Conditions: Lymphoma. Non-Hodgkin
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 121
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether Nivolumab is effective in the treatment of DLBCL in patients that have failed or are ineligible for ASCT

Detailed description:

Arms:
arm 1: Nivolumab 3 mg/kg solution intravenously every 2 weeks until progression or unacceptable toxicity

Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
CA209139
IND Number:
119380
Ex-US
Non-IND
EUDRACT Number
2013-003621-28
Date:
30-Oct-2013
Revised Date:
21-Jul-2016
Clinical Protocol CA209139
A Single-Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in Subjects with 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) After Failure of Autologous 
Stem Cell Transplant (ASCT) or After Failure of At Least Two Prior Multi-Agent Chemotherapy 
Regimens in Subjects Who Are Not Candidates for ASCT
(CheckMate 139: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 139)
Revised Protocol No.:03
Incorporates Amendment(s):05
Medical Monitor/Study Director
Kazunobu Kato, MD, PhD
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 
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Revised Protocol No.: 03
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Date: 21-Jul-2016
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions
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Date: 21-Jul-2016
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
03
21-Jul-2016
Incorporates Amendment 05
Amendment 05
21-Jul-2016
 
 
 
.
Revised Protocol 
02
23-Jul-2014
Incorporates Amendment 03
Amendment 03
23-Jul-2014
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 
 
 
 
Revised Protocol
01
06-Dec-2013
Incorporates Amendment 01
Amendment 01
06-Dec-2013
Based on FDA feedback; the number of failed prior multi-agent 
chemotherapy regimens required for subjects that are ineligible for 
ASCT was changed from 1 to 2. Criteria were added to exclude 
subjects that had received chest radiation ≤ 24 weeks from first dose of 
study drug, and those that had received 1000 mg of carmustine 
(BCNU) as part of their pre-transplant conditioning regimen. Other 
minor corrections/clarifications were also made.
Original Protocol
30-Oct-2013
Not applicable
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SYNOPSIS
Clinical Protocol CA209139
Protocol Title:  A Single-Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in Subjects with 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) After Failure of Autologous Stem Cell 
Transplant (ASCT) or After Failure of At Least Two Prior Multi-Agent Chemotherapy Regimens in Subjects Who 
Are Not Candidates for ASCT
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. Treatment beyond progression is allowed as specified in protocol section 4.3.8.
Study Phase:  2b
 
 
.
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 DLBCL who are refractory or have relapsed following 
ASCT or after failure of at least two prior multi-agent chemotherapy regimens in ASCT ineligible patients.
Secondary Objectives(s)

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
Study Design:  This is a single-arm Phase 2 study in subjects 18 years old with relapsed or refractory DLBCL or 
transformed lymphoma (TL) after failure of ASCT or after failure of at least two prior multi-agent chemotherapy 
regimens in subjects who are not ASCT candidates. Approximately 120 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 the 2007 revised International 
Working Group Criteria for Malignant Lymphoma criteria. 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 
Revised Protocol No.: 03
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obtaining informed consent) for determination of PD-L1 expression status is mandatory. Archival tissue should be 
submitted for all subjects if available.
Treatment Groups 
ASCT failure 
(n= 90)
or 
ASCT ineligible 
who have failed >2
prior therapies 
(n=30)
S
c
r
e
e
n
Nivolumab
(BMS-936558)
3 mg/kg every 2 
wksuntil 
treatment 
discontinuation
1°endpoint: ORR by IRRC
Evaluate first 37 
ASCT failure 
subjects treated 
for response*
Continue recruitment 
and treatment in both 
groups.
Nivolumab every 2 wks 
until treatment 
discontinuation
Recruitment and 
treatment 
stopped in both 
groups
Upon treatment 
discontinuation 
all subjects enter 
follow-up phase
* Recruitment and treatment of subjects in both groups (ASCT failure and ASCT ineligible) will continue as described during the evaluation of the first 37 ASCT 
failure subjects treated. 
It is anticipated that accrual will last 24 months, with approximately 150 subjects enrolled
Study Population: Subjects must meet all eligibility criteria specified in Sections 3.3.1and 3.3.2 of the protocol, 
including the following:
Key Inclusion Criteria (see Protocol Section 3.3.1 for full list of criteria):
Inclusion Criteria:
1.
Men and women 18 years of age.
2.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
3.
Biopsy confirmation of relapsed, refractory DLBCL, or transformed lymphoma (TL) prior to the initiation 
of study drug. DLBCL or TL should be pathologically confirmed by standard immunohistochemical or 
flow cytometric techniques. Subjects with grade 3b follicular lymphoma are excluded.
4.
Measurable disease on cross-sectional imaging that is 1.5 cm in the longest diameter and measureable in 
two perpendicular dimensions per computed tomography (spiral CT) or MRI
5.
Prior treatment as defined below:
a.
Subjects with relapsed or refractory DLBCL or TL after high-dose conditioning chemotherapy and 
ASCT, or
b.
Subjects with relapsed or refractory DLBCL or TL after at least 2 prior multi-agent chemotherapy 
regimens if ASCT ineligible. Ineligibility for ASCT will be determined using local institutional 
criteria.
Exclusion Criteria:
1)
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 the study drug
2)
Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
3)
ASCT 12 weeks prior to first dose of the study drug.
4)
Prior allogeneic SCT
5)
Known central nervous system lymphoma
6)
History of interstitial lung disease
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7)
Chest radiation 24 weeks prior to the first dose of study drug
8)
Carmustine (BCNU) 1000 mg received as part of pre-transplant conditioning regimen
Study Assessments: The primary endpoint is objective response rate (ORR), as determined by an independent 
radiologic review committee (IRRC) according to the 2007 revised International Working Group Criteria for 
Malignant Lymphoma. 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 120 treated subjects, placed into two 
groups of subjects based on prior ASCT failure [n = 90] or ASCT ineligibility [n = 30].
For the ASCT-failed cohort, a modified Simon's two-stage design will be used to test the null hypothesis that the 
true ORR is 20% (not considered clinically compelling). In the first stage, 37 subjects will be accrued. If there are 
8 or fewer responses in these 37 subjects, the study will be stopped. Otherwise, approximately 53 additional patients 
will be accrued to target a total of 90 treated subjects. The null hypothesis will be rejected if 25 or more responses 
are observed in 90 treated subjects. This design yields a one-sided type I error rate of 5% and power of 90% when 
the true response rate is 35%. 
For the ASCT ineligible cohort, the sample size of 30 treated subjects is determined to achieve a confidence interval 
(CI) width around the ORR estimate with a sufficient level of precision. If the observed number of subjects with 
ORR is 10 (33%), the width of the exact 2-sided 95% CI is 36% with a lower bound of 17.3%. 
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 for each cohort by binomial response rates and their corresponding 
two-sided 90% and 95% exact CIs. The method proposed by Atkinson and Brown will be used to estimate the CI for 
the ASCT failed cohort. This confidence interval takes into account the group sequential nature of the two-stage 
design. The Clopper-Pearson method will be used to estimate the CI for the ASCT ineligible cohort. 
The IRRC-assessed DOR will be summarized by cohort 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 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 
by cohort 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 AND STUDY RATIONALE ..................................................... 
 
 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
 
 
 
 
3.5 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 ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
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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 ................................................................................. 
 
4.3.3 Dose Modifications .................................................................................. 
4.3.4 Criteria to Resume Nivolumab Dosing .................................................... 
4.3.5 Treatment Discontinuation Criteria ........................................................ 
4.3.6 Treatment of BMS-936558-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 ...................................................................... 
5.4.6 Disease Response Evaluation .................................................................. 
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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
................................................................................................................................. 
7.1 Independent Radiology Review Committee (IRRC) ........................................ 
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) ............................................................................. 
 
8.4 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 ......................................................... 
 
8.4.3 Safety 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 .................................................................................. 
 
APPENDIX 2 2007 REVISED INTERNATIONAL WORKING GROUP CRITERIA 
FOR MALIGNANT LYMPHOMA ....................................................................... 
APPENDIX 3 REVISED INTERNATIONAL PROGNOSTIC INDEX (IPI) SCALE
................................................................................................................................. 
APPENDIX 4 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 5 ACUTE GVHD GRADING AND STAGING ..................................... 
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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 DLBCL or TL who 
are refractory or have relapsed following ASCT or after failure of at least two prior multi-agent 
chemotherapy regimens in ASCT ineligible patients.
1.3.2
Secondary Objectives

To assess the duration of response (DOR) based on IRRC assessments
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
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 progression free survival (PFS) based on IRRC assessment

To assess the ORR, based on investigator assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1. Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2. Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
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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.
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 or refractory DLBCL, 
or transformed lymphoma (TL), after failure of ASCT or after failure of at least two prior 
multi-agent chemotherapy regimens in subjects who are not ASCT candidates. Approximately 
120 subjects will be treated with nivolumab 3 mg/kg IV every 2 weeks. Subjects will be placed 
into treatment groups based on prior ASCT failure [n = 90] or ASCT ineligibility [n = 30]. 
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nivolumab
For the ASCT-failed cohort, a two-stage design will be used to test whether nivolumab yields a 
clinically compelling objective response rate. In the first stage, responses will be evaluated by 
the IRRC on the first 37 subjects treated. If there are 8 or fewer responses in these 37 subjects, 
the study will be stopped. In this case, the study will be terminated in both the ASCT-failed 
cohort as well as the ASCT ineligible cohort. Otherwise, approximately 53 additional subjects 
will be accrued into the ASCT-failed cohort to target a total of 90 treated subjects. The 
tolerability of the regimen will continue to be evaluated by the sponsor with the investigators to 
ensure that it is acceptable for continued enrollment. For the ASCT ineligible cohort a 
single-stage design will be used to estimate the objective response rate using approximately 
30 treated subjects.
NOTE: During the evaluation of response in the first 37 ASCT-failed subjects treated, 
recruitment and treatment of subjects will continue for both the ASCT-failed and ASCT 
ineligible cohorts.
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 will continue every 8 weeks through the first 8 months of treatment, 
every 12 weeks from months 9 to year 2, and then every 6 months until disease progression
(Table 5.4.1-1). An independent radiology review committee (IRRC) will also be utilized. The 
primary endpoint of this study is IRRC-assessed objective response rate (ORR), using the 2007
revised International Working Group Criteria for Malignant Lymphoma criteria (Appendix 2).
Secondary endpoints include IRRC-assessed duration of objective response (DOR), as well as 
complete remission rate (CRR), duration of CR, PR rate, duration of PR, and progression free 
survival (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
Treatment Groups 
ASCT failure 
(n= 90)
or 
ASCT ineligible 
who have failed >2
prior therapies 
(n=30)
S
c
r
e
e
n
Nivolumab
(BMS-936558)
3 mg/kg every 2 
wksuntil 
treatment 
discontinuation
1°endpoint: ORR by IRRC
Evaluate first 37 
ASCT failure 
subjects treated 
for response*
Continue recruitment 
and treatment in both 
groups.
Nivolumab every 2 wks 
until treatment 
discontinuation
Recruitment and 
treatment 
stopped in both 
groups
Upon treatment 
discontinuation 
all subjects enter 
follow-up phase
* Recruitment and treatment of subjects in both groups (ASCT failure and ASCT ineligible) will continue as described during the evaluation of the first 37 ASCT 
failure subjects treated. 
Study Duration
It is anticipated that accrual will last 18 months, with approximately 150 subjects enrolled. It is 
anticipated that the analysis of the primary endpoint will take place approximately 24 months 
from FPFV.
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Additional survival analysis will be conducted for up to 5 years beyond analysis of the primary 
endpoint.
This study will consist of three phases: screening, treatment, and follow-up.
Screening (see Table 5.1-1)

Begins by establishing the 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 DLBCL, or TL 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 study drug therapy prior to the determination of PD-L1 expression 
status.
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 may begin study drug treatment before bone marrow biopsy results become 
available; results need to be documented in the subject’s medical record later

The Revised International Prognostic Index (IPI) 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
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
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.
Treatment: (see Table 5.1-2)

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.

On-study laboratory assessments should be drawn within 72 hours prior to dosing.

Adverse event assessments should be documented at each clinic visit.

 

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 Sections 4.3.2 and 4.3.4.

Subjects will be evaluated for tumor response according to the 2007 revised International 
Working Group Criteria for Malignant Lymphoma (Appendix 2) 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. 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.

This phase ends when the subject is discontinued from study therapy. For a complete list of
reasons for treatment discontinuation, see Section 3.5 and 4.3.5.
Follow-Up Phase (See Table 5.1-3):

Begins when the decision to discontinue a subject from study therapy is made (no further
treatment with study therapy).
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
Subjects will have two follow-up visits for safety. Follow-up visit 1 (X01), 35 days from the 
last dose (+/- 7d) and follow-up visit 2 (X02) 80 days (+/- 7d) later. After X02, subjects will 
be followed every 3 months for ongoing drug-related adverse events until resolved, return to 
baseline or deemed irreversible, or until lost to follow-up, or withdrawal of study consent.


Subjects who discontinue study therapy for reasons other than disease progression or to 
receive an allogeneic or autologous stem cell transplant, 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 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 5.1-3
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit and 
tolerating study drug 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 DLBCL, or transformed lymphoma 
(TL), prior to the initiation of study drug.
i)
TL is limited to DLBCL. Subjects with Grade 3b follicular lymphoma are excluded. 
ii) DLBCL or TL 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 of 0-1 (Appendix 4).
c) Measurable disease: Subjects must have at least one lesion that is 15mm (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) Prior treatment as defined below;
i)
Subjects with relapsed DLBCL or TL after high-dose conditioning chemotherapy and 
ASCT, or
ii) Subjects with relapsed or refractory DLBCL or TL after at least 2 prior multi-agent 
chemotherapy regimens if ASCT ineligible. Ineligibility for ASCT will be determined 
using local institutional criteria.
For subjects with TL, chemotherapy regimens used for the treatment of follicular 
lymphoma can be considered as prior therapy provided these regimens utilized 
multi-agents in combination (excluding rituximab-based regimens without any 
cytotoxic drug )
Definition of Relapsed DLBCL

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 DLBCL

< 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 randomized / 
has not been treated). If re-enrolled, the subject must be re-consented.
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3. Physical and Laboratory Test Finding
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)
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’s 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 nivolumab plus 5 half-lives of nivolumab 
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 nivolumab plus 5 half-lives 
of nivolumab 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 
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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:
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.
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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.
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 3-4 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) Autologous Stem Cell Transplant (ASCT) 12 weeks prior to first dose of the study 
drug.
b) 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 the study drug.
c) 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
d) Prior allogeneic SCT.
e) Chest radiation 24 weeks prior to the first dose of study drug
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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
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.
 
 
 
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3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

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-specified 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 case report form (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 
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attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
TREATMENTS
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication, and 

Other drugs administered as part of the study that are critical to claims of efficacy 
(eg, 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
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 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. Specific instructions for using IVRS will be provided to the 
investigational site in a separate document.
The investigator (or designee) will register the subject for enrollment by following the 
enrollment procedures established by BMS. The following information is required for 
enrollment:

Date that informed consent was obtained

Date of birth

Gender at birth
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. 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.
4.3.1
Antiemetic Premedications
Antiemetic premedications should not be routinely administered prior to dosing of study drug.
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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:
o
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:
o
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.
 
 
 
 
 
 
 
 
 
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4.3.3
Dose Modifications
Dose reductions and escalations of nivolumab are not permitted.
4.3.4
Criteria to Resume Nivolumab Dosing
Subjects may resume treatment with nivolumab (BMS-936558) when the drug-related AE(s) 
resolve(s) to Grade 1 or baseline, 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, colitis or nephritis 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 time point per protocol.
If treatment is delayed > 6 weeks from the previous dose, 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 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
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:
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Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation
o
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 > 5x ULN

Concurrent AST or ALT > 3x ULN and total bilirubin > 2x 
ULN

Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation:
o
Grade 4 neutropenia 7 days
o
Grade 4 lymphopenia or leukopenia
o
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
o
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
o
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:
o
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 from the previous dose, the BMS medical 
monitor must be consulted. Tumor assessments should continue as per protocol 
even if dosing is interrupted
o
Dosing interruptions > 6 weeks from the previous dose, 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 from the previous dose, 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 
(BMS-936558) dosing.
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
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 BMS-936558-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthalgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated).

Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds 
promptly 
to 
symptomatic 
treatment 
[eg, 
antihistamines, 
non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours).
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or 
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 additional 
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nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: Life-threatening; pressor or ventilatory support 
indicated).

Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the Investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms. In 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 eCRF.
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4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Assessments (CA209139)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening, with confirmation of 
eligibility documented 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
Revised International Prognostic Index (IPI) at 
time of initial disease diagnosis
X
Refer to Appendix 3
Vital Signs and oxygen saturation
X
Temperature, BP, HR, O2 saturation by pulse oximetry (at rest and after exertion). 
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
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.
Urinalysis
X
Total protein, glucose, blood, leukocyte esterase, specific gravity, and pH, within 
14 days prior to first dose
Pregnancy Test 
X
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Table 5.1-1:
Screening Assessments (CA209139)
Procedure
Screening
Visit
Notes
Efficacy
 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 by 
spiral CT/MRI at the screening visit and at subsequent on-study assessments.
PET scan required at screening.
 
 
 
 
 
 
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).
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Table 5.1-2:
On Treatment Assessments (CA209139)
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, RR, 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
Adverse Events Assessment
X
X
X
Assessed using NCI CTCAE v. 4.0
X
X
X
Physical Measurements
X
X
X
Includes Weight and ECOG status
Laboratory Tests
X
X
X
extended on-treatment local laboratory assessments 
should be done within 72 hours prior to dosing for
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, 
phosphate, chloride, amylase, lipase, glucose, AST, 
ALT, total bilirubin, alkaline phosphatase, LDH.
limited on-treatment local laboratory assessments
should be done within 72 hours prior to dosing 
(beginning at Cycle 6 and every alternate dose 
thereafter (Cycle 8, 10, 12, 14 etc) and include: CBC 
with differential, LFTs (ALT, AST, total bilirubin, 
alkaline phosphatase) and creatinine.
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Table 5.1-2:
On Treatment Assessments (CA209139)
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Each cycle 
within 3 days 
prior to dosing
Notes
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.
Pregnancy Test
(WOCBP only)
X
See Note
Serum or urine 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
 
 
 
 
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Table 5.1-2:
On Treatment Assessments (CA209139)
Procedure
Cycle 1
Day 1
Cycle 1
Day 8
Each cycle 
within 3 days 
prior to dosing
Notes
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 (CA209139)
Procedure
Follow Up, Visits 1 
and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
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
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, TSH (reflex to 
free T3, free T4 for abnormal TSH 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
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Table 5.1-3:
Follow-up Assessments (CA209139)
Procedure
Follow Up, Visits 1 
and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
Notes
Efficacy Assessments
Spiral CT/MRI
PET scan
X
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 or MRI 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.
Investigator tumor assessment for subjects receiving 
subsequent allogeneic SCT or ASCT
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
 
 
 
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Table 5.1-3:
Follow-up Assessments (CA209139)
Procedure
Follow Up, Visits 1 
and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
Notes
 
Subject Status
Survival Status
X
X
Every 3 months after X02; may be accomplished by 
visit, phone contact or email, to update survival 
information and assess subsequent anti-cancer therapy
a Follow-up visit 1 (X01) = 35 days from the last dose +/- 7 days. Follow-up visit 2 (X02) = 80 days (+/- 7 days) from follow-up visit X01.
b Survival Follow-up visits to occur every 3 months from X02
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5.2
Study Materials
The following materials will be provided at study start:

NCI CTCAE version 4.0

BMS-936558 (nivolumab) Investigational Brochure

Pharmacy Binder

Laboratory manuals for collection and handling of blood (including PKs, biomarker and 
immunogenicity) and tissue specimens

Site manual for operation of interactive voice response system (IVRS)

Manual for entry of local laboratory data

Serious Adverse Event (or eSAE) case report forms

EQ-5D and EORTC QLQ-C30 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 should be 
performed within 28 days prior to first dose. 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 the first dose through the study treatment period (see Table 5.1-1).
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, amylase, lipase 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 visits or documented telephone calls/email 
correspondence to assess the subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
On-study weight, ECOG performance status, and vital signs should be assessed at each on-study 
visit prior to nivolumab dosing and ay 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 should be assessed at each on-study visit prior to nivolumab 
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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 treatment local laboratory assessments should be done within 72 hours prior to dosing;

Extended on-treatment local laboratory assessments: Cycle 1 (including day 1 and day 8) 
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, phosphate, chloride, amylase, lipase, glucose, AST, ALT, total bilirubin, 
alkaline phosphatase, LDH.

Limited on-treatment laboratory assessments: beginning at Cycle 6 (week 11) 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 testing to free T3, free T4 for abnormal TSH result) 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 Appendix 1 and 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.
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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.
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 CA209139 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 objective response rate (ORR), defined as a subject achieving 
either a partial remission (PR) or complete remission (CR) according to the 2007 revised 
International Working Group Criteria for Malignant Lymphoma (Appendix 2) The primary 
efficacy assessment, along with the secondary endpoints of DOR, CRR, CR duration, PRR, PRR 
duration, and PFS will be performed by an independent radiologic review committee (IRRC). 
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 Table 5.4.1-1. 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, 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. 
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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 the 2007 revised International Working Group Criteria for Malignant Lymphoma criteria. 
(Appendix 2)
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 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 spiral 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 criteria48. 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.
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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.
5.4.3
Specifications by Method of Assessment
5.4.3.1
Measurement of Lesions
All measurements should be recorded in the eCRF in metric notation (mm). All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
28 days before the beginning of treatment.
5.4.3.2
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 exam.
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 spiral CT/MRI slice thickness is 5 mm or less. When spiral CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
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 1 cm 
diameter as assessed using calipers. As previously noted, when lesions can be evaluated both by 
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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.
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’).
 
 
 
 
 
5.4.6
Disease Response Evaluation
The determination of disease response to study treatment will be made using 2007 revised 
International Working Group Response Criteria for Malignant Lymphoma (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 
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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).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered 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.) 
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 
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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 SAEs (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
7.1
Independent Radiology Review Committee (IRRC)
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 120 treated subjects, separated into 
two treatment groups based on prior ASCT failure [n=90] or ASCT ineligibility [n=30].
For the ASCT-failed cohort, a modified Simon's two-stage design will be used to test the null 
hypothesis that the true ORR is 20% (not considered clinically compelling). In the first stage, 
37 subjects will be accrued. If there are 8 or fewer responses in these 37 subjects, the study will 
be stopped. In this case, the study will be terminated in both the ASCT-failed cohort as well as 
the ASCT ineligible cohort. Otherwise, approximately 53 additional subjects will be accrued into 
the ASCT-failed cohort to target a total of 90 treated subjects. The null hypothesis will be 
rejected if 25 or more responses are observed in 90 treated subjects. This design yields a 
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one-sided type I error rate of 5% and power of 90% when the true response rate is 35%. The 
interim stopping rule for this design is identical to Simon’s ‘optimal’ 2-stage design50. However, 
the sample size at the final analysis is larger than required by Simon’s optimal design in order to 
provide additional subjects for safety evaluation. Table 8.1-1 provides the probabilities of 
stopping at different ORR using this rule.
Table 8.1-1:
Operating Characteristics of Stopping Rule
True ORR
P(early stop)
15%
0.91
20%
0.69
25%
0.40
30%
0.18
35%
0.06
40%
0.01
For the ASCT ineligible cohort, the sample size of 30 treated subjects is determined to achieve a 
confidence interval (CI) width around the ORR estimate with a sufficient level of precision. If 
the observed number of subjects with ORR is 10 (33%), the width of the exact 2-sided 95% CI is 
36% with a lower bound of 17.3%. Such an observation would provide evidence in support that 
the true ORR is greater than or equal to 17.3% with a Type I error rate of 5%.
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.
 
 
 
 
 
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8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective will be measured by the primary endpoint of IRRC-assessed objective 
response rate (ORR). It is defined as the number of subjects with a best overall response (BOR) 
of complete remission (CR) or partial remission (PR), according to the 2007 revised International 
Working Group Criteria for Malignant Lymphoma, divided by the number of treated subjects. 
The final analysis of the primary endpoint will occur at least 6 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 revised International Working group Criteria for Malignant Lymphoma 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 
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 duration of ORR (DOR) based on IRRC 
assessment. 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 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 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 complete remission rate (CRR) based 
on IRRC assessment. The 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, 
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 
response 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 revised IWG 
response 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 
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from first documentation of PR to the date of initial objectively documented progression as 
determined using the 2007 revised IWG response 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 progression free survival 
(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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 by cohort.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods
The IRRC-assessed ORR will be summarized for the ASCT failed and the ASCT ineligible 
cohorts separately by binomial response rates and their corresponding two-sided 95% exact CIs. 
In the ASCT failed cohort, the two-sided 90% CI will also be presented, corresponding to the 
1-sided 5% alpha from the modified Simon design. The method proposed by Atkinson and 
Brown51 will be used to estimate the CI for the ASCT failed cohort. This confidence interval 
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takes into account the group sequential nature of the two-stage design. The Clopper-Pearson 
method will be used to estimate the CI for the ASCT ineligible cohort. 
In the ASCT failed cohort, the null hypothesis will be rejected if 25 or more responses are 
observed in 90 treated subjects. Success of the ASCT ineligible cohort will be determined by a 
2-sided 95% CI lower bound greater than 17.3%. 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 by cohort for subjects who achieve PR or CR 
using the Kaplan-Meier (KM) product-limit method. Median values of DOR, along with 
two-sided 95% CIs (based on the log-log transformation) and range, will also be calculated.
IRRC-assessed CRR, PRR, and investigator-assessed ORR will be summarized by binomial 
response rates and their corresponding two-sided 95% CI using the Clopper-Pearson method.
Duration of CR and PR will be summarized similarly to DOR. IRRC-assessed PFS will be 
summarized descriptively by cohort 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.
 
 
 
 
 
 
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. All on-study AEs, drug-related, AEs, SAEs and drug-related SAEs 
will be tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ class and 
MedDRA preferred term. On-study lab parameters including hematology, chemistry, liver 
function, thyroid function, and renal function will be summarized using worst grade per NCI 
CTCAE v4.0 criteria.
 
 
 
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8.5
Interim Analyses
One interim analysis of IRRC-assessed ORR in the ASCT failure group will be performed when 
37 ASCT-failed subjects have been treated and those subjects still on treatment have completed 
the first tumor assessment (week 9) . In case the last assessment of some subjects show CR that 
has not yet been confirmed by PET, the interim analysis will take place after availability of the 
confirmation. If there are 8 or fewer responses in these 37 subjects, the study will be stopped. 
Otherwise, approximately 53 additional subjects will be accrued to target a total of 90 treated 
subjects in the ASCT failure group. Accrual and treatment will continue during the time period 
that the interim analysis is being conducted. This may result in more than 37 treated subjects in 
the event that the study is terminated for lack of efficacy. The tolerability of the regimen will 
continue to be evaluated by the sponsor with the investigators to ensure that it is acceptable for 
continued enrollment. Additional specifications of analyses produced at interim analysis (eg, on 
biomarkers, safety) will be addressed in the statistical analysis plan.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
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9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable.
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study 
drug 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
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
amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS.
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs.
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a sub investigator 
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
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The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator 
or BMS as related to the investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved investigational 
product)
Serious Adverse Event
Serious adverse event defined as any untoward medical 
occurrence that at any dose: results in death; is life 
threatening (defined as an event in which the subject was at 
risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it 
were more severe), requires inpatient hospitalization or 
causes prolongation of existing hospitalization; results in 
persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect; is an important medical event (defined 
as a medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention
[eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in 
an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in 
hospitalization.). For reporting purposes only, BMS also 
considers the occurrence of pregnancy, overdose (regardless 
of association with an AE), and cancer as important medical 
events.
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11
LIST OF ABBREVIATIONS
Term
Definition
ACTH
Adrenocorticotropic Hormone
AE
adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
Autologous Stem Cell Transplant 
AST
aspartate aminotransferase
AT
Aminotransferase (ALT or AST)
BID, bid
bis in die, twice daily
BMI
body mass index
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
CLcr
creatinine clearance
CLR
renal clearance
cm
centimeter
CNS
Central nervous system
CR
Complete remission
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CT
Computed tomograhpy
CTA
Clinical Trial Agreement 
CTCAE
Common Terminology Criteria for Adverse Events
D/C
discontinue
DILI
drug induced liver injury
dL
deciliter
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Term
Definition
DLBCL
Diffuse large B-Cell lymphoma
DOR
Duration of overall response rate (ORR)
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ELISA
enzyme-linked immunosorbent assay
eSAE
Electronic Serious Adverse Event 
ESR
Expedited Safety Report
FDA
Food and Drug Administration
FFPE
Formalin-Fixed Parafin-Embedded
FSH
follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
GVHD
Graft versus host disease
h
Hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
Bicarbonate
ASCT
High dose therapy and autologous stem cell transplantation
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus
HL
Hodgkin lymphoma
HR
heart rate
HRT
hormone replacement therapy
IB
Investigational Brochure
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ie
id est (that is)
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Term
Definition
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMP
investigational medicinal products
IND
Investigational New Drug
IRB
Institutional Review Board
IRRC
Independent radiologic review committee
IU
International Unit
IV
intravenous
IVRS
Interactive voice response system
K+
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
LFT
Liver function test
mAbs
monoclonal antibodies
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
mmHg
millimeters of mercury
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
ng
nanogram
NIMP
non-investigational medicinal products 
NHL
Non-Hodgkin lymphoma
NSAID
nonsteroidal anti-inflammatory drug
ORR
Objective response rate
OS
Overall survival 
PBMC
peripheral blood mononuclear cells
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Term
Definition
PD
pharmacodynamics
PD-1
Programmed death-1 receptor
PET
Positron emission tomography
PFS
Progression free survival 
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PR
Partial response 
qPCR
Quantitative real-time polymerase chain reaction
RBC
red blood cell
R-CHOP
Rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone
RT-PCR
Reverse transcription- polymerase chain reaction
SAE
serious adverse event
SCT
Stem cell transplant 
SmPC
Summary of product characteristics 
SNP
Single nucleotide polymorphisms
SOP
Standard Operating Procedures
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
T-HALF
Half life
TIL
tumor infiltrating lymphocytes
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
2007 REVISED INTERNATIONAL WORKING GROUP 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.
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.
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.
2. 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.
3. 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:
8. 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]).
9. 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.
10. 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.
11. 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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12. 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.
13. At least a 50% increase in the longest diameter of any single previously identified node 
> 1 cm in its short axis.
14. 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.
 
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APPENDIX 3
REVISED INTERNATIONAL PROGNOSTIC INDEX (IPI) SCALE*
Composite score determined by assigning 1 point for each of the following factors;

Age > 60 years

ECOG PS > 2

Elevated Serum LDH

More than 1 extranodal site

Stage III/IV disease (Ann Arbor staging)
 
 
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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
 
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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%
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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.
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SAP_001.pdf: 
Official Title of Study: 
A Single-Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in Subjects with 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) After Failure of Autologous 
Stem Cell Transplant (ASCT) or After Failure of At Least Two Prior Multi-Agent Chemotherapy 
Regimens in Subjects Who Are Not Candidates for ASCT 
 
NCT Number: NCT02038933   
 
Document Date (Date in which document was last revised): Oct 20, 2017 
 


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 DIFFUSE LARGE B-CELL 
LYMPHOMA (DLBCL) AFTER FAILURE OF AUTOLOGOUS STEM CELL 
TRANSPLANT (ASCT) OR AFTER FAILURE OF AT LEAST TWO PRIOR MULTI-
AGENT CHEMOTHERAPY REGIMENS IN SUBJECTS WHO ARE NOT 
CANDIDATES FOR ASCT
(CHECKMATE 139: CHECKPOINT PATHWAY AND NIVOLUMAB CLINICAL TRIAL 
EVALUATION 139)
PROTOCOL CA209-139
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................6
LIST OF FIGURES ....................................................................................................................7
2
STUDY DESCRIPTION ..........................................................................................9
2.1
Study Design ............................................................................................................9
2.2
Treatment Assignment............................................................................................11
2.3
Blinding and Unblinding.........................................................................................11
2.4
Protocol Amendments.............................................................................................11
2.5
Data Monitoring and Other External Committees ...................................................12
3
OBJECTIVES ........................................................................................................12
3.1
Primary Objective...................................................................................................12
3.2
Secondary Objectives .............................................................................................12
4
ENDPOINTS..........................................................................................................13
4.1
Primary endpoint ORR (IRRC-assessed).................................................................13
4.2
Secondary Endpoints ..............................................................................................14
4.2.1
Duration of Response (IRRC-assessed)...................................................................14
4.2.2
Complete Remission Rate and Duration (IRRC-assessed) .......................................15
4.2.3
Partial Remission Rate and Duration (IRRC-assessed)...........................................15
4.2.4
Progression Free Survival (IRRC-assessed)............................................................15
4.2.5
Objective Response Rate (Investigator-assessed) ....................................................16
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5
SAMPLE SIZE AND POWER...............................................................................20
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................21
6.1
Study Periods..........................................................................................................21
6.1.1
Baseline Period ......................................................................................................21
6.1.2
Post Baseline Period...............................................................................................21
6.2
Treatment Regimens...............................................................................................21
6.3
Populations for Analyses ........................................................................................21
6.3.1
Study Cohorts.........................................................................................................21
6.3.2
Analysis Populations ..............................................................................................21
7
STATISTICAL ANALYSES..................................................................................22
7.1
General Methods ....................................................................................................22
7.2
Study Conduct........................................................................................................22
7.2.1
Accrual...................................................................................................................22
7.2.2
Relevant Protocol Deviations..................................................................................23
7.3
Study Population ....................................................................................................23
7.3.1
Subject Disposition.................................................................................................23
7.3.2
Demographics and Other Baseline Characteristics.................................................23
7.3.3
Medical History......................................................................................................24
7.3.4
Prior therapy..........................................................................................................24
7.3.5
Baseline Examinations............................................................................................25
7.4
Extent of Exposure .................................................................................................25
7.4.1
Administration of Study Therapy.............................................................................25
7.4.2
Modifications of Study Therapy ..............................................................................26
7.4.2.1
Dose delays ............................................................................................................26
7.4.2.2
Infusion Interruptions and Rate Changes................................................................26
7.4.2.3
Dose Reductions/Escalation....................................................................................26
7.4.3
Concomitant Medications .......................................................................................26
7.5
Efficacy..................................................................................................................26
7.5.1
Primary endpoint of ORR  (IRRC-assessed)............................................................26
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7.5.1.1
ORR Subgroups......................................................................................................27
7.5.1.2
Sensitivity analyses for ORR...................................................................................28
7.5.2
Secondary Endpoint of Duration of Response (IRRC-assessed)...............................28
7.5.3
Secondary Endpoint of Complete Remission Rate and Duration (IRRC-
assessed) ................................................................................................................28
7.5.4
Secondary Endpoint of Partial Remission Rate and Duration (IRRC-
assessed) ................................................................................................................28
7.5.5
Secondary Endpoint of Progression Free Survival (IRRC-assessed) .......................29
7.5.5.1
Sensitivity analyses of PFS .....................................................................................29
7.5.6
Secondary Endpoint of Objective Response Rate (Investigator-assessed)................29
7.6
Safety.....................................................................................................................32
7.6.1
Deaths ....................................................................................................................32
7.6.2
Serious Adverse Events...........................................................................................32
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................32
7.6.4
Adverse Events Leading to Dose Modification........................................................32
7.6.5
Adverse Events .......................................................................................................32
7.6.6
Select Adverse Events .............................................................................................32
7.6.7
Immune modulating medication..............................................................................32
7.6.8
Multiple Events.......................................................................................................32
7.6.9
Clinical laboratory evaluations...............................................................................33
7.6.10
Vital Signs, Pulse Oximetry and Medical Procedures .............................................33
7.6.12
Pregnancy ..............................................................................................................33
7.6.13
Clinical Safety Program (CSP)...............................................................................33
7.6.14
Adverse Events by Subgroup...................................................................................33
7.6.15
Immune-mediated Adverse Events Analysis.............................................................33
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7.6.16
Other Events of Special Interest..............................................................................33
7.10
Interim Analysis .....................................................................................................37
8
CONVENTIONS....................................................................................................39
9
CONTENT OF REPORTS .....................................................................................40
10
DOCUMENT HISTORY........................................................................................41
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LIST OF TABLES
Table 2.1-1:
Schedule of Spiral CT/MRI Tumor Assessments ....................................10
Table 2.4-1:
Protocol Amendments ............................................................................11
Table 4.1-1:
2007 IWG Response Criteria for Malignant Lymphoma .........................14
Table 4.2.4-1:
Censoring scheme used in primary analysis of PFS.................................16
Table 5-1:
Operating Characteristics of Stopping Rule ............................................20
Table 7.4.1-1:
Administration of study therapy: definition of parameters.......................25
Table 10-1:
Document History ..................................................................................41
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LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic.........................................................................10
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9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
2
STUDY DESCRIPTION
2.1
Study Design
This is a single-arm Phase 2 study in subjects ≥18 years old with relapsed or refractory DLBCL,
or transformed lymphoma (TL), after failure of ASCT or after failure of at least two prior multi-
agent chemotherapy regimens in subjects who are not ASCT candidates. Approximately 120 
subjects will be treated with nivolumab 3 mg/kg IV every 2 weeks. Subjects will be placed into 
cohorts based on prior ASCT failure [n=90] or ASCT ineligibility [n=30].
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For the ASCT-failed cohort, a two-stage design will be used to test whether nivolumab yields a
clinically compelling objective response rate. In the first stage, responses will be evaluated by the 
IRRC on the first 37 subjects treated. If there are 8 or fewer responses in these 37 subjects, the 
study will be stopped. In this case, the study will be terminated in both the ASCT-failed cohort as 
well as the ASCT ineligible cohort. Otherwise, approximately 53 additional subjects will be 
accrued into the ASCT-failed cohort to target a total of 90 treated subjects. Recruitment and 
treatment of subjects in both cohorts (ASCT failed and ASCT ineligible) will continue as described 
during the evaluation of the first 37 ASCT failed subjects treated. The tolerability of the regimen 
will continue to be evaluated by the sponsor with the investigators to ensure that it is acceptable 
for continued enrollment. For the ASCT ineligible cohort a single stage design will be used to 
estimate the objective response rate using approximately 30 treated subjects.
Figure 2.1-1:
Study Design Schematic
Note: Stage 1 data review will be conducted internally by BMS senior management for decision to proceed to second  
stage.  
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 ORR, using the 2007 
revised International Working Group Criteria for Malignant Lymphoma criteria. Secondary 
endpoints include IRRC-assessed duration of response (DOR), as well as complete remission rate 
(CRR), partial remission rate (PRR) and their duration and progression free survival (PFS) as 
determined by IRRC assessment and ORR based on investigator assessment. 
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
Treatment Groups 
ASCT failure 
(n= 90)
or 
ASCT ineligible 
who have failed >2
prior therapies 
(n=30)
S
c
r
e
e
n
Nivolumab
(BMS-936558)
3 mg/kg every 2 
wksuntil 
treatment 
discontinuation
1°endpoint: ORR by IRRC
Evaluate first 37 
ASCT failure 
subjects treated 
for response*
Continue recruitment 
and treatment in both 
groups.
Nivolumab every 2 wks 
until treatment 
discontinuation
Recruitment and 
treatment 
stopped in both 
groups
Upon treatment 
discontinuation 
all subjects enter 
follow-up phase
* Recruitment and treatment of subjects in both groups (ASCT failure and ASCT ineligible) will continue as described during the evaluation of the first 37 ASCT 
failure subjects treated. 
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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
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 3 mg/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 02
(Incorporates Amendment 
03)
23-Jul-2014
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 assessments to be
performed on subjects that discontinue study treatment to 
receive an allogeneic SCT or ASCT
Revised Protocol 01
(Incorporates amendment 01)
06-Dec-2013
Per FDA mandatory recommendation:
The protocol title and other sections have been updated to 
indicate that subjects who are not candidates for ASCT must 
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Table 2.4-1:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
have failed at least 2 prior multi-agent chemotherapy regimens 
in order to meet eligibility requirements
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
Subjects that received ≥ 1000 mg of carmustine (BCNU) as 
part of their pre-transplant conditioning regimen
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
30-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 DLBCL or TL who
are refractory or have relapsed following ASCT or after failure of at least two prior multi-agent
chemotherapy regimens in ASCT ineligible patients.
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 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
 
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4
ENDPOINTS
4.1
Primary endpoint ORR (IRRC-assessed)
The primary objective will be measured by the primary endpoint of IRRC-assessed objective 
response rate (ORR). It is defined as the number of subjects with a best overall response (BOR) of 
complete remission (CR) or partial remission (PR), according to the 2007 revised International 
Working Group Criteria for Malignant Lymphoma (see Table 4.1-1), divided by the number of 
treated subjects. The final analysis of the primary endpoint will occur at least 6 months after the 
last enrolled subject’s first dose of study therapy (primary data lock time). 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 revised International Working group Criteria for 
Malignant  Lymphoma 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 subjects who continue treatment beyond progression, the BOR should be 
determined based on response designations recorded up to the time of the initial 2007 IWG defined 
progression. 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 (CR or PR), 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 > 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
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 initiation of the 
subsequent anticancer therapy. Stem Cell Transplant will be considered as subsequent therapy. 
This endpoint will only be evaluated in subjects with objective response of CR or PR.
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 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. 
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•
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 initiation of the subsequent anti-
cancer therapy. Stem Cell Transplant will be considered as subsequent therapy.
Table 4.2.4-1:
Censoring scheme used in primary analysis of PFS
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments and no death
First Dosing date
Not 
Progressed 
No on study tumor assessments and no 
death 
First Dosing date
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 
Clinical progression without evidence of 
progression per 2007 IWG criteria or No 
progression
Date of last tumor assessment with no documented 
progression 
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
Date of death 
Progressed
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.
 
 
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
The planned sample size for this study will be approximately 120 treated subjects, separated into
two cohorts  based on prior ASCT failure [n= approx. 90] or ASCT ineligibility [n= approx. 30].
For the ASCT-failed cohort, a modified Simon's two-stage design will be used to test the null
hypothesis that the true ORR is ≤ 20% (not considered clinically compelling). In the first stage, 37 
treated subjects will be accrued. If there are 8 or fewer responses in these 37 subjects, the study 
will be stopped. In this case, the study will be terminated in both the ASCT-failed cohort as well 
as the ASCT ineligible cohort. Otherwise, approximately 53 additional subjects will be accrued 
into the ASCT-failed cohort to target a total of 90 treated subjects. The null hypothesis will be
rejected if 25 or more responses are observed in 90 treated subjects. This design yields a one-sided 
type I error rate of 5% and power of 90% when the true response rate is 35%. The interim stopping 
rule for this design is identical to Simon’s “optimal” 2-stage design25, thereby limiting the 
expected number of subjects who receive treatment when the true response rate is not of clinical 
value. However, the sample size at the final analysis is larger than required by Simon’s optimal 
design in order to provide additional subjects for safety evaluation. Table 5-1 provides the 
probabilities of stopping at different ORR using this rule.
Table 5-1:
Operating Characteristics of Stopping Rule
True ORR
P(early stop)
15%
0.91
20%
0.69
25%
0.40
30%
0.18
35%
0.06
40%
0.01
For the ASCT ineligible cohort, the sample size of 30 treated subjects is determined to achieve a 
confidence interval (CI) width around the ORR estimate with a sufficient level of precision. If the 
observed number of subjects with ORR is 10 (33%), the width of the exact 2-sided 95% CI is 36% 
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with a lower bound of 17.3%. Such an observation would provide evidence in support that the true 
ORR is greater than or equal to 17.3% with a Type I error rate of 5%.
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 
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 SAP21.
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 SAP21.
6.2
Treatment Regimens
All subjects will be treated with nivolumab.
6.3
Populations for Analyses
6.3.1 Study Cohorts
ASCT-failed cohort: All subjects with prior ASCT (per CRF)
ASCT ineligible cohort: All subjects without prior ASCT (per CRF)
6.3.2 Analysis Populations
Within each cohort the following populations will be defined.
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•
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.
 
 
 
 
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)26,27. Rates at fixed time points will be derived from the Kaplan Meier estimate and 
corresponding confidence interval will be derived based on Greenwood formula28 for variance 
derivation and on log-log transformation applied on the survivor function S(t) 29.
7.2
Study Conduct
7.2.1 Accrual
The following will be summarized on the enrolled population for the 2 cohorts separately and on 
the pooled 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.
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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, refractory DLBCL, or transformed lymphoma (TL)
•
Subject without measurable disease at baseline
•
Subject with baseline ECOG >1
On-Study:
•
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
surgical resection of lesions, non palliative radiation therapy, or standard or investigational 
agents for treatment of cancer).
A summary table will be produced for the 2 cohorts separately and on the pooled population. A by 
subject listing will be produced.
7.3
Study Population
Analyses from this section will be produced for the 2 cohorts separately and on the pooled 
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, ≥65)
•
Gender, Race/Ethnicity
•
Region (US/Canada vs. Europe vs. Rest of World)
•
ECOG PS
•
weight
•
Smoking Status (Yes/No/Unknown)
•
Initial disease diagnosis (Diffuse Large B-Cell Lymphoma, Follicular Lymphoma)
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•
Time from the initial diagnosis to first transplant (< 1 year, 1 - < 2 year, 2 - < 3 year, 3 - < 4 
year, 4 - < 5 year, ≥ 5 year) (only for ASCT failed cohort )  
•
Time from the most recent transplant to first dose of nivolumab ) (< 1 year, 1 - < 2 year, 2 - < 
3 year, 3 - < 4 year, 4 - < 5 year, ≥ 5 year) (only for ASCT failed cohort) 
•
Time from initial disease diagnosis to first dose of nivolumab (< 1 year, 1 - < 2 year, 2 - < 3 
year, 3 - < 4 year, 4 - < 5 year, ≥5 year) 
•
Disease stage at initial diagnosis (Stage I-II-III-IV)
•
Revised International Prognostic Index (IPI) Score (0, 1, 2, 3, 4, 5) at initial diagnosis
•
Lymphoma involvement in bone marrow at baseline (Yes/No/Not Available)
•
Disease diagnosis at enrollment (DLBCL/Transformed Lymphoma, 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 product diameters of target lesions.
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 (excluding preparative regimen for 
ASCT): 
−
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 and second lines of therapy (e.g. R-CHOP, 
ICE) 
•
Number of subjects by type of regimen (BEAM, CBV, Other) received for preparation to
ASCT (for ASCT failed cohort only)
•
Number of prior systemic regimen received (0, 1, 2, 3, ≥4), excluding preparative regimen for 
ASCT subjects 
•
Best response to most recent prior regimen (CR vs PR vs SD vs Relapse/PD vs Unable to 
Determine vs Not reported) 
•
Best response before transplant  (for ASCT failed cohort)
•
Best response to ASCT (for ASCT failed cohort)
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•
Best response to regimen post ASCT (for ASCT failed cohort)
•
Time from completion of most recent prior regimen to treatment (< 3, 3 - 6, > 6 months)
•
Prior radiotherapy (yes or 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 for the 2 cohorts separately and 
on the pooled population.
7.4.1 Administration of Study Therapy
The following parameters will be summarized (descriptive statistics):
•
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
3 mg/kg every 2 weeks 
Dose
Dose(mg/kg) is defined as Total Dose administered (mg)/Most recent 
weight (kg). Dose administered in mg at each dosing date and weight 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
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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 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.
•
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. 
 
 
 
 
7.5
Efficacy
Unless otherwise specified analyses from this section will be produce by cohort separately. 
7.5.1 Primary endpoint of ORR  (IRRC-assessed)
The IRRC-assessed ORR (using 2007 revised International Working Group Criteria for Malignant 
Lymphoma criteria) will be summarized on the all subjects treated population by a binomial 
response rate. The method proposed by Atkinson and Brown will be used to estimate the CI for 
the ASCT-failed cohort if the responders at interim analysis are above the critical value, which is 
8 responders. This confidence interval takes into account the group sequential nature of the two 
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stage modified Simon design. The two-sided 90% CI will be presented, corresponding to the nature 
of the 1-sided 5% alpha from the modified Simon design. In addition, per protocol, the two-sided 
95% CI will be presented. However, if the responders are below the critical value and we don’t 
stop the study, we are no longer following the two-stage design. The two-sided confidence 
intervals for binomial proportions will be derived using the Clopper-Pearson method.
The Clopper-Pearson30 method will be used to estimate the two-sided 95% CI for the ASCT 
ineligible cohort, as well as 90% and 95% confidence intervals for ORR at interim analysis (IA). 
In the ASCT failed cohort, the null hypothesis will be rejected if 25 or more responses are observed 
in 90 treated subjects at the final analysis (FA). In case not exactly 90 treated subjects are available, 
success will be referenced to a 2-sided 90% CI lower bound greater than 20%.
Success of the ASCT ineligible cohort will be referenced to a 2-sided 95% CI lower bound greater 
than 17.3%.
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 (for subjects in the ASCT failed cohort only):
•
Age (<65, ≥65, ≥  65  and < 75, ≥75)
•
Region (US/Canada, Europe, Rest of the world).
•
Gender (Male, Female)
•
Race (white, black, Asian, and other)
•
Smoking status (yes/no)
•
ECOG (0, 1)
•
Time from the initial diagnosis to transplant (< 1 year, 1 - < 2 year, 2 - < 3 year, 3 - < 4 year, 
4 - < 5 year, >=5 year)
•
Number of prior therapies (1, 2, 3, >=4) excluding preparative regimen  
•
Time from most recent prior regimen to first dose of nivolumab (< 3 months, 3 - 6 months, >6 
months)
•
Refractory, Relapsed Lymphoma
•
DLBCL, Transformed Lymphoma
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•
IPI Score (0,1, 2, 3, 4,…)
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
categories (responders versus non-responders versus non-evaluable or no evidence of disease 
versus not reported) 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 by cohort 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 DOR 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.
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 Endpoint of Complete Remission Rate and Duration (IRRC-
assessed)
IRRC-assessed CRR will be summarized by cohort by a binomial response rate and its 
corresponding two-sided 95% exact CIs using the Clopper-Pearson31 method.
To further characterize CRR, the duration of CR will be summarized by cohort 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 cohort 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 by cohort 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.
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7.5.5 Secondary Endpoint of Progression Free Survival (IRRC-assessed)
IRRC-assessed PFS will be summarized descriptively by cohort 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 month will be estimated using KM 
estimates on the PFS curve. PFS rates at 6, 12, 18 and 24 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.
Subject listings of PFS will be produced.
7.5.5.1 Sensitivity analyses of PFS
Sensitivity analyses of PFS based on IRRC assessment will also be performed using the following 
modification of PFS primary definition.
•
PFS accounting for assessment after subsequent therapy: PFS will be defined similarly to the 
primary definition except that events (progression or death) and tumor assessments that 
occurred after subsequent anti-cancer therapy will be considered (no time point truncation).
7.5.6 Secondary Endpoint of Objective Response Rate (Investigator-assessed)
Investigator-assessed ORR will be summarized by cohort by a binomial response rate and its 
corresponding two-sided 95% exact CIs using the Clopper-Pearson31 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.
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7.6
Safety
All analyses from the Core Safety SAP21 will be produced for the ASCT-failed and ASCT 
ineligible cohorts pooled and for the ASCT-failed cohort separately.
7.6.1 Deaths
See Core Safety SAP21
7.6.2 Serious Adverse Events
See Core Safety SAP21
7.6.3 Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP21
7.6.4 Adverse Events Leading to Dose Modification
See Core Safety SAP21
7.6.5 Adverse Events
See Core Safety SAP21
7.6.6 Select Adverse Events 
See Core Safety SAP21with the exception that most of the analyses of select adverse events will 
be limited to the 30 days safety windows and will not be repeated with the 100 days safety 
windows. Plots of time to onset of select adverse events and tables of rates by timepoint of select 
adverse events will not be produced. Summary of any select, drug-related select, select endocrine, 
drug-related select endocrine AE by worst CTC grade will be produced. Summary of any select, 
drug-related select, select endocrine and drug-related select endocrine AE leading to 
discontinuation by worst CTC grade will also be produced.
7.6.7 Immune modulating medication 
See Core Safety SAP21
7.6.8 Multiple Events
See Core Safety SAP21
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7.6.9 Clinical laboratory evaluations
See Core Safety SAP21 with the exception that scatterplots for total bilirubin will not be produced.
7.6.10 Vital Signs, Pulse Oximetry and Medical Procedures
See Core Safety SAP21. A by-subject listing of the medical prodecures will be produced.
7.6.11 Immunogenicity Analysis
See Core Safety SAP21
7.6.12 Pregnancy
By-subject listing of pregnancy tests results will be provided 
7.6.13 Clinical Safety Program (CSP)
See Core Safety SAP21
7.6.14 Adverse Events by Subgroup
See Core Safety SAP21
7.6.15 Immune-mediated Adverse Events Analysis
IMAE analyses will include events, regardless of causality, occurring within 100 days of the last 
dose. These analyses are limited to subjects who received immunosuppressive medication for 
treatment of the event, with the exception of endocrine events (hypothyroidism/thyroiditis, 
hyperthyroidism, hypophysitis, diabetes mellitus, adrenal insufficiency), which will be included 
in the analysis regardless of treatment since these events are often managed without 
immunosuppression.
IMAEs, serious IMAEs, IMAEs leading to discontinuation, and IMAEs leading to dose delay or 
reduction will be summarized by worst CTC grade and presented by IMAE Category/PT. 
Time to onset, time to resolution, time to resolution with completion of immunosuppressive 
medication will be defined and summarized by IMAE category in the same manner as for select 
AEs (see Section 7.6.6 ) except that, other than for the endocrine category, the longest duration of 
IMAEs has to be associated with the use of an immune-modulating medication. Time to Resolution 
for Longest Any Grade or Grade 3-5 IMAE cluster per subject will be listed.
Use of immune-modulating medications for IMAE management will be summarized by IMAE 
category in a similar manner as for the select AEs (see Section 7.6.7 ).
IMAE rechallenge will be also summarized.
7.6.16 Other Events of Special Interest
In addition to select AE and immune-mediated AE, categories of other events of special interest 
(OESI) have been defined (i.e. myasthenic syndrome, Guillain-Barre syndrome, demyelination, 
pancreatitis, uveitis, encephalitis events). Worst CTC grade of any and drug-related OESI (both 
safety windows) will be summarized along with the time to onset and resolution. In addition, worst 
CTC grade of serious OESI and OESI leading to discontinuation will be summarized (both safety 
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windows). Lastly, OESI occurring within 100 days of the last dose in subjects who received 
immunosuppressive medication for treatment of the events will be tabulated by worst CTC grade 
and the time to onset and resolution will be provided.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.10 Interim Analysis
As per the 2-stage design of this study, one interim analysis of IRRC-assessed ORR in the ASCT 
failed cohort will be performed when 37 ASCT-failed subjects have been treated and those subjects 
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still on treatment have completed 8 weeks follow-up (after the first scheduled tumor assessment). 
If there are 8 or fewer responses in these 37 subjects, the study will be stopped (in both the ASCT-
failed and the ASCT ineligible cohorts). Otherwise, approximately 53 additional subjects will be 
accrued to target a total of 90 treated subjects in the ASCT failed group. Accrual and treatment 
will continue during the time period that the interim analysis is being conducted. This may result 
in more than 37 treated subjects in the event that the study is terminated for lack of efficacy. The 
tolerability of the regimen will continue to be evaluated by the sponsor with the investigators to 
ensure that it is acceptable for continued enrollment.
The following analyses will be performed at interim analysis on the first 37 ASCT-failed cohort 
treated subjects.
•
Pre-Treatment Subject Status Summary
•
End of treatment period subject status summary
•
Demographic characteristics summary
•
Baseline Physical Measurements summary
•
Other baseline characteristics summary
•
Prior cancer therapy summary
•
Cumulative dose and relative dose intensity summary
•
Best overall response, per IRRC
•
Time to response and duration of response, per IRRC
•
Event Chart for Tumor Response, Tumor Progression, Duration of Therapy and Death
•
Waterfall plot of best reduction in Target Lesion, per IRRC
•
Spider plot of Tumor Burden Change, per IRRC
•
Best overall response, per investigator
•
Kaplan Meier plot of PFS, per IRRC
•
Kaplan Meier plot of overall survival
•
Status of Censored Subjects, OS Analysis
•
Subsequent cancer therapy summary
•
Death summary
•
Summary of any adverse events by worst CTC grade (any grade, grade 3-4, grade 5), 5% cutoff, 
30 days safety window
•
Summary of  Drug-Related Adverse Events by Worst CTC Grade (Any Grade, Grade 3-4, 
Grade 5), no cutoff, 30 days safety window
•
Summary of Serious Adverse Events by Worst CTC Grade (Grade 1, Grade 2, Grade 3, Grade 
4, Grade 5, unknown grade, any grade), no cutoff, 30 days safety window
•
Summary of Drug-Related Serious Adverse Events by Worst CTC Grade (Any Grade, Grade 
3-4, Grade 5), no cutoff, 30 days safety window 
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•
Summary of  Adverse Events Leading to Discontinuation by Worst CTC Grade (Grade 1, 
Grade 2, Grade 3, Grade 4, Grade 5, unknown grade, any grade), no cutoff, 30 days safety 
window
•
Summary of  Any Select Adverse Events by Worst CTC Grade (Any Grade Grade 3-4 Grade 
5), no cutoff, 30 days safety window  
•
Summary of  Drug-Related Select Adverse Events by Worst CTC Grade (Any Grade, Grade 
3-4, Grade 5), no cutoff, 30 days safety window 
In addition, the following analyses will be also performed at interim analysis.
•
Demographic characteristics summary (ASCT Ineligible cohort and pooled with ASCT-Failed 
37 subjects)
•
Best overall response, per investigator  (ASCT Ineligible cohort)
•
Summary of Tumor Specimen Acquisition and Characteristics for PD-L1 (ASCT-Failed 37 
subjects and ASCT Ineligible cohort pooled)
•
Best Overall Response and Objective Response per Investigator for each PD-L1 Expression 
Status Group (ASCT-Failed 37 subjects, ASCT Ineligible and pooled)
•
Box Plot of PD-L1 Expression versus Response Status (ASCT-Failed 37 subjects and ASCT 
Ineligible cohort pooled)
•
Kaplan-Meier 
Plot 
of 
Overall 
Survival 
by 
PD-L1 
Status 
at 
Baseline
Kaplan-Meier Plot of Progression Free Survival per investigator by PD-L1 Status at Baseline 
(ASCT-Failed 37 subjects and ASCT Ineligible cohort pooled)
•
Kaplan-Meier Plot of Progression Free Survival per investigator by PD-L1 Status at Baseline 
(ASCT-Failed 37 subjects and ASCT Ineligible cohort pooled)
•
Best Overall Response and Objective Response per Investigator for each Cell of Origin 
Subtype (ASCT-Failed 37 subjects and ASCT Ineligible cohort pooled)
•
Best Overall Response and Objective Response per Investigator by Double-Hit Status (ASCT-
Failed 37 subjects and ASCT Ineligible cohort pooled)
•
Best Overall Response and Objective Response per Investigator by Epstein-Barr virus (EBV) 
Status 
(ASCT-Failed 
37 
subjects 
and 
ASCT 
Ineligible 
cohort 
pooled)
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 Specification31. Missing and partial Non-Study Medication Domain 
dates will be imputed using the derivation algorithm described in BMS Non-Study Medication 
Domain Requirements Specification32.
For death dates, the following conventions will be used for imputing partial dates:
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•
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 
missing.
•
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.
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10 DOCUMENT HISTORY
Table 10-1:
Document History
Version Number
Author(s)
Description
1.0
Initial version 02-Jun-2014
2.0
01-Sep-2014: updates based on revised protocol 02
Section 2.1: 
- Clarification that the 2007 revised IWG criteria is used.
- Addition of partial remission rate and duration in the list of 
secondary endpoints
Section 3.2: Addition of duration of CR and PR rate and duration
Section 3.3:
 
Section 4.1:
- Clarification that the 2007 revised IWG criteria is used.
- Clarification that for subjects treated beyond progression the BOR is 
recorded up to the initial progression
Section 4.2.1: Clarification that the 2007 revised IWG criteria is used.
Section 4.2.2: Addition of duration in section title
Section 4.2.3:Section added for the PR rate and duration endpoints 
descriptions
Section 4.2.4 : Clarification that the 2007 revised IWG criteria is used.
Table 4.2.4-1: clarifications added to the censoring scheme for PFS
Section 4.3.2: Clarification that the 2007 revised IWG criteria is used.
Section 4.3.7:
 
Section 4.3.8: 
 
Section 6.3.2: addition of subjects treated beyond progression 
population
Section 7.1: Remove last paragraph about analyses by cohort
Section 7.2.1: specify that analyses will be for the 2 cohorts separately 
and on the pooled population
Section 7.2.2: Specify that a summary table will be produced for the 2 
cohorts separately and on the pooled population
Section 7.3: specify that Analyses from this section will be produced 
for the 2 cohorts separately and on the pooled population
Section 7.3.2: 
- addition of >65 years old category
- clarification that the sum of product diameter is used
Section 7.4: Specify that the analyses will be done for the 2 cohorts 
separately and pooled
Section 7.5: Specify that Unless otherwise specified analyses from 
this section will be produce by cohort separately
Section 7.5.1: Clarification that the 2007 revised IWG criteria is used
Section 7.5.2: addition of range of DOR analysis
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Table 10-1:
Document History
Version Number
Author(s)
Description
Section 7.5.3: addition of duration of CR in title and range if duration 
of CR
Section 7.5.4: section added to include PR rate and duration analyses
Section 7.5.5.1: Clarification that sensitivity for PFS will take into 
account assessments AFTER subsequent therapy
Section 7.5.8:
 
Section 7.8 
Section 7.8.1: Specify that Unless otherwise specified all analyses 
from this section will be performed on the two cohorts separately
Section 7.8.1.1: 
 
Section 7.8.1.2: 
-
 
 
- Addition of the following analyses based only on pooled ASCT-
failed 37 subjects and ASCT ineligible cohorts at IA
- Frequency and percentage BOR based on investigator 
assessment
- ORR based on investigator assessment will be computed along 
with exact 95% CIs using the Clopper-Pearson method.  
- OS curves will be estimated using the Kaplan-Meier product 
limit method.  Two-sided, 95% confidence intervals for 
median OS will be computed.
- PFS based on investigator assessment curves will be estimated 
using the Kaplan-Meier product limit method.  Two-sided, 
95% confidence intervals for median PFS will be computed.
Sections 7.8.2, 7.8.3, 7.8.4 
 
Section 7.10: Addition of the following tables/figures at IA:
- Spider plot of Tumor Burden Change, per IRRC (on 37 ASCT-failed 
cohort treated subjects)
- Demographic characteristics summary (ASCT Ineligible cohort and 
pooled with ASCT-Failed 37 subjects)
- Best overall response, per investigator  (ASCT Ineligible cohort)
-
 
 
 
 
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Table 10-1:
Document History
Version Number
Author(s)
Description
-
 
 
 
 
 
 
 
 
 
2.1
o
Section 2.1: Note to the Subjects discontinue study 
therapy by proceeding to allogeneic SCT or ASCT for 
the tumor assessment schedule added under table 2.1-1
o
Section 3.1 and 3.2: Objective added to the two titles 
after primary and secondary. PR and ORR full name 
added.
o
Section 4.1: while defining TTR, CR or PR added after 
the first response.
o
Section: 4.2.1: Stem Cell Transplant will be considered 
as subsequent therapy added.
o
Section 4.2.4: Censoring scheme related to anticancer 
treatment  for PFS has been updated
last evaluable assessment updated by last assessment.     
o
Section 4.3.1.1: Immune-Mediated Adverse Events has 
been added
o
Section 4.3.3: The definition of overall survival rate at 
time T has been added.
o
Section 4.3.7: 
 
 
o
Section 6.3.2: 
 
 
 
        
     
        
           
         
  
         
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Table 10-1:
Document History
Version Number
Author(s)
Description
o
Section 7.3.2: Time from initial disease diagnosis to first 
dose of nivolumab or to transformation, time from 
transformation to first dose of nivolumab have been 
removed.
o
Section 7.3.4:  Number of subjects by type of prior 
therapy and Best response to most recent prior regimen 
have been updated
o
Section 7.5.1.2: BOR categories (responders versus non-
responders versus non-evaluable or no evidence of 
disease versus not reported) will be cross-tabulated by 
assessment type (Investigator vs IRRC) has been added
Subject-level graphics removed.
90% CI has been removed.
o
Section 7.5.5: Subject listings of PFS will not be 
produced.
o
Section 7.5.6: Investigator-assessed BOR and time to 
response, cumulative response rate and etc has been 
added.
o
Section 7.5.7.2: Subsequent therapy has been added.
o
Section 7.5.7.3: other efficacy analysis has been added.
o
Section 7.6.6: select adverse events added.
o
Section: 7.6.9: added with the exception that scatterplots 
for total bilirubin will not be produced.
o
Section 7.6.10: title updated. Added A by-subject listing 
of the medical prodecures will be produced.
o
Section 7.6.15: immune-mediated adverse events analysis 
added.
o
Section: 7.6.16: other events of special interest added.
o
Section 7.8 and 7.8.1: per Dako IHC assay added.
o
Section 7.5.1: Confidence interval for primary endpoints 
updated.
o
Section 7.5.1.1: IPI score is 0, 1, 2, 3, 4…
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