Conditions: Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 66
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether Nivolumab is effective in the treatment of Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL) and Relapsed/Refractory Primary Testicular Lymphoma (PTL)

Detailed description:

Arms:
arm 1: Specified dose on specified days arm 2: Specified dose on specified days

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

Protocol document:
Prot_001.pdf: 
Page:
1
Protocol Number:
CA209647
IND Number:
119,380
Ex US
non-IND
EUDRACT Number
2016-000894-19
Date:
13-Apr-2016
Revised Date:
29-Nov-2017
Clinical Protocol CA209647
A Phase 2, Open-label, Single-arm, Two-cohort Study of Nivolumab in Relapsed/Refractory 
Primary Central Nervous System Lymphoma (PCNSL) or Relapsed/Refractory Primary 
Testicular Lymphoma (PTL)
(CheckMate 647: CHECKpoint pathway and nivoluMAB clinical Trial Evaluation 647)
Revised Protocol Number: 04
Study Director/Medical Monitor
Manish Sharma, MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
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authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Revised Protocol No.: 04
Date: 29-Nov-2017
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 04
29-Nov-2017
To characterize nivolumab pharmacokinetic
 in the 
cerebrospinal fluid (CSF), lumbar puncture(s) (optional) have been 
added and will be obtained from consenting patients with
relapsed/refractory PCNSL or relapsed/refractory PTL with CNS 
involvement.
. 
Administrative 
Letter 06
04-Sep-2017
Corrected the appendix 6 of the protocol (Tumor Flare; Treatment
strategies during TF) by removing the CTCAE classification of cerebral 
edema.
Revised 
Protocol 03 
07-Apr-2017
Incorporates Amendment(s) 09
Amendment 09
07-Apr-2017

Changes to eligibility

To allow enrollment of subjects with PTL who  undergo 
orchiectomy 

To allow enrollment of subjects with PTL with measurable 
nodule disease  

To specify more precisely the first line of therapy in PCNSL and 
PTL 

To exclude subjects with significantly increased risk for bleeding 
complications 

To lower the dose of dexamethasone or equivalent allowed 14 
days prior to first dose of nivolumab to less than or equal to 
2 mg/day.

The use of CT Scans without PET scans will not be allowed for 
assessment for subjects with PTL. 

Added the possibility for administrative interim analyses.

Recommendations for the management of Tumor Flare have been 
added as Appendix 6.

Incorporates changes per Administrative Letters 04, 03, and 02.
Administrative 
Letter 04
07-Feb-2017
Change Medical Monitor address.
Administrative 
Letter 03
17-Nov-2016
To further clarify protocol requirements for tumor tissue submission at 
screening and correct typographic errors in Table 5.1-2.
Administrative 
Letter 02
20-Oct-2016
Clarify the protocol requirements for tumor tissue submission at 
screening.
Revised 
Protocol 02
05-Oct-2016
Incorporates Amendment(s) 05
Amendment 05
05-Oct-2016

To reflect update in the treatment management algorithms to be 
consistent with the updated nivolumab investigator brochure (IB) 
V15, updates to the acceptable methods of contraception in order 
to be consistent with the most recent version of BMS SOP and IB 
V15.
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Revised Protocol No.: 04
Date: 29-Nov-2017
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Document
Date of Issue
Summary of Change

To allow the enrollment of patients with PCNSL that cannot 
produce a minimum of 25 slides 
 
.

 

Other changes were made to resolve minor inconsistencies or to 
provide clarifications.
Revised 
Protocol 01
22-Jun-2016
Incorporates Amendment(s) 01
Amendment 01
22-Jun-2016

Subjects in the cohorts with PCNSL and PTL with brain and or 
spinal lesions are allowed to enroll if they are on 4 mg per day or 
less of dexamethasone.

Subjects who had undergone allogeneic stem cell transplant 
> 12 months prior to first dose of study drug, have no evidence of 
active graft versus host disease, and are not on systemic 
immunosuppressive therapy are allowed to participate in the study.

Neurologic Assessment in Neuro-Oncology (NANO) has been 
incorporated in the exploratory endpoints in the protocol.

If the dose of dexamethasone is increased during the screening 
period following the screening MRI, and if there is clinical 
worsening in neurological symptoms following the MRI, the MRI 
must be repeated.

Due to the rapidly progressing nature of CNS tumors, a brain MRI 
is to be performed within 14 days before the first dose of study 
treatment in both cohorts in order to accurately reflect the disease 
burden.

Language was added for the collection of prospective blood 
samples, and for BMS to retain residual blood and tissue samples, 
so that scientists can perform additional research.

Incorporation of other minor changes to correct and/or clarify 
protocol requirements.
Original 
Protocol
13-Apr-2016
Not applicable
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OVERALL RATIONALE FOR THE REVISED PROTOCOL 04
Revised Protocol 04 incorporates changes that will allow for the characterization of nivolumab 
pharmacokinetics (PK) in paired cerebrospinal fluid (CSF) and blood samples, 
 in 
the CSF of patients with relapsed/refractory PCNSL or relapsed/refractory PTL with central 
nervous system (CNS) involvement, who consent for lumbar puncture. The collection of CSF is 
an optional assessment; consent for the lumbar puncture is required.  
.
All revisions apply to future and currently enrolled patients.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section 
Number & 
Title
Description of Change
Brief Rationale

Section 5.1,
Flow 
Chart/Time and 
Events Schedule 
Table 5.1-2. 
CSF assessment 
note

The note for the CSF on-treatment 
assessment was revised to include 
text for collection of CSF for 
nivolumab PK and select 
biomarkers, and paired blood 
samples for PK (optional consent 
required).

 

Section 5.1,
Flow 
Chart/Time and 
Events Schedule 
Table 5.1-2. PK 
and 

Paired CSF and Blood PK and 
 added to 
procedures; 

Table 5.5-2 (added) provides 
sampling details. 
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section 
Number & 
Title
Description of Change
Brief Rationale
Immunogenicity 
Assessments 

Section 5.5,
Pharmacokinetic
 
 

Section 5.5 was revised and 
retitled to incorporate (optional) 
paired CSF collection and blood 
samples for PK,
 
 
 
. The previous
title of this section was 
Pharmacokinetic Assessments

Table 5.5-1, Pharmacokinetic & 
Immunogenicity Sample 
Scheduling was revised to 
Pharmacokinetic & 
Immunogenicity Blood Sample 
Scheduling

Table 5.5-2, Paired Cerebrospinal 
Fluid & Blood Sampling Schedule
has been added. This table 
provides the schedule for 
collection of paired CSF and 
blood samples for patients who 
consent to lumbar puncture. 
Footnotes provide additional 
guidance and instruction. 

For patients who are on-study 
prior to Revised Protocol 04, 
paired sampling CSF and blood 
sampling should begin with the 
cycle the patients are on. 
 
 
 
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section 
Number & 
Title
Description of Change
Brief Rationale

Section 5.5.1, 
Pharmacokinetic 
 
 
Sample 
Analysis
Section 5.5.1 was revised and retitled 
to incorporate CSF collection 
(optional) for PK
 
characterization. The previous title of 
this section was Pharmacokinetic 
Sample Analysis.
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section 
Number & 
Title
Description of Change
Brief Rationale
Throughout the 
protocol 
Minor editorial corrections or changes.
Minor, rationale not required. 
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SYNOPSIS
Clinical Protocol CA209647
Protocol Title: A Phase 2, Open-label, Single-arm, Two-cohort Study of Nivolumab in Relapsed/Refractory Primary 
Central Nervous System Lymphoma (PCNSL) or Relapsed/Refractory Primary Testicular Lymphoma (PTL)
(CheckMate 647: CHECKpoint pathway and nivoluMAB clinical Trial Evaluation 647)
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nivolumab (BMS-936558) monotherapy administered intravenously (IV) 240 mg every 2 weeks (Q2W)
for 8 cycles, followed by 480 mg every 4 weeks (Q4W) for a total treatment duration of 2 years, or until progressive 
disease (PD), unacceptable toxicity, or withdrawal of consent.
Study Phase: 2
Research Hypothesis: Treatment with nivolumab will demonstrate clinically meaningful efficacy in subjects with 
relapsed/refractory PCNSL or PTL.
Objectives: 
Primary Objectives:
To assess the clinical benefit of nivolumab in subjects with relapsed/refractory PCNSL or relapsed/refractory PTL as 
measured by overall response rate (ORR) by blinded Independent Central Review (BICR). 
Secondary Objectives:

To assess progression-free survival (PFS) based on BICR assessment for PCNSL or PTL, respectively

To assess ORR and duration of response (DOR) based on investigator assessment for PCNSL or PTL, respectively

To assess overall survival (OS) for PCNSL or PTL, respectively
.
Study Design: This is a Phase 2 open-label study to evaluate the safety and efficacy of nivolumab in subjects with 
relapsed/refractory PCNSL or PTL (Figure 1). Subjects should receive nivolumab at a dose of 240 mg as a 30-minute 
infusion on Day 1 of each treatment cycle for 8 cycle. Beginning with Cycle 9, subjects should receive nivolumab at 
a dose of 480 mg as a 30-minute infusion every 4 weeks (+/- 3 days), for a total of 2 years of treatment, or until 
progressive disease, unacceptable toxicity, or withdrawal of consent. Subjects should begin study treatment within 3 
calendar days of treatment assignment.
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Figure 1:
Study Design
PCNSL
N=45
Nivolumab
240 mg IV Q2W
for 8 cycles
PTL
N=20
Nivolumab
480 mg IV Q4W
2 years maximum
treatment duration
Nivolumab
480 mg IV Q4W
2 years maximum
treatment duration
Nivolumab
240 mg IV Q2W
for 8 cycles
Subjects with pathologically confirmed PCNSL or PTL who progressed
after or did not respond to at least 1 line of systemic therapy
Total treatment duration for 2 years or until PD, unacceptable toxicity, 
or withdrawal of consent. Tumor assessments for PCNSL every 2 
months for 2 years, then every 6 months until disease progression. 
Tumor assessments for PTL every 2 months for 6 months, then every 
3 months for 1.5 years, then every 6 months until disease progression. 
Continuous toxicity assessments during treatment phase and for first 
2 safety follow-up visits. Survival follow-up visits will occur every 3 
months thereafter.
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Study Population: Subjects must meet all eligibility criteria specified in Sections 3.3.1 and 3.3.2 of the protocol, 
including the following:
Inclusion criteria:
a)
Men and women, age 18 years old at the time of screening
b)
Subjects with pathologically confirmed PCNSL or PTL who progressed after or did not respond to at 
least 1 line of systemic therapy (PCNSL prior therapy may include:  high-dose methotrexate [HD-MTX], 
HD-MTX based regimen, high dose cytarabine, radiation therapy alone as treatment or as part of 
consolidation therapy, high-dose therapy with autologous stem cell transplant as part of consolidation 
therapy, and/or intraocular MTX alone or as part of consolidation therapy; PTL prior therapy may 
include: chemoimmunotherapy such as CHOP-R or any other regimens, with/without prophylactic 
radiation to contralateral testis or orchiectomy or intrathecal chemotherapy)
c)
Radiologically measurable disease within 28 days of first dose
d)
Karnofsky performance status of 70 or higher
Exclusion criteria:
a)
Intraocular PCNSL without evidence of brain disease. Patients with prior history of intraocular 
involvement treated only with intraocular methotrexate and no prior systemic therapy are excluded.
b)
PCNSL with systemic disease
c)
PCNSL patients who cannot undergo magnetic resonance imaging assessments
d)
Patients with brain stem lesions
e)
Active, known, or suspected autoimmune disease
f)
Known history of positive test for human immunodeficiency virus or known acquired immunodeficiency 
syndrome
g)
Prior treatment with an anti-programmed death ligand (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
Study Drug: Includes both Investigational (Medicinal) Products (IP/IMP) and Non-investigational (Medicinal)
Products (Non-IP/Non-IMP) as listed in Table 1.
Table 1: 
Study Drug for CA209647
Medication 
Potency 
IP/Non-IP 
Nivolumab
100 mg (10 mg/mL) and 40 mg 
(10mg/mL)
IP
Study Assessments: The primary endpoint is BICR-assessed ORR, and will be analyzed 6 months after last patient 
first treatment in each cohort. All treated subjects will be evaluated. The BICR-assessed objective response will be 
further characterized by the DOR. DOR is defined as the time from first response (partial response [PR] or complete 
response [CR]) to the date of initial objectively documented progression as determined using the International Primary 
CNS Lymphoma Collaborative Group (IPCG) criteria for PCNSL and Lugano 2014 response evaluation for PTL, as 
determined by BICR, or death due to any cause, whichever occurs first. The secondary endpoints are PFS based on 
BICR assessment, ORR and DOR based on investigator assessment, and OS. Tumor assessments for PCNSL will 
occur every 2 months for 2 years, then every 6 months until disease progression. Tumor assessments for PTL will 
occur every 2 months for 6 months, then every 3 months for 1.5 years, then every 6 months until disease progression. 
Toxicity assessments will be continuous during the treatment phase as well as during the first 2 safety follow-up visits. 
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Once subjects reach the survival follow-up phase, either in-person visits or documented telephone calls to assess the 
subject’s status are acceptable.
Statistical Considerations:
Sample Size:
The planned sample size for this study will be approximately 65 treated subjects, placed into 2 cohorts of subjects: 
PCNSL (N = 45), and PTL (N = 20).
In addition, Table 2 summarizes the 95% exact confidence interval (CI) for the target ORRs ranging from 28.9% to 
60% with sample size of 20 and 45. At observed ORR 28.9% with 45 PCNSL subjects, the lower bound of the 95% 
CI excludes the historical response rates in of 14% in recurrent primary central nervous system lymphoma. At 
observed ORR ≥ 40% with 20 PTL subjects, the lower bound of the 95% CI excludes the response rate of 14%.
The sample size for the PCNSL cohort was empirically determined to support expanded assessment of the benefit-
risk profile of nivolumab in PCNSL through observation of less common safety events. In particular, administration 
of nivolumab to 45 subjects provides 90% probability of observing at least 1 occurrence of any adverse event that 
would occur with 5% incidence in the population from which the sample is drawn.
Table 2:
Observed ORR with Exact 95 % CI
N
ORR
95% Exact CI
20
30%
[11.9% - 54.3%]
35%
[15.4% - 59.2%]
40%
[19.1% - 63.9%]
50%
[27.2% - 72.8%]
60%
[36.1% - 80.9%]
45
28.9% 
[16.4% - 44.3%]
40.0% 
[25.7% - 55.7%]
51.1% 
[35.8% - 66.3%]
60%
[44.3% - 74.3%]
Endpoints:
The primary objective will be measured by the primary endpoint of BICR-assessed ORR. It is defined as the number 
of subjects with a BOR of CR or PR, based on the IPCG criteria for PCNSL, and Lugano Classification 2014 response 
evaluation for PTL, divided by the number of treated subjects within each cohort. 
The BICR-assessed BOR is defined as the best response designation recorded between the date of first dose and the 
date of initial objectively documented progression per criteria or the date of subsequent therapy, whichever occurs 
first. 
The BICR-assessed PFS is defined as the time from first dosing date to the date of the first documented progression 
per criteria, as determined by BICR, or death due to any cause, whichever occurs first.
Investigator-assessed ORR and DOR are defined similarly as described for ORR and DOR per BICR assessment 
above, but will be assessed per investigator.
Analyses:
All analyses will be performed separately for each cohort. 
The analysis of the primary endpoint in each cohort will occur at least 6 months after last patient first treatment of 
each cohort.
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The ORR based on BICR assessment will be summarized by binomial response rates and their corresponding 
two-sided 95% exact CIs using the Clopper-Pearson method. The analysis of ORR per investigator is similar as ORR 
analysis per BICR, but based on investigator assessment.
DOR based on BICR assessment will be summarized for subjects who achieve PR or CR using the Kaplan-Meier 
product-limit method. Median values of DOR along with 2-sided 95% CIs and range will also be calculated. The same 
analysis will be performed for the duration of CR.
PFS based on BICR assessment and OS will be summarized by the Kaplan-Meier product-limit method. Median 
values along with two-sided 95% CIs based on the log-log transformation, will be calculated. The PFS rate at 6, 12,
and 24 months will also be calculated.
The analysis of ORR and DOR per investigator is similar as ORR and DOR analysis per BICR, but based on 
investigator assessment.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE REVISED PROTOCOL 04 ............................. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04............................ 
 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
. 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.3.4 MRI Contraindication .............................................................................. 
 
 
 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow-up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
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4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Nivolumab Dose and Schedule ................................................................ 
4.5.2 Dose Modifications for Nivolumab .......................................................... 
4.5.3 Dose Delay Criteria for Nivolumab ......................................................... 
4.5.4 Criteria to Resume Dosing for Nivolumab .............................................. 
4.5.5 Treatment Discontinuation Criteria for Nivolumab ................................ 
4.5.6 Nivolumab Treatment Beyond Progression ............................................. 
4.5.7 Management Algorithms for Immuno-Oncology Agents ......................... 
4.5.8 Treatment of Nivolumab-Related Infusion Reactions .............................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Assessment of Overall Tumor Burden and Disease ................................. 
 
5.5 Pharmacokinetic and CSF Biomarker Assessments ......................................... 
5.5.1 Pharmacokinetic and CSF Biomarker Sample Analysis .......................... 
 
 
 
 
 
 
 
5.7 Outcomes Research Assessments ..................................................................... 
5.7.1 EORTC QLQ-C30 and BN20 ................................................................... 
5.7.2 EQ-5D 3L ................................................................................................. 
5.8 Other Assessments ............................................................................................ 
5.8.1 Immunogenicity Assessments ................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
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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 BLINDED INDEPENDENT CENTRAL REVIEW ................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.2.1 Progression Free Survival Based on BICR Assessment ................. 
8.3.2.2 Objective Response Rate and Duration of Response Based on 
Investigator Assessment ........................................................................ 
8.3.2.3 Overall Survival .............................................................................. 
 
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......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.6.1 EORTC QLQ-C30 and QLQ-BN-20 ............................................... 
8.4.6.2 EQ-5D -3L ...................................................................................... 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 METHODS OF CONTRACEPTION ................................................... 
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APPENDIX 2 KARNOFSKY PERFORMANCE SCALES ........................................ 
 
APPENDIX 3 RESPONSE CRITERIA FOR PCNSL ................................................. 
 
APPENDIX 4 RESPONSE EVALUATION IN PTL .................................................. 
 
 
APPENDIX 6 TUMOR FLARE ................................................................................... 
 
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1.2
Research Hypothesis
Treatment with nivolumab will demonstrate clinically meaningful efficacy in subjects with 
relapsed/refractory PCNSL or PTL.
1.3
Objectives(s)
1.3.1
Primary Objective
To assess the clinical benefit of nivolumab in subjects with relapsed/refractory PCNSL or
relapsed/refractory PTL as measured by ORR by blinded Independent Central Review (BICR).
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1.3.2
Secondary Objectives

To assess PFS based on BICR assessment for PCNSL or PTL, respectively

To assess ORR and DOR based on investigator assessment for PCNSL or PTL, respectively

To assess overall survival (OS) for PCNSL or PTL, respectively
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 Harmonization (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Bristol-Myers Squibb (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 Brochure64 or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates, and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form (ICF) which will include all elements required by ICH, GCP, and applicable 
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regulatory requirements. The sample ICF will adhere to the ethical principles that have their origin 
in the Declaration of Helsinki.
Investigators must ensure the following:
1) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written ICF 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. 
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
CA209647 is a Phase 2, open-label, single-arm, 2-cohort study to estimate the safety and efficacy 
of nivolumab in subjects with relapsed/refractory PCNSL or PTL. Nivolumab 240 mg will be 
given every 2 weeks for 8 cycles. Beginning with Cycle 9, nivolumab 480 mg will be given every 
4 weeks for a total therapy duration of 2 years, or until progressive disease, unacceptable toxicity, 
or withdrawal of consent. Nivolumab will be administered as a 30-minute infusion. A finite 
treatment duration with immune therapies in this patient population remains an area of ongoing 
research; therefore the treatment duration chosen was 2 years.
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The study will further characterize safety and evaluate the antitumor activity of nivolumab in 
subjects with relapsed/refractory PCNSL or PTL who progressed after or did not respond to at 
least 1 line of systemic therapy. 
The primary endpoint is BICR-assessed ORR, and will be analyzed 6 months after last patient first 
treatment in each cohort.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied 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 
PCNSL
N=45
Nivolumab
240 mg IV Q2W
for 8 cycles
Nivolumab
480 mg IV Q4W
2 years maximum
treatment duration
Nivolumab
480 mg IV Q4W
2 years maximum
treatment duration
Nivolumab
240 mg IV Q2W
for 8 cycles
Subjects with pathologically confirmed PCNSL or PTL who progressed
after or did not respond to at least 1 line of systemic therapy
Total treatment duration for 2 years or until PD, unacceptable toxicity, 
or withdrawal of consent. Tumor assessments for PCNSL every 2 
months for 2 years, then every 6 months until disease progression. 
Tumor assessments for PTL every 2 months for 6 months, then every 
3 months for 1.5 years, then every 6 months until disease progression. 
Continuous toxicity assessments during treatment phase and for first 
2 safety follow-up visits. Survival follow-up visits will occur every 3 
months thereafter.
PTL
N=20
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through another mechanism at the discretion of BMS. BMS reserves the right to terminate access 
to BMS-supplied study drug if any of the following occur: a) the marketing application is rejected 
by a 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) Subject must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, and other requirements of the study.
2. Target Population
a) Subject must be 18 years of age or older
b) Subjects with pathologically confirmed PCNSL or PTL who progressed after or did not 
respond to at least 1 line of systemic therapy 
i)
PCNSL prior therapy may include HD-MTX, HD-MTX-based regimen, high-dose 
cytarabine, radiation therapy alone as treatment or as part of consolidation therapy, 
high-dose therapy with autologous stem cell transplant as part of consolidation therapy, 
and/or intraocular MTX alone or as part of consolidation therapy  
ii) PTL prior therapy may include chemo-immunotherapy (eg, CHOP-R or any other 
regimens), with/without prophylactic RT to contralateral testis or orchiectomy or 
intrathecal chemotherapy 
c) Measurable disease requirements on scans done within 28 days of first dose (14 days for 
MRI of the brain):
i)
PCNSL subjects should have at least 1 measurable extranodal brain lesion with the 
longest diameter > 1.0 cm on Gd-enhanced MRI
ii) PTL subjects should have either at least 1 measurable extranodal lesion with the longest 
diameter > 1.0 cm or at least 1 measurable nodal lesion with the longest diameter 
> 1.5 cm on fluorodeoxyglucose (FDG) PET/CT scan
d) Archived tumor block or unstained slides from biopsy. Histologically confirmed tissue will 
be required from the time of relapse or at the time of initial surgery.
e) Subjects must have a Karnofsky performance status of 70-100 (Appendix 2)
f)
Subject re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been treated). If 
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re-enrolled, the subject must be re-consented and assigned a new subject number by the 
IVRS.
g) Subjects with prior history of allogeneic transplant can participate if the transplant was 
performed at least 6 or more months before screening. If there is no prior history of Grade 
2 + acute graft versus host disease (GVHD), no history of extensive or Grade 4 chronic 
GVHD, or no immunosuppressive therapy for a minimum of 4 weeks with no clinically 
apparent GVHD. 
3. Physical and Laboratory Test Findings
Screening laboratory values must meet the following criteria (using Common Terminology 
Criteria for Adverse Events [CTCAE] v4.03):
a) White blood count (WBC) 2000/uL
b) Neutrophils 1500/uL
c) Platelets 100x103/uL
d) Hemoglobin 9.0 g/dL
e) Serum creatinine 1.5x upper limit of normal (ULN) or calculated creatinine clearance 
> 50 mL/min (using the Cockcroft-Gault formula)
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
f)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 3.0 x ULN 
g) Total bilirubin (TBILI) 1.5 x ULN (except subjects with Gilbert Syndrome who must 
have a total bilirubin level of < 3.0xULN)
4. Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) within 24 hours prior to the start of study drug
b) Women must not be pregnant or breastfeeding
c) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of study treatment with nivolumab and 5 months after the last dose of study treatment {i.e., 
30 days (duration of ovulatory cycle) plus the time required for the investigational drug to 
undergo approximately five half-lives.}
d) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 7 
months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}
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e) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
but still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, which have a 
failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to use 1 highly effective method of contraception as listed in 
Appendix 1.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Intraocular PCNSL without evidence of brain disease. Patients with prior history of 
intraocular involvement treated only with intraocular methotrexate and no prior systemic 
therapy are excluded.
b) PCNSL patients who cannot undergo MRI with contrast assessments
c) PCNSL patients with systemic disease
d) Patients with brain stem lesions
2. Medical History and Concurrent Diseases
a) Subjects with an active, known, or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
b) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease.65,66
For subjects with PCNSL and PTL with brain or spinal cord lesion: Subjects who have 
received 2 mg/day or less of dexamethasone equivalent in the 14 days prior to the first 
nivolumab dose are eligible for the study. Documentation that the dose has been stable or 
decreased for at least 14 days prior to the first dose of nivolumab is required. Subjects who 
have received doses of more than 2 mg/day of dexamethasone or equivalent within the 14 
days period prior to the first dose of nivolumab are excluded. 
NOTE: During study treatment, subjects may be treated with steroids including bolus doses 
for IMAEs or tumor flare detailed in Appendix 5 and Appendix 6, respectively, and in 
Sections 3.4.1 and 3.4.2. 
c) Subjects who have received chemotherapy within 3 weeks of study treatment (except: HD-
MTX within 2 weeks of treatment permitted if serum MTX levels < 1 M and meets other 
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lab criteria for inclusion), nitrosoureas within 6 weeks of treatment, therapeutic anti-cancer 
antibodies (such as rituximab) within 4 weeks, radio- or toxin immune-conjugates within 
10 weeks of treatment.
d) Received any investigational agent within 28 days or 5 half-lives (whichever is longer) 
prior to initiation of study treatment
e) Major surgery and/or radiotherapy within 14 days prior to initiation of study treatment
f)
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally
g) 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
h) Patients with serious or uncontrolled medical disorders
i)
Prior treatment with an 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
j)
PCNSL patients only: prior therapy with Bruton's tyrosine kinase (BTK) inhibitor 
(eg, ibrutinib)
k)
Patients on active anticoagulation therapy are excluded from this study. If a patient 
develops
a thromboembolic event
during the treatment period, treatment with
anticoagulation is permitted.
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection, and/or detectable virus
4. Allergies and Adverse Drug Reaction
a) History of severe allergy or hypersensitivity to study drug components
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a subject. Strict conditions apply and BMS approval is required.)
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
WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence 
of other biological or physiological causes. In addition, females under the age of 55 years must 
have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause.
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Females treated with hormone replacement therapy (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the washout 
period below are suggested guidelines and the investigators should use their judgement in checking 
serum FSH levels:

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. If the serum FSH level 
is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
3.3.4
MRI Contraindication
Study-related MRI imaging of the brain will be performed per the frequency specified in the 
protocol. Investigators may obtain additional follow-up MRI scans as medically indicated. For 
other locally performed imaging, it is the local imaging facility’s responsibility to determine, based 
on subject attributes (eg, allergy history, diabetic history, and renal status), the appropriate imaging 
modality, and contrast regimen for each subject. Imaging contraindications and contrast risks 
should be considered in this assessment. Subjects with renal insufficiency should be assessed as to 
whether or not they should receive contrast, and if so, what type and dose of contrast is appropriate. 
Specific to MRI, subjects with severe renal insufficiency (ie, estimated glomerular filtration rate
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this subject population, who should be excluded from the study. In addition, 
subjects with surgically implanted devices (pacemaker, deep brain stimulator, metallic implants, 
etc.) incompatible with MRI should not undergo such imaging techniques. The local imaging 
facility and investigator should determine the appropriate precautions or guidelines that should be 
instituted for subjects with tattoos, body piercings, or other body art.
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
 
 
 
 
 
 
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3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Disease progression, except as described in Section 4.5.6

Unacceptable toxicity, see Section 4.5.5

Any clinical 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, see Section 4.5.5

Pregnancy (as specified in Section 6.4)

Termination of the study by 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.
This is a survival study; therefore subjects discontinuing study treatment will remain on study for 
documentation of progression and death.
In the case of pregnancy, the investigator must immediately notify Sponsor or designee of this 
event. In most cases, the study drug(s) will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please contact the Sponsor or designee within 
24 hours of awareness of pregnancy. If the investigator determines a possible favorable benefit/risk 
ratio that warrants continuation of study drug, a discussion between the investigator and the 
Sponsor or designee must occur.
All subjects who discontinue study drug 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 
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ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow-up
In this study, OS is a secondary endpoint. Post study follow-up is of critical importance and is 
essential to preserving subject safety and study integrity. Subjects who discontinue study drug 
must continue to be followed every 3 months after the second follow-up visit, for collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or study 
conclusion. Survival follow-up may be accomplished by visit or phone contact.
BMS may request that survival data be collected on all treated subjects outside of the protocol-
defined window (Table 5.1-1). At the time of this request, each subject will be contacted to 
determine their survival status unless the subject has withdrawn consent for all contacts or is lost 
to follow-up.
In addition, for subjects who discontinue study therapy by proceeding to allogeneic stem cell 
transplant, 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 
stem cell transplant is documented.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by 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 as the inability to reach the subject after a minimum of 3 documented phone calls, faxes, 
or emails as well as lack of response by subject to 1 registered mail letter. All attempts should be 
documented in the subject’s medical records. If it is determined that the subject has died, the site 
will use permissible local methods to obtain the date and cause of death.
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If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational (Medicinal) Product (IP/IMP) and Non-investigational 
(Medicinal) Product (Non-IP/Non-IMP) and can consist of the following (Table 4-1):
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Table 4-1:
Study Drugs for CA209647
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging /
Appearance
Storage Conditions
(per label)
Nivolumab Solution for 
Injection
100 mg
(10 mg/ml) and 40 mg 
(10 mg/mL)
IP
Open label
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles.
240 mg kit contains: 2 
x 100-mg vials 
(10 mg/vial) and 1 x 
40-mg vial (4 mL/vial) 
or carton containing 5 
vials of 100 mg
2-8C. Protect from 
light and freezing.
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4.1
Investigational Product
An IP, also known as IMP 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 IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
In this protocol, the investigational product is nivolumab (BMS-936558).
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
IPs. 
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed
and BMS should be contacted immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration, and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be protected from light 
and freezing. If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab include laboratory 
coats and gloves.
For details on prepared drug storage and use time of nivolumab under room temperature/light and 
refrigeration, please refer to the nivolumab Investigator Brochure64 section for “Recommended 
Storage and Use Conditions” and/or Pharmacy Manual.
Infusion related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be provided by 
the sponsor and should be purchased locally if permitted by local regulations.
4.4
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 
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obtain the subject number in IVRS. Specific instruction for using IVRS will be provided to the 
investigational site in a separate document.
4.5
Selection and Timing of Dose for Each Subject
4.5.1
Nivolumab Dose and Schedule
Subjects should receive nivolumab at a dose of 240 mg as a 30-minute infusion on Day 1 of each 
treatment cycle for the first 8 cycles until progression, unacceptable toxicity, withdrawal of 
consent, or the study ends, whichever occurs first. Subjects should begin study treatment within 
3 calendar days of treatment assignment. Beginning with Cycle 9, subjects should receive 
nivolumab at a dose of 480 mg as a 30-minute infusion until progression, unacceptable toxicity, 
withdrawal of consent, or the study ends, whichever occurs first.
There will be no dose escalations or reductions of nivolumab allowed. Subjects may be dosed no 
less than 12 days from the previous dose. For Q4W dosing cycles, subjects may be dosed within a 
+/- 3-day window. Premedications are not recommended for the first dose of nivolumab.
Subjects should be carefully monitored for infusion reactions during nivolumab administration. If 
an acute infusion reaction is noted, subjects should be managed according to Section 4.5.8.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed.
Information regarding infusion details for nivolumab can be found in the Investigator Brochure.64
4.5.2
Dose Modifications for Nivolumab
Dose modifications are not allowed for nivolumab; for dose delay, see Section 4.5.3.
4.5.3
Dose Delay Criteria for Nivolumab
Tumor assessments should continue per protocol schedule, even if dosing is delayed.
Nivolumab administration should be delayed for the following:

Any Grade 2 non-skin, drug-related AE, with the following exception:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay

Grade 2 drug-related creatinine, AST, ALT, or TBILI abnormalities 

Any Grade 3 skin, drug-related AE

Any Grade 3 drug-related laboratory abnormality (excluding AST, ALT, or TBILI), with the 
following exceptions for lymphopenia, AST, ALT, or TBILI or asymptomatic amylase or 
lipase:

Grade 3 lymphopenia does not require dose delay

Any Grade 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication
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Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated, and resume nivolumab dosing when re-treatment criteria are met.
4.5.4
Criteria to Resume Dosing for Nivolumab
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade 1 
or baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue

Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity

For subjects with Grade 2 AST, ALT, or TBILI elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete

Subjects with combined Grade 2 AST/ALT AND TBILI values meeting discontinuation 
parameters (Section 4.5.5) should have treatment permanently discontinued

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor

Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor
4.5.5
Treatment Discontinuation Criteria for Nivolumab
Nivolumab treatment should be permanently discontinued for the following:

Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity OR requires systemic treatment 

Any Grade 3 non-skin, drug-related AE 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:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Grade 3 drug-related AST, ALT, or TBILI requires discontinuation*
Concurrent AST or ALT > 3xULN and TBILI > 2xULN
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* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug(s), a discussion between the investigator and the BMS Medical Monitor/designee must 
occur.

Any Grade 4 drug-related AE or laboratory abnormality, except for the following events which 
do not require discontinuation:

Grade 4 neutropenia 7 days

Grade 4 lymphopenia or leukopenia

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset

Grade 4 drug-related endocrinopathy AEs, such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose-controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the BMS Medical Monitor

Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a subject with a dosing delay 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 delayed. Periodic study visits to assess 
safety and laboratory studies should also continue every 6 weeks or more frequently if 
clinically indicated during such dosing delays.

Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor. Prior to re-initiating 
treatment in a subject with a dosing delay lasting > 6 weeks, the BMS Medical Monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays.

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing
4.5.6
Nivolumab Treatment Beyond Progression
Evidence indicates a minority of subjects treated with immunotherapy may derive clinical benefit 
despite initial evidence of PD,61 eg, due to inflammatory reaction simulating progression (“tumor 
flare” or pseudoprogression). Pseudoprogression is well described in neuro-oncology, and refers 
to radiographic enlargement of tumor lesions that would be interpreted as disease progression by 
conventional response criteria, but upon histologic examination reveals necrosis and/or 
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inflammation (treatment effect) and not disease progression.61 A similar phenomenon has been 
observed in various tumors when treated with immunotherapeutic agents, in which transient 
enlargement of lesions or appearance of new lesions is attributable to the influx of immune cells. 
These potential immune treatment effects complicate the evaluation of response and may lead to 
premature discontinuation of therapy. Furthermore, the time period to pseudoprogression or tumor 
flare with different immune therapies varies in different malignancies. See Appendix 6 for the 
management of tumor flare for subjects enrolled in this study. 
Subjects treated with nivolumab will be permitted to continue nivolumab treatment beyond initial 
progressive disease, assessed by the investigator, as long as they meet the following criteria:

Investigator-assessed clinical benefit

Tolerance of study drug

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases or from mass effect)

Subject provides written informed consent prior to receiving additional nivolumab treatment
All other elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply.
A radiographic assessment/scan should be performed within 8
weeks of 
initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor size 
or continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab.
If the investigator considers that the nivolumab subject continues to achieve clinical benefit by 
continuing treatment, the subject should remain on the trial and continue to receive monitoring 
according to the time and events schedule in Section 5.1.
If at the radiographic assessment/scan at 8 weeks of initial investigator-assessed progression 
(based on IPCG for brain in PCNSL, or Lugano for systemic disease and potential brain/spine 
lesions in PTL) the assessment determines continued PD but all the above criteria are met and the 
investigator considers the subject continues to achieve clinical benefit by continuing treatment, the 
subject may remain on the trial and continue to receive treatment and monitoring according to the 
time and events schedule in Section 5.1. Potential for clinical benefit should be balanced by clinical 
judgment as to whether the subject is clinically deteriorating and unlikely to receive benefit from 
continued treatment with nivolumab. 
A second radiographic assessment/scan should be performed within 8 weeks of second 
investigator-assessed progression to determine whether there has been a decrease in the tumor size 
or continued PD (based on IPCG for brain in PCNSL, or Lugano for systemic disease and potential 
brain/spine lesions in PTL). If this second 8-week radiographic assessment/scan determines 
continued PD, then the patient should discontinue therapy and enter the follow-up period.
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4.5.7
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an I-O agent in this 
protocol. Early recognition and management of AEs associated with I-O agents may mitigate 
severe toxicity. Management algorithms have been developed to assist investigators in assessing 
and managing the following groups of AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy

Skin

Neurological
The above algorithms are found in the nivolumab Investigator Brochure64 and Appendix 5 of this 
protocol.
4.5.8
Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgia, 
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 National Cancer 
Institute (NCI) CTCAE v4.03 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 required therapy or infusion interruption but responded
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
24 hours):
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
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/or bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% 
of the original infusion rate. Monitor subject closely. If symptoms recur, then no further 
nivolumab will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms (Grade 3: severe reaction, prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion], recurrence of symptoms following 
initial improvement, hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]; Grade 4: life threatening, pressor or ventilatory support indicated):

Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as subject’s medical record 
and CRF.
4.8
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. 
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Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
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 standard operating procedures and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study drug.
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.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Assessments (CA209647)
Procedure
Screening
Visit
Notes (Screening procedures are to occur within 28 days prior to first dose unless 
otherwise specified)
Eligibility Assessment
Informed Consent
X
This study permits the re-enrollment of a subject that has discontinued the study as a pre-
treatment failure (ie, subject has not been treated). If re-enrolled, the subject must be re-
consented and assigned a new subject number by the IVRS.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening
Medical History
X
Prior Systemic Therapy
X
Prior Radiation Therapy
X
Prior Surgery
X
Safety Assessments
Complete Physical Examination
X
Include assessment of lymph node areas (eg, submandibular, cervical, supraclavicular, axillary, 
or inguinal lymph node), abdominal organs (eg, spleen) and neurological examination
Performance Status
X
Karnofsky Performance Status
Vital Signs
X
Temperature, BP, HR.
Assessment of Signs and Symptoms
X
Required for the 28 days prior to first dose
Concomitant Medication Collection
X
Required for the 28 days prior to first dose
Laboratory Tests
X
CBC with differential, chemistry panel including LDH, AST, ALT, ALP, albumin, TBILI, 
BUN or serum urea level, uric acid, creatinine, phosphate, Ca, Mg, Na, K, Cl, glucose, 
amylase, lipase, TSH, Free T3, Free T4 within 14 days prior to first dose.
HIV, Hepatitis B surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) or HCV 
ribonucleic acid (RNA) within 28 days prior to first dose. 
Pregnancy Test
X
For WOCBP (Refer to Section 3.3.3) only and must be done within 24 hours of first dose
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Table 5.1-1:
Screening Assessments (CA209647)
Procedure
Screening
Visit
Notes (Screening procedures are to occur within 28 days prior to first dose unless 
otherwise specified)
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Table 5.1-1:
Screening Assessments (CA209647)
Procedure
Screening
Visit
Notes (Screening procedures are to occur within 28 days prior to first dose unless 
otherwise specified)
 
 
 
.
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Table 5.1-2:
On Treatment Procedures (CA209647)
Procedure
Cycle 1
Day 1
Cycle 2 & Beyond, 
Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified. Cycle 
duration is 2 weeks until 8 doses have been completed; 
subsequent cycles are 4 weeks in duration.
Safety Assessments
Targeted Physical Examination
X
X
Include assessment of lymph node areas (eg, submandibular, 
cervical, supraclavicular, axillary, or inguinal lymph node), 
abdominal organs (eg, spleen) and neurological examination 
Vital Signs
X
X
Temperature, BP, HR
Adverse Events Assessment
---------------------Continuously-----------------------
Assessed using NCI CTCAE v. 4.03
Review of Concomitant 
Medications
X
X
Physical Measurements
X
X
Includes weight 
Karnofsky Status
X
X
Laboratory Tests
X
To be done within 72 hours prior to dosing and include: CBC with 
differential, uric acid, BUN or serum urea level, creatinine, Ca, Mg, 
K, Cl, Na, amylase, lipase, glucose, phosphate, AST, ALT, TBILI, 
ALP, albumin, LDH.
Cycle 1 Day 1: Laboratory tests do not need to be repeated if 
performed within 14 days prior to first dose.
Thyroid Function Testing
See Note
Thyroid function testing (TSH with reflexive fT3 and fT4) is to be 
done every 6 weeks (every 3 infusions) for subjects receiving 
nivolumab at 240 mg Q2W, then every 8 weeks for subjects 
receiving nivolumab at 480 mg qw4 (every other infusion)
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 (1 week) regardless of dosing schedule.
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Table 5.1-2:
On Treatment Procedures (CA209647)
Procedure
Cycle 1
Day 1
Cycle 2 & Beyond, 
Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified. Cycle 
duration is 2 weeks until 8 doses have been completed; 
subsequent cycles are 4 weeks in duration.
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Table 5.1-2:
On Treatment Procedures (CA209647)
Procedure
Cycle 1
Day 1
Cycle 2 & Beyond, 
Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified. Cycle 
duration is 2 weeks until 8 doses have been completed; 
subsequent cycles are 4 weeks in duration.
Outcomes Research Questionnaire
EQ-5D 3L (PCNSL and PTL 
cohorts)
EORTC QLQ C30 (PCNSL and 
PTL cohorts)
EORTC QLQ-BN20 (PCNSL 
only)
X
X
Subjects will be asked to complete the questionnaires prior to dosing 
Day 1 Week 1 and then prior to each radiographic tumor assessment. 
Refer to Section 5.6.6 for more information.
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Table 5.1-2:
On Treatment Procedures (CA209647)
Procedure
Cycle 1
Day 1
Cycle 2 & Beyond, 
Day 1
Notes
All windows proposed are calendar days. Procedures must be 
done within 72h prior to dosing unless otherwise specified. Cycle 
duration is 2 weeks until 8 doses have been completed; 
subsequent cycles are 4 weeks in duration.
PK and Immunogenicity Assessments
PK and Immunogenicity Samples
See Table 5.5-1 for sampling details.
Paired CSF and Blood PK and 
Samples 
See Table 5.5.2 for sampling details.
Clinical Drug Supplies
Administer nivolumab
X
X
Subjects should receive nivolumab at a dose of 240 mg as a 
30-minute infusion on Day 1 of each treatment cycle for 8 cycles 
until Q4W dosing begins. Subjects may be dosed no less than 
12 days from the previous dose. For Q2W dosing cycles, subjects 
may be dosed within a 2-day window. Beginning with Cycle 9, 
subjects should receive nivolumab at a dose of 480 mg as a 
30-minute infusion every 4 weeks (3 days) for a maximum 2 years
of total treatment, or until PD, unacceptable toxicity, or withdrawal 
of consent.
IVRS
IVRS must be called up to 3 days prior to each dosing visit
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Table 5.1-3:
Follow-up Assessments (CA209647)
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), abdominal organs (eg, spleen) 
and neurological examination
Adverse Events Assessment
X
Laboratory Tests
X
Required for X01: 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).
Panel should also be performed at X02 if X01 results were 
abnormal.
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 stem cell transplant: To be assessed on Day 100, at 
6 months, at 1 year, and every year thereafter from the date of 
transplant until the first non-CR after SCT is documented. See 
Section 5.3.
Efficacy Assessments
Radiographic Tumor Assessment
Gadolinium-enhanced MRI of the brain
Gadolinium-enhanced MRI of the spine
FDG PET-CT
X
X
Only for subjects without documented progression at the end 
of treatment:
Tumor assessments in both PCNSL and PTL cohorts will occur 
every 6 months until disease progression or subsequent treatment
Subsequent Anticancer Therapy
X
X
Other Primary Malignancies
X
X
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Table 5.1-3:
Follow-up Assessments (CA209647)
Procedure
Follow Up,
Visits 1 and 2a
(X01 & X02)
Survival 
Follow-Up 
Visitsb
Notes
Eye Examination
(PCNSL and PTL with brain involvement)
X
Detailed ophthalmological examination with dilated fundus 
examination, slit lamp examination, and color photography of the 
exterior pole (only if positive findings at screening and for 
confirmation of response)
 
 
 
 
 
 
 
 
 
 
.
a Follow-up visit 1 (FU1) = 35 days from the last dose 7 days. Follow-up visit 2 (FU2) = 84 days (7 days) from follow-up visit 1.
b Survival follow-up visits to occur every 3 months (14 days) from FU2. BMS may request that survival data be collected on all treated subjects outside of the 
3-month specified window. At the time of this request, each subject will be contacted to determine their survival status unless the subject has withdrawn consent 
for all contact.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result and is the value by which study inclusion will be 
assessed, as it represents the subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1 may be repeated in an 
effort to find all possible well-qualified subjects. Consultation with the Medical Monitor may be 
needed to identify whether repeat testing of any particular parameter is clinically relevant.
5.2
Study Materials

NCI CTCAE version 4.03

Nivolumab Investigator Brochure64

Pharmacy Binder

Laboratory manuals for collection and handling of blood (including PKs, biomarker and 
immunogenicity) and tissue specimens

Site manual for operation of IVRS, including enrollment worksheet

Manual for submission of local laboratory results

QoL questionnaires

Pregnancy Surveillance Forms

Imaging Manual

Patient Alert Card
5.3
Safety Assessments
At screening, a medical history will be obtained to capture relevant underlying conditions. The 
screening examinations should include weight, height, Karnofsky status, blood pressure (BP), 
heart rate (HR), and temperature. 
Screening local laboratory assessments should be done within 14 days prior to treatment 
assignment and are to include: CBC with differential, chemistry panel including LFTs (ALT, AST, 
TBILI, ALP), amylase, lipase, uric acid, BUN or serum urea level, creatinine, Ca, Na, K, Cl, Mg, 
albumin, phosphate, LDH, glucose, and thyroid panel including TSH, free T3, and free T4.
Pregnancy tests for WOCBP must be performed within 24 hours prior to the initial administration 
of study drug. 
The following screening local laboratory assessments should be done within 28 days prior to 
treatment: Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA), and HIV testing.
While on-study the following local laboratory assessments are to be done within 3 calendar days 
prior to each dose:  CBC with differential, LFTs (ALT, AST, TBILI, ALP), BUN or serum urea 
level, creatinine, Ca, Mg, Na, K, Cl, phosphate, LDH, uric acid, amylase, lipase, albumin, glucose. 
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Thyroid function testing (TSH with reflexive fT3 and fT4) is to be done every 6 weeks 
(every 3 infusions) for subjects receiving nivolumab at 240 mg Q2W, then every 8 weeks for 
subjects receiving nivolumab at 480 mg Q4W (every other infusion).
On treatment pregnancy tests should be performed as per the schedule in the time and events table
(Table 5.1-2).
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase as well as during the first 2 safety follow-up visits. 
Once subjects reach the survival follow-up phase, either in-person visits or documented telephone 
calls to assess the subject’s status are acceptable.
For subjects who discontinue study therapy by proceeding to allogeneic stem cell transplant, 
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 transplant is 
documented. 
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.
Adverse events and laboratory values will be graded according to the NCI CTCAE version 4.03.
The start and stop time of the study therapy infusions and any interruptions or infusion rate 
reductions 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 SAE page.
On treatment local laboratory assessments are to be completed within 3 calendar days prior to 
dosing.
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 evaluations) 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.
If a subject shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary AEs, the subject should be immediately evaluated to 
rule out pulmonary toxicity, according to the suspected pulmonary toxicity management algorithm
(Appendix 5) and in the nivolumab Investigator Brochure.64
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
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5.3.1
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study investigator as per standard 
medical/clinical judgment. Additional details are provided in the study Imaging Manual.
Radiographic tumor assessments for PCNSL or PTL will be performed (Section 5.1).
5.4
Efficacy Assessments
Radiographic images will be collected for BICR.
5.4.1
Assessment of Overall Tumor Burden and Disease
Efficacy assessment will be conducted and reported on the eCRF using the appropriate efficacy 
assessment based on tumor type. Subjects with PCNSL will be evaluated using the modified 
International PCNSL Collaborative Group (IPCG) Criteria for PCNSL (Appendix 3), while 
subjects with PTL will be evaluated using the Lugano 2014 Classification (Appendix 4). 
The primary efficacy endpoint is ORR based on BICR assessment. BICR will also be used for the 
assessment of the secondary endpoint PFS. Investigator assessments will be also be used for the 
ORR and DOR secondary endpoints and the PFS exploratory endpoint.
Efficacy assessments will be required as follows (Section 5.1):

PCNSL (Appendix 3)

PTL (Appendix 4)
Baseline Staging 
PCNSL
All PCNSL subjects will undergo gadolinium-enhanced MRI of the brain (and of the spine for 
subjects with spinal symptoms) at the timepoints specified in Table 5.1-1and Table 5.1-2 for 
baseline assessment and on study response assessment purposes. Investigators may obtain more 
frequent follow-up MRI scans as medically indicated. Local radiologic assessment of tumor 
measurements will be used for clinical management and investigator-assessed clinical endpoints.
Subjects who are unable (due to existent medical condition, ie, pacemaker or implantable 
cardioverter-defibrillator device) or unwilling to have a brain MRI at baseline are excluded from 
the study (Section 3.3.4). Subjects who become unable to undergo MRI imaging after enrollment 
may continue in the study for assessment of OS as long as there is no safety issue which would 
require monitoring by MRI. 
Study sites will retain local access to the imaging results for safety and efficacy reading purposes. 
The study investigator will review the local MRI results as clinically appropriate to ensure that any 
potentially emergent clinical situations are addressed in a timely fashion. Clinically significant 
radiologic findings or changes from baseline scans will be coded as AEs or SAEs according to the 
criteria described below in Section 6. 
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At baseline, for staging purposes all PCNSL subjects will undergo the following procedures:

Gadolinium-enhanced MRI of the brain

Gadolinium-enhanced MRI of the spine (for subjects with spinal symptoms)

Whole-body FDG-PET or CT scan of the neck, chest, abdomen, pelvis, and other relevant body 
parts with suspected or known disease (to exclude patients with systemic disease)

Lumbar puncture for CSF cytology (before/1 week after surgical biopsy, when applicable)

Detailed ophthalmological examination, with dilated fundus examination, slit-lamp 
examination, and color photography of the posterior pole 

Bone marrow biopsy with aspirate, only if clinically indicated. 
If MRI of the spine, ophthalmological examination, CSF cytology, or bone marrow biopsy are 
positive for lymphoma involvement at baseline, these tests must be repeated for confirmation of 
objective response.
PTL
All PTL subjects will undergo fluorodeoxyglucose (FDG) PET-CT scans at the timepoints 
specified in Table 5.1-3 for baseline assessment and on study response assessment purposes. 
Investigators may obtain more frequent follow-up FDG PET-CT scans as medically indicated. 
Local radiologic assessment of tumor measurements will be used for clinical management and 
investigator-assessed clinical endpoints.
Study sites will retain local access to the imaging results for safety and efficacy reading purposes. 
The study investigator will review the local FDG PET-CT results as clinically appropriate to 
ensure that any potentially emergent clinical situations are addressed in a timely fashion. Clinically 
significant radiologic findings or changes from baseline scans will be coded as AEs or SAEs
according to the criteria described below in Section 6. 
At baseline, for staging purposes all PTL subjects will undergo the following procedures: 

FDG PET/CT scan

Gadolinium-enhanced MRI of the brain

Gadolinium-enhanced MRI of the spine (in subjects with spinal symptoms)

Bone marrow biopsy with aspirate, if clinically indicated

Lumbar puncture for CSF cytology, if clinically indicated

Eye examination for PTL patients with CNS involvement
If brain and/or spine MRI, bone marrow biopsy, or CSF cytology are positive for lymphoma 
involvement at baseline, these tests must be repeated for confirmation of objective response.
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On-study Assessment of Response 
PCNSL
Assessment of treatment response in subjects with PCNSL while on study requires the following 
assessments:

Gadolinium-enhanced MRI scan of the brain 

Gadolinium-enhanced MRI scan of the spine, if positive at baseline or if clinically indicated

Detailed ophthalmological examination with dilated fundus examination, slit-lamp 
examination, and color photography of the posterior pole, if clinically indicated and for 
confirmation of objective response

Whole-body CT scan, if clinically indicated

Lumbar puncture for CSF cytology, if clinically indicated

Bone marrow biopsy with aspirate, if clinically indicated
The criteria for response assessment are illustrated in Appendix 3. Additionally, objective response 
requires confirmation by repeat brain MRI at 8 weeks from the initially documented response. If
MRI of the spine, ophthalmological examination, CSF cytology, or bone marrow biopsy are 
positive for lymphoma involvement at baseline or on-study when warranted by symptoms, these 
tests should be also repeated at 8 weeks for confirmation of objective response.
PTL
Assessment of treatment response in subjects with PTL while on study requires the following 
assessments:

FDG PET-CT scan

Bone marrow biopsy with aspirate, if clinically indicated

Gadolinium-enhanced MRI scan of the brain and/or of the spine, if clinically indicated

Lumbar puncture for CSF cytology, if clinically indicated

Eye examination for PTL patients with CNS involvement
The criteria for response evaluation in PTL patients are described in Appendix 4. Additionally, 
objective response requires confirmation by repeat brain MRI at 8 weeks from the initially 
documented response (only for patients with CNS involvement per IPCG criteria). If bone marrow 
biopsy, brain and/or spine MRI, or CSF cytology are positive for lymphoma involvement at 
baseline or on-study when warranted by symptoms, these tests should be also repeated at 8 weeks
for confirmation of objective response.
Radiographic Assessments
Radiographic study evaluations will take place as outlined in Section 5.1.
Baseline assessments should be performed within 28 days prior to the first dose (14 days for MRI 
of the brain). A whole-body PET/CT is required at baseline for all subjects. 
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On-study assessments should include chest, abdomen, and pelvis, and all known sites of disease 
(including CNS and/or spine) and should use the same imaging method that was used at baseline. 
PCNSL subjects will be evaluated for tumor response by MRI at Week 8 from the first dose and 
continuing for every 8 weeks for the first 2 years (104 weeks). PTL subjects will be evaluated for 
tumor response by FDG-PET/CT or PET/MRI at Week 8 from the first dose and continuing for 
every 8 weeks for the first 6 months (26 weeks), then every 12 weeks for 18 months. After the first 
2 years, tumor assessments are to occur every 24 weeks until disease progression is documented.
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. At baseline, tumor lesions/lymph 
nodes will be categorized as measurable or non-measurable.
Measurable Lesions 

Focal uptake in nodal and extranodal sites that is in keeping with lymphoma, according to the 
distribution and/or CT characteristics, is considered involvement with lymphoma, including 
spleen, liver, bone, thyroid, and so on. 

Measured dominant lesions: Up to 6 of the largest dominant nodes, nodal masses, and 
extranodal lesions selected to be clearly measurable in 2 diameters. 

Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. A measurable node must have a longest 
diameter (LDi) > 1.5 cm. 

Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI 
involvement, cutaneous lesions, or those noted on palpation. A measurable extranodal 
lesion must have a LDi > 1.0 cm and may be included in the 6 representative, measured 
lesions (eg, hepatic nodules).

A sum of the product of the diameters (SPD) will be calculated for all target lesions (CNS and 
non-CNS) 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.
CT Measurements
For subjects staged with CT, up to 6 of the largest target nodes, nodal masses, or other 
lymphomatous lesions that are measurable in 2 diameters (LDi and shortest diameter) should be 
identified from different body regions representative of the patient’s overall disease burden and 
include mediastinal and retroperitoneal disease, if involved. A measurable node must have a LDi 
greater than 1.5 cm. Measurable extranodal disease (eg, hepatic nodules) may be included in the 6 
representative, measured lesions. For extranodal measurable lesion the LDi must be greater than 
1.0 cm. All other lesions (including nodal, extranodal, and assessable disease) should be followed 
as non-measured disease (eg, cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).
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Non-Measurable Lesions
Besides small lymph nodes (longest diameter < 10 mm), truly non-measurable lesions include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, or abdominal masses/abdominal organomegaly 
identified by physical exam that are not measurable by reproducible imaging techniques.
Any disease not selected as measured, dominant disease and truly assessable disease should be 
considered not measured. These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or that do not meet the requirements for measurability but are 
still considered abnormal, as well as truly assessable disease, which is any site of suspected disease 
that would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic 
response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow 
activation as a result of chemotherapy or myeloid growth factors).
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 CRF (eg, ‘multiple enlarged pelvic lymph nodes’ or multiple liver nodules’).
Bone Marrow Assessments
Bone marrow assessments should be done only if clinically indicated in both subjects with PCNSL 
or PTL. The biopsy/aspirate performed within 90 days prior to obtaining informed consent must 
be documented at screening or a bone marrow biopsy/aspirate must be performed during the 
screening period if clinically indicated. For PCNSL or PTL subjects with bone marrow 
involvement at screening, a bone marrow biopsy and aspirate will be required to confirm an 
objective response.
In addition to efficacy assessments, additional, optional, bone marrow biopsy and aspirate samples 
may be collected and submitted for biomarker studies.
CSF Assessments
CSF cytology should be done if clinically indicated. If performed within 90 days prior to obtaining 
informed consent they must be documented at screening or a lumbar puncture must be performed 
during the screening period. For PCNSL or PTL subjects with CSF involvement at screening, a 
lumbar puncture with CSF collection will be required to confirm an objective response.
 
 
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is an objective, quick, user-friendly and quantifiable evaluation of nine major domains for subjects 
with brain tumors. The domains include: gait, strength, ataxia, sensation, visual field, facial 
strength, language, level of consciousness, behavior and overall. Each domain is rated on a scale 
of 0 to 3 where 0 represents normal and 3 represents the worst severity. A given domain should be 
scored non-evaluable if it cannot be accurately assessed due to preexisting conditions, co-morbid 
events and/or concurrent medications. The evaluation is based on direct observation/testing 
performed during routine office visits. 
The NANO scale will be completed by the investigator or designated study physician prior to 
dosing on Day 1 Week 1 and then with each MRI (but must be completed before MRI scan results 
are reviewed with the subject).
5.5
Pharmacokinetic and CSF Biomarker Assessments
Blood samples for PK and immunogenicity assessments will be collected in all subjects. Paired 
 blood samples for PK 
 will also be collected in patients who consent to 
having lumbar punctures performed. Table 5.5-1 lists the sampling schedule to be followed for 
routine PK and immunogenicity samples. Blood samples should be drawn from a site other than 
the infusion site (ie, contralateral arm) on days of the infusion. All samples collected predose 
should be taken just prior to nivolumab administration, and end-of-infusion (EOI) samples should 
be taken as close to EOI as possible (preferably 2 minutes prior to EOI) on the contralateral arm 
(ie, the arm not for the infusion). All on-treatment PK time points are intended to align with days 
on which nivolumab is administered. If it is known that a dose is going to be delayed, then the 
predose sample should be collected just prior to the delayed dose. However, if a predose sample 
is collected but the dose is subsequently delayed, an additional predose sample should not be 
collected. Table 5.5-2 lists the sampling schedule to be followed for paired
 blood samples. 
For those patients who are on-study prior to Revised Protocol 04, sampling should begin with the 
cycle the patients are on, according to Table 5.5-2. Further details of blood collection, 
collection, processing, labeling, handling, storage, and shipment of samples will be provided in 
the Procedure Manual.
Table 5.5-1:
Pharmacokinetic & Immunogenicity Blood Sampling Schedule
Study Day
C1 – C8: 2-week cycles
C9 and beyond: 4-week 
cycles
Event
Time 
(Relative to Start of 
Infusion)
Hour: Min
Nivolumab PK
Blood Sample
Nivolumab 
Immunogenicity 
Sample
C1D1
predosea
00:00
X
X
C3D1
predosea
00:00
X
X
C7D1
predosea
00:00
X
X
C9D1
predosea
00:00
X
X
C9D1
EOIb
00:30
X
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Table 5.5-1:
Pharmacokinetic & Immunogenicity Blood Sampling Schedule
Study Day
C1 – C8: 2-week cycles
C9 and beyond: 4-week 
cycles
Event
Time 
(Relative to Start of 
Infusion)
Hour: Min
Nivolumab PK
Blood Sample
Nivolumab 
Immunogenicity 
Sample
C10D1
predosea
00:00
X
C13D1
predosea
00:00
X
X
C17D1
predosea
00:00
X
X
C21D1
predosea
00:00
X
X
D1 of every 6th cycle 
(24 weeks) after C21 
predosea
00:00
X
X
a All predose samples should be taken just prior to the start of nivolumab infusion (preferably within 30 minutes)
b EOI samples should be taken as close to the end of infusion as possible (preferably two minutes prior to EOI) on 
the contralateral arm (ie, the arm not for the infusion). Study sites should ensure accurate collection of the time and 
date for PK and immunogenicity assessment are obtained.
 
 
 
 
 
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y
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.7
Outcomes Research Assessments
Outcomes research data including health-related quality of life (QoL) and patient-reported 
symptom burden provide a more complete understanding of the impact of treatment by 
incorporating the patients’ perspective. Treatment-related toxicities have been identified as a 
significant problem in both PCNSL, where neurotoxicity has been attributed to cognitive 
dysfunction, and in PTL, where patient age has reduced tolerance to aggressive chemotherapies. 
The importance of capturing patient-reported outcomes data has become critically important as 
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symptom management and maintaining QoL are key metrics for assessing overall treatment 
benefit.
5.7.1
EORTC QLQ-C30 and BN20
The EORTC QLQ-C3068 is the most commonly used quality of life instrument in oncology trials. 
The instrument’s 30 items are divided among 5 functional scales (physical, role, cognitive, 
emotional, and social), 9 symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties), and a global health/quality of life 
scale. With the exception of 2 items included in the global health/quality of life scale, for which 
responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 
(Very much). Reduced cognitive function has been recognized as a significant problem in patients 
treated for PCNSL, and previous research has supported the validity of the cognitive functioning 
scale of the QLQ-C30 in a variety of populations. The EORTC QLQ-BN2069 is a validated 
measure of concerns and symptoms specific to brain neoplasms. The questionnaire’s 20 items are 
divided among multi-item scales measuring future uncertainty (4 items), visual disorders (3 items), 
motor dysfunction (3 items), and communication deficits (3  items), as well as single-item 
measures of problems with headaches, seizures, drowsiness, itchy skin, hair loss, lower extremity 
weakness, and bladder control. Each of the questionnaire’s items uses a 4-point response scale 
ranging from 1 (Not at all) to 4 (Very much). Raw scores for the QLQ-C30 and QLQ-BN20 are 
transformed to a 0-100 metric such that higher values indicate better functioning or QoL or a higher 
level of symptoms. The QLQ-C30 will be administered to all treated subjects in both the PCNSL 
and PTL cohorts, while the QLQ-BN20 will be administered to all treated subjects in the PCNSL 
cohort, during the on-study and follow-up phases as outlined in Section 5.1.
5.7.2
EQ-5D 3L
The EQ-5D-3L70 is a generic multi-attribute health-state classification system by which health is 
described in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension is evaluated using 3 levels: no problems, some problems, and 
severe problems. Responses to these 5 dimensions are converted into 1 of 243 unique EQ-5D 
health state descriptions, which range between no problems on all 5 dimensions (11111) to 
severe/extreme problems on all 5 dimensions (33333). Using appropriate country-specific value 
weighting algorithms, a respondent’s self-described health state can be converted into a utility 
representing the societal desirability of his/her own health. In addition, the EQ-5D includes a visual 
analogue scale (VAS) allowing a respondent to rate his/her health on a scale ranging from 0–100 
with 0 being the worst health state imaginable and 100 being the best health state imaginable. The 
EQ-5D-3L will be administered to all treated subjects in both the PCNSL and PTL cohorts during
the on-study, follow-up, and survival follow-up phases as outlined in Section 5.1.  
5.8
Other Assessments
5.8.1
Immunogenicity Assessments
Serum samples collected at timepoints identified in Section 5.1 will be analyzed by a validated 
immunogenicity assay. Additional characterization (ie, neutralizing antibodies) for any detected 
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anti-drug antibodies (ADA) response to nivolumab may also be performed using a validated 
functional cell-based assay. All on-treatment timepoints are intended to align with days on which 
study drug is administered, if dosing occurs on a different day, the immunogenicity sampling 
should be adjusted accordingly. Selected serum samples may be analyzed by an exploratory 
method that measures anti-nivolumab for technology exploration purposes; exploratory data will 
not be reported.
In addition, serum samples designated for PK or biomarker assessments may also be used for 
immunogenicity analysis if required (eg, insufficient volume for complete immunogenicity 
assessment or to follow up on suspected immunogenicity related AE).
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
AEs. The causal relationship can be 1 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.)
Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated 
mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection 
or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology 
which were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the subject’s CRF.
BMS will be reporting AEs to regulatory authorities and ethics committees according to local 
applicable laws including European Directive 2001/20/EC and FDA Code of Federal Regulations 
21 CFR Parts 312 and 320.
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

Results in death

Is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)

Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect 

Is an important medical event (defined as a medical event[s] that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug-induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)

Admission for administration of anticancer therapy in the absence of any other SAEs (see 
NOTE below) 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential 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.
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
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure64 represent the Reference Safety Information 
to determine expectedness of SAEs for expedited reporting. Following the subject’s written 
consent to participate in the study, all SAEs, whether related or not related to study drug, must be 
collected, including those thought to be associated with protocol-specified procedures. All SAEs 
must be collected that occur during the screening period and within 100 days of the last dose of 
nivolumab. For subjects assigned to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of treatment assignment. If applicable, SAEs must be collected 
that relate to any later protocol-specified procedure (eg, a follow-up biopsy). 
The investigator must 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 must be completed for any event where doubt exists regarding its seriousness. 
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 must 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 of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning.
In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture, electronic submission is the required 
method for reporting. In the event the electronic system is unavailable for transmission, paper 
forms must be used and submitted immediately. When paper forms are used, the original paper 
forms are to remain on site.
SAE Telephone Contact (required 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 must include the same investigator term[s] initially reported.) 
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If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
A SUSAR (Suspected, Unexpected Serious Adverse Reaction) is a subset of SAEs and will be 
reported to the appropriate regulatory authorities and investigators following local and global 
guidelines and requirements.
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6.2
Nonserious Adverse Events
A nonserious AE 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). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
All nonserious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
Every AE must be assessed by the investigator with regard to whether it is considered immune-
mediated. For events which are potentially immune-mediated, additional information will be 
collected on the subject’s CRF.
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 electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at 
approximately 5 half-lives after product administration, the investigator must immediately notify 
the BMS Medical Monitor/designee of this event and complete and forward a Pregnancy 
Surveillance Form to BMS Designee within 24 hours of awareness of the event and in accordance 
with SAE reporting procedures described in Section 6.1.1.
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In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy.
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 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3xULN
AND
2. Total bilirubin > 2xULN, 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.
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7
BLINDED INDEPENDENT CENTRAL REVIEW
A blinded independent central review will be conducted of the images and relevant clinical data in 
this study. The activities and processes regarding the independent read will be outlined in the 
CA209-647 Imaging Review Charter.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The planned sample size for this study will be approximately 65 treated subjects, placed into 
2 cohorts of subjects: PCNSL (N = 45), and PTL (N = 20).
In addition, Table 8.1-1 summarizes the 95% exact confidence interval (CI) for the target ORRs 
ranging from 28.9% to 60% with sample size of 20 and 45. At observed ORR 28.9% with 
45 PCNSL subjects, the lower bound of the 95% CI excludes the historical response rates in of 
14% in recurrent primary central nervous system lymphoma 41. At observed ORR ≥ 40% with 20 
PTL subjects, the lower bound of the 95% CI excludes the response rate of 14%. 
The sample size for the PCNSL cohort was empirically determined to support expanded 
assessment of the benefit-risk profile of nivolumab in PCNSL through observation of less common 
safety events. In particular, administration of nivolumab to 45 subjects provides 90% probability 
of observing at least 1 occurrence of any AE that would occur with 5% incidence in the population 
from which the sample is drawn.
Table 8.1-1:
Observed ORR with Exact 95 % CI
N
ORR
95% Exact CI
20
30%
[11.9% - 54.3%]
35%
[15.4% - 59.2%]
40%
[19.1% - 63.9%]
50%
[27.2% - 72.8%]
60%
[36.1% - 80.9%]
45
28.9% 
[16.4% - 44.3%]
40.0% 
[25.7% - 55.7%]
51.1% 
[35.8% - 66.3%]
60%
[44.3% - 74.3%]
8.2
Populations for Analyses
Within each cohort the following populations will be defined:

All Enrolled Subjects: All subjects who signed an ICF and were registered into the IVRS

All Treated Subjects: All subjects who received at least 1 dose of nivolumab. This is the 
primary population for safety and efficacy analyses
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
PK Subjects: All subjects with available serum time-concentration data from subjects dosed 
with nivolumab

Immunogenicity Evaluable Subjects: All treated subjects with baseline and at least 
1 postbaseline immunogenicity assessment
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective will be measured by the primary endpoint of BICR-assessed ORR. It is 
defined as the number of subjects with a best overall response (BOR) of CR or PR, based on the 
IPCG Criteria for PCNSL21 and Lugano 2014 response evaluation for PTL,22 divided by the 
number of treated subjects within each cohort. 
The BICR-assessed BOR is defined as the best response designation recorded between the date of 
first study drug dose and the date of initial objectively documented progression per criteria or the 
date of subsequent therapy, whichever occurs first. 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 BICR-assessed objective response will be further characterized by the DOR, defined as the 
time from first response (CR or PR) to the date of initial objectively documented progression as 
determined using the IPCG Criteria for PCNSL and Lugano 2014 response evaluation for PTL, as 
determined by BICR, 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 tumor assessment. Subjects 
who start subsequent anticancer therapy without a prior reported progression will be censored at 
the last 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 analysis of the primary endpoint in each cohort will occur at least 6 months after last patient 
first treatment in each cohort.
8.3.2
Secondary Endpoint(s)
Secondary endpoints will be analyzed at the same time as the primary endpoint.
8.3.2.1
Progression Free Survival Based on BICR Assessment
PFS is defined as the time from first dosing date to the date of the first documented progression 
using the IPCG Criteria for PCNSL and Lugano 2014 response evaluation for PTL, as determined 
by BICR, 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 tumor 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 tumor assessment prior to initiation of the subsequent anti-cancer therapy.
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8.3.2.2
Objective Response Rate and Duration of Response Based on 
Investigator Assessment
Investigator-assessed ORR and DOR are defined similarly as described for ORR and DOR per 
BICR assessment above, but will be assessed per investigator.
8.3.2.3
Overall Survival
OS is defined as the time from first dosing date to the date of death. For subjects without
documentation of death, OS will be censored on the last date the subject was known to be alive.
 
 
 
 
 
8.4
Analyses
All analyses will be performed separately for each cohort.
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline laboratory results will be summarized using descriptive statistics for all 
treated subjects.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods
The BICR-assessed ORR will be summarized by binomial response rates and their corresponding 
two-sided 95% exact CI using the Clopper-Pearson method.
The BICR-assessed DOR will be summarized by cohort for subjects who achieve PR or CR using 
the Kaplan-Meier 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. 
8.4.2.2
Secondary Endpoint Methods
The BICR-assessed PFS will be summarized by the Kaplan-Meier product-limit method. Median 
values along with two-sided 95% CIs based on the log-log transformation, will be calculated. 
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BICR-assessed PFS will be evaluated in all treated subjects. The BICR-assessed PFS rate at 6, 12, 
and 24 months will also be calculated.
The analysis of ORR per investigator is similar as ORR analysis per BICR, but based on 
investigator assessment.
The analysis of DOR per investigator is similar as DOR analysis per BICR, but based on 
investigator assessment.
OS will be summarized by the Kaplan-Meier product-limit method. Median values along with two-
sided 95% CIs based on the log-log transformation, will be calculated. OS will be evaluated in all 
treated subjects. OS rate at 6, 12, and 24 months will also be calculated.
 
8.4.3
Safety Analyses
The safety analysis will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.03 by treatment group. AEs, drug-related AEs, SAEs, and 
drug-related SAEs will be tabulated using worst grade per NCI CTCAE v.4.03 criteria by system 
organ class and preferred term. On-study lab parameters including hematology, chemistry, liver 
function, and renal function will be summarized using worst grade per NCI CTCAE v.4.03 criteria.
8.4.4
Pharmacokinetic Analyses
The nivolumab concentration-time data obtained in this study may be analyzed separately or 
combined with data from other studies in the clinical development programs to develop or refine 
population PK models. These models may be used to evaluate the effects of intrinsic and extrinsic 
covariates on the PK of nivolumab and to determine measures of individual exposure (such as 
steady-state peak, trough, and time-averaged concentration). In addition, model-determined 
exposures may be used for exposure-response analyses. Results of population PK and exposure-
response analyses would be reported separately.
8.4.6
Outcomes Research Analyses
Analyses will be done by cohort.
8.4.6.1
EORTC QLQ-C30 and QLQ-BN-20
All randomized subjects who have an assessment at baseline and at least 1 subsequent assessment 
while on treatment will be analyzed. Questionnaire completion rates at each assessment at each 
timepoint will be estimated for both the QLQ-C30 and the QLQ-BN20. Scores and post-baseline 
changes in scales of the EORTC QLQ-C30 and the QLQ-BN20 will be summarized at each 
assessment timepoint using appropriate descriptive statistics (ie, N, mean with standard deviation 
and 95% CI, median, first and third quartiles, minimum, maximum).
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8.4.6.2
EQ-5D -3L
All randomized subjects who have an assessment at baseline and at least 1 subsequent assessment 
while on treatment will be analyzed. Questionnaire completion rates at each assessment at each 
timepoint will be estimated for both the EQ-5D-3L VAS, and EQ-5D-3L utility index. Scores and 
post-baseline changes in scores for the EQ-5D-3L VAS and EQ-5D-3L utility index will be 
summarized at each assessment timepoint using appropriate descriptive statistics (ie, N, mean with 
SD and 95% CI, median, first and third quartiles, minimum, maximum). UK preference-weighting 
algorithm will be used to derive EQ-5D-3L VAS and EQ-5D-3L utility index in base case.
8.4.7
Other Analyses 
Methodology for exploratory analyses including NANO assessment will be described in the 
statistical analysis plan.
Immunogenicity will be reported for ADA positive status (such as persistent positive, neutralizing 
positive, only last sample positive, baseline positive, and other positive) and ADA negative status, 
relative to baseline. Effect of immunogenicity on safety, efficacy, biomarkers, and PK may be 
explored. Additional details will be described in the Statistical Analysis Plan.
8.5
Interim Analyses
Administrative interim analyses of the data may be performed at several times prior to completion 
of the study in order to facilitate program decisions.
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 
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approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a schedule 
of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
AE tracking/reporting, protocol required assessments, and/or drug accountability records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
BMS 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 
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specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product. 
Records or logs must comply with applicable regulations and guidelines and should include the 
following:

Amount received and placed in storage area

Amount currently in storage area

Label identification number or batch number 

Amount dispensed to and returned by each subject, including unique subject identifiers

Amount transferred to another area/site for dispensing or storage

Nonstudy disposition (eg, lost, wasted) 

Amount destroyed at study site, if applicable

Amount returned to BMS

Retain samples for bioavailability/bioequivalence, if applicable

Dates and initials of person responsible for IP 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 
electronic SAE form and Pregnancy Surveillance form, respectively. If electronic SAE form is not 
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available, a paper SAE form can be used. 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 and 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 the External Principal Investigator designated 
at protocol development.
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study must adhere to the publication requirements set forth in the clinical 
trial agreement (CTA) governing participation in the study. These requirements include, but are 
not limited to, submitting proposed publications to BMS at the earliest practicable time prior to 
submission or presentation and otherwise within the time period set forth in the CTA.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
This also means that abstinence is the preferred and usual lifestyle of the 
patient. This does not mean periodic abstinence (eg, calendar, ovulation, 
symptothermal, profession of abstinence for entry into a clinical trial, 
post-ovulation methods) and withdrawal, which are not acceptable 
methods of contraception. Women must continue to have pregnancy tests.
Acceptable alternate methods of highly effective contraception’s must be 
discussed in the event that the subject chooses to forego complete 
abstinence.
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LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminases
BBB
blood-brain barrier
BICR
blinded independent central review
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
CI
confidence interval
CL
geometric mean clearance
CMV
cytomegalovirus
CNS
central nervous system
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form, paper or electronic
CSF
cerebrospinal fluid
CTA
clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DFS
disease-free survival
DILI
drug-induced liver injury
DLBCL
diffuse large B-cell lymphoma
DNA
deoxyribonucleic acid
DOR
duration of response
EBV
Epstein-Barr virus
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Term
Definition
EFS
event-free survival
EOI
end of infusion
EORTC
European Organization for Research and Treatment of Care
EU
European Union
FDG
fluorodeoxyglucose
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GVHD
Graft versus host disease
HD-ASCT
high-dose chemotherapy followed by hematopoietic stem-cell rescue
HD-MTX
high-dose methotrexate
HIV
Human Immunodeficiency Virus
HL
Hodgkin’s Lymphoma
HR
heart rate
HRT
hormone replacement therapy
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IFN
interferon
IMAE
immune-mediated adverse events
IMP
investigational medicinal products
I-O
immuno-oncology
IP
investigational product
IPCG
International PCNSL Collaborative Group
IRB
Institutional Review Board
IV
intravenous
IVRS
interactive voice response system
LDi
longest diameter
MRI
magnetic resonance imaging
MTX
methotrexate
NANO
Neurologic Assessment in Neuro-Oncology
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Term
Definition
NHL
non-Hodgkin’s lymphoma
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PCNSL
primary central nervous system lymphoma
PD
pharmacodynamics
PD
programmed death
PFS
progression-free survival
PK
pharmacokinetics
PMBCL
primary mediastinal B-cell lymphoma
PPK
population pharmacokinetics
PTL
primary testicular lymphoma
Q2W
every 2 weeks
Q4W
every 4 weeks
QLQ-BN20
European Organization for Research and Treatment of Care Brain Cancer 
Module
QLQ-C30
European Organization for Research and Treatment of Care General 
Cancer Module
QoL
quality of life
RCC
renal cell carcinoma
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
RT
radiation therapy
SAE
serious adverse event
SEER
Surveillance, Epidemiology, and End Results
SPD
sum of the product of the diameters
SUSAR
suspected, unexpected serious adverse reaction
TBILI
total bilirubin
TIL
tumor infiltrating lymphocyte
ULN
upper limit of normal
US
United States
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Term
Definition
VAS
visual analog rating scale
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 1
METHODS OF CONTRACEPTION
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use 
one of the highly effective methods of contraception listed below. Male subjects must inform their 
female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as follows:
1) Progestogen only hormonal contraception associated with inhibition of ovulation.
2) Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena
3) Nonhormonal IUDs, such as ParaGard
4) Bilateral tubal occlusion
5) Vasectomised partner with documented azoospermia 90 days after procedure
Vasectomised partner is a highly effective birth control method provided that partner 
is the sole sexual partner of the WOCBP trial participant and that the vasectomised 
partner has received medical assessment of the surgical success.
6) Intrauterine hormone-releasing system (IUS).
7) Complete abstinence
Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
(refer to Glossary of Terms)
Complete abstinence is an acceptable form of contraception for all study drugs and 
must be used throughout the duration of the study treatment (plus approximately 5 half-
lives of the investigational drug plus 30 days).
It is not necessary to use any other method of contraception when complete abstinence 
is elected.
Subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 5.1.
Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the subject.
UNACCEPTABLE METHODS OF CONTRACEPTION
1) Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2) Withdrawal (coitus interruptus)
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3) Spermicide only
4) Lactation amenorrhea method (LAM)
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APPENDIX 2
KARNOFSKY PERFORMANCE SCALES 
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort, some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most personal needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death nor imminent
20
Very sick; hospitalization necessary; active support treatment is necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
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APPENDIX 3
RESPONSE CRITERIA FOR PCNSL
Subjects with PCNSL will be evaluated using the International Primary CNS Lymphoma 
Collaborative Group (IPCG) Criteria for PCNSL14. 
Table 1:
Response criteria for PCNSL
Response
Criteria
Brain imaging
Corticosteroid 
dose 
Eye examination
CSF cytology
Complete 
response (CR)
No contrast enhancement 
None
Normal
Negative
Unconfirmed 
complete 
response (CRu)
No contrast enhancement
Any
Normal
Negative
Minimal abnormality
Any 
Minor RPE abnormality 
Negative 
Partial response 
(PR)
50% decrease in 
enhancing tumor
Irrelevant 
Minor RPE abnormality 
or normal
Negative
No contrast enhancement 
Irrelevant 
Decrease in vitreous 
cells or retinal infiltrate
Persistent or 
suspicious
Progressive 
disease (PD)
25% increase in lesion 
Irrelevant 
Recurrent or new ocular 
disease 
Recurrent or 
positive 
Any new site of disease: 
CNS or systemic 
Source: Abrey et al., 2005
Complete Response (CR): 

Complete disappearance of all enhancing abnormalities on gadolinium-enhanced MRI.

No evidence of active ocular lymphoma as defined by absence of cells in the vitreous and 
resolution of any previously documented retinal or optic nerve infiltrates. Chronic changes of 
the retinal pigment epithelium in the setting of a prior retinal or optic nerve infiltrate does not 
preclude the definition of a CR. Detailed ophthalmologic examination with dilated fundus 
examination, slit-lamp examination and color photography of the posterior pole, and lumbar 
puncture for cytology are required only if these studies were initially positive or became 
positive during treatment and if clinically indicated by new symptoms or signs.

Lumbar puncture for CSF cytology is necessary to confirm cytologic response observed in the 
ventricular CSF. 

At the time a CR is determined, the patient should have discontinued corticosteroids for at least 
2 weeks. 

Residual lesions (other than lesions < 10 mm) if presumed to be non-malignant should be 
further investigated (eg, by PET scans) before CR can be accepted. 

If there was evidence of PET abnormality suspicious for systemic disease then PET has to be 
repeated to confirm CR (Radiology comment)
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
All subjects who appear to achieve CR require the following:

Confirmation scan at 8 weeks

Repeat CSF cytology, bone marrow biopsy and aspirate, and ophthalmologic examination 
if involved at baseline 
Unconfirmed CR (CRu): Any patient who fulfills all criteria for CR but continues to require 
corticosteroid therapy at any dose should be considered an unconfirmed CR. Subjects with a 
persistent minor abnormality on follow-up ophthalmologic examination (persistent non- malignant 
cells in the vitreous, alteration of the retina/optic nerve that is not consistent with tumor infiltration) 
may be considered a CRu if this abnormality is unlikely to represent ocular lymphoma.
Partial response (PR) requires all of the following:

A 50% decrease in the contrast-enhancing lesion seen on MRI as compared with baseline 
imaging.

Corticosteroid dose is irrelevant to the determination of PR.

Ophthalmologic examination should show a decrease in the vitreous cell count or retinal/optic 
nerve cellular infiltrate but may continue to show persistent malignant or suspicious cells. 
Color photos of the posterior pole of the eye should be obtained to document improvement in 
retinal/optic nerve infiltrates.

CSF cytologic examination may be negative or continue to show persistent malignant or 
suspicious cells in subjects with a 50% decrease in the primary brain lesion. 

No new sites of disease. In the setting of primary leptomeningeal lymphoma, PR is not 
recognized; all subjects should be categorized as CR, CRu, stable disease, or progressive 
disease.
Stable disease (SD) is defined as less than a PR but is not progressive disease (PD).
Progressive disease requires the following:

A more than 25% increase in the contrast-enhancing lesion seen on MRI as compared with 
baseline or best response (comparison should be made to the smallest of multiple lesions).

Progression of ocular disease as indicated by an increase in the vitreous cell count or 
progressive retinal or optic nerve infiltration.

Appearance of any new lesion or site of disease (ocular, leptomeningeal or systemic) during 
or at the end of therapy.
Relapsed disease (only applicable to subjects with a prior CR, CRu) requires the following:

Appearance of any new lesion.
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APPENDIX 4
RESPONSE EVALUATION IN PTL
Subjects with PTL will be evaluated for response using a 2 compartment model, where the 2014 
Lugano Classification will be used for systemic lesions and the IPCG criteria will be used for CNS 
lesions.
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Table 1:
Revised Criteria for Response Assessment: 2014 Lugano 
Classification
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*The recommendations from Lugano Classification is to use a 5 point scale to assess the metabolic 
response in PET-CT based response.
Response Evaluation for systemic lesions in PTL: 
CR (Complete Remission)
The designation of CR requires all of the following be met:
1) Complete disappearance of all detectable clinical evidence of disease.
a) PET-CT-based response: A score of 3 is considered to represent complete metabolic 
response.
b) CT based response: Target node/nodal masses must regress to 1.5 cm in LDi, with no 
extralymphatic sites of disease
2) Organ involvement: Absence of organomegaly 
3) Bone marrow: No evidence of FDG- avid disease in marrow. If there was evidence of 
involvement of bone marrow with lymphoma at screening/baseline and a biopsy was 
performed (PTCL), a bone marrow biopsy will be required to confirm CR.
4) The presence of residual symptoms in the absence of detectable disease by imaging does not 
preclude the designation of CR.
PR (Partial Remission)
The designation of PR requires all of the following:
1) PET-CT based response: Score of 4 or 5, provided  reduced uptake compared with base line 
and absence of structural progression development on CT Scan.
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2) CT based response: 50% regression in SPD of up to 6 measurable nodal and extranodal 
lesions
3) Splenic and hepatic nodules must regress by 50% in length beyond normal.
4) Bone marrow: reduced uptake compared with baseline. If there is evidence of nodal response 
but persistent focal changes in the marrow consider further evaluation 
SD (Stable Disease)
SD is defined as the following:
1) PET-CT based response: no metabolic response, score of 4 or 5 with no significant changes 
from baseline.
2) CT based response: < 50% decrease from baseline, absence of new lesions  
3) Bone marrow: no change from baseline.
PD: Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
1) PET-CT based response: Score of 4 or 5 with increase in intensity from baseline or interim 
scan/ or any new FDG avid focus consistent with malignant lymphoma 
2) CT based response: New node, new or recurrent splenomegaly, progression of existing lesions  
Response Evaluation for CNS lesions in PTL: 
The IPCG criteria as described in Appendix 3 will be used for PTL patients with CNS lesions.
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APPENDIX 6
TUMOR FLARE
Tumor Flare in CNS tumors:
Tumor flare (TF): Immunomodulatory agents, such as immune checkpoint inhibitors, may be
associated with clinical and imaging findings during treatment, suggestive of progressive disease
(PD) despite evidence of clinical benefit (tumor flare or pseudo-progression).1,2 This
phenomenon has been well described with checkpoint blockade therapy in solid tumors, with an 
incidence of 10% in melanoma and 3% in lung cancer.3 Furthermore, this has also been reported 
anecdotally in lymphomas.4 Pseudoprogression appears as tumor progression or radiographic 
progression with target lesion size increase. Often it may be associated with mixed responses, 
which include good response (i.e., shrinkage) but increased tumor size or even new lesion 
appearance elsewhere. The patient may or may not present with deterioration in clinical 
symptoms. Considering this finding as PD could lead to patients being prematurely removed
from a treatment from which they actually stand to benefit. Therefore it is important to remain 
cognizant of this effect during treatment. 
Few important characteristics observed with TF are outlined below:

Tumor inflammation is the intended effect of anti-tumor immune therapies, so tumor 
flare is consistent with eventual benefit. As it is important not to abandon immunotherapy 
prematurely, these observations have led to development of immune-related response 
criteria.1,4

TF may be more clinically evident, i.e. lead to early development of symptoms, in CNS 
tumors than in tumors of other sites due to their intracranial location. 

TF is indistinguishable from disease progression (thus sometimes called 
‘pseudoprogression’), and thus presents a major clinical challenge.
It is ordinarily not possible to determine whether increased neurologic symptoms and/or 
radiographic findings represent tumor progression or transient TF. Observation, sometimes 
prolonged, is required to make this determination.

In some settings, moreover, adverse effects of other concomitant treatment (such as RT) 
may be equally as likely. 

Less frequently adverse effects of immunotherapy on normal brain tissues may be 
possible.
In other Central Nervous System trials of nivolumab (alone or with ipilimumab), clinical 
findings of TF have been highly variable, based on the location of the lesion, including 
confusion, aphasia, hemiplegia, seizure, etc. Because of this neurologic heterogeneity, we have 
used the overall diagnostic term “Tumor Flare” in order to capture it systematically in our 
adverse event database. 
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Treatment strategies during TF:

Corticosteroids (e.g. dexamethasone 4-8 mg/day) are generally fairly effective in 
reversing neurologic dysfunction, perhaps more effective than might be seen with disease 
progression. They may be tapered as quickly as tolerated (in contrast to systemic IMAEs 
such as pneumonitis, for which very slow tapering is advised). If acute or severe 
neurologic deterioration, dexamethasone bolus of 10-20 mg intravenously or 
corticosteroid equivalent, once, can be considered, followed by a smaller dose for 
maintenance such as 2-4mg daily, to be rapidly tapered off once neurologic deficits 
improve.

If symptoms are moderate to severe, delay of immune treatment is appropriate. 

Generalized effects of increased pressure, including midline shift, hydrocephalus, 
obliteration of sulci, etc. have also been noted, but are non-specific. 

Imaging changes are sometimes more striking than clinical AEs; if radiographic findings 
are not associated with clinical deterioration, immune treatment need not be delayed. 
Cerebral edema on imaging by itself need not be a criteria for drug discontinuation.

Investigations on potential radiographic features which could assist in discriminating TF
from disease progression are in progress.
If surgically accessible, a diagnostic biopsy may be feasible. 

As always, there is concern that a representative sample be obtained. 

A predominance of necrosis, and inflammation is consistent with TF, and very helpful in 
allaying the concern generated by clinical and imaging changes. Unfortunately, of course, 
a biopsy may confirm tumor progression.

In such cases, we would encourage that the immune treatment be resumed. 
Every patient is different; consultation with the Medical Monitor and review of the imaging is 
often useful.
 
 
 
 
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SAP_000.pdf: 
Official Title of Study: 
A Phase 2, Open-label, Single-arm, Two-cohort Study of Nivolumab in Relapsed/Refractory 
Primary Central Nervous System Lymphoma (PCNSL) or Relapsed/Refractory Primary 
Testicular Lymphoma (PTL) 
NCT Number: NCT02857426 
Document Date (Date in which document was last revised): February 9, 2018 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 2, OPEN-LABEL, SINGLE-ARM, TWO-COHORT STUDY OF NIVOLUMAB 
IN RELAPSED/REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM 
LYMPHOMA (PCNSL) OR RELAPSED/REFRACTORY PRIMARY TESTICULAR 
LYMPHOMA (PTL)
CHECKMATE 647: CHECKPOINT PATHWAY AND NIVOLUMAB CLINICAL TRIAL 
EVALUATION 
PROTOCOL CA209-647
VERSION # 1.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................7
2.3
Blinding and Unblinding...........................................................................................7
2.4
Protocol Amendments...............................................................................................8
2.5
Data Monitoring Committee .....................................................................................9
3
OBJECTIVES ..........................................................................................................9
3.1
Primary Objective.....................................................................................................9
3.2
Secondary Objectives ...............................................................................................9
4
ENDPOINTS..........................................................................................................10
4.1
Primary Endpoint(s) ...............................................................................................10
4.2
Secondary Endpoint(s)............................................................................................11
4.2.1
Progression Free Survival Based on BICR Assessment...........................................11
4.2.2
Objective Response Rate and Duration of Response Based on Investigator 
Assessment .............................................................................................................12
4.2.3
Overall Survival .....................................................................................................12
4.3.1
PFS Per Investigator ..............................................................................................12
4.3.2
Safety and Tolerability............................................................................................12
4.3.4
Pharmacokinetics ...................................................................................................14
4.3.5
Immunogenicity ......................................................................................................14
4.3.6
Outcomes Research ................................................................................................14
5
SAMPLE SIZE AND POWER...............................................................................19
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................19
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6.1
Study Periods..........................................................................................................19
6.1.1
Baseline Period ......................................................................................................19
6.1.2
Post Baseline Period...............................................................................................20
6.2
Treatment Regimens...............................................................................................20
6.3
Populations for Analyses ........................................................................................20
7
STATISTICAL ANALYSES..................................................................................21
7.1
General Methods ....................................................................................................21
7.2
Study Conduct........................................................................................................22
7.2.1
Accrual...................................................................................................................22
7.2.2
Relevant Protocol Deviations..................................................................................22
7.3
Study Population ....................................................................................................22
7.3.1
Subject Disposition.................................................................................................22
7.3.2
Demographics and Other Baseline Characteristics.................................................22
7.3.3
Medical history- Concurrent diseases.....................................................................23
7.3.4
Prior therapy agents...............................................................................................23
7.3.5
Baseline examinations ............................................................................................24
7.4
Extent of Exposure .................................................................................................24
7.4.1
Administration of study therapy ..............................................................................24
7.4.2
Modifications of Study Therapy ..............................................................................25
7.4.2.1
Dose delays ............................................................................................................25
7.4.2.2
Dose delays ............................................................................................................25
7.4.2.3
Infusion Interruptions and Rate Changes................................................................25
7.4.2.4
Dose Reductions/Escalation....................................................................................25
7.4.3
Concomitant Medications.......................................................................................26
7.5
Efficacy..................................................................................................................26
7.5.1
Primary analysis on BICR-assessed ORR ...............................................................26
7.5.2
Secondary Efficacy Endpoints.................................................................................27
7.5.2.1
PFS assessed by BICR............................................................................................27
7.5.2.2
ORR, BOR, TTR and DOR by investigator..............................................................27
7.5.2.3
Overall Survival (OS) .............................................................................................27
7.5.2.4
Efficacy Analyses for Both PFS and OS..................................................................28
7.5.2.5
Efficacy for Participants Treated Beyond Progression............................................28
7.5.3
Subset Analyses ......................................................................................................29
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7.5.4
Interim Analysis......................................................................................................29
7.6
Safety.....................................................................................................................29
7.6.1
Deaths ....................................................................................................................29
7.6.2
Serious Adverse Events...........................................................................................29
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................29
7.6.4
Adverse Events Leading to Dose Modification........................................................30
7.6.5
Adverse Events .......................................................................................................30
7.6.6
Select Adverse Events .............................................................................................30
7.6.7
Immune Modulating Medication .............................................................................30
7.6.8
Multiple Events.......................................................................................................30
7.6.9
Other Events of Special Interest..............................................................................30
7.6.10
See Core Safety SAP.Immune-Mediated Adverse Events .........................................30
7.6.11
Laboratory Parameters...........................................................................................30
7.6.11.1
Hematology ............................................................................................................30
7.6.11.2
Serum Chemistry ....................................................................................................30
7.6.11.3
Electrolytes.............................................................................................................30
7.6.11.4
Additional Analyses ................................................................................................30
7.6.12
Vital Signs and Pulse Oximetry...............................................................................30
7.6.13
Immunogenicity Endpoints......................................................................................31
7.6.14
Pregnancy ..............................................................................................................31
7.6.15
Adverse Events by Subgroup...................................................................................31
7.7
Pharmacokinetics....................................................................................................31
7.8.1
PD-L1 Analyses......................................................................................................31
7.8.1.1
Distribution of Baseline PD-L1 expression .............................................................32
7.8.1.2
Association between PD-L1 status at baseline and efficacy measures .....................32
7.8.2
Analyses on 9p24.1 Alterations...............................................................................32
7.8.3
EBV Status..............................................................................................................33
7.9
Outcomes Research Analyses .................................................................................33
7.9.1
EQ-5D-3L questionnaire ........................................................................................33
7.9.2
EORTC-QLQ-C30..................................................................................................33
7.9.3
EORTC-QLQ-BN-20...............................................................................................34
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8
CONVENTIONS....................................................................................................35
9
CONTENT OF REPORTS .....................................................................................36
11
DOCUMENT HISTORY........................................................................................36
LIST OF TABLES
Table 2.4-1:
Protocol Amendments ..............................................................................8
Table 4.2.1-1:
Censoring scheme used in primary analysis of PFS.................................11
Table 4.3.6-1:
Analysis Time Windows for EQ-5D-3L Assessments for PCNSL...........14
Table 4.3.6-2:
Analysis Time Windows for EQ-5D-3L Assessments for PTL................15
Table 5-1:
Observed ORR with Exact 95 % CI........................................................19
Table 7.4.1-1:
Administration of study therapy: definition of parameters.......................24
Table 11-1:
Document History ..................................................................................36
LIST OF FIGURES
Figure 2.1-1:
Study Design............................................................................................7
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Research Hypothesis:  
Treatment with nivolumab will demonstrate clinically meaningful efficacy in subjects with 
relapsed/refractory PCNSL or PTL.
Schedule of Analyses:
The analysis of the primary endpoint in each cohort will occur at least 6 months after last patient 
first treatment in each cohort. Secondary endpoints will be analyzed at the same time as the primary 
endpoint.
2
STUDY DESCRIPTION
2.1
Study Design
CA209647 is a Phase 2, open-label, single-arm, 2-cohort study to estimate the safety and efficacy 
of nivolumab in participants with relapsed/refractory PCNSL or PTL. Nivolumab 240 mg will be 
given every 2 weeks for 8 cycles. Beginning with Cycle 9, nivolumab 480 mg will be given every 
4 weeks for a total therapy duration of 2 years, or until progressive disease, unacceptable toxicity, 
or withdrawal of consent. Nivolumab will be administered as a 30-minute infusion. A finite 
treatment duration with immune therapies in this patient population remains an area of ongoing 
research; therefore the treatment duration chosen was 2 years.
The study will further characterize safety and evaluate the antitumor activity of nivolumab in 
participants with relapsed/refractory PCNSL or PTL who progressed after or did not respond to at 
least 1 line of systemic therapy. 
The primary endpoint is BICR-assessed ORR, and will be analyzed 6 months after last patient first 
treatment in each cohort.
This study will consist of 3 phases: screening, treatment, and follow-up. The study design 
schematic is presented in Figure 2.1-1.
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Figure 2.1-1:
Study Design
2.2
Treatment Assignment
Participants will be identified and informed consent obtained. Participants must be enrolled into 
the study by the interactive web response system (IVRS) to obtain the participant number. The 
investigator or designee will register the participant for enrollment by following the procedures 
established by BMS. 
2.3
Blinding and Unblinding
Not applicable. This is an open-label study.
PCNSL
N=45
Nivolumab
240mg IV Q2W
for 8 cycles
Nivolumab
480 mg IV Q4W
2 years maximum
treatment duration
Nivolumab
480 mg IV Q4W
2 years maximum
treatment duration
Nivolumab
240 mg IV Q2W
for 8 cycles
Subjects with pathologically confirmed PCNSL or PTL who progressed
after or did not respond to at least 1 line of systemic therapy
Total treatment duration for 2 years or until PD, unacceptable toxicity, 
or withdrawal of consent. Tumor assessments for PCNSL every 2 months 
for 2 years, then every 6 months until disease progression. Tumor 
assessments for PTL every 2 months for 6 months, then every 3 months 
for 1.5 years, then every 6 months until disease progression. Continuous 
toxicity assessments during treatment phase and for first 2 safety follow-
up visits. Survival follow-up visits will occur every 3 months thereafter.
PTL
N=20
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2.4
Protocol Amendments
Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Change
Revised
Protocol 04
29-Nov-2017
To characterize nivolumab pharmacokinetic 
 in the
cerebrospinal fluid (CSF), lumbar puncture(s) (optional) have been
added and will be obtained from consenting patients with 
relapsed/refractory PCNSL or relapsed/refractory PTL with CNS 
involvement.
 
Administrative
Letter 06
04-Sep-2017
Corrected the Appendix 6 of the protocol (Tumor Flare; Treatment
strategies during TF) by removing the CTCAE classification of 
cerebral edema.
Revised
Protocol 03
07-Apr-2017
Incorporates Amendment(s) 09
Amendment 09
07-Apr-2017
Changes to eligibility
- To allow enrollment of subjects with PTL who undergo orchiectomy
- To allow enrollment of subjects with PTL with measurable nodule 
disease
- To specify more precisely the first line of therapy in PCNSL and PTL
- To exclude subjects with significantly increased risk for bleeding 
complications
- To lower the dose of dexamethasone or equivalent allowed 14 days 
prior to first dose of nivolumab to less than or equal to 2mg/day.
The use of CT Scans without PET scans will not be allowed for 
assessment for subjects with PTL.
Added the possibility for administrative interim analyses.
Recommendations for the management of Tumor Flare have been 
added as Appendix 6.
Incorporates changes per Administrative Letters 04, 03, and 02.
Administrative
Letter 04
07-Feb-2017
Change Medical Monitor address.
Administrative
Letter 03
17-Nov-2016
To further clarify protocol requirements for tumor tissue submission at 
screening and correct typographic errors in Table 5.1-2 of the protocol.
Administrative
Letter 02
20-Oct-2016
Clarify the protocol requirements for tumor tissue submission at 
screening.
Revised
Protocol 02
05-Oct-2016
Incorporates Amendment(s) 05
Amendment 05
05-Oct-2016
To reflect update in the treatment management algorithms to be 
consistent with the updated nivolumab investigator brochure (IB) V15, 
updates to the acceptable methods of contraception in order to be 
consistent with the most recent version of BMS SOP and IB V15.
To allow the enrollment of patients with PCNSL that cannot produce a 
minimum of 25 slides 
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Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Change
Other changes were made to resolve minor inconsistencies or to 
provide clarifications.
Revised
Protocol 01
22-Jun-2016
Incorporates Amendment(s) 01
Amendment 01
22-Jun-2016
Subjects in the cohorts with PCNSL and PTL with brain and or spinal 
lesions are allowed to enroll if they are on 4 mg per day or less of 
dexamethasone.
Subjects who had undergone allogeneic stem cell transplant 
> 12 months prior to first dose of study drug, have no evidence of active 
graft versus host disease, and are not on systemic immunosuppressive 
therapy are allowed to participate in the study.
Neurologic Assessment in Neuro-Oncology (NANO) has been 
incorporated in the exploratory endpoints in the protocol.
If the dose of dexamethasone is increased during the screening period 
following the screening MRI, and if there is clinical worsening in 
neurological symptoms following the MRI, the MRI must be repeated.
Due to the rapidly progressing nature of CNS tumors, a brain MRI is 
to be performed within 14 days before the first dose of study treatment 
in both cohorts in order to accurately reflect the disease burden.
Language was added for the collection of prospective blood samples, 
and for BMS to retain residual blood and tissue samples, so that 
scientists can perform additional research.
Incorporation of other minor changes to correct and/or clarify protocol 
requirements.
2.5
Data Monitoring Committee 
Not applicable.
3
OBJECTIVES
3.1
Primary Objective
To assess the clinical benefit of nivolumab in subjects with relapsed/refractory PCNSL or 
relapsed/refractory PTL as measured by ORR by blinded Independent Central Review (BICR).
3.2
Secondary Objectives

To assess progression free survival (PFS) based on BICR assessment for PCNSL or PTL, 
respectively
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
To assess ORR and duration of response (DOR) based on investigator assessment for PCNSL 
or PTL, respectively

To assess overall survival (OS) for PCNSL or PTL, respectively
 
 
 
 
 
 
 
 
 
 
 
 
 
4
ENDPOINTS
4.1
Primary Endpoint(s)
The primary objective will be measured by the primary endpoint of BICR-assessed ORR. It is 
defined as the number of participants with a best overall response (BOR) of CR, unconfirmed 
complete response (CRu) or PR, based on the IPCG Criteria for PCNSL and Lugano 2014 response 
evaluation for PTL, divided by the number of treated participants within each cohort. 
The BICR-assessed BOR is defined as the best response designation recorded between the date of 
first study drug dose and the date of initial objectively documented progression per criteria or the 
date of subsequent therapy, whichever occurs first. For purposes of analysis, if a participant
receives one dose and discontinues the study without assessment or receives subsequent therapy 
prior to assessment, this participant will be counted in the denominator (as non-responder).
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The BICR-assessed objective response will be further characterized by the time to response (TTR) 
and duration of response (DOR).
TTR is defined as the time from first dosing date to the date of the first response, based on BICR 
assessment. TTR will be evaluated for responders only.
DOR is defined as the time from first response (CR, CRu or PR) to the date of initial objectively 
documented progression as determined using the IPCG Criteria for PCNSL and Lugano 2014 
response evaluation for PTL, as determined by BICR, or death due to any cause, whichever occurs 
first. For participants who neither progress nor die, the DOR will be censored on the date of their 
last tumor assessment. Participants who start subsequent anticancer therapy without a prior 
reported progression will be censored at the last tumor assessments prior or on the first subsequent 
anticancer therapy date. The censoring scheme of DOR will be the same as the primary censoring 
scheme for PFS. This endpoint will only be evaluated in participants with objective response of 
CR, CRu or PR.
4.2
Secondary Endpoint(s)
4.2.1
Progression Free Survival Based on BICR Assessment
PFS is defined as the time from first dosing date to the date of the first documented progression 
using the IPCG Criteria for PCNSL and Lugano 2014 response evaluation for PTL, as determined 
by BICR, or death due to any cause, whichever occurs first. Participants who die without a reported 
progression and did not start a subsequent therapy will be considered to have progressed on the 
date of their death. Participants who did not progress or die will be censored on the date of their 
last tumor assessment. Participants who did not have any on study assessments and did not die will 
be censored on the first dosing date. Participants who started any subsequent anti-cancer therapy 
without a prior reported progression will be censored at the last tumor assessment prior to initiation 
of the subsequent anti-cancer therapy.
The censoring scheme is summarized in Table 4.2.1-1.
Table 4.2.1-1:
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
Censored 
No on-study tumor assessments and no 
death 
First dosing date
Censored
New subsequent anticancer therapy started 
without a prior reported progression by 
IPCG/Lugano 2014 criteria  
Date of last evaluable tumor assessment prior 
to or on the date of initiation of the subsequent 
anti-cancer therapy
Censored 
Progression per IPCG / Lugano 2014 
criteria documented at a scheduled or 
unscheduled visit and no subsequent 
anticancer therapy started before
Date of the first documented tumor 
progression per IPCG/Lugano 2014 criteria
Progressed 
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Table 4.2.1-1:
Censoring scheme used in primary analysis of PFS
Situation 
Date of Progression or Censoring 
Outcome 
Participant progression free, no death and 
no subsequent anti-cancer therapy started
Date of last evaluable tumor assessment per 
IPCG/Lugano 2014 criteria
Censored 
Death without prior progression per IPCG/ 
Lugano 2014 criteria and no subsequent 
anticancer therapy started
Date of death 
Progressed 
4.2.2
Objective Response Rate and Duration of Response Based on 
Investigator Assessment
Investigator-assessed ORR and DOR are defined similarly as described for ORR and DOR per 
BICR assessment above, but will be assessed per investigator.
4.2.3
Overall Survival
Overall Survival (OS): defined as the time between the first dosing date and the date of death. 
Participants who are alive at the time of analysis will be censored at last known alive date (LKAD).
The overall survival rate at time T is defined as the probability that a subject is alive at time T 
following first dosing date.
 
 
 
 
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
The planned sample size for this study will be approximately 65 treated participants, placed into 
2 cohorts of participants: PCNSL (N = 45), and PTL (N = 20).
In addition, Table 5-1 summarizes the 95% exact confidence interval (CI) for the target ORRs 
ranging from 28.9% to 60% with sample size of 20 and 45. At observed ORR 28.9% with 
45 PCNSL participants, the lower bound of the 95% CI excludes the historical response rates in of 
14% in recurrent primary central nervous system lymphoma. At observed ORR ≥ 40% with 
20 PTL participants, the lower bound of the 95% CI excludes the response rate of 14%. 
The sample size for the PCNSL cohort was empirically determined to support expanded 
assessment of the benefit-risk profile of nivolumab in PCNSL through observation of less common 
safety events. In particular, administration of nivolumab to 45 participants provides 90% 
probability of observing at least 1 occurrence of any AE that would occur with 5% incidence in 
the population from which the sample is drawn.
Table 5-1:
Observed ORR with Exact 95 % CI
N
ORR
95% Exact CI
20
30%
[11.9% - 54.3%]
35%
[15.4% - 59.2%]
40%
[19.1% - 63.9%]
50%
[27.2% - 72.8%]
60%
[36.1% - 80.9%]
45
28.9% 
[16.4% - 44.3%]
40.0% 
[25.7% - 55.7%]
51.1% 
[35.8% - 66.3%]
60%
[44.3% - 74.3%]
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Baseline Period
Baseline evaluations or events will be defined as evaluations or events that occur before the date 
and time of the first dose of study treatment.
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not 
collected, the following definitions will apply:

Pre-treatment AEs will be defined as AEs with an onset date prior to but not including the day 
of the first dose of study treatment
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
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.
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. 
See Core Safety SAP.
6.2
Treatment Regimens
All participants will be treated with nivolumab 240 mg, given every 2 weeks for 8 cycles. 
Beginning with Cycle 9, nivolumab 480 mg will be given every 4 weeks for a total therapy duration 
of 2 years, or until progressive disease, unacceptable toxicity, or withdrawal of consent.
6.3
Populations for Analyses
Within each cohort the following populations will be defined.

All enrolled participants: All participants who signed an informed consent form and were 
registered into the IVRS.

All treated participants: All participants who received at least one dose of study medication. 
This is the primary dataset for efficacy and safety.

All treated participants enrolled pre-amendment 9: All treated participants who signed their 
informed consent before protocol amendment 9 (up to March 24, 2017). 

All treated participants enrolled post-amendment 9: All treated participants who signed 
their informed consent after protocol amendment 9 (after March 24, 2017). 

All treated participants with high dose corticosteroids at baseline: All treated participants who 
received > 2mg per day of dexamethasone equivalent within 14 days prior first Nivolumab 
dose date.

All treated participants without high dose corticosteroids at baseline: All treated participants 
who received 2mg per day of dexamethasone equivalent within 14 days prior first Nivolumab 
dose date.
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
Response evaluable participants: All treated participants who have baseline and at least one 
on-study evaluable tumor measurement.
 
 

Serum PK participants: All participants with available serum concentration time data from 
participants dosed with nivolumab

CSF PK participants: All participants with available CSF concentration time data from 
participants dosed with nivolumab

Immunogenicity evaluable participants: All treated participants with baseline and at least 
1 post baseline immunogenicity assessment

Outcomes research participants: All treated participants who have an assessment at baseline 
(Visit 1 assessment prior to administration of drug) and at least 1 subsequent assessment 
(separately for each outcome research measure EuroQol (EQ)-5D-3L scoring function, 
QLQ-C30, QLQ-BN20 and NANO).

Nivolumab participants treated beyond progression: All participants who received at least 
one dose of nivolumab after the date of initial progression based on investigator assessment.
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 participants falling into each category, 
grouped by treatment (with total). Percentages given in these tables will be rounded and, therefore, 
may not always sum to 100%. Continuous variables will be summarized by cohort (with total) 
using the mean, standard deviation, median, minimum and maximum values.
Time to event distribution (e.g., progression free survival, overall survival 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)5,6. Rates at 
fixed time points (e.g., PFS at 6 months) will be derived from the Kaplan Meier estimate and 
corresponding confidence interval will be derived based on Greenwood formula for variance 
derivation and on log-log transformation applied on the survivor function S(t)7.
Confidence intervals for binomial proportions will be derived using the Clopper-Pearson method1.
All analyses will be performed separately for each cohort upon completion of follow-up for the 
primary endpoint in each cohort. There will be no 
multiplicity adjustment for p-values.
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7.2
Study Conduct
7.2.1
Accrual
The following will be summarized on the enrolled population: 

Number of participants accrued by country and investigational site

Number of participants accrued by month
A by participant listing of accrual will be produced.
7.2.2
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations. Non-
programmable relevant eligibility and on-treatment protocol deviations, as well as significant (both 
programmable and non-programmable) eligibility and on-treatment protocol deviations will be 
reported through ClinSIGHT listings.
At entrance:

Participants without measurable disease at baseline 

Participant with baseline Karnofsky performance status < 70

Participants with pathologically confirmed PCNSL or PTL who didn’t meet the eligibility 
criteria of progressing after or not responding to at least 1 line of systemic therapy

For subjects enrolled afterprotocol amendment 9, patients had more than 2mg/day 
dexamethasone equivalent in the 14 days prior to the first nivolumab dose
On-Study:

Participants receiving concurrent anti-cancer therapy (systemic, surgery, non-palliative 
radiotherapy, transplant) other than nivolumab.
A summary table and a by participant listing of relevant protocol will be produced.
7.3
Study Population
7.3.1
Subject Disposition
The total number of participants enrolled (treated or not) will be presented along with the reason 
for not being treated.
Number of participants 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 
participants. All baseline presentations will identify participants with missing measurements. 

Age (descriptive statistics)
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
Age categories (< 30, 30 and < 45, 45 and < 60, 60)

Gender (male, female)

Race (white, black or african american, asian, american indian or alaska native, native hawaiian 
or other pacific islander, other)

Baseline Karnofsky Performance Status (median and range, 90, 70 and < 90, < 70)

Weight (descriptive statistics)

Time from initial disease diagnosis to first dose of study medication (median, range, 
< 3 months; 3 months) 

Region (US/Canada, Europe, Rest of the World)

Smoking Status (Yes, No, Unknown)

Disease stage at initial diagnosis (PTL cohort only ) (stage 1 or 2, 3, 4, unknown)

Disease status at study entry (relapsed, refractory, or  relapsed and refractory)

CNS involvement at study entry (PTL cohort only ) (Yes, No, unknown)

Ocular involvement (Yes, No, unknown)

All lesions (Investigator Tumor Assessments at Baseline): sites of diseases, number of disease 
sites per participant

Target Lesions (Investigator Tumor Assessments at Baseline): Presence of target lesions, site 
of target lesion, sum of product diameters of target lesions.
The same analysis would be performed by subjects enrolled pre- vs. post-amendment 9 for PCNSL 
cohort as well as by subjects high dose versus low dose of corticosteroids at baseline.
7.3.3
Medical history- Concurrent diseases
General medical history will be listed by participant and pretreatment events will be tabulated. 
7.3.4
Prior therapy agents
For participants with PCNSL, prior therapy includes high-dose methotrexate (HD-MTX), HD-
MTX-based regimen, high-dose cytarabine, radiation therapy alone as treatment or as part of 
consolidation therapy, high-dose therapy with autologous stem cell transplant as part of 
consolidation therapy, and/or intraocular MTX alone or as part of consolidation therapy.
For participants with PTL, prior therapy includes chemo-immunotherapy (e.g., CHOP-R or any 
other regimens), with/without prophylactic RT to contralateral testis or orchiectomy or intrathecal 
chemotherapy.
The following will be summarized for PCNSL and PTL (as appropriate):

Number of participants who received Prior Systemic Cancer Therapy by type (such as but may 
not be limited to Immunotherapy by Monoclonal Antibodies, Steroid, Chemotherapy – Other 
than anthracyclines, Chemotherapy - Anthracyclines, Kinase Inhibitors, Immunomodulary 
Derivatives, Radioimmunotherapy, Other)

Number of participants by type of regimen for first and second lines of therapy
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
Number of lines of prior systemic therapies received (median, range, 1, 2,)

Time from completion of most recent prior regimen to treatment (median, range, < 3, 3 - 6, 
> 6 months)

Prior radiotherapy (yes or no, not reported)

Prior orchiectomy (yes or no, not reported)

Prior autologous transplant (Yes, No, Not reported)

Prior allogeneic transplant (Yes, no, Not reported)

Prior surgery related to cancer (Yes, No, Not reported)
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 participant will also be provided.
7.3.5
Baseline examinations
Participants with abnormal baseline physical examination will be tabulated by examination criteria 
and by cohort.
7.4
Extent of Exposure
Analyses in this section will be performed in all treated participants.
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 participants who discontinued study 
therapy. Participants 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-participant 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
240mg Q2W for first 8 cylces; 480 Q4W starting cycle 9
Dose
Dose mg is defined as Total Dose administered (mg). Dose administered in 
mg at each dosing.
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Table 7.4.1-1:
Administration of study therapy: definition of parameters
nivolumab
Cumulative Dose
Cum dose (mg) is sum of the doses (mg) administered to a participant
during the treatment period.
Cumulative Planned Dose
For subjects who only receive 240mg Q2W up to cycles 8, cumulative 
planned dose in cycles 1-8 is (min(Last dose date within cycles 1-8 + 14 
day, death date) - Start dose date) x 480mg / 28 day
For subjects receive 480 Q4W starting cycle 9, cumulative planned dose
from cycle 9 is (min(Last dose date + 28 day, death date) - Start dose date 
of cycle 9) x 480mg / 28 day
Relative dose intensity (%)
Cum dose /Cumulative Planned Dose x 100
Duration of treatment 
Last dose date - Start dose date +1
7.4.2
Modifications of Study Therapy
7.4.2.1
Dose delays
7.4.2.2
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 - < 43, 
43 days. Reason for dose delay will be retrieved from CRF dosing pages.
The following parameters will be summarized:

Number of participants with at least one dose delayed, number of dose delayed per participant, 
Length of Delay and Reason for Dose Delay
7.4.2.3
Infusion Interruptions and Rate Changes
The following parameters will be summarized:

Number of participants with at least one dose infusion interruption, number of infusion 
interruptions per participant and the reason for interruption.

Number of participants with at least one IV infusion rate reduction, number of IV infusion rate 
reduction per participant and the reason for reduction
7.4.2.4
Dose Reductions/Escalation
There will be no dose escalations or reductions of nivolumab allowed. 
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7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary.
The following summary tables will be provided: 

Concomitant medications (participants with any concomitant medication, participants by 
medication class and generic term).

Median and range of corticosteroids
A by-participant listing will accompany the tables.
7.5
Efficacy
Unless specifically mentioned, all efficacy analyses will be performed by two cohorts separately.
7.5.1
Primary analysis on BICR-assessed ORR
The BICR-assessed ORR will be summarized by cohort for all treated participants by a binomial 
response rate. The Clopper-Pearson method1 will be used to estimate the two-sided 95% 
confidence interval. 
Best overall response (BOR) will be summarized by response category (CR, CRu, PR, SD, PD, 
Non-evaluable, and not reported).
To assess tumor response kinetics, time to response will be analyzed using the KM methodology 
for all treated participants by cohort. 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 to response + 1 day of all participants in that cohort.
The BICR-assessed DOR will be summarized by cohort for participants who achieve PR, CRu or 
CR using the Kaplan-Meier 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. 
The following participant-level graphics will also be provided by cohort: 

For the responders only, time courses of the following events of interest will be graphically 
displayed: tumor response, tumor progression, last dose received, and death.

For response evaluable participants, a waterfall plot showing the best reduction in target lesion 
will be produced. A spider plot showing the percentage of tumor size changes over time will 
also be produced. 
The efficacy assessment slit lamp examination including the CNS ocular involvement over time 
relative to the 1st and the last doses will be listed. This may only includes patients with CNS ocular 
involvement at baseline.
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7.5.2
Secondary Efficacy Endpoints
7.5.2.1
PFS assessed by BICR
The BICR-assessed PFS assessment will be summarized descriptively by cohort using the Kaplan-
Meier (KM) product-limit method for each cohort. Median values of PFS, along with two-sided 
95% CIs (based on the log-log transformation), will also be calculated.
The BICR-assessed PFS rates at 3 and 6 months will be estimated using KM estimates on the PFS 
curve. PFS rates at 9, 12, 18, 24, 36 months may also be estimated depending on whether minimum 
follow-up will be longer than or equal to timepoint to generate the rate. Associated two-sided 95% 
CIs will be calculated.
The source of the BICR-assessed PFS event (death vs. progression) will be summarized. The status 
of participants who are censored in the PFS Kaplan-Meier analysis will be tabulatedusing 
following categories:

On-study (on treatment or progression-free in follow-up). 

Off-study: (lost to follow-up, withdraw consent other).

Received subsequent anti-cancer therapy.
PFS assessed by investigator will be analyzed similarly to the BICR assessed PFS.
7.5.2.2
ORR, BOR, TTR and DOR by investigator
The ORR, BOR, TTR and DOR assessed by investigator will be analyzed similarly to the same 
endpoints assessed by BICR.
7.5.2.3
Overall Survival (OS)
The OS curves will be estimated using the Kaplan-Meier (KM) product-limit method. Two-sided, 
95% confidence intervals for median OS will be constructed based on a log-log transformed CI 
for the survivor function S(t). 
Survival rates at 3, 6, 9, 12, 18, 24, 36 months may also be estimated using KM estimates on the 
OS curve for each cohort. Minimum follow-up must be timepoint to generate the rate. Associated 
two-sided 95% CIs will be calculated using the Greenwood’s formula for variance derivation and 
on log-log transformation applied on the survivor function S(t).
The status of participants who are censored in the OS Kaplan-Meier analysis will be tabulated 
using following categories:

On-study (on-treatment or in follow-up).

Off-study (lost to follow-up, withdraw consent, etc.).
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7.5.2.4
Efficacy Analyses for Both PFS and OS
Participant Follow-up 
The minimum follow-up will be reported. The minimum follow-up is defined as the time interval 
between the last patient’s first dosing date of the considered cohort and the clinical cutoff date.
The extent of follow-up defined as the time between first dosing date and last known date alive 
(for participants who are alive) or death date (for participants who died) will be summarized 
descriptively (median, min, max) for all treated participants.
The currentness of follow-up, defined as the time between last OS contact (i.e., last known date 
alive or death date) and data cut-off date, will be summarized. Participants who died before data 
cut-off date will automatically have zero value for currentness of follow-up. For participants with 
last known date alive after data cut-off date, they will have zero value for currentness of follow-
up as well. The currentness of follow-up will be categorized into the following categories: 0 days, 
1-3 months, 3-6 months, 6-9 months, 9-12 months and months.
Follow-Up Therapy
The following information pertaining to subsequent therapies will be summarized:
Number and percentage of participants receiving subsequent therapies including:

Chemotherapy by drug name.

Immunotherapy (anti-PD1 agents, anti-CTLA4 agents and others, by drug name).

Other investigational agent by drug name.

Surgery.

Radiotherapy.

Autologous transplant

Allogeneic transplant
A participant listing of follow-up therapy will be produced for participants who had any 
subsequent therapy.
By-subject listings will be provided for study related procedures including eye fundus 
examination, eye stereo color fundus photography, lumbar puncture, and lymphoma pet scan. 
For subjects who underwent subsequent allogeneic transplant, by-subject listings will be provided 
with the following information: transplant characteristics, best response to transplant, GVHD, 
characteristics of acute GVHD and other transplant complications.
7.5.2.5
Efficacy for Participants Treated Beyond Progression
Individual time course of tumor burden change from baseline in target lesions, per investigator, 
will be generated for nivolumab participants treated beyond progression (spider plot).
The duration of treatment and number of doses beyond progression will be summarized.
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7.5.3
Subset Analyses
The influence of enrolment prior versus after protocol amendment 9 and the influence on high 
versus lowdose of dexamethasone prior to the first dose of nivolumab on the efficacy measures 
will be evaluated descriptively by analyzing the following efficacy endpoints on each subset:

BICR-assessed best overall response (BOR) will be summarized by response category (CR, 
CRu, PR, SD, PD, Non-evaluable, and not reported).

BICR-assessed time to response (TTR) will be analyzed using the KM methodology. 

BICR-assessed DOR will be summarized for participants who achieve PR, CRu or CR using 
the Kaplan-Meier 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. 

The BICR-assessed PFS assessment will be summarized descriptively using the Kaplan-Meier 
(KM) product-limit method. Median values of PFS, along with two-sided 95% CIs (based on 
the log-log transformation), will also be calculated.

The OS curves will be estimated using the Kaplan-Meier (KM) product-limit method. Two-
sided, 95% confidence intervals for median OS will be constructed based on a log-log 
transformed CI for the survivor function S(t). 
To study the effect of steroid use at baseline, objective response status (responder vs non-
responder) may be modeled by a logistic regression with baseline steroid use as a continuous 
variable. For PFS and OS, a Cox proportional hazards model with baseline steroid use as a 
continuous variable may be applied.
7.5.4
Interim Analysis
Not applicable.
7.6
Safety
A subset of tables and listings from the Core Safety SAP will be analyzed. Details will be included 
in the DPP.
7.6.1
Deaths
See Core Safety SAP.
7.6.2
Serious Adverse Events
See Core Safety SAP.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP.
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7.6.4
Adverse Events Leading to Dose Modification
See Core Safety SAP.
7.6.5
Adverse Events
See Core Safety SAP.
7.6.6
Select Adverse Events 
See Core Safety SAP.
7.6.7
Immune Modulating Medication
See Core Safety SAP.
7.6.8
Multiple Events
See Core Safety SAP.
7.6.9
Other Events of Special Interest
7.6.10
See Core Safety SAP.Immune-Mediated Adverse Events
See Core Safety SAP.
7.6.11
Laboratory Parameters
The analysis population for each laboratory test is restricted to treated participants who underwent 
that laboratory test.
7.6.11.1
Hematology
See Core Safety SAP.
7.6.11.2
Serum Chemistry
See Core Safety SAP.
7.6.11.3
Electrolytes
See Core Safety SAP.
7.6.11.4
Additional Analyses
See Core Safety SAP.
7.6.12
Vital Signs and Pulse Oximetry
See Core Safety SAP.
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7.6.13
Immunogenicity Endpoints
See Core Safety SAP
7.6.14
Pregnancy
See Core Safety SAP.
7.6.15
Adverse Events by Subgroup
See Core Safety SAP.
7.7
Pharmacokinetics
The listing of concentration of nivolumab in CSF and in serum will be provided in CSR.
The nivolumab concentration data in serum or in CSF obtained in this study may be combined 
with data from other studies in the clinical development program to develop or refine a population 
PK model. This model may be used to evaluate the effects of intrinsic and extrinsic covariates on 
the PK of nivolumab and to determine measures of individual exposure (such as steady-state peak, 
trough, and time-averaged concentration). In addition, model determined exposures may be used 
for exposure-response analyses. Results of population PK and exposure response-analyses would
be reported separately outside of the study CSR.
 
 
 
 
 
 
 
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7.9
Outcomes Research Analyses
The outcome research analyses will be performed using all outcome research participants.
7.9.1
EQ-5D-3L questionnaire
Participant’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
and change from baseline will be summarized using descriptive statistics (N, mean, SD, median, 
25th and 75th percentiles, minimum, maximum) by cohort.
Proportion of participants reporting problems for the 5 EQ-5D dimensions at each assessment time 
point will be summarized by level of problem by cohort. Percentages will be based on number 
participants assessed at assessment time point.EQ-5D questionnaire completion rate, defined as 
the proportion of questionnaires actually received out of the expected number (i.e., number of 
participants on treatment or in follow up), will be calculated along with reason for the questionnaire 
not completed and summarized for each assessment time point by cohort.A by-participant listing 
of EQ-5D with the problem levels for each of the 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression), health state (5 dimensions digits combined in a 5-digit 
number) and EQ-VAS will be provided. 
7.9.2
EORTC-QLQ-C30
Baseline measures will be summarized using descriptive statistics (N, mean, standard deviation, 
median, first and third quartiles, minimum, maximum) for each QLQ-C30 item, as well as global 
and functional scales by cohort, based on participants with a baseline measurement.
Post-baseline time point measures and change from baseline will be summarized using descriptive 
statistics (N, mean, standard deviation, median, first and third quartiles, minimum, maximum) for 
global, functional, and symptom scales at each assessment time point by cohort. This analysis will 
be performed in participants who have an assessment at baseline and at least one on-study 
assessment.
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EORTC-QLQ-C30 questionnaire completion rate, defined as the proportion of questionnaires 
actually received out of the expected number (i.e., number of participants on treatment or in follow 
up), will be calculated along with reason for the questionnaire not completed and summarized for 
each assessment time point by cohort.
A by-participant listing containing all single items on the questionnaire, five functional scales, 
global health status, and nine symptom scales will be provided.
7.9.3
EORTC-QLQ-BN-20
Baseline measures of the transformed scales will be summarized using descriptive statistics (N, 
mean, standard deviation, median, first and third quartiles, minimum, maximum) for 4 domains 
and 7 single items by cohort, based on participants with a baseline measurement.
Post-baseline measures and change from baseline of the transformed scales will be summarized 
using descriptive statistics (N, mean, standard deviation, median, first and third quartiles, 
minimum, maximum) for 4 domains and 7 single items at each assessment time point by cohort. 
This analysis will be performed in participants who have an assessment at baseline and at least one 
on-study assessment.
EORTC-QLQ-BN-20 questionnaire completion rate, defined as the proportion of questionnaires 
actually received out of the expected number (i.e., number of participants on treatment or in follow 
up), will be calculated along with reason for the questionnaire not completed and summarized for 
each assessment time point by cohort.
A by-participant listing containing all single items on the questionnaire, four functional domains, 
and seven single items will be provided.
 
 
 
 
 
 
 
 
 
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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 Specification10. Missing and partial Non-Study Medication Domain 
dates will be imputed using the derivation algorithm described in BMS Non-Study Medication 
Domain Requirements Specification11.
For death dates, the following conventions will be used for imputing partial dates:
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known alive date and the maximum will be 
considered as the death date.

If the month or the year is missing, the death date will be imputed as the last known alive date.

If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known alive date.
For date of progression, the following conventions will be used for imputing partial dates:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day.

If the day and month are missing or a date is completely missing, it will be considered as 
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 of RCC 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.
Safety conventions from Programming may be summarized separately in an appendix.
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9
CONTENT OF REPORTS
All analyses describe in this SAP will be included in the final Clinical Study Report. Refer to the 
Data Presentation Plan for mock-ups of all tables and listings.
 
 
 
 
 
 
 
 
 
 
 
 
 
11
DOCUMENT HISTORY
Table 11-1:
Document History
Version Number
Author(s)
Description
1.0
 
Initial version- 09 Feb 2018
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