% CI lower bound is greater than 20%. This translates in observing at 
least 27 responders out of 90 treated subjects. 
As sensitivity analysis, a summary of IRRC-assessed ORR based on response evaluable subjects 
instead of all treated subjects will also be presented.
8.4.2.2
Secondary Endpoint Methods
The IRRC-assessed DOR will be summarized for subjects who achieve PR or CR using the 
Kaplan-Meier (KM) product-limit method. Median value of DOR, along with two-sided 95% CI 
(based on the log-log transformation) and range, will also be calculated.
IRRC-assessed CRR, PRR and investigator-assessed ORR will be summarized similarly to the 
primary endpoint. Duration of CR and PR will be summarized similarly to DOR. IRRC-assessed 
PFS will be summarized descriptively using the KM product-limit method. Median value of PFS, 
along with two-sided 95% CI (based on the log-log transformation), will also be calculated.
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8.4.2.3
Exploratory Endpoint Methods
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0. All on-study AEs, drug-related AEs, SAEs, and 
drug-related SAEs will be tabulated using worst grade per NCI CTCAE v4.0 criteria by system 
organ class and MedDRA preferred term. On-study lab parameters including hematology, 
chemistry, liver function, thyroid function, and renal function will be summarized using worst 
grade per NCI CTCAE v4.0 criteria.
8.4.4
Pharmacokinetic Analyses
The nivolumab concentration data obtained in this study may be combined with data from other 
studies in the clinical development program to develop or refine a population PK model. This 
model may be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of 
nivolumab to determine measures of individual exposure (such as steady-state peak, trough, and 
time-averaged concentration). Model determined exposures may be used for exposure-response 
analyses. Results of population PK and exposure-response analyses will be reported separately.
8.4.5
Biomarker Analyses
Methodology for exploratory biomarker analyses is described in the statistical analysis plan.
8.4.6
Outcomes Research Analyses
The analysis of EORTC QLQ-C30 will be performed in all treated subjects who have an 
assessment at baseline (Visit 1 assessment prior to administration of drug) and at least 
1 subsequent assessment.
All scales and single items are scored on categorical scales and linearly transformed to 
0-to-100 scales with higher scores for a functional scale representing higher levels of 
functioning, higher scores for the global health status/quality of life representing higher levels of 
global health status/quality of life and higher scores for a symptom scale representing higher 
level of symptoms. Data will be analyzed as change from baseline scores. Baseline and change 
from baseline in EORTC QLQ-C30 global health status/QoL composite scale data and the 
remaining EORTC QLQ-C30 scale data will be summarized using descriptive statistics (N, 
mean, standard deviation, median, first and third quartiles, minimum, maximum) at each of the 
assessment time points. In addition, the percentage of subjects demonstrating a clinically 
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meaningful deterioration (defined as a 10 point change from baseline) will be presented for each 
scale at each assessment timepoint. Percentages will be based on number subjects assessed at 
assessment time point.
As previously mentioned in Section 5.1, the EQ-5D comprises 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety) and a VAS. EQ-5D data will be described in the 
following three ways:

Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time 
point will be summarized using descriptive statistics. (N, mean, standard deviation, median, 
first and third quartiles, minimum, maximum).

Proportion of subjects reporting problems for the 5 EQ-5D dimensions at each assessment 
time point will be summarized by level of problem. Percentages will be based on number 
subjects assessed at assessment time point

A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression), health state 
(5 dimensions digits combined in a 5-digit number) and EQ-VAS will be provided.
8.4.7
Other Analyses 
8.4.7.1
Immunogenicity Analyses
Immunogenicity may be reported for ADA positive status (such as persistent positive, 
neutralizing positive, only last sample positive, baseline positive) and ADA negative status, 
relative to baseline. Effect of immunogenicity on safety, efficacy, biomarkers and PK may be 
explored. Additional details will be described in the SAP.
8.5
Interim Analyses
Not applicable.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
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
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. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
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9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug is inventoried and dispensed. Records or logs must comply with applicable regulations and 
guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

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. 
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The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form .For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool. 
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:

External Principal Investigator designated at protocol development.
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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GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator 
or BMS as related to the investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, 
Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event defined as any untoward medical 
occurrence that at any dose: results in death; is life 
threatening (defined as an event in which the subject was at 
risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it 
were more severe), requires inpatient hospitalization or 
causes prolongation of existing hospitalization; results in 
persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect; is an important medical event (defined 
as a medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in 
an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in 
hospitalization.). For reporting purposes only, BMS also 
considers the occurrence of pregnancy, overdose (regardless 
of association with an AE), and cancer as important medical 
events.
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LIST OF ABBREVIATIONS
Term
Definition
ACTH
Adrenocorticotropic Hormone
AE
adverse event
ADA
Anti-Drug Antibody
ADL
Activities of daily living
Ag
Antigen
AIDS
Acquired ImmunoDeficiency Syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
ASCT
Autologous Stem Cell Transplant 
AST
aspartate aminotransferase
AT
aminotransaminases
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
BCL
B-cell lymphoma
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
cm
centimeter
Cmax, CMAX
maximum observed concentration
CMV
cytomegalovirus
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Term
Definition
CNS
Central nervous system
CR
Complete remission
CRF
Case Report Form, paper or electronic
CRR
complete remission rate
CRO
Contract Research Organisation
CT
computed tomography
CTA
Clinical Trial Agreement
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse large B-cell lymphoma
dL
deciliter
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic acid
DOR
Duration of Response
EBV
Epstein-Barr Virus
ECG
electrocardiogram
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ELISA
enzyme-linked immunosorbent assay
EOI
End of Infusion
EORTC
European Organisation for Research and Treatment of Cancer
FFPE
formalin-fixed, paraffin-embedded
FL
Follicular Lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
FSH
follicle stimulating hormone
FU
Follow-up
g
gram
GCB
germinal center B cells
GCP
Good Clinical Practice
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Term
Definition
GVHD
Graft-Versus-Host Disease
h
hour
HBV
hepatitis B virus
HCV
hepatitis C virus
HCG
human chorionic gonadotropin
HD-ASCT
high-dose therapy and autologous stem cell transplantation
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator brochure
IFN-
interferon-gamma
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL
Interleukine
IMP
investigational medicinal products
IND
Investigational New Drug
I-O
Immuno-oncology
IRB
Institutional Review Board
IRRC
independent radiology review committee
ITIM
Immunoreceptor Tyrosyne Inhibitory Motif
IU
International Unit
IV
intravenous
IVRS
Interactive voice response system
K+
potassium
kg
kilogram
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Term
Definition
KM
Kaplan-Meier
L
liter
LDH
lactate dehydrogenase
LFT
liver function test
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
MLR
Mixed Lymphocyte Reaction
MRI
Magnetic resonance imaging
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
NCI
National Cancer Institute
NHL
Non-Hodgkin Lymphoma
NIMP
non-investigational medicinal products 
ORR
Overall response rate
P
Phosphorus
PBMC
peripheral blood mononuclear cell
PET
Positron emission tomography
PFS
progression free survival
PK
pharmacokinetics
QLQ
Quality of life questionnaire
QoL
Quality of life
qPCR
quantitative real-time polymerase chain reaction
RCC
Renal Cancer Carcinoma
R-CHOP
Chemotherapy regimen: cyclophosphamide, hydroxydaunorubicin, 
oncovir, prednisone
RECIST
Response Evaluation Criteria In Solid Tumors
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Term
Definition
RIT
Radio Immunotherapy
RNA
Ribonucleic acid
RT-PCR
reverse transcription polymerase chain reaction 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCT
Stem Cell Transplant
SNP
single nucleotide polymorphisms
SOP
Standard Operating Procedures
SPD
Sum of the Product of the Diameters
t
temperature
T. bili
Total bilirubin
T-HALF
Half life
TILs
tumor infiltrating lymphocytes
TSH
Thyroid stimulating hormone
TTP
Time To Progession
ULN
Upper limit of normal
VAS
visual analog rating scale
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
WOCBP
women of childbearing potential
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12
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55 Tshushima F, Tanaka K, Otsuki N, et al. Predominant expression of B7-H1 and its 
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66 Yang ZZ, Novak AJ, Stenson MJ, et al. Intratumoral CD4+CD25+ regulatory T-cell-
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conventional CD4+ T cells to T-regulatory cells. Int J Cancer 2009;124(1):239-44. 
68 Yang ZZ, Novak AJ, Ziesmer SC, et al. CD70+ non-Hodgkin lymphoma B cells induce 
Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood 2007;
110(7):2537-44.
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69 Carreras J, Lopez-Guillermo A, Fox BC, et al. High numbers of tumor-infiltrating FOXP3-
positive regulatory T cells are associated with improved overall survival in follicular 
lymphoma. Blood 2006;108(9):2957-64. Epub 2006 Jul 6.
70 Lee AM, Clear AJ, Calaminici M, et al. Number of CD4+ cells and location of forkhead box 
protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with 
outcome. J Clin Oncol. 2006;24(31):5052-9. Epub 2006 Oct 10.
71 Ramsay AG, Clear AJ, Kelly G, et al. Follicular lymphoma cells induce T-cell immunologic 
synapse dysfunction that can be repaired with lenalidomide: implications for the tumor 
microenvironment and immunotherapy. Blood 2009;9:114(21):4713-20. doi: 10.1182/blood-
2009-04-217687. Epub 2009 Sep 28.
72 Richendollar BG, Pohlman B, Elson P, Hsi ED. Follicular programmed death 1-positive 
lymphocytes in the tumor microenvironment are an independent prognostic factor in 
follicular lymphoma. Hum Pathol. 2011;42(4):552-7. doi: 10.1016/j.humpath.2010.08.015. 
Epub 2011 Jan 15.
73 Myklebust JH, Irish JM, Brody J, et al. High PD-1 expression and suppressed cytokine 
signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells.
Blood 2013;121(8):1367-76. doi: 10.1182/blood-2012-04-421826. Epub 2013 Jan 7 
74 Gribben JG. How I treat indolent lymphoma. Blood 2007;109:4617-26.
75 Dreyling M. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v181-3.
76 Feuerlein K, Zucca E, Ghielmini M. First-line treatment of follicular lymphoma: a patient-
oriented algorithm. Leuk Lymphoma. 2009;50:325-34.
77 van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome 
of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without 
rituximab during induction: results of a prospective randomized phase 3 intergroup trial. 
Blood 2006;108:3295-301.
78 McLaughlin P, White CA, Grillo-Lopez AJ, Maloney DG. Clinical status and optimal use of 
rituximab for B-cell lymphomas. Oncology (Williston Park) 1998;12(12):1763-9.
79 Ujjani C, Cheson B. Efficacy of bendamustine in rituximab-refractory indolent B-cell non-
Hodgkin lymphoma: review of a pivotal trial. Future Oncol. 2011;7(1):9-14. doi: 
10.2217/fon.10.169.
80 Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90–labeled 
ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients 
with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's 
lymphoma. J Clin Oncol. 2002;20:2453–63.
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81 Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan 
radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's 
lymphoma. J Clin Oncol. 2002;20:3262-9.
82 Horning SJ, Younes A, Jain V, et al. Efficacy and safety of tositumomab and iodine-131 
tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol. 
2005;23:712-9.
83 Leahy MF, Turner JH. Radio-immunotherapy of indolent non-Hodgkin lymphoma with 131I-
rituximab in routine clinical practice: 10–year, single institution experience of 142 
consecutive patients. Blood 2010;2010:23.
84 Rohatiner AZ, Nadler L, Davies AJ, et al. Myeloablative therapy with autologous bone 
marrow transplantation for follicular lymphoma at the time of second or subsequent 
remission: Long-term follow-up. J Clin Oncol 2007;25:2554-2559.
85 Bierman PJ, Vose JM, Anderson JR, et al. High-dose therapy with autologous hematopoietic 
rescue for follicular low-grade non-Hodgkin's lymphoma. J Clin Oncol 1997;15:445-450.
86 Cao TM, Horning S, Negrin RS, et al. High-dose therapy and autologous hematopoietic-cell 
transplantation for follicular lymphoma beyond first remission: The Stanford University 
experience. Biol Blood Marrow Transplant 2001;7:294-301.
87 Safar V, Gastinne T, Milpied N, et al. Very long term follow-up of autologous stem cell 
transplantation in follicular lymphoma: A retrospective single-institution experience. Ann 
Oncol 2008;19:183.
88 Bastion Y, Brice P, Haioun C, et al. Intensive therapy with peripheral blood progenitor cell 
transplantation in 60 patients with poor-prognosis follicular lymphoma. Blood 1995;86:3257-
3262.
89 Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free 
survival and survival in relapsed follicular non-Hodgkin's lymphoma: Results from the 
randomized European CUP trial. J Clin Oncol 2003;21:3918-3927.
90 van Besien K, Loberiza FRJr, Bajorunaite R, et al. Comparison of autologous and allogeneic 
hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003;102:3521-3529.
91 Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell 
transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with 
fludarabine, cyclophosphamide, and rituximab. Blood 2008;111:5530-5536.
92 Hari P, Carreras J, Zhang MJ, et al. Allogeneic transplants in follicular lymphoma: Higher 
risk of disease progression after reduced-intensity compared to myeloablative conditioning. 
Biol Blood Marrow Transplant 2008;14:236-245.
93 Tomblyn M, Brunstein C, Burns LJ, et al. Similar and promising outcomes in lymphoma 
patients treated with myeloablative or nonmyeloablative conditioning and allogeneic 
hematopoietic cell transplantation. Biol Blood Marrow Transplant 2008;14:538-545.
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94 Tomblyn MR, Ewell M, Bredeson C, et al. Autologous versus reduced-intensity allogeneic 
hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin 
lymphoma beyond first complete response or first partial response. Biol Blood Marrow 
Transplant 2011;17:1051-1057.
95 Cheson BD, Pfistner B, Juweld ME, et al. Revised Response Criteria for Malignant 
Lymphoma. J Clin Oncol 2007;25(5):579-586.
96 Manuel M, Tredan O, Bachelot T, et al. Lymphopenia combined with low TCR diversity 
(divpenia) predicts poor overall survival in metastatic breast cancer patients. 
Oncoimmunology 2012;1(4):432-440.
97 Clopper, CJ and Pearson, ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika 1934; 26:404-413.
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APPENDIX 1
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 2
2007 INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR MALIGNANT LYMPHOMA
2007 IWG Response Criteria for Malignant Lymphoma
Response
Definition
Nodal masses
Spleen, Liver
Bone marrow
CR
Disappearance of 
all evidence of 
disease
(a) FDG-avid or PET positive 
prior to therapy; residual mass of 
any size permitted if PET negative
(b) Variably FDG-avid or PET 
negative; regression to normal 
size on CT
Not palpable, 
nodules 
disappeared
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology,
immunohistochemistry
should be negative
PR
Regression of 
measurable 
disease and no 
new sites
50% decrease in SPD of up to 6 
largest dominant masses (index 
lesions); no increase in size of 
other nodes (non-index lesions)
(a) FDG-avid or PET positive 
prior to therapy; one or more PET 
positive at previously involved 
site
(b) Variably FDG-avid or 
PET negative; regression 
on CT
50% decrease 
in SPD of 
nodules (for 
single nodule in
greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified
SD
Failure to attain 
CR/PR or PD
(a) FDG-avid or PET positive 
prior to therapy; PET positive at 
prior sites of disease and no new 
sites on CT or PET
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT
N/A
N/A
Relapsed 
disease
or PD
Any new lesion or 
increase by 50% 
of previously
involved sites 
from nadir
Appearance of a new lesion(s) 
> 1.5 cm in any axis, 50% 
increase in SPD of more than one 
node (index lesions), or 50% 
increase in longest diameter of a 
previously identified node > 1 cm 
in short axis.
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior 
to therapy
> 50% increase 
from nadir in 
the SPD of any 
previous lesions
New or recurrent 
involvement
Key: CR = complete remission CT = computed tomography; FDG = [18F] fluorodeoxyglucose; IWG = International 
Working Group; NA = Not applicable; PD = progressive disease; PET = positron-emission tomography; PR = 
partial remission; SD = stable disease; SPD = sum of the product of the diameters.
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CR (Complete Remission)
The designation of CR requires the following:
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms, if present before therapy.
2. a.
Typically [18F] fluorodeoxyglucose (FDG)-avid lymphoma: in patients with no 
pretreatment positron emission tomography (PET) scan or when the PET scan was positive 
before therapy, a post-treatment residual mass of any size is permitted as long as it is PET 
negative.
3. b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on computed tomography (CT) scan to normal size (1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in their long axis and > 1.0 cm in their short axis before treatment 
must have decreased to 1.0 cm in their short axis after treatment.
4. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear. However, determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen 
may reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or 
causes other than lymphoma.
5. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is 
made must be adequate (with a goal of > 20 mm unilateral core). If the sample is 
indeterminate by morphology, it should be negative by immunohistochemistry. A sample that 
is negative by immunohistochemistry but demonstrates a small population of clonal 
lymphocytes by flow cytometry will be considered a CR until data become available 
demonstrating a clear difference in patient outcome.
PR (Partial Remission)
The designation of PR requires all of the following:
1. At least a 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the 
largest dominant nodes or nodal masses. These nodes or masses should be selected according 
to all of the following: they should be clearly measurable in at least 2 perpendicular 
dimensions; if possible they should be from disparate regions of the body; and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
2. No increase should be observed in the size of other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, in the 
greatest transverse diameter.
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present.
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5. Bone marrow assessment is irrelevant for determination of a PR, if the sample was positive 
before 
treatment. 
However, 
if 
positive, 
the 
cell 
type 
should 
be 
specified 
(eg, large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the 
above criteria but have persistent morphologic bone marrow involvement will be considered 
partial responders. When the bone marrow was involved before therapy and a clinical CR 
was achieved but with no bone marrow assessment after treatment, patients should be 
considered partial responders.
6. No new sites of disease should be observed.
7. FDG:
a) Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET should be positive in at least 
1 previously involved site.
b) Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria should be 
used. In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with 1 or at most 2 residual masses that have regressed by > 50% on CT; those 
with more than 2 residual lesions are unlikely to be PET negative and should be 
considered partial responders.
SD (Stable Disease)
SD is defined as the following:
1. A patient is considered to have SD when he or she fails to attain the criteria needed for a CR 
or PR but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]).
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with no 
new areas of involvement on the post-treatment CT or PET scan.
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan.
PD: Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
Lymph nodes should be considered abnormal if the long axis is > 1.5 cm regardless of the short 
axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if 
its short axis is > 1.0. Lymph nodes 1.0 x 1.0 cm will not be considered abnormal for relapse 
or progressive disease.
1. Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, even if 
other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site 
should only be considered relapsed or PD after confirmation with other modalities. In 
patients with no prior history of pulmonary lymphoma, new lung nodules identified by CT 
are mostly benign. Thus, a therapeutic decision should not be made solely on the basis of the 
PET without histologic confirmation.
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2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be 
considered PD, a lymph node with a diameter of the short axis of < 1.0 cm must increase by 
50% and to a size of 1.5 x 1.5 cm or > 1.5 cm in the long axis.
3. At least a 50% increase in the longest diameter of any single previously identified node 
> 1 cm in its short axis.
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion 
was PET positive before therapy unless the lesion is too small to be detected with current 
PET systems (< 1.5 cm in its long axis by CT).
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (eg, pleural effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical examination, it is found to be 
histologically negative.
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is 
not deemed necessary or appropriate for use (eg, a trial in patients with MALT lymphoma), 
response should be assessed as above, but only using CT scans. However, residual masses should 
not be assigned CRu status, but should be considered partial responses.
Reference: Cheson BD, Pfisner B, Juweid ME, et al. Revised Response Criteria for Malignant Lymphoma. Journal 
of Clinical Oncology 2007;25:579-586. 
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APPENDIX 3
FLIPI SCALE
Composite score determined by assigning 1 point for each of the following factors;

Age (> 60 years vs 60 years)

Serum LDH level (above normal vs normal or below)

Number of involved nodal areas (> 4 vs 4)

Ann Arbor stage (III-IV vs I-II)

Hemoglobin level (< 120 g/L vs 120 g/L)
Reference:
Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004 Sep 
1;104(5):1258-65. Epub 2004 May 4. PubMed PMID: 15126323.
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APPENDIX 4
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUSa
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655..
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APPENDIX 5
ACUTE GVHD GRADING AND STAGING
Table 1:
Extent of Organ Involvement
Stage
Skin
Liver
Gut
1
Rash on < 25% of skina
Bilirubin 2 - 3 mg/dLb
Diarrhea > 500 mL/dayc or 
persistent nausead
2 
Rash on 25 - 50% of skin 
Bilirubin 3 - 6 mg/dL 
Diarrhea > 1000 mL/day 
3 
Rash on > 50% of skin 
Bilirubin 6 - 15 mg/dL 
Diarrhea > 1500 mL/day 
4 
Generalized erythroderma with 
bullous formation 
Bilirubin >15 mg/dL 
Severe abdominal pain with or 
without ileus 
Gradee
I 
Stage 1 - 2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
--
Stage 2 - 3 or 
Stages 2 - 4 
IVf
Stage 4 
Stage 4 
--
a Use “Rules of Nines” (Table 2) or burn chart to determine extent of rash.
b Range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin has been 
documented.
c Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body 
surface area. Downgrade one stage if an additional cause of diarrhea has been documented.
d Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
e Criteria for grading given as minimum degree of organ involvement required to confer that grade.
f Grade IV may also include lesser organ involvement with an extreme decrease in performance status.
Table 2:
Percent Body Surfaces
Body Area
Percent
Total Percentage
Each Arm 
9%
18%
Each Leg 
18%
36%
Chest & Abdomen
18%
18%
Back 
18%
18%
Head 
9%
9%
Pubis 
1%
1%
Ref.: Przepiorka et al. Bone Marrow Transplant 1995;15(6):825.
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Stage of Chronic GVHD
Limited: Localized skin involvement resembling localized scleroderma with or without liver 
involvement; no other organ involvement.
Extensive: Generalized skin and/or multiple organ involvement.
Ref. Sullivan KM, Blood 1981;57:267.
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Page:
1
Protocol Number:
CA209140
IND Number:
119,380
Ex-US
Non-IND
EUDRACT Number
2013-003645-42
Date:
06-Dec-2013
Protocol CA209140: A Single-Arm, Open-Label Phase 2 Study of Nivolumab (BMS-
936558) in Subjects with Relapsed or Refractory Follicular Lymphoma (FL)
(CheckMate 140: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 140)
Amendment Number 02
Site Number: All
Medical Monitor
Kazunobu Kato, MD, PhD
24-hr Emergency Telephone Number:
Bristol-Myers Squibb Research and Development
Oncology Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
5 Research Parkway
Wallingford, CT 06492
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS). 
This amendment must be maintained with the referenced protocol.
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2
Amendment Rationale:
The main objective of this amendment is to implement a mandatory recommendation received 
from the U.S. Food and Drug Administration (FDA) as follows:

The exclusion criterion has been added to exclude the subjects who received chest radiation 
24 weeks prior to first dose of the study drug.
Justification for this exclusion criterion is that pneumonitis has been noted in the current 
Investigator Brochure as a treatment-related serious adverse event (SAE). The FDA notes that 
“Radiation pneumonitis can occur in patients who have received chest radiation up to 24 weeks 
after radiation therapy.”  Chest radiation is not commonly used in the subjects eligible for this 
protocol, and this amendment will comply with the FDA recommendation without altering the 
basic study population or trial design.
Additional updates were also made to the protocol including items such as clarifying the 
schedule of tumor assessment, correcting typographical and formatting errors,
 
.
Changes to the Protocol:
1. Section 3.1, Study Design and Duration, Treatment
a) Bullet point 8: Corrected “Subjects will be evaluated for response according to revised 
International Working Group Criteria beginning at Week 9 (Day 1 of Cycle 5) and 
continuing every 8 weeks (7 days) for the first eight months of treatment, then every 
12 weeks up to 2 years of treatment, continuing every 6 months beyond 2 years of 
treatment, until disease progression. If the subject discontinues treatment prior to disease 
progression, tumor assessment will continue in the follow-up phase
2. Section 3.3.2 Exclusion Criteria:
a) Added Criterion 5 e): Chest radiation 24 weeks prior to first dose of the study drug. 
4. Section 5.3.1, Imaging Assessment for the Study: Corrected typo in “Image acquisition 
guidelines and submission process will be outlined in the CA209140 Imaging Manual to be 
provided by the corelab.
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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Protocol Number:
CA209140
IND Number:
119,380
Ex-US
Non-IND
EUDRACT Number
2013-003645-42
Date:
23-Jul-2014
Protocol CA209140: A Single-Arm, Open-Label Phase 2 Study of Nivolumab (BMS-
936558) in Subjects with Relapsed or Refractory Follicular Lymphoma (FL). 
(CheckMate 140: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 140)
Amendment Number 03
Site Number: All
Medical Monitor
Kazunobu Kato, MD, PhD
24-hr Emergency Telephone Number:
Bristol-Myers Squibb Research and Development
Oncology Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
5 Research Parkway
Wallingford, CT 06492
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS). 
This amendment must be maintained with the referenced protocol.
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Amendment Rationale:

One of the main purposes of this global amendment is to modify a few eligibility criteria to 
facilitate subject enrollment: 

Rationale to authorize subject population with prior autologous SCT outside a window of 
12 weeks prior to first dose of study therapy.
Recent evidence indicates that Autologous Stem Cell Transplant (ASCT) may provide 
clinical benefits for patients with relapsed follicular lymphoma (FL).1,2 A European 
randomized study has confirmed the superiority of the ASCT arm over the standard 
therapy arm in relapsed FL.3 Additional retrospective studies provide further evidence 
supporting the clinical benefits of using ASCT for relapsed FL patients.1,4 The optimal 
timing for ASCT remains uncertain, however, as the clinical benefits from ASCT have 
been limited to a large extent to patients with relapsed FL. A similar benefit, however, 
has not been observed in the front-line setting.2 Therefore, the current use of ASCT in 
relapsed FL can vary depending on each country or on each transplant center.5
Nevertheless, the current ESMO Clinical Practice Guidelines recognizes that high-dose 
chemotherapy with ASCT prolongs PFS and OS and should be specifically considered in 
patients with short-lived first remissions after failure of rituximab-containing regimens.6
The present NCCN guideline for NHL also lists high-dose therapy with ASCT as one of 
the second-line consolidation or extended dosing options. Thus, based on these data, it is 
appropriate to enroll patients who have had previous ASCT for BMS-sponsored 
CA209140 study.

Rationale to modify exclusion criterion 4b
A randomized study testing R-CHOP (n = 202) vs CHOP (n = 197) shows that Grade 3 
or 4 adverse events related to the infusion of rituximab were observed in 19 patients in 
the CHOP-plus-rituximab group (9%); the most frequent of these were respiratory 
symptoms (with or without bronchospasm), chills, fever, and hypotension. In all cases, 
the symptoms disappeared after the infusion was slowed or stopped, and no patient died 
as a result of such an adverse event. All patients were able to receive further cycles of 
CHOP plus rituximab without recurrence of Grade 3 or 4 infusion-related reactions. 
Exclusion criteria of history of severe hypersensitivity reaction to any monoclonal 
antibody is reworded to allow for subjects who experienced Grade 3 - 4 infusion-related 
reaction with the first dose of rituximab, but who were able to receive subsequent 
rituximab without recurrence of Grade 3 or 4 infusion-related reaction to be eligible.
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
Another objective of this amendment is to remove the interim analysis and extend the 
duration of follow-up required for all subjects prior to performing the final analysis of the 
primary endpoint:

Rationale to remove the Interim Analyses
In the original protocol, an interim analysis of independent radiologic review 
(IRRC)-assessed ORR is planned to be performed after the first 37 subjects have been 
treated and those subjects who remain on treatment have completed a minimum of 
8 weeks follow-up. Updated results from the FL cohort (n = 10) in the ongoing Phase 1 
study (CA209039) indicate that the time to response may be longer than the protocol 
assumptions for both the interim and final analyses with late responses observed 
10 months after the administration of the first dose of nivolumab. In particular, two out of 
four responders with FL achieved the first OR at Week 39. Consequently, the estimated 
cumulative response rate at 8, 16, 24 and 48 weeks are 10, 20, 20, 40%, respectively
Thus, the planned interim analysis at 8 weeks after the first dose date of the subjects who 
remain on treatment in the original protocol is not expected to adequately evaluate the 
clinical efficacy of nivolumab. Furthermore, since the observed response rate for 
nivolumab from the updated Phase 1 data shows a higher response rate (40%) than the 
preliminary data (25%) supporting the original protocol assumptions, an interim analysis 
for futility should be removed from the study.

Rationale for extending the timing of the final analysis of the primary endpoint from 
6 months to 1 year after the last enrolled subject’s first dose of study therapy
Late responses, occurring up to 39 weeks from the initial dose, were observed in the FL 
cohort of the Phase 1 study (CA209039) in recently updated results. In the original 
protocol, the primary endpoint analysis is planned to be performed after six months 
follow-up for the last patient enrolled in this study. Thus, subjects enrolled late in the 
study and experiencing late response will have insufficient follow-up time after the first 
response to adequately characterize the duration of response. Taking the late responses 
observed in the CA209039 study into consideration, extending the evaluation of DOR 
with longer follow-up, until 1 year after the last enrolled subject’s first dose of study 
therapy, is likely to provide more scientifically meaningful clinical outcome.

This global amendment will also clarify that subject may start study drug before Bone 
Marrow biopsy results become available:
The purpose of a bone marrow biopsy/aspirate is to determine the extent of disease 
(lymphoma) involvement in the bone marrow before starting study drug treatment. 
Results of a bone marrow biopsy (pathological reports) may not be able to be confirmed 
before the first dose of study drug. Because bone marrow biopsy results will not change 
eligibility, it is acceptable that sites cannot confirm the results of a bone marrow biopsy as 
long as sites can verify the documentation that a bone marrow biopsy was performed. The 
results of a bone marrow biopsy can be confirmed later.
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
The last main objective of this amendment is to authorize subject to continue study treatment 
beyond progression:
Immunotherapeutic agents produce atypical clinical response patterns, which are not usually 
observed in conventional chemotherapy. Two distinct non-conventional patterns have been 
reported: 1) a reduction in total tumor burden despite of the appearance of new lesion(s), 
and 2) responses after a transit increase in total tumor burden in an initial phase, followed by 
subsequent tumor shrinkage. Therefore, it is important to avoid premature discontinuation of 
the study drug as nivolumab might induce non-conventional response patterns in some 
patients. Under the current discontinuation criteria (Section 3.5), subjects must stop the study 
drug when investigator assessment determines disease progression using the 2007 Revised 
IWG Response Criteria. The change in this amendment will permit the subjects to continue 
on the study drug beyond investigator-assessed disease progression in certain cases.

Additional modifications are as described below:

Incorporate other minor changes to correct and/or clarify protocol requirements.
The revisions in this global amendment apply to all subjects.
This amendment will impact data analysis.
Changes to the Protocol: 
1. Synopsis, Secondary objectives
a) 2nd bullet, assessment of duration of CR added.
b) New bullet added as 3rd bullet: “to assess the PR rate and the duration of PR based on 
IRRC assessment 
2. Synopsis, Exploratory Objectives
3. Synopsis, Study Design
a) 5th sentence corrected
b) 7th sentence corrected with revised secondary endpoints
c) Study design schematic corrected to reflect the removal of the interim analysis
d) 2nd paragraph, duration of accrual corrected
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4. Synopsis, Study Population
a) First sentence: Corrected to “Male and female, age 18 and above, with relapsed or 
refractory follicular lymphoma after failure of at least two prior lines of therapy (each 
containing anti-CD 20 antibody and/or an alkylating agent) will be eligible to participate 
in the study.”
b) 2nd sentence: dimension in mm added 
5. Synopsis, Study Assessments
a) 1st and 2nd sentences corrected
b) New paragraph added after last paragraph for documenting GVDH at different time 
points after study discontinuation for allogeneic SCT
6. Synopsis, Statistical Considerations, Sample Size: 2nd paragraph deleted and replaced by a 
new one 
7. Synopsis, Statistical Considerations, Endpoints: 2nd sentence corrected with revised 
secondary endpoints
8. Synopsis, Statistical Considerations, Analysis
a) 1st paragraph modified to reflect the new method to analyze the primary endpoint 
b) 3rd paragraph, 1st sentence modified to include PR rate
c) 3rd paragraph, new sentence added after 1st sentence 
9. Section 1.3.2, Secondary Objectives
a) 2nd bullet, assessment of duration of CR added.
b) New bullet added as 3rd bullet: “To assess the PR rate and the duration of PR based on 
IRRC assessment” 
10. Section 1.3.3, Exploratory Objectives
13. Section 3.1, Study Design and Duration
a) 2nd and 3rd paragraphs deleted to reflect the removal of the interim analysis 
b) 4th paragraph, 5th and 6th sentences corrected
c) Figure 3.1-1 corrected to reflect the removal of the interim analysis
14. Section 3.1, Study Design and Duration, Study Duration: 1st sentence corrected to reflect the 
timing extension of the analysis of the primary endpoint
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15. Section 3.1, Study Design and Duration, Screening 
a) 3rd bullet, 2nd sub-bullet, 2nd sentence deleted 
b) 3rd bullet, new sub-bullet: “Subjects may initiate the study drug before the outcome of 
PD-L1 expression status becomes available.”
c) 4th bullet corrected
d) 4th bullet, 2nd sub-bullet corrected
e) 4th bullet, new sub-bullet added as 3rd sub-bullet
16. Section 3.1, Study Design and Duration, Treatment
a) 1st bullet, new sentence added: “Subsequently, women of childbearing potential 
(WOCBP) must have a pregnancy test every 4 weeks (± 7 days) regardless of dosing 
schedule.”
b) New bullet after 2nd bullet added: “Subjects may be dosed no less than 12 days between 
doses and no more than 3 days after the scheduled dosing date. Dose given after the 
3-day window is considered a dose delay. A maximum delay of 42 days between doses is 
allowed.”
c) 3rd bullet: Corrected to: “All of the vital signs will be collected after Cycle 1 within 
72 hours prior to dosing.”
d) 4th bullet, 2nd sentence deleted
e) 6th bullet, text added indicating that treatment beyond progression is allowed in certain 
instances as described in Section 4.3.8
f)
8th bullet corrected
g) 9th bullet corrected
17. Section 3.1, Study Design and Duration, Follow-up
a) 4th bullet: Corrected to: “Subjects who discontinue study therapy for reasons other than 
disease progression or allogeneic SCT or ASCT will continue to have radiographic 
assessments at the intervals described in the Treatment Phase until disease progression, 
lost to follow-up, or withdrawal of study consent.”
b) New bullet after 4th bullet added: “For subjects who discontinue study therapy by 
proceeding to allogeneic SCT or ASCT, tumor assessment by the investigator will be 
required after allogeneic SCT or ASCT (see Section 3.6). For the subjects who 
discontinue study therapy by proceeding to allogeneic SCT, acute and chronic Graft-
Versus-Host Disease (GVHD) documentation will also be simultaneously collected (see 
Section 5.3).”
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18. Section 3.3.1, Inclusion Criteria:
a) Criterion 2, Target Population
i)
c): Modified with conversion in mm added and MRI added
ii) d): 
(1) Corrected to “Treatment of FL consisting of 2 prior treatment lines; each of the 
two prior treatment lines must include anti-CD 20 antibody and/or an alkylating 
agent 
(eg, 
bendamustine, 
cyclophosphamide, 
ifosfamide, 
chlorambucil, 
melphalan, busulfan, nitrosoureas). At least one of the two prior treatment lines 
must include rituximab.”
(2) Definition of Refractory FL, 2nd and 3rd bullets corrected
b) Criterion 4, Age and Reproductive Status
i)
Sub-bullet f) moved after sub-bullet e)
19. Section 3.3.2, Exclusion Criteria
a) Criterion 4, Allergies and Adverse Drug Reaction, b): Corrected to “History of severe 
hypersensitivity reaction to any monoclonal antibody with the following exception: 
Subjects who experienced Grade 3 - 4 infusion-related reaction with the first dose of 
rituximab, but who were able to receive subsequent rituximab without recurrence of 
Grade 3 or 4 infusion-related reaction are eligible”
b) Criterion 5, Prohibited  Treatments and/or Therapies, 
i)
d): Corrected to: “Autologous SCT 12 weeks prior to first dose of study drug”
ii) New criterion 5f) added: “Carmustine (BCNU) 1000 mg received as part of pre-
transplant conditioning regimen”
20. Section 3.5, Discontinuation of Subjects from Treatment:
a)
Corrections were made to the first bullet and text was added referencing Section 4.3.8 
for guidance on continued treatment beyond disease progression
b) 4th bullet removed and new mandatory paragraph added after last bullet to comply with 
the revised wording of the protocol model document
21. Section 3.6, Post Treatment Study Follow up: Added new paragraph after 1st paragraph: “In 
addition, subjects who discontinue study therapy by proceeding to allogeneic SCT or ASCT 
will require tumor assessment (CR or non-CR) by the investigators according to the 2007 
revised IWG Response Criteria for Malignant Lymphoma on Day 100, at 6 months, 1 year 
and every year thereafter from the date of stem cell infusion until the first non-CR after SCT 
is documented (see Section 5.4). For the subjects who discontinue study therapy by 
proceeding to allogeneic SCT, documentation of acute and chronic GVHD will be 
simultaneously collected (see Section 5.3).”
22. Section 4.3, Selection and Timing of Dose for Each Subject, 1st paragraph, 7th sentence: 
Corrected to “Subjects may be dosed no less than 12 days between doses and no more than 
3 days after the scheduled dosing date.”
23. Section 4.3.1, Antiemetic Premedications: The text “See Section 4.3.6 for premedication 
recommendations following a nivolumab related infusion reaction.” was removed.
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24. Section 4.3.5, Treatment Discontinuation Criteria
a) 2nd bullet corrected
b) 2nd bullet, new sub-bullet added after 1st sub-bullet : « Grade 3 drug-related 
endocrinopathies adequately controlled with only physiologic hormone replacement do 
not require discontinuation”
c) 3rd bullet: New 4th sub-bullet added: “Grade 4 amylase or lipase abnormalities that are 
not associated with symptoms or clinical manifestations, or radiographic signs of 
pancreatitis. It is recommended to consult with the BMS Medical Monitor for Grade 4 
amylase or lipase abnormalities”
d) New bullet added after 3rd bullet: “Grade 3 or 4 drug-related endocrinopathy AEs such as 
adrenal insufficiency, ACTH (Adrenocorticotropic Hormone) deficiency, hyper- or 
hypothyroidosis, or glucose intolerance, which resolve or are adequately controlled with 
physiologic hormone replacement (steroids, thyroid hormones) or glucose controlling 
agents, respectively, may not require discontinuation after discussion with and approval 
from the BMS Medical Monitor.”  
e) Text was added to the “Disease Progression” bullet, referencing Section 4.3.8 for 
guidance on continued treatment beyond disease progression
f)
New bullet after last bullet: “Subject who initiated the preparative regimen for allogeneic 
SCT or ASCT after the first dose of nivolumab treatment.”
25. Section 4.3.7: New section created: “Guidelines for assessment and management of tumor 
lysis syndrome”
26. Section 4.3.7, Treatment Beyond Progression: Re-categorized as Section 4.3.8 and new 
sub-sections added authorizing the treatment beyond progression
27. Section 5.1, Flow chart/Time and Events Schedule, Table 5.1-1, Screening Procedural 
Outline (CA209140):
a) Laboratory Tests: Clarified in the notes that either hepatitis C antibody (HCV Ab) or 
HCV RNA can be performed at screening, bicarbonates testing deleted, and amylase and 
lipase testing should be performed
b) Pregnancy test, Notes corrected: “for WOCBP only (serum or urine - local/site)”
c) Bone Marrow Aspirate: Text added to clarify the requirements for performing a bone 
marrow biopsy/aspirate at screening and the submission of optional bone marrow aspirate 
samples.
28. Section 5.1, Flow chart/Time and Events Schedule, Table 5.1-2, Short-term Procedural 
Outline (CA209140): 
a) Title of 4th column: Clarified that procedures can be performed every 2 weeks within 
3 days prior to dosing 
b) Vital Signs and Oxygen Saturation: Clarified in the Notes that O2 saturation by pulse 
oximetry will also be performed after exertion.
c) Laboratory Tests: Added in the notes that amylase and lipase testing are to be performed 
during the extended local laboratory assessment 
d) Thyroid Function Testing: Notes corrected
e) Pregnancy test, Procedure: Corrected to “Pregnancy Test for WOCBP”, and Notes 
corrected to better describe that testing frequency is regardless of dosing schedule
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29. Section 5.1, Flow chart/Time and Events Schedule, Table 5.1-3, Follow-Up Assessments 
(CA209140):
a) Adverse Events Assessment: Notes added
b) Laboratory Tests: Clarified in the Notes that phosphorus and bicarbonate testing are 
deleted
c) Pregnancy Test, Procedure corrected to “Pregnancy Test (for WOCBP only)”
d) New Safety Procedure added: GVHD assessment
e) New efficacy assessment added: Tumor Assessment by the Investigator (CR or non-CR)
f)
EQ-5D procedure: Clarified in the Notes that EQ-5D during the survival follow-up will 
be assessed during a clinic visit or via a phone contact
30. Section 5.3, Safety Assessments:
a) 2nd paragraph: 
i)
Clarified that either hepatitis C antibody (HCV Ab) or Hepatitis C RNA (HCV RNA) 
test can be performed at screening 
ii) Clarified that pregnancy test must be performed two times prior to first dose
b) 3rd paragraph, last sentence: Clarified that subject’s status in the survival follow-up 
phase can also be contacted by emails 
c) 6th paragraph, 1st bullet: amylase and lipase added as local laboratory assessments, and 
bicarbonate deleted
d) 7th paragraph: Clarified that TSH testing is being performed regardless of dosing 
schedule
e) New paragraph added after last paragraph for documenting GVDH at different time 
points after study discontinuation for allogeneic SCT
31. Section 5.4, Efficacy Assessments: 
a) 1st and 2nd sentences corrected
b) New paragraph added
32. Section 5.4.1, Radiographic Assessments: 3rd and 4th  paragraphs corrected
33. Table 5.4.1-1, Schedule of Spiral CT/MRI Tumor Assessments: Note added to the table
34. Section 5.4.2.1, Measurable Lesions: Paragraph corrected with measurements reported in mm
35. Section 5.4.3.3, Spiral CT/MRI Scan: New paragraph added
36. Section 5.4.5, Bone Marrow Assessments: Paragraphs corrected
37. Section 5.4.6, Disease Response Evaluation:
a) Sentence corrected
b) New paragraph added after first sentence
38. Section 5.5, Pharmacokinetic Assessments: Clarified PK sampling when a dose is delayed
39. Table 5.5-1, Sampling Schedule: Footnote “a” corrected
40. Section 5.6, Biomarker Assessments, Bone Marrow Aspirates:
a) 1st paragraph corrected
b) New paragraph added after 1st paragraph
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45. Section 5.9, Results of Central Assessments: 2nd sentence deleted
46. Section 6.4, Pregnancy: new paragraph added to the end of the section to comply with the 
revised wording of the protocol model document
47. Section 8.1, Sample Size Determination: Full section corrected
48. Section 8.2, Populations for Analyses: 5th and 6th bullets corrected.
49. Section 8.3.1, Primary Endpoint: 1st paragraph, 2nd, 3rd, 4th, 5th and last sentences 
corrected
50. Section 8.3.2, Secondary Endpoint: 
a) 2nd sentence corrected
b) Added new sentence after 2nd sentence: “Subjects who start subsequent therapy without 
a prior reported progression will be censored at the last evaluable tumor assessments 
prior to initiation of the subsequent anticancer therapy.”
c) 2nd paragraph, 3rd and 4th paragraphs corrected
i)
2nd sentence corrected
ii) New sentences added after last sentence to clarify the evaluation of duration of CR
d) New paragraph added after 2nd paragraph to define PR rate.
e) 3rd paragraph, first sentence corrected
f)
4th paragraph, first sentence corrected
51. Section 8.3.3, Exploratory Endpoint: 1st sentence corrected
52. Section 8.4.2.1, Primary Endpoint Methods, 1st paragraph: Method used corrected
53. Section 8.4.2.2, Secondary Endpoint Methods: 1st and 2nd paragraphs corrected 
54. Section 8.4.2.3, Exploratory Endpoint Methods: 
55. Section 8.4.7.1, Immunogenicity Analyses: 1st sentence corrected
56. Section 8.5, Interim Analyses: Section removed as not applicable anymore
57. Section 11, List of Abbreviations: Added ACTH and GVHD to the list.
58. Section 12, References: Deleted and added references to reflect the changes in the text.
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59. Appendix 2, International Working Group Criteria for Nonhodgkin Lymphoma: Title 
corrected to “2007 International Working Group Response Criteria for Malignant 
Lymphoma”.
60. Appendix 5, Acute GVHD Grading and Staging added.
AMENDMENT RATIONALE’S REFERENCES
1 Gouill S, De Guibert S, Planche L, et al.; GELA and GOELAMS. Impact of the use of 
autologous stem cell transplantation at first relapse both in naive and previously rituximab 
exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study. 
Haematologica 2011;96(8):1128-35.
2 Laport GG. Changing role of stem cell transplantation in follicular lymphoma. Hematology Am 
Soc Hematol Educ Program 2012;2012:417-25.
3 Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression free survival 
and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized 
European CUP trial. J Clin Oncol 2003;21:3918-3927.
4 Montoto S, Canals C, Rohatiner AZ, et al.; EBMT Lymphoma Working Party. Long-term 
follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 
693 patients with follicular lymphoma: an EBMT registry study. Leukemia 2007;21(11):2324-3.
5 Montoto S, Corradini P, Dreyling M, et al. Indications for hematopoietic stem cell 
transplantation in patients with follicular lymphoma: a consensus project of the EBMT-
Lymphoma Working Party. Haematologica. 2013;98(7):1014-21.
6 Dreyling M, Ghielmini M, Marcus R, et al.; ESMO Guidelines Working Group. Newly 
diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Ann Oncol 2011 Sep;22 Suppl 6:vi59-63.
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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Page:
1
Protocol Number:
CA209140
IND Number:
119,380
EUDRACT Number
2013-003645-42
Date:
21-Jul-2016
Protocol CA209140: An Open-Label Phase 2 Study of Nivolumab (BMS-936558) or 
Nivolumab plus Rituximab in Subjects with Relapsed or Refractory Follicular Lymphoma (FL)
(CheckMate 140: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 140)
Amendment Number 04
Site Number: All
Study Director/Central Medical Monitor
24-hr Emergency Telephone Number:
Bristol-Myers Squibb Research and Development
Oncology Clinical Research and Development
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
Route 206 & Province Line Road
Lawrenceville, NJ 08543
5 Research Parkway
Wallingford, CT 06492
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS). 
This amendment must be maintained with the referenced protocol.
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Amendment Rationale:
Safety management algorithms were updated in the Investigator Brochure, requiring revision of 
the Appendix 1 algorithms. This revision applies to all subjects receiving study drug, or who 
have discontinued study drug and are being treated for suspected pulmonary toxicity, skin 
toxicity and nephrotoxicity.
Changes to the Protocol: 
1. Updated Appendix 1 Algorithm for Renal, Pulmonary and Skin to match with updated 
Nivolumab IB v15 and Erratum 01 to Nivolumab IB v15.
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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SAP_001.pdf: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT  
 
A SINGLE-ARM, OPEN-LABEL PHASE 2 STUDY OF NIVOLUMAB (BMS-936558) IN 
SUBJECTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA (FL) 
(CHECKMATE 140: CHECKPOINT PATHWAY AND NIVOLUMAB CLINICAL TRIAL 
EVALUATION 140) 
 
 
PROTOCOL CA209-140 
 
VERSION # 3.1 
 


Statistical Analysis Plan 
CA209140 
BMS-936558 
nivolumab 
 
2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT .....................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
1 
BACKGROUND AND RATIONALE .........................................................................6 
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 and Other External Committees ......................................................10 
3 
OBJECTIVES .............................................................................................................10 
3.1 
Primary objective ........................................................................................................10 
3.2 
Secondary objectives ..................................................................................................10 
3.3 
Exploratory Objectives ...............................................................................................11 
4 
ENDPOINTS ..............................................................................................................11 
4.1 
Primary endpoint ORR (IRRC-assessed) ...................................................................11 
4.2 
Secondary Endpoints ..................................................................................................12 
4.2.1 
Duration of Response (IRRC-assessed) ......................................................................12 
4.2.2 
Complete Remission Rate and Duration (IRRC-assessed) .........................................13 
4.2.3 
Partial Remission Rate and Duration (IRRC-assessed) .............................................13 
4.2.4 
Progression Free Survival (IRRC-assessed) ..............................................................13 
4.2.5 
Objective Response Rate (Investigator-assessed) ......................................................14 
4.3 
Exploratory Endpoints ................................................................................................15 
4.3.1 
Safety and Tolerability ................................................................................................15 
4.3.1.1 
Immune-Mediated Adverse Events .............................................................................15 
4.3.2 
Progression Free Survival (investigator-assessed) ....................................................15 
4.3.3 
Overall Survival ..........................................................................................................15 
4.3.4 
Other efficacy endpoints .............................................................................................15 
4.3.5 
Pharmacokinetics .......................................................................................................16 
4.3.6 
Immunogenicity ...........................................................................................................16 
4.3.7 
Outcome Research ......................................................................................................16 


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4.3.7.1 
EORTC-QLQ-C30 ......................................................................................................16 
4.3.7.2 
EuroQoL EQ-5D .........................................................................................................17 
4.3.8 
Biomarker Data ..........................................................................................................18 
4.3.8.1 
PD-L1 Expression per Dako IHC assay .....................................................................18 
4.3.8.2 
Other Biomarkers .......................................................................................................18 
5 
SAMPLE SIZE AND POWER ..................................................................................19 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES .......................................................................................................19 
6.1 
Study Periods ..............................................................................................................19 
6.1.1 
Baseline Period ...........................................................................................................19 
6.1.2 
Post Baseline Period ...................................................................................................20 
6.2 
Treatment Regimens ...................................................................................................20 
6.3 
Populations for Analyses ............................................................................................20 
6.3.1 
Analysis Populations ..................................................................................................20 
7 
STATISTICAL ANALYSES .....................................................................................21 
7.1 
General Methods .........................................................................................................21 
7.2 
Study Conduct ............................................................................................................21 
7.2.1 
Accrual ........................................................................................................................21 
7.2.2 
Relevant Protocol Deviations .....................................................................................21 
7.3 
Study Population .........................................................................................................22 
7.3.1 
Subject Disposition .....................................................................................................22 
7.3.2 
Demographics and Other Baseline Characteristics ...................................................22 
7.3.3 
Medical History ..........................................................................................................23 
7.3.4 
Prior therapy ..............................................................................................................23 
7.3.5 
Baseline Examinations ................................................................................................23 
7.4 
Extent of Exposure .....................................................................................................23 
7.4.1 
Administration of Study Therapy ................................................................................23 
7.4.2 
Modifications of Study Therapy ..................................................................................24 
7.4.2.1 
Dose delays .................................................................................................................24 
7.4.2.2 
Infusion Interruptions and Rate Changes ...................................................................24 
7.4.2.3 
Dose Reductions/Escalation .......................................................................................25 
7.4.3 
Concomitant Medications ...........................................................................................25 
7.5 
Efficacy .......................................................................................................................25 


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7.5.1 
Primary endpoint of ORR (IRRC-assessed) ...............................................................25 
7.5.1.1 
ORR Subgroups ..........................................................................................................25 
7.5.1.2 
Sensitivity analyses for ORR .......................................................................................26 
7.5.2 
Secondary Endpoint of Duration of Response (IRRC-assessed) ................................26 
7.5.3 
Secondary Enpoint of Complete Remission Rate (IRRC-assessed) ............................26 
7.5.4 
Secondary Endpoint of Partial Remission Rate and Duration (IRRC-
assessed) .....................................................................................................................27 
7.5.5 
Secondary Endpoint of Progression Free Survival (IRRC-assessed) .........................27 
7.5.6 
Secondary Endpoint of Objective Response Rate (Investigator-assessed) .................28 
7.5.7 
Exploratory Endpoints ................................................................................................28 
7.5.7.1 
Progression Free Survival (investigator-assessed) ....................................................28 
7.5.7.2 
Overall Survival ..........................................................................................................28 
7.5.7.3 
Other efficacy analysis ...............................................................................................29 
7.6 
Safety ..........................................................................................................................30 
7.6.1 
Deaths .........................................................................................................................30 
7.6.2 
Serious Adverse Events ...............................................................................................30 
7.6.3 
Adverse Events Leading to Discontinuation of Study Therapy ..................................30 
7.6.4 
Adverse Events Leading to Dose Modification ...........................................................31 
7.6.5 
Adverse Events ............................................................................................................31 
7.6.6 
Select Adverse Events .................................................................................................31 
7.6.7 
Immune modulating medication .................................................................................31 
7.6.8 
Multiple Events ...........................................................................................................31 
7.6.9 
Clinical laboratory evaluations ..................................................................................31 
7.6.10 
Vital Signs and Pulse Oximetry ..................................................................................31 
7.6.11 
Immunogenicity Analysis ............................................................................................31 
7.6.12 
Pregnancy ...................................................................................................................31 
7.6.13 
Clinical Safety Program (CSP) ..................................................................................31 
7.6.14 
Adverse Events by Subgroup ......................................................................................31 
7.6.15 
Immune-mediated Adverse Events Analysis ...............................................................31 
7.7 
Pharmacokinetics ........................................................................................................32 
7.8 
Biomarker Analyses ....................................................................................................32 
7.8.1 
PD-L1 Expression .......................................................................................................32 
7.8.1.1 
Descriptive Statistics of PD-L1 Expression and PD-L1 Status ..................................32 


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7.8.1.2 
Evaluation of Associations between PD-L1 Status and Efficacy Measures ...............32 
7.8.1.3 
Association of select AE and PD-L1 expression .........................................................33 
7.9 
Outcome Research Analyses ......................................................................................33 
7.9.1 
EORTC-QLQ-C30 Questionnaire ..............................................................................33 
7.9.2 
EQ-5D Questionnaire .................................................................................................33 
7.10 
Interim Analysis ..........................................................................................................34 
8 
CONVENTIONS ........................................................................................................34 
9 
CONTENT OF REPORTS .........................................................................................35 
10 
DOCUMENT HISTORY ...........................................................................................35 
11 
REFERENCES ...........................................................................................................36 
 
 
 
LIST OF TABLES 
Table 2.1-1: 
Schedule of Spiral CT/MRI Tumor Assessments ........................................9 
Table 2.4-1: 
Protocol Amendments ..................................................................................9 
Table 4.1-1: 
2007 IWG Response Criteria for Malignant Lymphoma ..........................12 
Table 4.2.4-1: 
Censoring scheme used in primary analysis of PFS ..................................14 
Table 4.3.7.1-1: 
Time Windows for EORTC-QLQ-C30 Assessments ................................17 
Table 5-1: 
Observed ORR with Exact 95% CI ...........................................................19 
Table 7.4.1-1: 
Administration of study therapy: definition of parameters ........................24 
Table 10-1: 
Document History ......................................................................................35 
 
 
 
LIST OF FIGURES 
Figure 2.1-1: 
Study Design Schematic ..............................................................................8 
 
 




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Research Hypothesis: 
Treatment with nivolumab will lead to clinical benefit, as demonstrated by an improved clinically 
meaningful objective response rate, including durable responses with substantial magnitude of 
tumor reduction in subjects with refractory FL who have failed therapy with both rituximab and 
an alkylating agent. 
Schedule of Analyses: 
The final analysis of the primary endpoint will occur at least 12 months after the last enrolled 
subject’s first dose of study therapy. It is anticipated that accrual will last 18 months, with 
approximately 115 subjects enrolled (90 subjects treated). It is anticipated that the analysis of the 
primary endpoint will take place approximately 30 months from FPFT. Additional survival 
analysis will be conducted for up to 5 years beyond analysis of the primary endpoint.  


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2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is a single-arm Phase 2 study in subjects ≥ 18 years old with relapsed FL after failure of at 
least two prior lines of therapy (each containing rituximab and/or an alkylating agent). 
Approximately 90 subjects will be treated with nivolumab 3mg/kg IV every 2 weeks.  
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first 
dose. Each 14-day dosing period will constitute a cycle. Radiographic study evaluations will take 
place in accordance with Table 2.1-1. A PET scan is required at baseline for all subjects, and to 
confirm a complete response (CR). Baseline assessments should be performed within 28 days prior 
to the first dose, utilizing spiral CT or MRI. An independent radiology review committee (IRRC) 
will also be utilized. The primary endpoint of this study is IRRC-assessed objective response rate 
(ORR), using revised 2007 International Working Group (IWG) Criteria for Malignant Lymphoma 
criteria. Secondary endpoints include IRRC-assessed duration of response (DOR), as well as 
complete remission rate (CRR) and PFS as determined by IRRC assessment and ORR based on 
investigator assessment.   
The study design schematic is presented in Figure 2.1-1 
 
Figure 2.1-1: 
Study Design Schematic 
 
 
 
FL who have failed 
2 prior lines of 
therapy
S
c
r
e
e
n
BMS-936558
3 mg/kg every 
2 wks until 
treatment 
discontinuation
Primary endpoint: 
ORR by IRRC
Secondary endpoints 
include:
Duration of Response , 
CR Rate and PFS based 
on IRRC assessment
ORR based on 
investigator assessment
Follow-up Phase


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Table 2.1-1: 
Schedule of Spiral CT/MRI Tumor Assessments 
Time On Study 
Assessment 
Frequency 
Assessment Week 
(day 1 of week shown) 
Assessment Window 
Dose 1 to 8 
Months 
Every 8 weeks 
9, 17, 25, 33 
± 1 week 
Month 9 to 2 
Years 
Every 12 weeks 
45, 57, 69, 81, 93 
± 2 weeks 
> 2 Years 
Every 6 months 
119, 145, 171+ 
± 3 weeks 
 
Note: Once subjects discontinue study therapy by proceeding to allogeneic SCT or ASCT, they 
will not undergo radiographic assessments as per the frequency described here, but will be 
followed using the following schedule. Tumor assessment (CR or non-CR) will be assessed by the 
investigator according to the 2007 IWG criteria and will be required on Day 100, at  
6 months, 1 year and every year thereafter from the date of stem cell infusion until the first non-
CR after SCT is documented. 
2.2 
Treatment Assignment 
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an interactive voice response system (IVRS) to 
obtain the subject number. Every subject that signs the informed consent form must be assigned a 
subject number in IVRS. Since this is a single arm study, all enrolled subjects who meet eligibility 
criteria will be treated with nivolumab at 3mg/kg IV every 2 weeks. 
2.3 
Blinding and Unblinding 
Not applicable 
2.4 
Protocol Amendments 
This SAP incorporates the following protocol amendments. 
Table 2.4-1: 
Protocol Amendments 
Amendments 
Date of Issue 
Summary of Major Changes 
Revised Protocol Number: 03 
Incorporates amendment 04 
21-JUL-2016 
Update of Annex 1 of Protocol Algorithm for safety 
Management 
Revised Protocol Number: 02 
Incorporates amendment 03 
23-JUL-2014 
Removes the interim analyses and extends the duration of 
follow-up required for all subjects prior to performing the 
final analysis of the primary endpoint. 
Modifies a few eligibility criteria to facilitate enrollment. 


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Table 2.4-1: 
Protocol Amendments 
Amendments 
Date of Issue 
Summary of Major Changes 
Allows for continued treatment of subjects in certain 
instances where protocol-defined progression criteria have 
been met. 
The amendment also serves to clarify various protocol 
requirements to ensure consistency in the execution of the 
study including secondary and exploratory objectives, 
 
 
. 
Revised Protocol Number: 01 
Incorporates amendment(s) 02 
and administrative letter 01 
06-Dec-2013 
Per FDA mandatory recommendation: 
Exclusion criteria have been added to exclude the following 
subjects 
Subjects that have received chest radiation ≤ 24 weeks prior 
to first dose of the study drug 
Additional updates were also made to the protocol including 
items such as correcting typographical and formatting errors, 
including errors in the biomarker sampling schedule in  
Table 5.6-1 
Original Protocol 
04-Oct-2013 
Not applicable 
 
2.5 
Data Monitoring and Other External Committees 
An IRRC will be utilized in this study for determination of IRRC-assessed primary (ORR) and 
secondary (DOR, CRR, PFS) endpoints. The IRRC will review all available tumor assessment 
scans for all treated subjects. Details of IRRC responsibilities and procedures will be specified in 
the IRRC charter. 
There will be no data monitoring committee for this study. 
 
3 
OBJECTIVES 
3.1 
Primary objective 
To assess the clinical benefit of nivolumab, as measured by independent radiologic review 
committee (IRRC) assessed objective response rate (ORR) in subjects with FL who have failed 
therapy with both rituximab and an alkylating agent. 
3.2 
Secondary objectives 
• To assess the duration of response (DOR) based on IRRC assessments 
• To assess the complete remission rate (CRR) and the duration of CR based on IRRC 
assessment 


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• To assess the partial remission (PR) rate and the duration of PR based on IRRC assessment 
• To assess progression free survival (PFS) based on IRRC assessment 
• To assess the objective response rate (ORR), based on investigator assessments 
3.3 
Exploratory Objectives 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
ENDPOINTS 
4.1 
Primary endpoint ORR (IRRC-assessed) 
The primary objective will be measured by the primary endpoint of IRRC-assessed ORR. It is 
defined as the number of subjects with a best overall response (BOR) of CR or PR, according to 
the 2007 IWG criteria (see Table 4.1-1), divided by the number of treated subjects. The final 
analysis of the primary endpoint will occur at least 12 months after the last enrolled subject’s first 
dose of study therapy. The BOR is defined as the best response designation recorded between the 
date of first dose and the date of initial objectively documented progression per the 2007 IWG 
criteria or the first subsequent therapy date per IRRC, whichever occurs first.  
The first subsequent therapy date per IRRC is determined by the IRRC based on non-palliative 
radiotherapy, local tumor treatment, systemic anti-cancer therapy and Stem Cell Transplant with 
a start date on or after the first study therapy date.  
For subjects without documented progression or subsequent therapy, all available response 
designations will contribute to the BOR determination. For purposes of analysis, if a subject 
receives one dose and discontinues the study without assessment or receives subsequent therapy 
prior to assessment, this subject will be counted in the denominator (as non-responder). 
The IRRC-assessed objective response will be further characterized by the time to response (TTR). 
TTR is defined as the time from first dosing date to the date of the first response (PR or CR), as 
assessed by the IRRC. 


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Table 4.1-1: 
2007 IWG Response Criteria for Malignant Lymphoma 
Response 
Definition 
Nodal masses 
Spleen, Liver 
Bone marrow 
CR 
Disappearance 
of all evidence 
of disease 
(a) FDG-avid or PET positive 
prior to therapy; residual mass of 
any size permitted if PET 
negative 
(b) Variably FDG-avid or PET 
negative; regression to normal 
size on CT 
Not palpable, 
nodules 
disappeared 
 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease in SPD of up to 
6 largest dominant masses (index 
lesions); no increase in size of 
other nodes (non-index lesions) 
(a) FDG-avid or PET positive 
prior to therapy; one or more PET 
positive at previously involved 
site 
(b) Variably FDG-avid or  
PET negative; regression  
on CT 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive 
prior to therapy; PET positive at 
prior sites of disease and no new 
sites on CT or PET 
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
N/A 
N/A 
Relapsed 
disease 
or PD 
 
Any new lesion 
or increase by  
≥ 50% of 
previously 
involved sites 
from nadir 
 
Appearance of a new lesion(s)  
> 1.5 cm in any axis, ≥ 50% 
increase in SPD of more than one 
node (index lesions), or ≥ 50% 
increase in longest diameter of a 
previously identified node > 1cm 
in short axis. 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior 
to therapy 
> 50% increase 
from nadir in 
the SPD of any 
previous lesions 
 
New or recurrent 
involvement 
 
 
Key: CR = complete remission CT = computed tomography; FDG = [18F] fluorodeoxyglucose; IWG = International 
Working Group; NA = Not applicable; PD = progressive disease; PET = positron-emission tomography;  
PR = partial remission; SD = stable disease; SPD = sum of the product of the diameters 
4.2 
Secondary Endpoints 
4.2.1 
Duration of Response (IRRC-assessed) 
Duration of response (DOR) is defined as the time from first response (CR or PR) to the date of 
initial objectively documented progression as determined using the 2007 revised International 


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Working Group Criteria for Malignant Lymphoma or death due to any cause, whichever occurs 
first. For subjects who neither progress nor die, the DOR will be censored on the date of their last 
evaluable tumor assessment. Subjects who start subsequent therapy without a prior reported 
progression will be censored at the last evaluable tumor assessments prior to or on the first 
subsequent therapy date per IRRC. This endpoint will only be evaluated in subjects with objective 
response of CR or PR. Ongoing responders are defined as responders who did not progress, did 
not die, are not off study and did not started a subsequent therapy. 
Duration of Stable Disease will also be evaluated for subjects with SD as best response. Duration 
of SD is defined as the time between the first dose date to the date of the first documented 
progression, as determined by IRRC, or death due to any cause, whichever occurs first. Subjects 
who neither progress nor die will be censored at the same time they will be censored for the DOR 
analysis. 
4.2.2 
Complete Remission Rate and Duration (IRRC-assessed) 
The complete remission rate (CRR) is defined as the number of subjects with a BOR of CR 
according to the 2007 revised International Working Group Criteria for Malignant Lymphoma, 
based on IRRC assessment, divided by the number of treated subjects. 
To further characterize CRR, the duration of CR will also be evaluated in subjects with objective 
response of CR. Duration of CR is defined as the time from first documentation of CR (the date of 
first negative FDG-PET scan or the date of first documentation of no disease involvement in the 
bone marrow (if required), whichever occurs later) to the date of initial objectively documented 
progression as determined using the 2007 IWG criteria or death due to any cause, whichever occurs 
first. Censoring will be applied as per DOR definition. 
4.2.3 
Partial Remission Rate and Duration (IRRC-assessed) 
The partial remission rate (PRR) is defined as the number of subjects with a BOR of PR according 
to the 2007 revised International Working Group Criteria for Malignant Lymphoma, based on 
IRRC assessment, divided by the number of treated subjects. 
To further characterize PRR, the duration of PR will also be evaluated in subjects with objective 
response of PR. Duration of PR is defined as the time from first documentation of PR to the date 
of initial objectively documented progression as determined using the 2007 IWG criteria or death 
due to any cause, whichever occurs first. Censoring will be applied as per DOR definition. 
4.2.4 
Progression Free Survival (IRRC-assessed) 
Progression free survival (PFS) is defined as the time from first dosing date to the date of the first 
documented progression, as determined by an IRRC according to the 2007 revised International 
Working Group Criteria for Malignant Lymphoma, or death due to any cause, whichever occurs 
first.  
• Subjects who have no baseline tumor assessment will be censored at their first dosing date. 


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• Subjects who have baseline tumor assessment and who die without a reported progression will 
be considered to have progressed on the date of their death.  
• Subjects who did not progress or die will be considered as not progressed and will be censored 
on the date of their last assessment. 
• Subjects who did not have any on study assessments and did not die will be censored on the 
first dosing date.  
• Subjects who started any subsequent anti-cancer therapy without a prior reported progression 
will be censored at the last assessment prior to or on their first subsequent therapy date. 
 
Table 4.2.4-1: 
Censoring scheme used in primary analysis of PFS 
Situation  
Date of Progression or Censoring  
Outcome  
No baseline tumor assessments 
First Dosing date 
Not 
Progressed  
No on study tumor assessments and no 
death  
First Dosing date 
Not 
Progressed 
No progression per 2007 IWG criteria and 
no new anti-cancer treatment started 
Date of last tumor assessment with no documented 
progression per the 2007 IWG criteria  
Not 
Progressed 
New anticancer treatment started without a 
prior reported progression per 2007 IWG 
criteria 
Date of last tumor assessment prior or on the date 
of initiation of the subsequent anti-cancer therapy 
Not 
Progressed  
Progression per 2007 IWG criteria 
documented between scheduled visits or at 
scheduled visit without prior new anticancer 
treatment started 
Date of the first documented tumor progression per 
the 2007 IWG criteria 
Progressed  
Death without progression per 2007 IWG 
criteria and without prior new anticancer 
treatment started 
Date of death  
Progressed  
 
To further characterize PFS, progression by response to most recent prior systemic cancer therapy 
and progression by number of prior systemic cancer therapy lines may also be evaluated. 
4.2.5 
Objective Response Rate (Investigator-assessed) 
Investigator-assessed ORR is defined similarly as described for the primary endpoint above 
(Section 4.1) and will be further characterized by TTR and DOR. 
First subsequent therapy date per Investigator is defined as the earliest start date on or after the 
first study therapy date among systemic anti-cancer therapy, stem cell transplant, non-palliative 
radiotherapy and local tumor treatment (non-palliative radiotherapy or other). 


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4.3 
Exploratory Endpoints 
 
 
 
 
 
) 
 
 
 
 
 
s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.3.7 
Outcome Research 
4.3.7.1 
EORTC-QLQ-C30 
Health-related quality of life (HRQoL) will be assessed using the European Organization for 
Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire Version 3. It is a 30-item 
instrument that has gained wide acceptance in oncology clinical studies. The EORTC QLQ-C30 
is composed of multi-item and single scales. These include five functional scales (physical, role, 
emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting, and pain) and a 
global health status/QOL scale and six single items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea and financial difficulties). All scales and single items meet the standards for reliability. 
The reliability and validity of the questionnaire is highly consistent across different language-
cultural groups30. Except for the overall health status and global quality of life items, responses 
for all items are 4 point categorical scales ranging from 1 (Not at all) to 4 (Very much). The overall 
health status/quality of life responses are 7-point Likert scales. 
Data will be scored according to the algorithm described in the EORTC QLQ-C30 scoring manual, 
as follows: 
Functional scales: 
• Physical functioning: (1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100 
• Role functioning: (1 - ((Q6+Q7)/2-1)/3) * 100 
• Emotional functioning: (1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100 
• Cognitive functioning: (1 - ((Q20+Q25)/2-1)/3) * 100 
• Social functioning: (1 - ((Q26+Q27)/2-1)/3) * 100 
Global health status: 
• Global health status/QoL: ((Q29+Q30)/2-1)/6 * 100 
Symptom scales/items: 
• Fatigue: ((Q10+Q12+Q18)/3-1)/3 * 100 
• Nausea and vomiting: ((Q14+Q15)/2-1)/3 * 100 
• Pain: ((Q9+Q19)/2-1)/3 * 100 


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• Dyspnea: ((Q8-1)/3 * 100 
• Insomnia: (Q11-1)/3 * 100 
• Appetite loss: (Q13-1)/3 * 100 
• Constipation: (Q16-1)/3 * 100 
• Diarrhea: (Q17-1)/3 * 100 
• Financial difficulties: (Q28-1)/3 * 100 
Missing values will be imputed for missing items by “assuming that the missing items have values 
equal to the average of those items which are present” for any scale in which at least half the items 
are completed. A scale in which less than half of the items are completed will be treated as missing. 
This is the method proposed in the scoring manual. A questionnaire will be considered as received 
if at least one of the 15 scales is non-missing (after imputation). 
All questionnaires completed at baseline and on-study will be assigned to a time-point according 
to the windowing criteria in Table 4.3.7.1-1 and included in the analysis. In case a subject has two 
on-study assessments within the same window, the assessment closest to the time-point will be 
used. And, in the case of two assessments at a similar distance to the time-point, the latest one will 
be chosen. In the event where the subject has no assessment at all in a specific window, the 
observation will be treated as missing for that time-point. 
Table 4.3.7.1-1: 
Time Windows for EORTC-QLQ-C30 Assessments 
Nominal Time-Point 
Time Window 
Week 1 (Baseline) 
Prior to first dose on Day 1 
Week 9  
Day 2 thru Day 85, inclusive 
Every 8 weeks up to week 25  
Nominal Day (+ 28 days / - 27 days,  inclusive) 
Week 33 
Day 198 thru Day 267, inclusive  
Every 12 weeks thereafter 
Nominal Day (+ 42 days / - 41 days,  inclusive) 
Follow-up 1 
NA 
Follow-up 2 
NA 
 
4.3.7.2 
EuroQoL EQ-5D 
Subjects’ overall health status will be assessed using the EuroQol Group’s self-reported health 
status measure (EQ-5D-3L)31. EQ-5D essentially has 2 components- the EQ-5D descriptive 
system and the EQ visual analogue scale (EQ VAS).   
The EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, 
some problems, severe problems. Once the data have been collected and a database created, a 
scoring function can be used to assign a value (i.e., EQ-5D index score) to self-reported health 
states from a set of population-based preference weights. 


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The EQ VAS records the subject’s self-rated health state on a 100-point vertical, visual analogue 
scale (0 = worst imaginable health state; 100 = best imaginable health state)32. 
4.3.8 
Biomarker Data 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
  
 
  
 
 
 
4.3.8.2 
Other Biomarkers 
 
 
 


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5 
SAMPLE SIZE AND POWER 
The planned sample size for this study will be approximately 90 treated subjects. The sample size 
was determined based on two considerations: the ability to produce a CI which would exclude an 
ORR of 20%, which is not considered clinically relevant and provide sufficient information for a 
reliable understanding of the safety profile. 
Assuming the true ORR is 35%, the study has approximately 87% power to reject the null 
hypothesis that the true ORR is ≤ 20%, considering a 2-sided alpha of 5%. In addition, Table 5-1 
summarizes the 95% exact CI for the target ORRs ranging from 30% to 44% with sample size of 
90. At observed ORR ≥ 30%, the lower bound of the 95% CI excludes 20%. 
Table 5-1: 
Observed ORR with Exact 95% CI 
True ORR 
95% Exact CI 
30% 
[20.8%-40.6%] 
34% 
[24.7%-45.2%] 
40% 
[29.8%-50.9%] 
44% 
[34.0%-55.3%] 
 
 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES 
6.1 
Study Periods 
6.1.1 
Baseline Period 
Baseline evaluations or events will be defined as evaluations or events that occur before the date 
and time of the first dose of study treatment. 
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not 
collected, the following definitions will apply: 
• Pre-treatment AEs will be defined as AEs with an onset date prior to but not including the day 
of the first dose of study treatment 
• Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as 
evaluations with a date on or prior to the day of first dose of study treatment 
If there are multiple valid assessments, the assessment that is closest to day (and time if collected) 
of the first dose of study treatment will be used as the baseline in the analyses. If multiple 


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assessments are collected at the same date (and time if collected), the assessment with the latest 
database entry date (and time if collected) will considered as baseline. 
6.1.2 
Post Baseline Period 
On-treatment AEs will be defined as AEs with an onset date-time on or after the date-time of the 
first dose of study treatment (or with an onset date on or after the day of first dose of study 
treatment if time is not collected or is missing). An AE will be counted as on-treatment if the event 
occurred within 30 days (or 100 days depending on analysis) of the last dose of study treatment. 
Refer to Core SAP29. 
On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as 
evaluations taken after the day (and time, if collected and not missing) of first dose of study 
treatment. An evaluation will be counted as on-treatment if it occurred within 30 days (or  
100 days depending on analysis) of the last dose of study treatment. Refer to Core SAP29. 
6.2 
Treatment Regimens 
All subjects will be treated with nivolumab. 
6.3 
Populations for Analyses 
6.3.1 
Analysis Populations 
The following populations will be defined. 
• All enrolled subjects: All subjects who signed an informed consent form and were registered 
into the IVRS. 
• All treated subjects: All enrolled subjects who received at least one dose of nivolumab. This 
is the primary population for efficacy and safety. 
• All response evaluable subjects: All treated subjects who have baseline and at least one on-
study evaluable tumor measurement. 
• PK subjects: All enrolled subjects with available serum time-concentration data from subjects 
dosed with nivolumab. 
• Immunogenicity evaluable subjects: all treated subjects with baseline and at least one post 
baseline immunogenicity assessment. 
• All PD-L1 tested subjects: All enrolled subjects who had a tumor tissue sample available for 
assessment of PD-L1 expression. 
• All PD-L1 evaluable subjects: All treated subjects with quantifiable baseline PD-L1 
expression 
• Biomarker subjects: All treated subjects with available biomarker data. 
• Outcomes Research subjects: all treated subjects who have an assessment at baseline  
(Visit 1 assessment prior to administration of drug) and at least 1 subsequent assessment (for 
EORTC QLQ-C30 and EQ-5D separately). 
 


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7 
STATISTICAL ANALYSES 
7.1 
General Methods 
Unless otherwise noted, the bulleted titles in the following subsections describe tabulations of 
discrete variables, by the frequency and proportion of subjects falling into each category. 
Percentages given in these tables will be rounded and, therefore, may not always sum to 100%. 
Continuous variables will be summarized using the mean, standard deviation, median, minimum 
and maximum values. 
Time to event distribution (e.g. progression free survival, overall survival, time to response, and 
duration of response) will be estimated using Kaplan Meier techniques. Median survival time 
along with 95% CI will be constructed based on a log-log transformed CI for the survivor function 
S(t)33,34. Rates at fixed time points will be derived from the Kaplan Meier estimate and 
corresponding confidence interval will be derived based on Greenwood formula35 for variance 
derivation and on log-log transformation applied on the survivor function S(t) 36. 
7.2 
Study Conduct 
7.2.1 
Accrual 
The following will be summarized on the enrolled population:  
• Number of subjects accrued by country and investigational site 
• Number of subjects accrued by month 
A by subject listing of accrual will be produced. 
7.2.2 
Relevant Protocol Deviations 
The following programmable deviations 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 ClinSIGHT listings. 
At entrance: 
• Subjects without documented relapsed or refractory FL. 
• Subjects without treatment of FL consisting of ≥ 2 prior treatment lines; each of the two prior 
treatment lines must include a CD20 and/or an alkylating agent (e.g., bendamustine, 
cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, nitrosoureas). At least one 
of the prior treatment lines must include rituximab. 
• Subject without measurable disease at baseline. 
• Subject with baseline ECOG not in (0, 1). 


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On-Study: 
• Any concurrent antineoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy, or standard or investigational agents 
for treatment of cancer). 
A by subject listing will be produced. 
7.3 
Study Population 
7.3.1 
Subject Disposition 
The total number of subjects enrolled (treated or not) will be presented along with the reason for 
not being treated. 
Number of subjects who discontinued treatment along with corresponding reason will also be 
tabulated. 
7.3.2 
Demographics and Other Baseline Characteristics 
Descriptive statistics will be summarized the following baseline characteristics for all treated 
subjects. All baseline presentations will identify subjects with missing measurements. Listings will 
also be provided. 
• Age (descriptive statistics) 
• Age categories (< 65, ≥ 65 and < 75, ≥ 75) 
• Gender, Race/Ethnicity 
• Region (US/Canada vs. Europe vs. Rest of World) 
• ECOG PS (0, 1, >1, Not Reported) 
• weight 
• Smoking Status (current/former vs never smoker vs. unknown) 
• Time from initial disease diagnosis to first dose of nivolumab (descriptive statistics and  
(< 1 year, 1 - < 2 year, 2 - < 3 year, 3 - < 5 year, 5 - < 7 year, 7 - < 10 year, ≥ 10 years)  
• Disease stage at initial diagnosis (Stage I-II-III-IV) 
• Follicular lymphoma international prognostic index (FLIPI) Score (0, 1, 2, 3, 4, 5) at initial 
diagnosis 
• Lymphoma involvement in bone marrow at baseline (Yes/No/Not Reported) 
• Disease status at study entry (Relapse, Refractory) 
• All lesions (Investigator Tumor Assessments at Baseline): sites of diseases, number of disease 
sites per subject 
• Target Lesions (Investigator Tumor Assessments at Baseline): Presence of target lesions, site 
of target lesion, sum of diameters of target lesions. 


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7.3.3 
Medical History 
General medical history will be listed by subject and pretreatment events will be tabulated. 
7.3.4 
Prior therapy 
The following will be summarized: 
• Number of subjects by type of prior therapy received: 
− Immunotherapy by Monoclonal Antibodies 
− Steroid 
− Chemotherapy – Anthracyclines 
− Chemotherapy – Other than Anthracyclines 
− Kinase Inhibitors 
− Immunomodulary Derivatives 
− Radioimmunotherapy 
− Other 
• Number of subjects per type of regimen for first line of therapy (e.g. R-CHOP vs R-CVP vs 
OTHER)  
• Number of prior systemic cancer therapy lines received (0, 1, 2, 3, 4, ≥ 5) 
• Best response to most recent prior systemic cancer therapy (CR vs. PR vs. SD vs. Relapse/PD 
vs. Unable to Determine vs. Not Applicable vs. Not Reported) (Note: Not Applicable is used 
when the agent is a conditioning regimen for stem cell transplant) 
• Time from completion of most recent prior regimen to treatment (< 3, 3 - 6, > 6 months) 
• Prior radiotherapy (yes, no) 
• Prior autologous transplant (yes, no) 
Other Prior therapy: 
• Prior/current non-study medication classified by anatomic and therapeutic classes. 
Medication will be reported using the generic name. A listing by subject will also be provided. 
7.3.5 
Baseline Examinations 
Percentage of subjects with abnormal baseline physical examination will be tabulated by 
examination criteria. 
7.4 
Extent of Exposure 
Analyses in this section will be performed in all treated subjects. 
7.4.1 
Administration of Study Therapy 
The following parameters will be summarized (descriptive statistics): 


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• Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90 
- < 110%; ≥ 110%.  
• Number of doses received (summary statistics) 
• Cumulative dose  
• 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. Median duration 
of treatment and associated 95% CI will be provided. 
• A by-subject listing of dosing of study medication (record of study medication, infusion details, 
dose change) and a listing of batch number will be also provided. 
Table 7.4.1-1: 
Administration of study therapy: definition of parameters 
 
nivolumab 
Dosing schedule per protocol 
3mg/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 are 
collected on the CRF. 
Cumulative Dose 
Cum dose (mg/kg) is sum of the doses (mg/kg) administered to a subject 
during the treatment period. 
Relative dose intensity (%) 
Cum 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 
7.4.2.1 
Dose delays 
Treatment may be delayed for up to a maximum of 6 weeks from the last dose. A dose will be 
considered as actually delayed if the delay is exceeding 3 days (i.e., greater than or equal to  
4 days from scheduled dosing date). Length of delay is defined as (duration of previous cycle in 
days - 14). Dose delays will be divided into following categories: 4 - < 8 days, 8 - < 15 days, 15 - 
< 42, ≥ 42 days. Reason for dose delay/omission will be retrieved from CRF dosing pages. 
The following parameters will be summarized. 
• Number of subjects with at least one dose delayed, number of dose delayed per subject, Length 
of Delay and Reason for Dose Delay 
7.4.2.2 
Infusion Interruptions and Rate Changes 
The following parameters will be summarized: 
• Number of subjects with at least one dose infusion interruption, number of infusion 
interruptions per subject and the reason for interruption. 


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• Number of subjects with at least one IV infusion rate reduction, number of IV infusion rate 
reduction per subject and the reason for reduction 
7.4.2.3 
Dose Reductions/Escalation 
There will be no dose escalations or reductions of nivolumab allowed.  
7.4.3 
Concomitant Medications 
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary. 
The following summary tables will be provided:  
• Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term). 
A by-subject listing will accompany the table. 
7.5 
Efficacy 
7.5.1 
Primary endpoint of ORR (IRRC-assessed) 
The IRRC-assessed ORR (using revised IWG Criteria for Malignant Lymphoma criteria) will be 
summarized on the all subjects treated population by a binomial response rate. The Clopper-
Pearson37 method will be used to estimate the two-sided 95% CI. 
BOR will be summarized by response category. 
Summary statistics of time to objective response will be provided for subjects who achieve PR or 
CR, as assessed by the IRRC. CR requires confirmation by PET. To assess tumor response kinetics, 
time to response will also be analyzed using the KM methodology for all treated subjects. Kaplan-
Meier curve will represent the cumulative rate of response over time. For the non-responders, time 
to response will be censored at the maximum time of response + 1 day of all subjects. Cumulative 
Response Rates will be tabulated for Week 9, Month 4, 6, 8, 12 and 18, and overall Response Rate 
will be provided. 
7.5.1.1 
ORR Subgroups 
To assess consistency of ORR, IRRC-assessed ORR (primary analysis) will be summarized for 
the following subgroups: 
• Age (< 65, ≥ 65 and < 75, ≥ 75) 
• Region (US/Canada, Europe, Rest of the world). 
• Gender (Male, Female) 
• Race (White, Black or African American, Asian, and Other (pooling all other possibilities) 
• Smoking status (current/former vs never smoker vs unknown) 


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• ECOG (0, 1, >1, NOT REPORTED) 
• Number of prior therapies (0, 1, 2, 3, 4, ≥ 5) 
• Prior Autologous Transplant (Yes, No) 
• Time from most recent prior systemic cancer therapy to first dose of nivolumab (< 3 months, 
3 - 6 months, > 6 months) 
• Refractory, Relapsed Lymphoma (which is the disease diagnosis status at study entry) 
• FLIPI Score (0-1, 2, 3, 4-5) 
Categories including less than 5 subjects may be collapsed. Analyses of subgroups of less than 5 
subjects may not be provided. 
7.5.1.2 
Sensitivity analyses for ORR  
• As sensitivity analysis, a summary of IRRC-assessed ORR based on response evaluable 
subjects instead of all treated subjects will also be presented. Clopper Pearson 95% CI will be 
used in this analysis. 
• To assess concordance between IRRC (primary analysis) and investigator assessments, BOR 
will be cross-tabulated by assessment type (Investigator vs IRRC). Concordance Rate of 
Responders will be computed as the frequency with which Investigator and IRRC agree on 
classification of a subject as responder/non responder as a proportion of the total number of 
subjects assessed. 
7.5.2 
Secondary Endpoint of Duration of Response (IRRC-assessed) 
The DOR will be summarized for subjects who achieve PR or CR as determined by IRRC using 
KM product-limit method. Two-sided, 95% confidence intervals for median DOR will be 
constructed based on log-log transformation. Range of duration of response and the number of 
ongoing responders will also be presented. In addition, the percentage of responders still in 
response at different time points (3, 6 and 12 months) will be presented based on the DOR KM 
plot.  
The status of subjects who are censored in the duration of response analysis will be tabulated using 
the following categories:  
• received subsequent anti-cancer therapy 
• off-study (with reason) 
Duration of stable disease will also be estimated using KM product-limit method for subjects with 
SD as best response. Two-sided, 95% confidence intervals for median duration of SD will be 
computed. 
7.5.3 
Secondary Enpoint of Complete Remission Rate (IRRC-assessed) 
IRRC-assessed CRR will be summarized by a binomial response rate and its corresponding two-
sided 95% exact CIs using the Clopper-Pearson37 method. 


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To further characterize CRR, the duration of CR will be summarized for subjects who achieve CR 
as determined by IRRC using KM product-limit method. Two-sided, 95% confidence intervals for 
median duration of CR will be constructed based on log-log transformation. Range of duration of 
CR will also be presented. 
7.5.4 
Secondary Endpoint of Partial Remission Rate and Duration (IRRC-
assessed) 
IRRC-assessed PRR will be summarized by a binomial response rate and its corresponding two-
sided 95% exact CIs using the Clopper-Pearson31 method. 
To further characterize PRR, the duration of PR will be summarized for subjects who achieve PR 
as determined by IRRC using KM product-limit method. Two-sided, 95% confidence intervals for 
median duration of PR will be constructed based on log-log transformation. Range of duration of 
PR will also be presented. 
7.5.5 
Secondary Endpoint of Progression Free Survival (IRRC-assessed) 
IRRC-assessed PFS will be summarized descriptively using the Kaplan-Meier (KM) product-limit 
method. Median values of PFS, along with two-sided 95% CIs (based on the log-log 
transformation), will also be calculated. 
The source of progression (death vs. progression) will be summarized. 
The status of subjects who are censored in the PFS Kaplan-Meier analysis will be tabulated using 
following categories: 
• Received subsequent anti-cancer therapy (Stem Cell Transplant, other) 
• Still on-treatment 
• Progression-free in follow-up 
• Off-study: (lost to follow-up, withdrew consent, other). 
KM curve of PFS will be generated. PFS rates per IRRC at 6, 9 and 12 months will be estimated 
using KM estimates on the PFS curve. PFS rates at 18, 24 and 36 months may also be estimated 
depending on whether minimum follow-up will be longer than timepoint to generate the rate. 
Associated two-sided 95% CIs will be calculated. 
KM curves of PFS by response of most recent prior systemic cancer therapy as well as KM curves 
of PFS by number of prior systemic anti-cancer therapy lines will also be generated. Some 
categories may be collapsed to have sufficient number of subjects in each category. Median values 
of PFS in each category along with two-sided 95% CIs (based on the log-long transformation) will 
also be calculated. 


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7.5.6 
Secondary Endpoint of Objective Response Rate (Investigator-
assessed) 
Investigator-assessed ORR will be summarized by a binomial response rate and its corresponding 
two-sided 95% exact CIs using the Clopper-Pearson37 method. 
Investigator-assessed BOR will be summarized by response category. 
Summary statistics of time to objective response will be provided for subjects who achieve PR or 
CR, as assessed by the Investigator. CR requires confirmation by PET. To assess tumor response 
kinetics, time to response will also be analyzed using the KM methodology for all treated subjects. 
Kaplan-Meier curve will represent the cumulative rate of response over time. For the non-
responders, time to response will be censored at the maximum time of response + 1 day of all 
subjects. Cumulative Response Rates will be tabulated for Week 9, Month 4, 6, 8, 12 and 18, and 
overall Response Rate will be provided. 
7.5.7 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.6 
Safety 
All analyses from the Core Safety SAP29 will be produced. 
7.6.1 
Deaths 
See Core Safety SAP29. 
7.6.2 
Serious Adverse Events 
See Core Safety SAP29. 
7.6.3 
Adverse Events Leading to Discontinuation of Study Therapy 
See Core Safety SAP29. 


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7.6.4 
Adverse Events Leading to Dose Modification 
See Core Safety SAP29. 
7.6.5 
Adverse Events 
See Core Safety SAP29. 
7.6.6 
Select Adverse Events  
See Core Safety SAP29. 
7.6.7 
Immune modulating medication  
See Core Safety SAP29. 
7.6.8 
Multiple Events 
See Core Safety SAP29. 
7.6.9 
Clinical laboratory evaluations 
See Core Safety SAP29. 
7.6.10 
Vital Signs and Pulse Oximetry 
See Core Safety SAP29. 
7.6.11 
Immunogenicity Analysis 
See Core Safety SAP29. 
7.6.12 
Pregnancy 
By-subject listing of pregnancy tests results will be provided  
7.6.13 
Clinical Safety Program (CSP) 
See Core Safety SAP29. 
7.6.14 
Adverse Events by Subgroup 
See Core Safety SAP29. 
7.6.15 
Immune-mediated Adverse Events Analysis 
See Core Safety SAP29. 


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7.7 
Pharmacokinetics 
The nivolumab concentration data obtained in this study may be combined with data from other 
studies in the clinical development program to develop or refine a population PK model. This 
model may be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of 
nivolumab and to determine measures of individual exposure (such as steady-state peak, trough, 
and time-averaged concentration). In addition, model determined exposures may be used for 
exposure-response analyses. Results of population PK and exposure response-analyses will be 
reported separately. 
7.8 
Biomarker Analyses 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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7.9 
Outcome Research Analyses 
7.9.1 
EORTC-QLQ-C30 Questionnaire 
Unless otherwise specified, the analysis of EORTC QLQ C-30 will be performed in all treated 
subjects who have an assessment at baseline and at least one subsequent assessment. Analyses will 
be performed. 
Baseline measures will be summarized using descriptive statistics (N, mean, standard deviation, 
median, first and third quartiles, minimum, maximum) for each QLQ-C30 item, as well as global 
and functional scales, based on subjects with a baseline measurement. 
Change from baseline will be summarized using descriptive statistics (N, mean, standard deviation, 
median, first and third quartiles, minimum, maximum) for each QLQ-C30 item, as well as global 
and functional scales at each assessment time point. In addition, the percentage of subjects 
demonstrating a clinically meaningful deterioration (defined as a 10 point change from baseline) 
will be presented for each scale at each assessment timepoint. Percentages will be based on number 
subjects assessed at baseline and at assessment time point. 
EORTC-QLQ-C30 questionnaire completion rate, defined as the proportion of questionnaires 
actually received out of the expected number (i.e., number of subjects on treatment or in follow 
up), will be calculated and summarized for each assessment time point. 
A by subject listing of QLQ-C30 with each QLQ-C30 item, functional scales and global health 
status will be provided. 
7.9.2 
EQ-5D Questionnaire 
Unless otherwise specified, the analysis of EQ-5D will be performed in all treated subjects who 
have an assessment at baseline and at least one subsequent assessment. Analyses will be 
performed. 


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Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
will be summarized using descriptive statistics (N, mean, SD, median, 25th and 75th percentiles, 
minimum, maximum). 
Proportion of subjects reporting problems for the 5 EQ-5D dimensions at each assessment time 
point will be summarized by level of problem. Percentages will be based on number subjects 
assessed at assessment time point. 
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions (mobility, self-
care, usual activities, pain/discomfort and anxiety/depression), health state (5 dimensions digits 
combined in a 5-digit number) and EQ-VAS will be provided.  
Results of EQ5D-Index will be presented separately and will be described in the GHEOR SAP. 
7.10 
Interim Analysis 
No interim analysis planned. Interim analyses may be conducted if it is necessary in order to make 
decisions regarding further development. Summaries and listings of efficacy and safety will be 
provided. Interim analyses will not impact the study duration and the trial will continue as planned. 
 
8 
CONVENTIONS 
The following conventions may be used for imputing partial dates for analyses requiring dates: 
For missing and partial adverse event onset dates, imputation will be performed using the Adverse 
Event Domain Requirements Specification38. Missing and partial Non-Study Medication Domain 
dates will be imputed using the derivation algorithm described in BMS Non-Study Medication 
Domain Requirements Specification39. 
For death dates, the following conventions will be used for imputing partial dates: 
• If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known alive date and the maximum will be 
considered as the death date. 
• If the month or the year is missing, the death date will be imputed as the last known alive date  
• If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known alive date 
For date of progression, the following conventions will be used for imputing partial dates: 
• If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. 
• If the day and month are missing or a date is completely missing, it will be considered as 
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• In case, the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression. 
For other partial/missing dates, the following conventions will be used: 
• If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day. 
• If both the day and the month are missing, “July 1” will be used to replace the missing 
information. 
• If a date is completely missing, it will be considered as missing. 
The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days. 
Duration (e.g. time from first diagnosis to first dosing date, duration response, and time to 
response) will be calculated as follows: 
Duration = (Last date - first date + 1) 
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted. 
 
9 
CONTENT OF REPORTS 
All analyses described in the SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables, figures and listings 
 
10 
DOCUMENT HISTORY 
Table 10-1: 
Document History 
Version Number 
Author(s) 
Description 
1.0 
Cécile Dorange 
Initial version 13-May-2014 
2.0 
Anne Sumbul 
Updated on 25-Sep-2015 
3.0 
Anne Sumbul 
Updated on 24-Apr-2017 
• 
Reference to Protocol v3 (21JUL16) 
• 
Clarify PFS censoring scheme 
• 
Addition of definition of ongoing 
responder 
• 
Add PFS and OS rate at 9 and 36 
months 
• 
Add Time to Next Treatment 
• 
Add PFS by response to most recent 
prior systemic cancer therapy 


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Table 10-1: 
Document History 
• 
Add PFS by number of prior systemic 
cancer therapy line 
• 
 
 
 
 
 
• 
Clarify management of raw PD-L1 
result = “<1%” 
• 
Analysis of IMAE is now referring to 
nivo core safety SAP 
• 
Clarify notion of subsequent therapy 
3.1 
Anne Sumbul 
Updated on 27-Jun-2017 
• 
Removed “not reported” for prior 
transplant and prior radiotherapy 
• 
Add “Not Applicable” to the codelist 
of best response to prior systemic 
cancer therapy 
• 
Add R-CVP as category for first line 
therapy 
• 
 
 
 
 
• 
 
 
 
 
 
11 
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SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2010/, based on November 2012 SEER data submission, 
posted to the SEER web site, 2013. 
2  Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: 
Clinical features of the major histologic subtypes: Non-Hodgkin's Lymphoma Classification 
Project. J Clin Oncol 1998;16:2780-2795. 
3  Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's 
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4  Horning SJ. Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin 
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5  Villa D, Crump M, Panzarella T, et al. Autologous and allogeneic stem-cell transplantation for 
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6  Ardeshna KM, Smith P, Norton A. Long-term effect of a watch and wait policy versus 
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7  Al-Tourah AJ, Gill KK, Chhanabhai M, et al. Population-based analysis of incidence and 
outcome of transformed non-Hodgkin's lymphoma. J Clin Oncol 2008;26:5165-5169. 
8  Montoto S, Davies AJ, Matthews J, et al. Risk and clinical implications of transformation of 
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