Randomized, Open-label, Phase 3 Trial of Nivolumab Plus Brentuximab Vedotin Versus Brentuximab Vedotin Alone in Participants With Relapsed Refractory or Ineligible for Autologous Stem Cell Transplant (ASCT) Advanced Stage Classical Hodgkin Lymphoma (CheckMate 812: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 812)
Phase: PHASE3
Conditions: Hodgkin's Disease
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CA209812
IND Number:
119,380
EUDRACT Number
2017-000847-41
Date
22-Feb-2017
Revised Date
08-Jan-2020
Clinical Protocol CA209812
Randomized, Open-label, Phase 3 Trial of Nivolumab plus Brentuximab vedotin  versus 
Brentuximab vedotin alone in Participants with Relapsed Refractory or Ineligible for Autologous 
Stem Cell Transplant (ASCT) Advanced Stage Classical Hodgkin Lymphoma (CheckMate 812: 
CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 812)
Revised Protocol Number: 01 
Incorporates Administrative Letters 01, 02, and 03.
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CA209812
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Revised Protocol No.: 01
Date: 08-Jan-2020
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Clinical Protocol
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BMS-936558
nivolumab
Revised Protocol No.: 01
Date: 08-Jan-2020
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 01
08-Jan-2020
As of 17-Oct-2019, the Sponsor informed all study sites 
that enrollment into the study was permanently 
discontinued.

Efficacy assessments are now based on investigator 
assessments. 

Survival follow-up will stop at the last safety follow-up 
visit.
Changes per Administrative Letters 01, 02 and 03, as 
applicable, are now incorporated into the protocol.
Appendix 5, Management Algorithms For Immuno-
Oncology Agents, has been updated.
Administrative Letter 03
07-Jan-2020
Administrative Letter 02
21-Aug-2017
 correction of 
inconsistencies between synopsis and protocol language; 
addition of SAE assessments during screening; clarification 
of version 4.03 is used for CTCAE; removal of inconsistent 
reference to the Bv Investigator Brochure.
Administrative Letter 01
13-Apr-2017
Updated the schedule of activities table by adding an 
omitted measurement of cardiac ejection fraction at 
screening. Minor clarification to the ejection fraction 
inclusion criteria language was nade.
Original Protocol
22-Feb-2017
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BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 01:
On 17-Oct- 2019, the Sponsor, BMS, notified all study sites that enrollment into CheckMate 812
was permanently discontinued. The Sponsor’s decision was based on discussions 
 
regarding the feasibility of completing enrollment into CheckMate 812 in the rapidly evolving 
treatment landscape for Classical Hodgkin Lymphoma (cHL). The decision to discontinue 
enrollment is not related to any efficacy or safety concerns in CheckMate 812. 
For currently enrolled participants, at the investigator’s discretion, the same study treatment can 
be continued if the participant is considered to have clinical benefit. Assessments of efficacy and 
safety will continue at the time points defined in the protocol; however, efficacy assessments are 
now based on investigator assessments. 
 
For 
participants who continue study treatment, BMS will continue to provide study drugs, per country 
requirements, until the participant meets the protocol discontinuation criteria. Participants who 
discontinue all study drugs will continue safety follow-up per protocol requirements. Survival 
follow-up stops at the last safety Follow-up Visit 2 as presented in the Schedule of Activities. 
Additional changes include the incorporation of changes per Administrative Letters 01, 02, and 03
that remain applicable and the update of Appendix 5: Management Algorithms For Immuno-
Oncology Agents.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Synopsis 
Section 2 Schedules of 
Activities: Tables 2-1, 2-2, 
2-3. 
Section 3.3 Benefit/Risk 
Assessment
Section 5.1 Overall Design, 
Figure 5.1-1
Section 5.2 Number of 
Participants.
Section 6 Study Population
Section 6.4.1 Retesting 
During Screening or Lead-in
On 17-Oct- 2019 all study sites 
were notified that enrollment into 
CheckMate 812 was permanently 
discontinued.
Survival follow-up will stop at the 
last safety Follow-up Visit 2. All 
efficacy assessment will be based 
on investigator assessment. 
The Sponsor’s decision was based on 
discussions 
 regarding the
feasibility of completing enrollment into 
CheckMate 812 in the rapidly evolving 
treatment landscape for Classical
Hodgkin Lymphoma (cHL). The 
decision to discontinue enrollment is not 
related to any efficacy or safety concerns 
in CheckMate 812.
Modification of study assessments,
based on the close in enrollment for this 
study.
Revised Protocol No.: 01
Date: 08-Jan-2020
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Section 2 Schedule of 
Activities Table 2-1, 
Screening Procedural Outline 
(BMS-936558)
Per Administrative Letter 02 
(21-Aug-2017), cardiac ejection 
fraction and monitor for serious 
adverse events were added to the 
screening assessments.  
These assessments have been 
incorporated into the protocol text per 
BMS standard practice for incorporating 
changes of administrative letters into the 
subsequent revised protocol.
Section 4 Objectives and 
Endpoints, Table 4-1 
Objectives and Endpoints 
Section 5.1 Overall Design, 
Figure 5.1-1
Section 5.1.1 Data 
Monitoring Committee
Section 9.1 Imaging 
Assessment for the Study
Per Revised Protocol 01, efficacy 
assessment will be based on 
investigator assessment.
As enrollment was discontinued, the 
Sponsor decided to discontinue efficacy 
assessments by BICR.
Section 6.1 Inclusion Criteria 
4) Physical and Laboratory 
Test Finding b) 
Per Administrative Letter 02 
(21-Aug-2017), echocardiography 
was no longer required for 
evaluation of left ventricular 
ejection fraction over 50% at rest. 
This change has been incorporated into 
the protocol text per BMS standard 
practice for incorporating changes of 
administrative letters into the subsequent 
revised protocol.
Section 7.1.4, Management 
Algorithms for Immuno-
Oncology Agents
Addition of myocarditis to the list of 
management algorithms for 
immuno-oncology agents
Alignment with updates in Appendix 5: 
Management Algorithms for 
Immuno-oncology Agents
Section 7.1.6, Dose 
Discontinuation Criteria 
(Nivolumab) 
Neurologic toxicity and 
myocarditis added  to the list of 
Grade 3 study treatment-related
adverse events of any duration that 
require discontinuation
Alignment with current standard for 
nivolumab. 
Section 9. Study Asssesements 
and Procedures
Documentation 
of 
GvHD
for 
participants who discontinue study
therapy by proceeding to allogeneic 
SCT will stop at Follow-up Visit 2.
Modification of study assessments, 
based on the close in enrollment for this 
study
Revised Protocol No.: 01
Date: 08-Jan-2020
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Section 9.2.5 Pregnancy
The length of time for reporting of 
pregnancy by the investigator as 
detailed in this section of the 
protocol has been changed from 5 
half-lives after product 
administration, to 5 half-lives plus 
30 days after product 
administration. 
Alignment with contraceptive 
requirements that are presented in 
inclusion criteria.
Section 10 Statistical 
Considerations
Added paragraph to address close of 
enrollment, total number of 
participants randomized and 
changes to the statistical section. 
Minor revisions to align with the 
Sponsor’s decision to stop 
enrollment in the sudy and the 
change from BICR to investigator 
assessments for efficacy. 
Alignment of statistical section to 
protocol changes previously described. 
Section 11: References.
Reference 27 from original protocol 
deleted and all subsequent references 
renumbered
Corrections for references for product 
information for brentuximab vedotin. 
Appendix 5: Management 
Algorithms For Immuno-
Oncology Agents
Management algorithm for hepatic 
adverse events - deletion of footnote: 
I-O therapy may be delayed rather 
than discontinued if AST/ALT 8 x 
ULN or T.bili 5 x ULN.
Addition of Myocarditis Adverse 
Event Management Algorithm.
Updated 
per 
nivolumab 
program 
standard.
Revised Protocol No.: 01
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR REVISED PROTOCOL 01: ..................................... 
 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01 ......................... 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Nivolumab Mechanism of Action ............................................................. 
 
3.2.2 Brentuximab Vedotin Mechanism of Action ............................................ 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Brentuximab Vedotin ............................................................................... 
 
5.5.2 Nivolumab ................................................................................................ 
 
5.5.3 Pharmacokinetics Supporting Dosing Rationale ..................................... 
 
5.5.4 Rationale for Nivolumab 30-minute Infusion .......................................... 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Dose Delay Criteria (Nivolumab) ............................................................ 
 
7.1.2 Criteria to Resume Study treatment (Nivolumab) .................................... 
 
 
7.1.4 Management Algorithms for Immuno-Oncology Agents ......................... 
 
7.1.5 Treatment of Infusion-related Reactions (Nivolumab/Brentuximab 
Vedotin) ....................................................................................................... 
 
7.1.6 Dose Discontinuation Criteria (Nivolumab) ........................................... 
 
7.1.7 Dose Discontinuation Criteria (Brentuximab Vedotin) ........................... 
 
7.1.8 Dose Delay Criteria (Nivolumab and Brentuximab Vedotin) .................. 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
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7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Nivolumab ................................................................................................ 
 
7.4.2 Brentuximab vedotin ................................................................................ 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Permitted Therapy .......................................................................... 
 
7.7.2.2 Imaging Restriction and Precautions ............................................. 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Imaging Assessment for the Study............................................................ 
 
9.1.2 Disease Response Evaluation .................................................................. 
 
9.1.3 B Symptoms .............................................................................................. 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital signs................................................................................................. 
 
9.4.3 Electrocardiograms ................................................................................. 
 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.5 Imaging Safety Assessment ...................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
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10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.4 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ................................................................................................................. 
 
APPENDIX 6 LUGANO 2014 CLASSIFICATION FOR INITIAL EVALUATION, 
STAGING, AND RESPONSE FOR HODGKIN LYMPHOMA ........................... 
 
APPENDIX 7 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 8 HASENCLEVER SCORE (INTERNATIONAL PROGNOSIS 
SCORE) .................................................................................................................. 
 
APPENDIX 9 ACUTE GVHD GRADING AND STAGING ..................................... 
 
 
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1
SYNOPSIS
Protocol Title: Randomized, Open-label, Phase 3 Trial of Nivolumab plus Brentuximab vedotin versus 
Brentuximab vedotin alone in Participants with Relapsed Refractory or Ineligible for Autologous Stem Cell 
Transplant (ASCT) Advanced Stage Classical Hodgkin Lymphoma
(CheckMate 812: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 812)
Study Phase: 3
Rationale:
The programmed death-1 (PD-1) cell surface membrane receptor is a member of the CD28 family 
of T-cell co-stimulatory receptors.1 PD1 expression is a marker of T cell exhaustion and is 
associated with immune evasion in tumors. Hodgkin Lymphoma (HL) is characterized by genetic 
predisposition for over expression of programmed death (PD)-1 ligands. There are multiple 
mechanisms identified for upregulation of PD-L1 & PD-L2 in HL. Additionally CD30 is a cell 
membrane protein of the tumor necrosis factor family. CD30 is highly expressed in HL on the 
Reed Sternberg cells. Given the abundant expression of PD-1 ligands and CD30 in HL, the two 
proteins provide opportunity to target specific molecules associated with tumor growth and 
progression. Ongoing trials with the combination of brentuximab vedotin (BV) and nivolumab 
appear promising. Nivolumab and BV have demonstrated encouraging single agent activity in the 
treatment of relapsed HL. Since both drugs are effective as single agents, it is likely that the 
combination may have better efficacy as compared to either agent alone. A Phase 1/2 trial of the 
BV and nivolumab combination is ongoing in adults with Relapsed/Refractory Hodgkin 
Lymphoma after failure of first-line therapy. This study is actively enrolling (ClinicalTrials.gov 
identifier: NCT02572167). In this study, patients have been treated for a total of 4 cycles with 
combination regimen. Overall, the combination has been well tolerated with none of the
participants requiring dose discontinuation due to toxicities. All patients were able to tolerate 
4 cycles of combination regimen. The majority of adverse events including immune-related 
adverse events were low grades (1 and 2). Preliminary results are indicative of a highly efficacious 
regimen in a sample size n= 20, with an Objective Overall Response Rate of 90% and Complete 
Metabolic Response of 62%. Similar findings have been observed in another ongoing trial, the 
ECOG ACRIN trial E4412 (ClinicalTrials.gov identifier: NCT01896999). The preliminary data 
from the E4412 trial with a sample size (N=10) for relapsed/refractory patients has demonstrated 
an ORR of 100% and CR of 63%. Although the studies are ongoing and numbers are small, 
preliminary findings are suggestive of an effective and tolerable regimen in a refractory patient 
population with high unmet need. 
On 17-Oct- 2019, all study sites were notified that the Sponsor, Bristol-Myers Squibb, had decided 
to permanently discontinue enrollment in CheckMate 812. The Sponsor’s decision was based on 
discussions 
 regarding the feasibility of completing enrollment into CheckMate 812 
as designed. Difficulty in enrollment of this study is linked to the rapid evolution in the US cHL
treatment landscape and particularly with respect to the use of BV in earlier lines of treatment.
This evolution has led to a decrease in the pool of patients potentially eligible for CheckMate 812. 
Revised Protocol No.: 01
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The decision to discontinue enrollment is not related to any efficacy or safety concerns in 
CheckMate 812. For currently enrolled participants, at the investigator’s discretion, the same study 
treatment can be continued if the participant is considered to have clinical benefit. Assessments of 
efficacy and safety will continue per protocol; however, efficacy assessments will be done by 
investigator.
 
 
 For participants who continue study treatment, 
BMS will continue to provide study drugs, per country requirements, until the participant meets
the protocol discontinuation criteria. Participants who discontinue all study drugs will continue 
safety follow-up per protocol requirements. Survival follow-up will stop at safety follow-up Visit 
2, as presented in the Schedule of Activities. 
Study Population:
As of 17-Oct-2019 enrollment in this study was stopped at the decision of the Sponsor. A total of 
23 participants have been randomized.
Males and females, ages 18 and above, with relapsed/refractory cHL, with one of the following:
a) Autologous Stem Cell Transplant (ASCT) ineligible patients
Chemo-resistant disease (unable to achieve CR or PR to salvage chemotherapy) or any significant 
coexisting medical condition (cardiac, renal, pulmonary, or hepatic dysfunction) are likely to have 
a negative impact on tolerability of ASCT. Note: Sponsor review and approval of participants 
< 65 years of age who are not ASCT candidates is required before randomization. Participants 
must have received at least 2 prior chemotherapy regimens (BV can be included as one regimen) 
b) Patients after failure of ASCT:

Documented absence of CR after 90 days from stem cell infusion for the most recent ASCT

Documented relapsed disease (after CR) or disease progression (after PR or SD)
Both for a) and b), participants who are naïve to BV or who were sensitive to the most recent BV 
treatment are eligible. Participants must demonstrate BV sensitivity as defined by documented PR 
or CR from the most recent BV treatment, and by no disease progression during the most recent 
BV treatment or no early relapse within 3 months after last dose of the most recent BV based on 
medical record. For b), prior treatment with BV may have been as a single agent or in combination 
with chemotherapy and may have occurred during any line of therapy (eg, induction, salvage, or 
consolidation post-ASCT). Of note, documentation of response following consolidation therapy 
with BV is not required, as it is assumed that the patients are in remission at the time of 
consolidation.
Other key inclusion criteria include ECOG PS 0-1 and biopsy confirmation of cHL prior to 
initiation of study drug. 
Key exclusion criteria include known CNS lymphoma, nodular 
lymphocyte-predominant HL, and active interstitial pneumonitis or CT evidence of Grade 1 
pneumonitis. See Section 6 of the protocol for full list of criteria.
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Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare progression free survival of 
nivolumab+BV 
vs. 
BV 
based 
on 
investigator assessments

Progression Free Survival (PFS): defined as time from date 
of randomization to death, or disease progression.
Secondary

To compare the complete response rate of 
nivolumab+BV 
vs. 
BV 
based 
on 
investigator assessments

To assess objective response rate and 
duration of response based on investigator 
assessments.

To assess duration of complete response 
based on investigator assessments.

To assess overall survival of participants 
treated with nivolumab + BV vs BV.

Complete Response Rate (CRR): defined as proportion of 
participants who have achieved complete response (Lugano 
2014 conference)

Objective Response Rate (ORR): defined as the proportion 
of participants who have achieved complete response or 
partial response (Lugano 2014 classification)

Duration of response or duration of complete response 
(DOR or DOCR): defined as the time from first response or 
complete response to the date of initial objectively 
documented progression as determined using the 2014 
Lugano classification or death due to any cause

Overall Survival (OS): defined as the time between the date 
of randomization and the date of death..
Overall Design:
This is a 1:1 randomized, open-label phase 3 study in advanced cHL participants 18 years old 
who are relapsed refractory or ineligible for autologous stem cell transplant (ASCT). Patients will 
be balanced in the 2 groups in regards to prior therapies. Approximately 340 participants will be 
treated in one of two arms: 1) nivolumab 360 mg IV every 3 weeks until progression or 
unacceptable toxicity (except for patients in CR who can discontinue at 2 years) plus BV 1.8 mg/kg 
IV every 3 weeks for 16 cycles, or until progression or unacceptable toxicity, whichever occurs 
first or 2) BV alone 1.8 mg/kg every 3 weeks for 16 cycles, or until progression or unacceptable 
toxicity, whichever occurs first. Treatment may also be discontinued if the participant meets other 
criteria for discontinuation of study drug outlined in Section 8.1 of the protocol. Participants
receiving nivolumab who achieve CR may discontinue treatment after a maximum of 2 years of 
therapy, provided that there is no prohibitive toxicity. Participants can be BV- naïve, or can have 
prior BV treatment as a single agent or in combination in any line of therapy. Randomization 
stratification will be performed on the following two factors: 1) Prior ASCT status (YES/NO). 
2) Prior BV use (YES/NO). Participants will be balanced based on the stratification factors per 
arm.
Participants will undergo screening evaluations to determine eligibility within 28 days prior to first 
dose. Each 21-day dosing period will constitute a cycle.
Study visits and endpoint measurements will occur as indicated in Table 2-1 though Table 2-3 in 
the protocol. 
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Any participant who discontinues the study treatment prior to progression will be followed for 
progression, then survival, in the follow up phase of the study.
As of 17-Oct-2019, enrollment in this study was stopped at the decision of the Sponsor. For 
currently enrolled participants, at the investigator’s discretion, the same study treatment can be 
continued if the participant is considered to have clinical benefit. Assessments of efficacy and 
safety will continue per protocol; however, efficacy assessments will be done by investigator. 
 
 
 For participants who continue the study treatment, BMS will continue to provide 
study drugs, per country requirements, until the participant meets the protocol discontinuation 
criteria. Participants who discontinue all study drugs will continue safety follow-up per protocol 
requirements. Survival follow-up will stop at safety follow-up visit 2 as presented in the Schedule 
of Activities.
Number of Participants: 

# Screened: Approximately 400 were planned to be screened.

# Randomized: Approximately 340 with 170 participants in the nivolumab + BV arm, 170
in the BV arm were antipated. A total of 23 participants were randomized before 
enrollment was stopped (17-Oct-2019) per the decision of the Sponsor..

Screen Failure Rate: 15%
Treatment Arms and Duration:
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Abbreviations: BV = brentuximab vedotin; PFS = progression-free survival; CRR =  complete response rate; OS 
overall 
survival; 
ORR = objective response rate; DOCR = duration of complete response; DOR =  duration of response 
Study treatment:

Randomized Investigational Arm: Nivolumab (360 mg flat dose) every 3 weeks until 
progression or unacceptable toxicity+ BV (1.8 mg/kg) every 3 weeks for 16 cycles, 
progression, or unacceptable toxicity, whichever occurs first

Randomized Control Arm: BV (1.8 mg/kg) every 3 weeks for 16 cycles, progression,
or unacceptable toxicity, whichever occurs first
Study Drug for CA209812
Medication 
Potency 
IP/Non-IP 
Nivolumab (BMS-936558) Solution for Injection
100 mg (10 mg/mL) 
and 40 mg (10 mg/mL)
IP
Brentuximab Vedotin Powder for Solution for Injection
50 mg
IP
Other medications used as support medication for preventative, diagnostic, or therapeutic reasons, 
as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. 
Study drug preparation and administration instructions will be provided in a separate manual.
Statistical Considerations
As of 17-Oct-2019, enrollment in this study was stopped at the decision of the Sponsor. At the 
time enrollment was stopped, 23 participants had been randomized.  No formal statistical testing 
or inferential analyses will be performed. The statistical analyses as previously planned will only 
be conducted if appropriate in the final analysis. Further details are presented in the SAP.
Sample Size:
The planned sample size for this study was to be approximately 340 randomized participants. The 
sample size of the study accounts for the primary efficacy endpoint, PFS. PFS will be evaluated 
for treatment effect at the overall alpha level of 0.05 (two-sided) with 90% power.
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EAST version 6.3 was used for sample size/power computations.
As of 17-Oct-2019 enrollment in this study was stopped at the decision of the Sponsor. At the time 
enrollment was stopped, 23 participants had been randomized.
Endpoints:
Primary Endpoints:
The primary objectives in the study will be measured by the primary endpoint of PFS by 
investigator assessments.
Secondary Endpoints:
The secondary objectives in the study will be measured by:

CRR, ORR, DOR, and DOCR assessed by investigator.

OS
Analyses:
PFS Analysis
The primary endpoint PFS based on investigator assessment will be compared in two randomized 
arms via a two-sided, log-rank test stratified by the same factors used in randomization. 
Participants who die without a reported progression 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 randomization date. A participant who initiates a subsequent anti-cancer 
therapy will be censored on the date of last tumor assessment prior or on the start date of their 
subsequent anti-cancer therapy. Sensitivity analyses will be performed using different PFS 
definitions to assess the robustness of the primary analysis. The PFS curve, median and PFS rate 
at 6, 12, 18, and 24 months for each randomized arm will be estimated using the Kaplan-Meier 
product-limit method. Two sided, 95% confidence intervals for median PFS will be computed by 
Brookmeyer and Crowley method. A two-sided, 95% confidence interval for the PFS rates will be 
computed by Greenwood method. The HR and corresponding two-sided 100 * (1-α)% (α adjusted 
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for the interim analysis) confidence interval will be estimated in a Cox proportional hazards model 
using randomized arm as a single covariate, stratified by the same factors used in randomization
CRR/CMR Analysis
CRR/Complete Metabolic Response (CMR) based on investigator assessment will be compared in 
two randomized arms via a two-sided, Cochran-Mantel-Haenszel (CMH) test stratified by the same 
factors used in randomization. An estimate of the treatment odds ratio between the nivolumab + 
BV and BV arm along with corresponding two-sided 95% CIs and p-value will be presented. The 
estimate of the CRR/CMR and associated exact two-sided 95% CIs (by Clopper and Pearson 
method) will be presented for both arms.
When the primary endpoint, PFS, is statistically significant, the secondary endpoint CRR/CMR 
will be tested. The hierarchical testing procedure that ensures the study-wise type I error is 
controlled at 5% levels will be described in the SAP.
ORR, DOR, DOCR and OS Analysis
ORR will be computed in each treatment group along with the exact 95% CI using 
Clopper-Pearson method.
Duration of response (or complete response) in each treatment group will be estimated using KM 
product-limit method for participants who achieve PR or CR (or CR only). Median values along 
with two-sided 95% CI will be calculated.
The OS curves for each treatment group will be estimated using the Kaplan-Meier product-limit 
method. Two-sided, 95% confidence intervals for median OS will be provided. For participants 
without documentation of death, OS will be censored on the last date the participant was known 
to be alive.
Safety Analysis
Safety analyses will be performed in all treated participants. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.03. All on-study AEs, treatment-related, AEs, SAEs and 
treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v4.03 criteria by 
system organ class and MedDRA preferred term. On-study lab parameters including hematology, 
chemistry, liver function, thyroid function, and renal function will be summarized using worst 
1grade per NCI CTCAE v4.03 criteria.
1 Pardoll D: Does the immune system see tumors as foreign or self? Ann Rev Immunol. 2003; 
21:807-39.
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SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (BMS-936558)
Procedure
Screening
Visita
Notes
Enrollment was stopped as of 17-Oct-2019.
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to
first dose
Medical History
X
Prior Systemic Therapy
X
Safety Assessments
Physical Examination
X
Physical Measurements
X
Include Height, Weight, and ECOG performance Status (Appendix 7)
Hasenclever-Index for Hodgkin's Disease also 
known as IPS at Initial Diagnosis
X
Composite score, see Appendix 8.
Vital Signs
X
Includes body temperature, seated blood pressure (BP) and heart rate. Should be 
performed 14 days prior to first dose
Cardiac Ejection Fraction 
X
Assessment of cardiac ejection fraction within 28 days prior to first dose
(Added as part of Administrative Letter 02 [21-Aug-2017])
Monitor for Serious Adverse Events
X
(Added as part of Administrative Letter 02 [21-Aug-2017])
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 14 days prior to
first dose.
Concomitant Medication Collection
X
Within 14 days prior to first dose
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Table 2-1:
Screening Procedural Outline (BMS-936558)
Procedure
Screening
Visita
Notes
Enrollment was stopped as of 17-Oct-2019.
Laboratory Tests
X
Complete blood count (CBC) with differential, Chemistry panel including LDH, AST, 
ALT, ALP, T.Bili, BUN or serum urea level, uric acid, creatinine, Ca, Mg, Na, K, Cl, P, 
glucose, albumin, amylase, lipase, thyroid stimulating hormone (TSH) (reflex to free T3, 
free T4 for abnormal TSH result), c-reactive protein ,hepatitis B surface antigen (HBV 
sAg), and hepatitis C antibody (HCV Ab) or HCV ribonucleic acid (RNA) within 14 
days prior to first dose.
Urinalysis
X
Total protein, glucose, blood, leukocyte esterase, specific gravity, and pH, within 14 
days prior to first dose.
Pregnancy Test
X
For WOCBP only (serum or urine - local/site)
ECG
X
Within 28 days prior to first dose
Pulmonary Function Test (PFT)
X
Must include testing for diffusing capacity of the lung for carbon monoxide (DLCO).
Within 28 days prior to first dose
Efficacy
 Assessments
Radiographic Tumor Assessment
FDG PET-CT or PET-MRI scan from vertex to 
toes 
X
Must be performed within 28 days prior to first dose.
FDG-PET scan from vertex to toes is required at screening.
CT portion of PET-CT must be of diagnostic quality. If low dose CT used, then a 
separated dedicated CT or MRI of the chest, abdomen and pelvis and other known sites 
of disease must be acquired.
Collection of tumor tissue 
X
Submission of tumor tissue (FFPE tumor tissue block or 25 unstained slides) from a 
biopsy performed during screening is mandatory. If this is not possible, the following 
exceptions are allowed:
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Table 2-1:
Screening Procedural Outline (BMS-936558)
Procedure
Screening
Visita
Notes
Enrollment was stopped as of 17-Oct-2019.
1) Participants who do not have any accessible lesions, or
2) Participants who have archival tissue from a previous tumor biopsy 
. These participants must submit archival tissue from the 
most recent tumor biopsy if archival tissues are available from tumor biopsies at multiple 
timepoints. While submission of archival tissue from the most recent tumor biopsy is
mandatory, archival tissue from other tumor biopsy is strongly encouraged. For example, 
participants who mandatorily submit archival tissue from a tumor biopsy at relapse may 
optionally submit archival tissue for tumor biopsy at initial diagnosis.
Biopsy samples should be excisional, incisional, or core needle. Tumor biopsies (FFPE) 
for IHC of tumor and TIL and RNALater for gene expression.
IVRS/Clinical Drug Supplies
Phone calls to IVRS/Randomize
X
Phone calls must be made to IVRS as follows:
For subject number assignment at the time informed consent is obtained and trigger 1st 
shipment of drug.
a Within 28 days prior to first dose
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Table 2-2:
Procedural Outline During the Treatment Period (CA209812)
Procedure
Cycle 1 Day 1 -
Disease 
Progression or 
Unacceptable 
Toxicity
Notes
All windows proposed are calendar days. Procedures must be done within 
72h prior to dosing unless otherwise specified. Dosing is to be performed 
every 3 weeks
Safety Assessments
Targeted Physical Examination
X
Lymph node areas (for example, but not limited to, submandibular, cervical, 
supraclavicular, axillary, or inguinal lymph node), and abdominal organs (eg,
spleen, liver)
Vital Signs 
X
Includes body temperature, respiratory rate (RR), and seated blood pressure (BP) 
and heart rate.
Physical Measurements
X
Within 72 hours prior to dosing. Includes Weight and ECOG performance status
(Appendix 7)
Adverse Events Assessment
Continuously
See Appendix 2/Section 9.2. Assessed using NCI CTCAE v. 4.03.
Serious Adverse Events Assessment
Continuously
See Appendix 2/Section 9.2. Assessed using NCI CTCAE v. 4.03
Review of Concomitant Medications
X
See section 7.7
Laboratory Tests
X
Within 72 hours prior to dosing to include CBC w/differential, AST, ALT, ALP, 
TBili, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, phosphate, LDH, 
glucose, amylase, lipase, c-reactive protein, albumin
Thyroid Function Testing
See note
TSH (reflex to free T3 and free T4 if abnormal result) to be performed every 9
weeks (7 days) from first dose regardless of dosing schedule.
Pregnancy Test for WOCBP
X
See note
Serum or urine within 24 hours prior to first dose and then at least once every 4 
weeks (7 days) regardless of dosing schedule.
Efficacy Assessments
Radiographic Tumor Assessment
FDG-PET-CT or PET-MRI scans from vertex to 
toes
See note
FDG PET-CT or PET-MRI will be performed at the end of cycle 5, 10, 15, and 
every 5 cycles until disease progression.
FDG PET-CT or PET-MRI can be performed as clinically warranted for suspicion 
of recurrence during the non-protocol specified time points
B symptoms
See note
Collected Day 1 (prior to dosing) of every other cycle (cycle 1, 3, etc)
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Table 2-2:
Procedural Outline During the Treatment Period (CA209812)
Procedure
Cycle 1 Day 1 -
Disease 
Progression or 
Unacceptable 
Toxicity
Notes
All windows proposed are calendar days. Procedures must be done within 
72h prior to dosing unless otherwise specified. Dosing is to be performed 
every 3 weeks
Clinical Drug Supplies
Administer Study Drug
X
IVRS should be called within 3 days prior to study treatment administration to 
receive vial assignment.
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Table 2-3:
Procedural Outline after the Treatment Period (CA209812) - Follow Up
Procedure
X, Follow-Up, 
Visits 1 and 2a
Notes
Safety Assessments
Targeted Physical 
Examination
X
Lymph node areas (for example, but not limited to, submandibular, cervical, supraclavicular, axillary, or 
inguinal lymph node), and abdominal organs (eg, spleen, liver)
Serious Adverse Events 
Assessment
X
SAEs related to any later protocol-specified procedure must be collected
Adverse Events Assessment
X
Non-serious AEs and SAEs must be collected up to 100 days after study treatment discontinuation. 
Peripheral Neuropathy 
X
Any AEs of peripheral neuropathy must be followed until resolution or end of study, whichever occurs 
first.
Monitoring for (in)fertility
X
Completion of CRF through Safety Follow-up Visit 2. 
Monitoring for
cardiotoxicity and 
pulmonary toxicities
X
Completion of CRF through Safety Follow-up Visit 2 and work up as indicated (for clinical symptoms)
Monitoring for secondary 
neoplasms
X
Completion of CRF through Safety Follow-up Visit 2. 
Laboratory Tests
X
During Follow-up visit 1 and Follow-up visit 2: CBC with differential, BUN or serum urea level, serum 
creatinine, sodium, potassium, calcium, magnesium, chloride, glucose, AST, ALT, total bilirubin, alkaline 
phosphatase, LDH.
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result)
Every 9 weeks
Pregnancy Test (WOCBP 
only)
X
Serum or urine (WOCBP only)
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Table 2-3:
Procedural Outline after the Treatment Period (CA209812) - Follow Up
Procedure
X, Follow-Up, 
Visits 1 and 2a
Notes
Efficacy Assessments
B Symptoms
X
To be collected only at Follow-up Visit 1
Radiographic Assessments
FDG-PET CT or FDG MRI
scan from vertex to toes b
See note
For participants who discontinue study treatment prior to disease progression, no further FDG-PET CT or 
PET MRI will be obtained.
Participant Status
Survival Status 
X
Survival follow-up will stop after safety Follow-up Visit 2. 
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Table 2-3:
Procedural Outline after the Treatment Period (CA209812) - Follow Up
Procedure
X, Follow-Up, 
Visits 1 and 2a
Notes
Subsequent anti-lymphoma 
therapies
X
It can be accomplished by visit or phone contact to assess subsequent anti-cancer therapy. Per Revised 
Protocol 01, stop after safety Follow-up Visit 2.
Post-nivolumab stem cell 
transplant follow-up (if 
applicable)
X
Completion of associated eCRF page. Per Revised Protocol 01, stop after safety Follow-up Visit 2.
GVHD Assessments
X
Only for participants who discontinued study therapy by proceeding to allogeneic SCT. See Section 9 and 
Appendix 9. Per Revised Protocol 01, stop after safety Follow-up Visit 2.
a X, Follow-up visit 01 occurs 35 days 7 days from last dose and Follow-up visit 02 occurs 100 days 7 days from the last dose.
b Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest and a contrast enhanced MRI of the abdomen and pelvis may be
obtained. CTs and MRIs should be acquired with a slice thickness of 5 mm or less with no gap (contiguous).
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3
INTRODUCTION
This study strives to improve disease control while minimizing treatment burden by incorporating 
two novel agents, nivolumab and brentuximab vedotin (BV), as salvage therapy in patients with 
relapsed Hodgkin Lymphoma (HL).The study targets patients who have relapsed after autologous 
stem cell transplant (ASCT) or are ineligible for ASCT.
Hodgkin lymphoma is a lymphoid malignancy characterized by the presence of multinucleated 
Reed-Sternberg cells, which are generally accepted to be of B-cell origin and usually account for 
only 1% to 10% of the cells in the tumor tissue.1 The majority of cells in HL tumor tissue are a 
mixed infiltrate of various lymphoid cells, including regulatory T-cells and macrophages.1 The
updated 2008 WHO classification recognizes two histologic groups: nodular lymphocyte 
predominant, which accounts for about 5% of all HL cases, and “classical” HL (cHL) which 
accounts for the remainder.1
In the totality of cancer epidemiology, HL represents a small percentage of all patients diagnosed 
with malignancy, yet it affects many considered as young adults. Approximately 8,500 new cases 
of HL are estimated to be diagnosed in the US in 2016 and more than 1,100 deaths from HL are 
expected.2 The prevalence of HL in the US in 2013 was estimated to be 193,545. The median age 
of diagnosis of HL in the US is 38 years; there is a bimodal age-specific incidence pattern, in which 
the incidence is highest between 15 and 34 years, declines between ages 35 and 54, and increases 
again after 55 years.3
Improvements in the use of combined chemotherapy and radiotherapy in advanced stage newly 
diagnosed cHL have resulted in durable remission rates of approximately 60% to 80%.2,4
However, the remaining approximately 30% of patients will either relapse or have primary
refractory disease. Failure to achieve complete response (CR) at the end of first-line therapy is 
considered as treatment failure. Salvage multi-agent chemotherapy, followed by ASCT, can only 
provide long-term disease control in approximately half of the patients with relapsed or refractory 
disease but at the price of additional acute and long-term toxicity. Patients who relapse after ASCT 
have an extremely poor prognosis and constitute a group with high unmet medical need. 
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3.2
Background
High-dose chemotherapy with ASCT remains the optimal option to achieve a durable remission in 
patients with HL who have relapsed or are refractory to the standard frontline combination 
chemotherapy.12 Furthermore with ASCT approximately 50% of the patients are cured.4
Unfortunately, the remaining 50% of ASCT patients do not experience long-term disease control 
with median overall survival of approximately 27 months.13 In particular, the prognosis remains 
exceedingly poor for patients who experience relapse or progressive HL within one year after 
ASCT where the median survival time is approximately 1.2 years.14 Several small clinical studies 
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have examined various agents in the ASCT relapsed HL population with uniformly poor results. 
Therefore, the therapeutic options for these patients remain very limited. This underscores the need 
for more effective regimens for the treatment of relapsed, refractory HL. 
Brentuximab vedotin is approved for patients who have progressed after ASCT or after failure of 
at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.
In a pivotal phase 2 study of 102 patients with relapsed or refractory HL following ASCT, 
treatment with BV 1.8 mg/kg every 3 weeks resulted in an objective response rate (ORR) of 75% 
(95% CI: 64.9, 82.6). 15 The CR rate was 34% (95% CI: 25.2, 44.4) and the median progression-
free survival (PFS) for all patients on study was 5.6 months (95% CI: 5.0, 9.0). Longer follow up
showed that the median overall survival (OS) and median PFS were 40.5 months (95% CI: 28.7, 
61.9) and 9.3 months (95% CI: 7.1, 12.2), respectively. The estimated 5-year OS and PFS rates 
were 41% (95% CI: 31, 51) and 22% (95% CI: 13, 31), respectively. It should also be noted that
BV is effective at the time of retreatment.16 Brentuximab vedotin is currently being developed by 
Seattle Genetics for the treatment of hematological malignancies.
Nivolumab has demonstrated promising activity as single agent in relapsed HL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Brentuximab vedotin and nivolumab have demonstrated promising single-agent activity in HL. 
Additionally, both drugs work through distinct mechanisms of action. Given that both agents have 
demonstrated significant activity in HL, combination therapy could potentially be more effective 
in the salvage treatment setting than administration of either agent alone. Moreover, both agents 
are well tolerated, have few overlapping toxicities, and can be infused in the outpatient setting.
3.2.1
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses7,18,19.
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.20 Collectively, these signals govern the 
balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA. 21 PD-1 signaling has been shown to inhibit CD28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes. 22These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50: 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50: 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 
and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction. Using a cytomegalovirus 
(CMV) re-stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall 
response indicates that nivolumab augmented IFN-γ secretion from CMV specific memory T cells 
in a dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine 
analog of nivolumab enhances the anti-tumor immune response and result in tumor rejection in 
several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).23
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3.2.2
Brentuximab Vedotin Mechanism of Action
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) consisting of 
3 components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30; 2) the 
microtubule-disrupting agent monomethyl auristatin E (MMAE); and 3) a protease-cleavable 
linker that covalently attaches MMAE to cAC10. The primary mechanism of anticancer activity 
of brentuximab vedotin is binding of the ADC to CD30-expressing cells, followed by 
internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. 
Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently 
inducing cell cycle arrest and apoptotic death of the cell.24
Additionally brentuximab vedotin has shown to induce Immunogenic Cell Death (ICD). 25 ICD is 
a distinct cell killing mechanism mediated through toll-like receptor ligands which can abrogate 
the inhibitory effect of tumor immunosuppressive microenvironment and reinitiate the immune
responses. Possible immune modulatory properties of BV were demonstrated in a report analyzing 
its effects in CD30+ Hodgkin Lymphoma cell lines. Brentuximab vedotin was evaluated for its 
ability to induce endoplasmic reticulum stress. It was shown that BV up-regulated the apoptotic 
endoplasmic reticulum sensor, C/EBP homologous protein, in a dose-dependent manner, which 
resulted in cleavage and activation of ATF6, a transcription factor required for induction of ER 
stress. The net results were induction of endoplasmic reticulum stress and ICD markers. Induction 
of ICD was associated with activation of immune reaction. It was concluded that exposure of 
dendritic cells to BV-killed tumor cells evoked an inflammatory phenotype including an increase 
in co-stimulatory markers CD86 and MHC Class II antigens, and activation of nuclear factor ⱪB 
(NFⱪB) an intermediate of the inflammatory signaling pathway. This suggests additional BV
anti-tumor effects by activating the innate immune response, although this effect remains to be 
validated, as the observations are early and ex vivo.
3.3
Benefit/Risk Assessment
Approximately 70% of patients with cHL are cured with conventional chemotherapy, and 30% of 
patients will either relapse or have primary refractory disease. Salvage multi-agent chemotherapy, 
followed by ASCT, can only provide long-term disease control in approximately half of the 
patients with relapsed or refractory disease. Patients with HL who failed ASCT represent an area 
of substantial unmet medical need.
 
 
However, nivolumab and BV have 
the potential for clinically relevant adverse events including pulmonary toxicity, hepatotoxicity, 
diarrhea/colitis, endocrinopathies, nephrotoxicity, peripheral neuropathy
and cytopenias. 
Nevertheless, ongoing trials with the combination have demonstrated that the combination is 
tolerable. To date, serious AEs with both agents have been manageable with prompt diagnosis and 
initiation of corticosteroids, dose interruption, and adequate supportive care. 
 
 
 
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Extensive details on the safety profile of nivolumab are available in the Investigator Brochure, and 
will not be repeated here. Overall, the safety profile of nivolumab is manageable and generally 
consistent across completed and ongoing clinical trials with no MTD reached at any dose tested 
up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively few high-grade (Grades 3 
to 4) AEs related to study drug. There was no pattern in the incidence, severity, or causality of AEs 
with respect to nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 5. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. 
Notable adverse events observed with brentuximab vedotin treatment of various cancers to date 
include peripheral neuropathy, infusion-related reactions, and cytopenias; and, less commonly, 
progressive multifocal leukoencephalopathy (PML), Stevens-Johnson syndrome, toxic epidermal 
necrolysis, tumor lysis syndrome, acute pancreatitis, pulmonary toxicity, and hepatotoxicity. In 
addition, concomitant use of brentuximab vedotin and bleomycin is contraindicated due to 
pulmonary toxicity that occurred in some patients receiving this combination of treatments.
Additional details on the safety profile of nivolumab, including results from other clinical studies,
are also available in the nivolumab IB.26 Similar information on the safety profile of BV is 
provided in the package insert, summary of product characteristics (SmPC), or equivalent 
document for brentuximab vedotin
Please see Section 3.1 for an explanation of changes made to the study protocol per Revised 
Protocol 01 due to Sponsor’s decision, communicated to all study sites on 17-Oct-2019 to 
permanently discontinue enrollment in CheckMate 812.
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare progression free survival of 
nivolumab + BV vs
BV
per investigator 
assessment. 

Progression Free Survival (PFS): defined as time from 
date of randomization to death, or disease progression.
Secondary

To compare the complete response rate of 
nivolumab + BV vs
BV per investigator 
assessment.

To assess objective response rate and duration 
of response per investigator assessment.

To assess duration of complete response per 
investigator assessment.

To assess overall survival of participants treated 
with nivolumab + BV vs BV.

Complete Response Rate (CRR): defined as proportion 
of participants who have achieved complete response 
(Lugano 2014 classification)

Objective Response Rate (ORR): defined as the 
proportion of participants who have achieved complete 
response 
or 
partial
response 
(Lugano 
2014 
classification)

Duration of response or duration of complete response 
(DOR or DOCR): defined as the time from first 
response or complete response to the date of initial 
objectively documented progression as determined 
using the 2014 Lugano classification or death due to 
any cause

Overall Survival (OS): defined as the time between the 
date of randomization and the date of death.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
5
STUDY DESIGN
5.1
Overall Design
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
Abbreviations: BV = brentuximab vedotin; PFS = progression-free survival; CRR =  complete response rate; OS 
overall 
survival; 
ORR = objective response rate; DOCR = duration of complete response; DOR =  duration of response. 
This is a 1:1 randomized, open-label Phase 3 study in advanced cHL participants 18 years old 
who are relapsed refractory or ineligible for ASCT. Patients will be balanced in the 2 groups in 
regards to prior therapies. Approximately 340 participants will be treated in one of 2 arms. In one 
arm, participants will receive nivolumab 360 mg IV every 3 weeks until progression or 
unacceptable toxicity (except for patients in CR who can discontinue at 2 years) plus BV 1.8 mg/kg 
IV every 3 weeks for up to 16 cycles, or until disease progression or unacceptable toxicity, 
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whichever occurs first. In the other arm, participants will receive BV alone 1.8 mg/kg every 
3 weeks for up to 16 cycles, disease progression, or unacceptable toxicity, whichever occurrs first. 
Discontinuation of study therapy can also occur if the participant meets other criteria outlined in 
Section 8.1. Participants receiving nivolumab who achieve CR may discontinue treatment after a 
maximum of 2 years of therapy, provided that there is no prohibitive toxicity. Participants can be 
brentuximab vedotin-naïve, or can have prior BV treatment as a single agent or in combination in 
any line of therapy. Randomization stratification will be performed on the following two factors: 
1) Prior ASCT status (YES/NO). 2) Prior BV use (YES/NO). Participants will be balanced based 
on the stratification factors per arm. The two arms will be balanced in regards to these stratification 
factors.
Participants will undergo screening evaluations to determine eligibility within 28 days prior to first
dose. Each 21-day dosing period will constitute a cycle.
Study visits and endpoint measurements will occur as indicated in Table 2-1 though Table 2-3. 
Any participant who discontinues the study treatment prior to progression will be followed for 
progression, then survival, in the follow up phase of the study. 

No dose reductions or escalations of nivolumab are permitted. Skipped doses will not be made 
up. For dose modifications or reductions of BV, see Section 7.4.2.

Duration of study participation: Randomization is within 28 days of the screening. The 
recruitment period is approximately 34 months with a follow up of 4 years after the last patient 
first visit (LPFV). Participants will receive active treatment of nivolumab until progression or 
unacceptable toxicity plus BV for 16 cycles or until progression or unacceptable toxicity, 
whichever comes first, or BV alone up to 16 cycles, or until progression or unacceptable 
toxicity, whichever occurs first. The treatment period will be followed by a survival follow up 
period.
As of 17- Oct- 2019, enrollment in this study was stopped at the decision of the Sponsor. For 
currently enrolled participants, at the investigator’s discretion, the same study treatment can be 
continued if the participant is considered to have clinical benefit. Assessments of efficacy and 
safety will continue per protocol; however, efficacy assessments will be done by investigator. 
 
 
 For participants who continue the study treatment, BMS 
will continue to provide study drugs, per country requirements, until the participant meets the 
protocol discontinuation criteria. Participants who discontinue all study drugs will continue safety 
follow-up per protocol requirements. Survival follow-up will stop at safety Follow-up Visit 2 as 
presented in Table 2-3.
5.1.1
Data Monitoring Committee and Other External Committees
The participants’ safety will be monitored on an ongoing basis. The BMS medical monitor is a 
physician responsible for reviewing, on a systematic and continuous basis, the safety of 
participants on this study. This includes a review of serious and non-serious adverse events, 
including all hematological and non-hematological events. In addition, a BMS medical safety team 
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(MST) routinely reviews safety signals across the entire nivolumab program. The MST is 
independent from the BMS medical monitor. The MST has the primary responsibility within BMS 
for assessing emerging safety trends, identifying potential safety signals, notifying appropriate 
stakeholders of relevant findings, and implementing risk management plans. The MST is
responsible for reviewing data from all sources including non-clinical studies and clinical trials, 
monitoring the progress of various nivolumab safety support activities, and recommending and 
implementing necessary changes to the safety plan and any other specific safety-related activities. 
Safety conference calls with investigators and representatives of the sponsor will be held regularly
until all participants have entered the FU/observational phase or discontinued the study. BMS 
clinical and safety team will assess safety in conjunction with the investigators, and will make 
appropriate modifications of the regimen based on safety assessment, if necessary.
5.2
Number of Participants
Approximately 400 participants were planned to be screened, such that approximately 
340 participants were to be randomized to receive either nivolumab + BV or BV in a 1:1 ratio. 
This targeted number of 400 enrolled participants considered that 15% will be screen failures. 
See Section 6.4 for more information on the definition of screen failure and Section 10.1 for a 
description of the sample size calculation.
As of 17- Oct- 2019, enrollment in this study was stopped at the decision of the Sponsor. The 
decision to discontinue enrollment is not related to any efficacy or safety concerns in 
CheckMate 812. At the time enrollment was stopped, 23 participants had been randomized.
5.3
End of Study Definition
The start of the trial is defined as signature of the informed consent form by the first screened 
participant. End of trial is defined as when all participants have completed safety Follow-up 
Visit 2. Study completion is defined as the date of the last patient/last visit for safety Follow-up 
Visit 2.
5.4
Scientific Rationale for Study Design
Harnessing host immune response is an important antitumor strategy. In this context, reversing the 
effects of exhaustive T cells by checkpoint inhibitors is actively explored as an effective immune 
therapy in clinical trials. PD-1 inhibitors have demonstrated ability to abolish immunosuppression 
in the tumors by restoring T cell activation.6,27,28 Agents with ability to enhance effector cells and 
up-regulate tumor antigens have the potential to enhance the efficacy of check- point inhibitors 
such as nivolumab. The MHC class II antigen processing pathway is altered in tumors, thereby 
precluding efficient presentation of T cell epitopes.29 One strategy to increase the efficacy of check 
point blockade is by combining with agents which possess the ability to enhance the effects of 
MHC Class II molecules to increase antigen presentation. 
Brentuximab vedotin mediates its effects through induction of apoptosis. Furthermore, BV has 
also shown to induce immunogenic cell death (ICD). 25
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Nivolumab induces robust T-cell activation. This results in augmentation of host anti-tumor 
immune response.
Collectively, this combination has a high potential of becoming an effective novel therapy due to 
additive and synergistic effects.
5.5
Justification for Dose
5.5.1
Brentuximab Vedotin 
The recommended dose for BV per its prescribing information is 1.8 mg/kg via intravenous (IV) 
infusion administered every 3 weeks (first day of every treatment cycle). This dose and schedule 
was evaluated in two pivotal Phase 2 studies in subjects with CD30-positive hematologic 
malignancies who were treated with BV for a maximum of 16 cycles (approximately 1 year).
5.5.2
Nivolumab
Nivolumab will be administered as a flat dose of 360 mg once every 3 weeks (Q3W). The safety 
and efficacy of 360 mg Q3W flat dose of nivolumab is expected to be similar to the approved dose 
of 3 mg/kg Q2W.
The nivolumab dose of 360 mg Q3W was selected based on clinical data and modeling and 
simulation approaches using population PK (PPK) and exposure-response analyses of data from 
studies in multiple tumor types (melanoma, non-small-cell lung cancer [NSCLC], and renal cell 
carcinoma [RCC]) where body weight normalized dosing (mg/kg) has been used.
Population PK analyses have shown that the exposure to nivolumab increased dose proportionally 
over the dose range of 0.1 to 10 mg/kg administered every 2 weeks, and no clinically meaningful 
differences in PK across ethnicities and tumor types were observed. Nivolumab clearance and 
volume of distribution were found to increase as the body weight increases, but less than 
proportionally with increasing weight, indicating that mg/kg dosing represents an over-adjustment 
for the effect of body weight on nivolumab PK. Using the PPK model, the overall distributions of 
nivolumab average steady-state exposures (Cavgss) are comparable after treatment with either 
nivolumab 3 mg/kg every 2 weeks (Q2W) or 360 mg Q3W. The flat dose regimen of 360 mg Q3W 
is predicted to result in approximately 23% higher maximum steady state concentrations (Cmaxss) 
and approximately 6% lower steady state trough concentrations (Cminss) compared to the 
reference regimen of 3 mg/kg Q2W. Across the various tumor types in the clinical program, 
nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and the 
relationship between nivolumab exposure produced by 3 mg/kg and efficacy and safety has been 
found to be relatively flat. Although nivolumab Cmaxss is predicted to be higher following 360 mg 
Q3W, these exposures are predicted to be within the exposure ranges observed at doses up to 
10 mg/kg Q2W used in the nivolumab clinical program, and are not considered to put participants 
at increased risk. The exposures predicted following administration of nivolumab 360 mg Q3W 
are on the flat part of the exposure-response curves for previously investigated tumors, melanoma 
and NSCLC, and are not predicted to affect efficacy. Based on these data, nivolumab 360 mg Q3W 
is expected to have similar efficacy and safety profiles to nivolumab 3 mg/kg Q2W.
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5.5.3
Pharmacokinetics Supporting Dosing Rationale
The pharmacokinetics (PK) of nivolumab was studied in subjects over a dose range of 0.1 to 
20 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. 
Based on a population pharmacokinetic (PPK) analysis using data from patients with various tumor 
types, including melanoma, NSCLC, and RCC and a time varying CL model, nivolumab clearance 
was shown to decrease over time, with a median maximal reduction from baseline values of 
approximately 25% resulting in a geometric mean steady state clearance (CLss) (% coefficient of 
variation [CV%]) of 8.2 mL/h [53.9%]. The decrease in CLss is not considered to be clinically 
relevant. The geometric mean [CV%] volume of distribution at steady state (Vss) is 6.8 L (27.3%), 
and elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were 
reached by approximately 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic 
accumulation was approximately 3.7-fold. The exposure to nivolumab increased dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The clearance 
of nivolumab increased with increasing body weight. The PPK analysis suggested that the 
following factors had no clinically important effect on the clearance of nivolumab: age (29 to 
87 years), gender, race, baseline LDH, PD-L1, solid tumor type, baseline tumor size, and hepatic 
impairment. Although ECOG status, baseline glomerular filtration rate (GFR), albumin, and body 
weight had an effect on nivolumab CL, the effect was not clinically meaningful. PPK analysis 
suggested that nivolumab CL in subjects with cHL was approximately 32% lower relative to 
subjects with NSCLC; however, the lower CL in cHL subjects was not considered to be clinically 
relevant as nivolumab exposure was not a significant predictor for safety risks for these patients.
Full details on the clinical pharmacology aspects of nivolumab can be found in the Investigator 
Brochure (IB).26
5.5.4
Rationale for Nivolumab 30-minute Infusion
Long infusion times place a burden on participants and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30-minutes duration in 
participants will diminish the burden, provided no change in safety profile. Previous clinical 
studies show that nivolumab has been administered safely over 60 minutes at doses ranging up to 
10 mg/kg over long treatment duration. In Study CA209010, (a Phase 2, randomized, double 
blinded, dose-ranging study of nivolumab in participants with advanced/metastatic clear cell RCC) 
a dose association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg, and 18.5% at 10 mg/kg). All the events were Grade 1 - 2 and were 
manageable. An infusion duration of 30 minutes for 360 mg doses of nivolumab is not expected 
to present safety concerns compared to the prior experience at 10-mg/kg nivolumab dose infused 
over a 60-minute duration.
Note that, in ongoing study CA209436, BV is administered in a 30-minute infusion, followed by 
a 30-minute pause, and a 30-minute infusion of nivolumab. See Section 7.1 for details concerning 
conditions of administration of this combination therapy in the present study.
6
STUDY POPULATION
As of 17-Oct-2019, enrollment in this study was stopped at the decision of the Sponsor. 
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6.1
Inclusion Criteria
For entry into the study, the following criteria MUST be met.
1) Signed Written Informed Consent
a) Participants must have signed and dated an Institutional Review Board/Independent Ethics 
Committee (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 participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
b) Participants must have a pathologic diagnosis of cHL who are relapsed or refractory with 
one of the following:
i)
ASCT ineligible patients
Chemo-resistant disease (unable to achieve CR or PR to salvage chemotherapy) or any 
significant coexisting medical condition (cardiac, renal, pulmonary, or hepatic 
dysfunction) are likely to have a negative impact on tolerability of ASCT. Note: 
Sponsor review and approval of participants <65 years of age who are not ASCT 
candidates is required before randomization. Participants must have received at least 2 
prior chemotherapy regimens (BV can be included as one regimen).
ii) Patients after failure of ASCT
(1).Documented absence of CR after 90 days from stem cell infusion for the most 
recent ASCT
(2).Documented relapsed disease (after CR) or disease progression (after PR or SD)
Both for i) and ii), participants who are naïve to BV or who were sensitive to the most 
recent BV treatment are eligible. Participants must demonstrate BV sensitivity as defined 
as best response of PR or CR per investigator assessment, and by no disease progression 
during the most recent BV treatment or no early relapse or progression within 3 months 
after last dose of the most recent BV based on medical record. For ii), prior treatment with 
BV may have been as a single agent or in combination with chemotherapy and may have 
occurred during any line of therapy (eg, induction, salvage, or consolidation post-ASCT). 
Of note, documentation of response following consolidation therapy with BV is not 
required, as it is assumed that the patients are in remission at the time of consolidation.
c) Must have at least one lesion that is > 15 mm (1.5 cm) in the longest diameter on 
crosssectional imaging and measureable in two perpendicular dimensions on CT (or MRI) 
and FDG avid by PET
d) Biopsy confirmation of cHL prior to the initiation of study treatment. cHL should be 
pathologically confirmed by standard IHC or flow cytometric techniques. Archived tumor 
block or unstained slides from biopsy are acceptable. Histologically confirmed tissue will 
be required from the time of relapse or at the time of initial surgery
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e) Participant re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / 
has not been treated). If re-enrolled, the participant must be re-consented.
3) Age and Reproductive Status
a) Males and Females, ages 18 or age of majority
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
2 methods of contraception for the duration of treatment with study treatments nivolumab
and BV plus 5 half-lives of study treatment plus 30 days (duration of ovulatory cycle) for 
a total of 6 months post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
2 methods of contraception (listed in Appendix 4) for the duration of treatment with study 
treatment(s) nivolumab and BV, plus 5 half-lives of the study treatment plus 90 days 
(duration of sperm turnover) for a total of 7 months post-treatment completion. In addition, 
male participants must be willing to refrain from sperm donation during this time. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements,
and still must undergo pregnancy testing as described in this section.
Please refer to Appendix 4 for detailed WOCBP definition and contraception guidance.
Investigators shall counsel WOCBP, and male participants 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 (Appendix 4).
4) Physical and Laboratory Test Findings
a) Screening laboratory values must meet the following criteria and should be obtained within 
14 days prior to first dose:
i)
Absolute neutrophil count 1000/L (no WBC growth factors for prior 14 days)
ii) Platelets 50 x106/mL (no platelet transfusions for prior 14 days)
iii) Hemoglobin 8.5 g/dL (no RBC transfusions for prior 7 days)
iv) Creatinine clearance (CrCL) 30 mL/min (measured using the Cockcroft-Gault 
formula below):
Female CrCL = (140 - age in years) x weight in kg x 0.8
72 x serum creatinine in mg/dL
Male CrCL = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
v) AST/ALT 2.5 x ULN
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vi) Total bilirubin 1.5 x ULN (except participants with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL)
b) Participants require left ventricular ejection fraction over 50% at rest. (Changed per 
Administrative Letter 02, 21-Aug-2019). 
c) Pulmonary Function Test with diffusing capacity of the lung for carbon monoxide (DLCO) 
60% (hemoglobin-adjusted)
6.2
Exclusion Criteria
1) Target Disease Exceptions
a) Known central nervous system lymphoma.
b) Participants with nodular lymphocyte-predominant HL.
2) Medical History and Concurrent Diseases
a) Participants 
with 
known 
history 
of 
pancreatitis 
or 
progressive 
multifocal 
leukoencephalopathy (PML)
b) Participants with active interstitial pneumonitis or CT evidence of Grade 1 pneumonitis.
i)
If the participant has a history of interstitial pneumonitis, they must have CT evidence 
of resolution.
c) Participants with neuropathy Grade 2, infection Grade 3, or documented history of 
coronary artery disease, cardiovascular accidents, or congestive heart failure (CHF)
class III/IV.
d) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study treatment administration, 
impair the ability of the participant to receive protocol therapy, or interfere with the 
interpretation of study results
e) Prior malignancies (other than HL) are excluded unless a complete remission was achieved 
at least 3 years prior to study entry and no additional therapy is required or anticipated to 
be required during the study period (exceptions include, but are not limited to, 
non-melanoma skin cancers; in situ bladder cancer, in situ gastric cancer, or in situ colon 
cancers; in situ cervical cancers/dysplasia; in situ carcinoma of the prostate; or breast 
carcinoma in situ).
f)
Participants with an active, known or suspected autoimmune disease. Participants 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.
For any cases of uncertainty, it is recommended that a BMS medical monitor be consulted 
prior to signing informed consent.
g) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days of study treatment administration. Inhaled or topical steroids, and adrenal 
replacement doses 10mg daily are permitted in the absence of active autoimmune disease.
h) Evidence of active brain metastases on brain imaging (ie, MRI or contrast CT).
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3) Prior/Concomitant Therapy
a) ASCT 30 days prior to first dose of study treatment
b) Prior chemotherapy within 4 weeks, nitrosureas within 6 weeks, therapeutic anticancer 
antibodies within 4 weeks, radio- or toxin or major surgery within 2 weeks prior to first 
dose of study treatment.
c) Carmustine (BCNU) 600mg/m2 received as part of the pre-transplant conditioning 
regimen.
d) Prior radiation therapy within 3 weeks, or chest radiation 24 weeks prior to first dose of 
the study treatment.
e) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways.
f)
Prior allogeneic transplant
g) BV refractory patients as identified by a failure to achieve a PR or CR, relapse, or 
progression within 3 months of receiving BV treatment (BV treatment as defined by: 
patients who previously received BV as a single agent or in combination with 
chemotherapy in any line of treatment [eg, induction, salvage, or consolidation 
post-ASCT]).
4) Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative)
b) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
i)
Testing for HIV must be performed at sites where mandated locally
5) Allergies and Adverse Drug Reaction
a) History of allergy to drug components
History of severe hypersensitivity reaction Grade 3 to any monoclonal antibody with the 
following exception: participants who experienced Grade 3 or 4 infusion-related reaction 
with the first dose of rituximab, but who were able to receive subsequent rituximab without 
recurrence of Grade 3 or 4 infusion-related reaction are eligible.
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances, a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb [BMS] approval is 
required).
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
c) Females who are pregnant or breastfeeding
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Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Enrollment and Randomization (randomized arms) is the value by 
which study inclusion will be assessed, as it represents the participant’s most current clinical state.
Laboratory parameters and/or assessments that are included in the Screening Procedural Outline, 
Table 2-1, may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
Enrollment in this study was stopped on 17-Oct-2019 at the decision of the Sponsor. 
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study enrollment 
and randomization.
Study treatment includes 2 Investigational [Medicinal] Products (IPs/IMPs) (Table 7-1). In this 
study, the IPs/IMPs are nivolumab and BV.
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an
unauthorized indication, or when used to gain further information about the authorized form.
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Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection) will not be 
supplied by the sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current version of the IB26 and/or pharmacy manual for complete storage, 
handling, dispensing, and infusion information for nivolumab. See also the Nivolumab IB 
(Section 3 of the IB) or prescribing information (eg, USPI30 [Section 11], SmPC31 [EMA version, 
Sections 1, 2, 3 of the SmPC]), or country-specific product label for more information.
For the constituents of brentuximab vedotin (BV)35,32 see the current version of the associated 
product labels and SmPCs (respectively footnoted) for more information. 
Premedications or medications used to treat infusion-related reactions should be sourced by the 
investigative sites if available and permitted by local regulations.
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Table 7-1:
Study treatments for CA209812
Product Description / 
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
Nivolumab
(BMS-936558-01) Solution 
for Injection
100 mg 
(10 mg/mL) 
IP
Open Label
Clear to opalescent colorless to pale 
yellow liquid. May contain particles.
Carton contains 5 vials of 100mg
2° to 8°C. Protect from light 
and freezing
Brentuximab Vedotin 
Powder for Solution for 
Injectiona
50 mg
IP
Open-label
White to off-white lyophilized 
preservative-free cake or powder in a 
single-use vial for reconstitution
2to 8C. Protect from light 
and freezing
a May be obtained by the investigational sites in certain countries as local commercial product (which may be available as a different potency/package size than 
listed above) if local regulations allow. Locally sourced marketed product utilized for this study should be prepared and stored in accordance with the package 
insert, summary of product characteristics (SmPC), or equivalent document.
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7.1
Treatments Administered
Infusions will be performed over a period of once every 3 weeks. Participants should begin study 
treatment within 3 calendar days of randomization. Participants will be monitored continuously 
for AEs while on study. Study treatment modifications (eg, dose delay or discontinuation) will be 
based on specific laboratory and AE criteria (Section 7.4). Doses of study treatment may be 
interrupted, withheld, or discontinued depending on how well the participant tolerates the study 
treatment. Treatment with nivolumab will be continued as described in Section 5.1 until disease 
progression or unacceptable toxicity. Participants treated with nivolumab who achieve a CR may 
discontinue treatment after a maximum of 2 years of therapy, provided that there is no prohibitive 
toxicity. Administration of BV should be discontinued after a maximum of 16 cycles, or until 
disease progression or unacceptable toxicity, whichever occurs first.
All participants who discontinue therapy will be followed through Safety Follow-up Visit 2.
Nivolumab and Brentuximab vedotin arm
Participants should receive nivolumab at a dose of 360 mg as a 30-minute infusion on Day 1 of 
each treatment cycle until progression, unacceptable toxicity, withdrawal of consent, or the study 
ends, whichever occurs first. No dose escalations or reductions of nivolumab are allowed. 
Premedications are not recommended for the first dose of nivolumab. For 30-minute infusions, 
infusion durations are 5 minutes. For Q3W dosing cycles, participants may be dosed within a 
3 day window.
For participants in the nivolumab/BV arm, BV will be administered first as a 30-minute infusion 
followed by a minimum 30-minute rest prior to the nivolumab infusion. Brentuximab vedotin will 
be administered as a 1.8 mg/kg dose on Day 1 of each treatment cycle every 3 weeks for 16 cycles. 
In the absence of infusion-related reactions, the infusion rate for all participants should be 
calculated in order to achieve a 30-minute infusion period. Brentuximab vedotin must not be 
administered as an IV push or bolus nor mixed with other medications. Dosing of BV is based on 
participant’s actual body weight. Doses must be adjusted for participants who experience a 10% 
change in weight from baseline. Other dose adjustments for changes in body weight are permitted 
per institutional standard. An exception to weight-based dosing is made for participants weighing 
greater than 100 kg; doses will be based on 100 kg for these individuals. Rounding is permissible 
within 5% of the nominal dose.
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is to be administered as an IV infusion through 
a 0.2-micron to 1.2-micron pore size, low-protein binding in-line filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. Nivolumab injection can be 
infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP to protein concentrations as low as 1 mg/mL. Instructions for dilution 
and infusion of nivolumab injection may be provided in the clinical protocol, pharmacy binder, or 
pharmacy reference sheet. Care must be taken to assure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent. 
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Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
Participants may continue on nivolumab or BV alone if required to discontinue one of the study 
medications. It is recommended to consult with the medical monitor before discontinuing one of 
the study medications. 
Participants should be carefully monitored for infusion reactions during study treatment 
administration. If an acute infusion reaction related to nivolumab is noted, participants should be 
managed according to Section 7.1.5.
Brentuximab Vedotin arm
Brentuximab Vedotin will be administered as a 1.8 mg/kg dose on Day 1 of each treatment cycle 
every 3 weeks for 16 cycles as a 30-minute infusion. In the absence of infusion-related reactions, 
the infusion rate for all participants should be calculated in order to achieve a 30-minute infusion 
period. Brentuximab vedotin must not be administered as an IV push or bolus nor mixed with other 
medications. Dosing of BV is based on participant’s actual body weight. Doses must be adjusted 
for participants who experience a 10% change in weight from baseline. Other dose adjustments 
for changes in body weight are permitted per institutional standard. An exception to weight-based
dosing is made for participants weighing greater than 100 kg; doses will be based on 100 kg for 
these individuals. Rounding is permissible within 5% of the nominal dose.
7.1.1
Dose Delay Criteria (Nivolumab)
Dose delays during a given study treatment cycle are permitted in this study. Should withholding 
the dose be required for a period of time outside the dosing window, study treatment must be 
omitted and the next study treatment administration performed if and only if criteria in 
Section 7.1.2 are met. See Section 7.4 for instructions concerning skipped doses.
Participants may be dosed up to 3 days before or after the scheduled date if necessary. The target 
date of subsequent study treatments is based on the actual date of dose #1.
Nivolumab administration should be delayed for the following:

Grade 2 non-skin, drug-related adverse event, with the exception of fatigue

Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities

Grade 3 skin, drug-related adverse event

Grade 3 drug-related laboratory abnormality, with the following exceptions: 

Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay

Grade 3 AST, ALT, Total Bilirubin will require dose discontinuation 

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants 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.
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If toxicity is related to nivolumab then BV can be continued. Similarly, if toxicity is related to BV, 
then nivolumab can be continued. Nivolumab can be resumed in combination with BV if these 
criteria for resuming treatment are met. Withholding dose of nivolumab for > 6 weeks during the 
combination phase is permitted. Under certain circumstances treatment is permitted even if 
nivolumab was held for > 6 weeks. Medical monitor has to be contacted to discuss the case and to 
grant permission.
7.1.2
Criteria to Resume Study treatment (Nivolumab)
Participants may resume study treatment with study treatment when the study treatment-related 
AE(s) resolve to Grade 1 or baseline value, with the following exceptions:

Participants may resume study treatment in the presence of Grade 2 fatigue

Participants who have not experienced a Grade 3 study treatment-related skin AE may resume 
study treatment in the presence of Grade 2 skin toxicity

Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 7.1.6) should have study treatment permanently 
discontinued

Study treatment-related pulmonary toxicity, diarrhea, colitis, uveitis or neurological toxicity, 
must have resolved to baseline before study treatment is resumed. Participants 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

Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor. Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement

For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete
If the criteria to resume study treatment are met, the participant should restart study treatment at 
the next scheduled timepoint per protocol. However, if the study treatment is withheld past the 
window period of the next scheduled timepoint per protocol to ensure adequate recovery from the 
adverse event or tapering of immunosuppression, the dosing should continue to be withheld until 
the subsequent scheduled timepoint.
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7.1.4
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

Myocarditis
The above algorithms are found in the IB26 and Appendix 5 of this protocol.
7.1.5
Treatment of Infusion-related Reactions (Nivolumab/Brentuximab 
Vedotin)
Infusion-related reactions may occur during the infusion of study treatment(s). The infusion should 
be administered at a site properly equipped and staffed to manage anaphylaxis should it occur. All 
supportive measures consistent with optimal patient care should be given throughout the study 
according to institutional standards. Supportive measures may include extending the infusion time 
and/or administering medications for infusion-related reactions.
Infusion or hypersensitivity reactions may occur to either brentuximab vedotin or nivolumab. If 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthalgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. Infusion 
reactions should be graded according to NCI CTCAE (Version 4.03) guidelines. 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 Common Technology Criteria for Adverse Events (NCI CTCAE, Version 4.03) 
guidelines.
Subjects who experience a Grade 1 or Grade 2 infusion-related reaction should be premedicated 
for subsequent infusions. Premedication should be given at least 30 minutes prior to dosing study 
drug(s) and should include an antihistamine and corticosteroid. Recommended doses are: 
diphenhydramine 25
to 50 mg IV (or equivalent) and methylprednisolone 40 mg IV 
(or equivalent). In addition, acetaminophen/paracetamol 325 to 1000 mg and ranitidine 50 mg IV 
may be given. If the onset of a reaction occurs during an infusion, the infusion may be interrupted 
for treatment of the infusion-related reaction, including treatment with antihistamines, 
corticosteroids, and/or bronchodilator therapy, as appropriate. Subjects who experience a Grade 3 
infusion-related reaction to brentuximab vedotin or nivolumab may potentially receive additional 
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treatment with the study drug(s) at the discretion of the investigator after discussion with the 
sponsor.
If anaphylaxis or a Grade 4 infusion-related reaction occurs, administration of the implicated 
agent(s) (brentuximab vedotin and/or nivolumab) should be immediately and permanently 
discontinued. The investigator should begin an IV infusion of normal saline and treat the 
participant 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. Participant should be monitored until the investigator is comfortable 
that the symptoms will not recur.
In case of late-occurring hypersensitivity symptoms to nivolumab (eg, appearance of a localized 
or generalized pruritus within 1 week after nivolumab treatment), symptomatic treatment may be 
given (eg, oral antihistamine or corticosteroids).
7.1.6
Dose Discontinuation Criteria (Nivolumab)
Nivolumab treatment should be permanently discontinued for the following:

Any Grade 2 study treatment-related uveitis or eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment

Any Grade 3 non-skin, study treatment-related AE lasting > 7 days or recurs, with the 
following exceptions for laboratory abnormalities, study treatment-related uveitis, 
pneumonitis, 
bronchospasm, 
hypersensitivity 
reactions, 
infusion 
reactions, 
and 
endocrinopathies:
o
Grade 3 study treatment-related uveitis, pneumonitis, bronchospasm, neurologic 
toxicity, myocarditis, hypersensitivity reaction, or infusion reaction of any duration 
require discontinuation

Grade 3 study treatment-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation. Adrenal insufficiency 
requires discontinuation regardless of control with hormone replacement. 
o
Grade 3 study treatment-related laboratory abnormalities do not require treatment 
discontinuation except:

Grade 3 study treatment-related thrombocytopenia > 7 days or associated with 
clinically significant bleeding requires discontinuation*

AST or ALT > 8 x ULN or Total Bilirubin > 5 x ULN requires discontinuation 
requires discontinuation

Concurrent AST or ALT > 3 x ULN and Total Bilirubin > 2 x ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment(s) will be
permanently discontinued. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment(s), a discussion between 
the investigator and the BMS Medical Monitor/designee must occur.
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
Any Grade 4 study treatment-related adverse event or laboratory abnormality (including but 
not limited to creatinine, AST, ALT, or TBili), except for the following events which do not 
require discontinuation
o
Grade 4 neutropenia 7 days
o
Grade 4 lymphopenia or leukopenia
o
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis. Consult Medical Monitor for Grade 4 amylase 
and lipase abnormalities 
o
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset
o
Grade 4 study treatment-related endocrinopathy AEs such as adrenal insufficiency, 
ACTH (adrenocorticotropic hormone) deficiency, hyper- or hypothyroidosis, or 
glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (steroids, thyroid hormones) or glucose controlling agents, 
respectively, may not require discontinuation after discussion with and approval from 
the BMS Medical Monitor.

If dosing is withheld for > 6 weeks from the previous dose with the following exceptions:
o
Dosing withholdings to allow for prolonged steroid tapers to manage study 
treatment-related adverse events are allowed. Prior to re-initiating study treatment in a 
participant with dose omissions lasting > 6 weeks, the BMS medical monitor must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
withheld.
o
Dosing withholdings > 6 weeks that occur for non-study treatment-related reasons may 
be allowed if approved by the BMS medical monitor. Prior to re-initiating study 
treatment in a participant with dose omissions lasting > 6 weeks, the BMS medical 
monitor must be consulted. Tumor assessments should continue as per protocol even if 
dosing is withheld.

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued dosing

Disease progression as determined by investigator assessment following the guidelines given 
by the Lugano 2014 Classification

Participant who initiated the preparative regimen for allogeneic stem cell transplant (allogeneic 
SCT) or ASCT after the first dose of study treatment

Initiation of antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy, or standard or investigational agents 
for treatment of cancer)
7.1.7
Dose Discontinuation Criteria (Brentuximab Vedotin)
Brentuximab vedotin treatment should be permanently discontinued for reasons provided in Table 
7.4.2-1. Dose delays of more than 3 weeks may be allowed after discussion with the study medical 
monitor.
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7.1.8
Dose Delay Criteria (Nivolumab and Brentuximab Vedotin)
If the nivolumab dose is delayed, treatment can be continued with BV. Similarly, if the BV dose 
is delayed, treatment can be continued with nivolumab. See Section 7.4 for instructions concerning 
dosage modifications.
7.2
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log-in information and directions on how to 
access the IRT. After the participant’s initial eligibility is established and informed consent has 
been obtained, the participant must be enrolled into the study by calling an IRT and be assigned a 
participant number. Specific instructions for using IRT will be provided to the investigational site 
in the IRT manual. The randomization procedures will be carried out via permuted blocks within 
each stratum. Stratification will be performed on two factors: 1) Prior ASCT status (YES/NO). 
2) Prior BV use (YES/NO).
Once registered, participants who have signed the ICF and met all eligibility criteria will be ready 
to be randomized. The following information is required for participant randomization:

Participant number

Date of birth

Prior therapies and types of therapy (chemotherapy, ASCT)
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2).
7.3
Blinding
This is an open-label study, blinding procedures are not applicable.
7.4
Dosage Modification
The BMS medical monitor should be contacted when any dose is reduced, regardless of the 
causality.
7.4.1
Nivolumab
Dose reductions and escalations of nivolumab are not permitted.
7.4.2
Brentuximab vedotin
The recommended dose modifications for BV treatment associated toxicity are provided in Table 
7.4.2-1. Doses reduced for BV-related toxicity should not be re escalated without discussion with 
the sponsor. Dose escalation of BV beyond 1.8 mg/kg is not permitted. Dose reductions below 
1.2 mg/kg are not allowed.
If BV treatment is delayed for any reason, other treatments must be continued. Participants who 
require delay of BV should be re-evaluated frequently and BV dosing resumed when re-treatment 
criteria are met. Dose delays of more than 3 weeks may be allowed after discussion with the study 
medical monitor.
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Recommendations for management of infusion related reactions due to BV are described in 
Section 7.1.5. 
Participants who discontinue nivolumab treatment due to a treatment-related AE may continue 
treatment with BV for a maximum of 16 cycles, or until disease progression or unacceptable 
toxicity, whichever occurs first. Participants who discontinue BV due to a treatment-related AE 
may continue to receive nivolumab treatment until disease progression or unacceptable toxicity.
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Table 7.4.2-1:
Dose Modifications for Brentuximab Vedotin
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Peripheral Neuropathy
Continue at same 
dose level
Hold until peripheral 
neuropathy resolves to 
Grade 1and then 
resume treatment at 
1.2 mg/kga
Withhold (delay) until toxicity resolves to 
Grade 2 or baseline, then resume treatment at 
1.2 mg/kg or discontinue if reduction has already 
occurred.
Discontinue treatment
Non-hematologic 
(except peripheral 
neuropathy)
Continue at same
dose level
Continue at same dose 
level
Withhold (delay) dose until toxicity is Grade 2 
or has returned to baseline, then resume 
treatment at the same dose levelb
Withhold dose until toxicity is 
Grade 2 or has returned to 
baseline, then reduce dose to 1.2
mg/kg and resume treatment, or 
discontinue at the discretion of 
the investigatora,b,c
Hematologicd
Continue at same 
dose level
Continue at same dose 
level
Withhold (delay) until toxicity resolves to 
Grade 2 or baseline, then resume treatment at 
the same dose level.e Growth factor support 
(G-CSF or GM-CSF) should be considered for 
subsequent cycles. If Grade 4 neutropenia recurs 
despite growth factor support, consider 
discontinuation.
Discontinue treatment
a Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with dose delays
b Participants who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without dose delay
c Treatment should be discontinued for participants who experience Grade 4 infusion-related reactions.
d Support with blood product transfusions allowed per institutional standard of care.
e Participants who develop Grade 3 or 4 lymphopenia may continue study treatment without dose delay.
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7.5
Preparation/Handling/Storage/Accountability
The investigational products (nivolumab) should be stored in a secure area according to local 
regulations. It is the responsibility of the investigator to ensure that investigational product is only 
dispensed to study Participants. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment (nivolumab) 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 treatment arise, the study 
treatment should not be dispensed and the site should contact BMS immediately.
Detailed drug preparation, storage, administration, and drug accountability instructions for BV are 
provided in the Pharmacy Binder, SmPC, country-specific product label, or current prescribing 
information.35
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure treatment is accurately administered. This includes 
documentation of treatment storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by 
the sponsor and should be purchased locally if permitted by local regulations.
Further instructions for the storage, handling, and preparation of nivolumab Solution for Infusion 
will be provided to the clinical sites in the IB26 and pharmacy manual. Further guidance and 
information for final disposition of unused study treatment are provided in Appendix 2.
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability as well as the 
participant’s medical records and eCRF.
7.7
Concomitant Therapy
Concomitant medications are recorded at baseline and throughout the treatment phase of the study 
in the appropriate section of the CRF. All medications (prescriptions or over the counter 
medications) continued at the start of the study or started during the study and different from the 
study treatment must be documented in the concomitant therapy section of the CRF.
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):

Immunosuppressive agents
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
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.2)

Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of cHL)
Supportive care for disease-related symptoms may be offered to all participants on the trial.
The investigator should contact and confirm agreement with the BMS medical monitor (and 
acknowledgement from the contract research organization medical monitor) prior to the 
administration of any new concomitant medications.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications after enrollment or within 
14 days of dosing are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.7.2.1
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
7.7.2.2
Imaging Restriction and Precautions

It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed 
regarding whether they should receive contrast and if so, what type and dose of contrast is 
appropriate. Specific to MRI, participants with severe renal insufficiency (ie, estimated 
glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) are at increased risk of nephrogenic 
systemic fibrosis. MRI contrast should not be given to these participants. In addition, 
participants are excluded from MRI if they have tattoos, metallic implants, pacemakers, etc.

The ultimate decision to perform an MRI in an individual participant in this study rests with 
the site radiologist, the investigator, and the standard set by the local Ethics Committee.
7.8
Treatment After the End of the Study
At the end of the treatment period, BMS will not continue to provide BMS supplied study treatment 
to participants/investigators unless BMS chooses to extend the study. The investigator should 
ensure that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of nivolumab is 
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terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government sponsored or private 
health program. In all cases, BMS will follow local regulations
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue the investigational product(s) for any of the following reasons:

Disease progression as determined by investigator assessment following the guidelines given 
in Appendix 6

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Additional protocol specified reasons for discontinuation.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
during a clinical trial, the study treatment must be discontinued immediately. In most cases, the 
study treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy. If the investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Table 2-3. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
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8.1.1
Post Study Treatment Study Follow-up
In this study, PFS is a key endpoint of the study. Post study follow-up is of critical importance and 
is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed in line with Section 2 through Safety 
Follow-up Visit 2. Study objectives and endpoints are listed in Table 4-1. 
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants 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 treatment 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 participant 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.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’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 participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
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9
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities. 

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
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 participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure.
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.
For participants who discontinue study therapy by proceeding to allogeneic SCT, documentation 
of hyper-acute, acute and chronic GVHD will be captured until the first non-CR after SCT is 
documented through safety Follow-up Visit 2. [Appendix 9]. Investigators will make telephone 
contact with the participant’s hematologist /oncologist /transplant physician to obtain this 
information if the participant is being followed by another physician.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 2.
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9.1.1
Imaging Assessment for the Study
Per Revised Protocol 01, images will no longer be submitted to an imaging core lab. . 
9.1.2
Disease Response Evaluation
The determination of disease response to study treatment will be made using the Lugano 2014 
Classification (Appendix 6).
Surveillance assessments for ongoing study treatment decisions will be completed by the 
investigator using the Lugano 2014 Classification. Per the Lugano criteria, PET-negative scans are 
defined on the 5-point scale as scores of 1, 2, or 3 (where 1 = no uptake above background; 
2 = uptake mediastinum; and 3 = uptake > mediastinum but liver) and PET-positive scans, as 
scores of 4 or 5 (where 4 = uptake moderately higher than liver; 5 = uptake markedly higher than 
liver and/or new lesions).36 Response on PET scans should be reported as CMR, PMR, SMD 
(stable metabolic disease), or PMD (progressive metabolic disease).
See Section 7.1.1 for information concerning CT findings that indicate progression. Response on 
CT scans should be reported as complete response (CR), partial response (PR), stable disease, or 
progressive disease (PD).
In case of equivocal scan results, sites should discuss the case with a BMS medical monitor. 
Re-imaging will be required 12 weeks of the original scan showing equivocal disease progression. 
Dosing may continue during the interval of confirming disease progression.
9.1.3
B Symptoms
The presence or absence of B symptoms will be assessed during and after treatment. B symptoms 
are defined as:
1) Unexplained weight loss of more than 10% during the last 6 months, or 
2) Unexplained, persistent, recurrent fever with temperatures above 38 degree Celsius during the 
previous month, or 
3) Recurrent drenching night sweats during the previous month.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of nivolumab. For participants randomized/assigned to treatment and never treated with study 
treatment, SAEs should be collected for 30 days from the date of randomization.
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All nonserious adverse events (not only those deemed to be treatment related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
In the present study, AEs, treatment-related AEs, SAEs, and treatment-related SAEs occurring 
> 100 days after the last study treatment administration during the long-term follow-up periods 
will be recorded on the eCRF and will be tabulated for AEs of special interest for 
immuno-oncology agents and for BV. Effects on long-term fertility and evolution of secondary 
neoplasms will be assessed.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. 
Immune-mediated 
adverse 
events 
are 
AEs 
consistent 
with 
an 
immune-mediated mechanism or immune-mediated component for which non-inflammatory 
etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with 
an alternate etiology which were exacerbated by the induction of autoimmunity. As an 
immuno-oncology (I-O) agent, nivolumab is associated with unique AEs, whose mechanism of 
action is consistent with a potential inflammatory mediated process. These unique immune-related 
AEs, referred to as “select AEs” in the nivolumab IB and “adverse events of special interest” in 
this protocol, have not typically been observed with cytotoxic agents. Select AEs have been 
categorized into 7 areas: pulmonary toxicity, gastrointestinal toxicity, hepatotoxicity, 
endocrinopathy, skin toxicity, neurological toxicity and renal toxicity. Select AEs have occurred 
with low frequency (< 5%), are manageable, and are reversible with treatment interruption, 
discontinuation, or with the use of corticosteroid and/or other immunosuppressants. Select AEs, in 
particular pneumonitis, are considered clinically meaningful as they require greater vigilance and 
for early recognition and prompt intervention. Therefore, management algorithms have been 
developed and implemented for each immunologically associated select AE category (refer to IB26
and Appendix 5 of the protocol).
 
Contacts for SAE reporting are specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until [the 
follow-up contact], at the timepoints specified in the Schedule of Activities (Section 2). 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 participants. All nonserious 
adverse events (not only those deemed to be treatment related) should be collected continuously 
during the treatment period and for a minimum of 100 days following discontinuation of study 
treatment. All SAEs must be collected that occur during the screening period and within 100 days 
of the last dose of study treatment. For participants randomized and never treated with study drug, 
SAEs should be collected for 30 days from the date of randomization.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. 
 
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Sections 5.6.1 and 5.6.2 in the IB26 represent the Reference Safety Information to determine 
expectedness of serious adverse events for expedited reporting. Following the participant’s written 
consent to participate in the study, all SAEs, whether related or not related to study treatment, must 
be collected, including those thought to be associated with protocol-specified procedures.
If applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study treatment or protocol-specified procedure.

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious.

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment 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). 
 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
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Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A 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.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives and 30 days 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 Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
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9.2.6
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 participant to have study treatment
discontinued or interrupted

Any laboratory test result abnormality that required the participant 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).
9.2.7
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 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
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.
9.3
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 9.2).
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For this study, any dose of nivolumab greater than 10 mg/kg within a 24-hour time period will be 
considered an overdose. Also, any dose of BV exceeding 180 mg in a 24-hr period will be 
considered an overdose.
In the event of an overdose the [investigator/treating physician] should:
1) Contact the Medical Monitor immediately
2) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
All screening assessments should be performed as indicated in Section 2 and within a maximum 
of 28 days prior to randomization.
Baseline disease assessments should be performed within 28 days prior to randomization. 
At Screening:

Medical history will be obtained to capture relevant underlying conditions

Physical examinations should include weight, height, ECOG Performance Status, BP), heart 
rate, and temperature

Screening laboratory assessments will be conducted locally
During the Treatment Period:

Participants will perform assessments as outlined in Section 2 and detailed in the Notes column

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 serious adverse event page

Participants will be evaluated for safety if they have received any study treatment. Laboratory 
testing will be performed locally

Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations

Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used for 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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At Follow-Up:

Toxicity assessments will be continuous during the first two safety follow-up visits. 

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 treatment related toxicities 
resolve, return to baseline, or are deemed irreversible
9.4.1
Physical Examinations
Refer to Schedule of Activities, Section 2.
9.4.2
Vital signs
Refer to Schedule of Activities, Section 2.
9.4.3
Electrocardiograms
Refer to Schedule of Activities, Section 2.
9.4.4
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report

All protocol specified laboratory tests are to be completed within 3 calendar days prior to 
dosing, analyzed and reported by the local lab
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations

Results of safety laboratory collections (ie, Chemistry and Hematology) must be obtained and 
reviewed in advance of study treatment dosing

Laboratory parameters assessed in this study are identified in Table 9.4.4-1.
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Table 9.4.4-1:
Clinical Safety Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Sodium
Alanine aminotransferase (ALT)
Potassium
Total bilirubin (TBili)
Chloride
Direct bilirubin
Calcium
Alkaline phosphatase
Phosphorus
Lactate dehydrogenase (LDH)
Magnesium
Serum Creatinine
Amylase
Blood Urea Nitrogen (BUN) or serum urea level
Albumin
C-reactive protein
Uric acid 
Fasting glucose
Creatinine clearance
Thyroid Function Testing
TSH
Free T4
Free T3
Urinalysis 
Total Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Serology
Hep B/C (HBV sAG, HCV antibody or HCV RNA)
Other Analyses
Pregnancy test (WOCBP only: screening, predose, discharge)
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9.4.5
Imaging Safety Assessment
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. 
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10
STATISTICAL CONSIDERATIONS
As of 17-Oct-2019, enrollment in this study was stopped at the decision of the Sponsor. At the 
time enrollment was stopped, 23 participants had been randomized. No formal statistical testing 
or inferential analyses will be performed. The statistical analyses as previously planned will only 
be conducted if appropriate in the final analysis. Further details are presented in the SAP.
10.1
Sample Size Determination 
The planned sample size for this study was to be approximately 340 randomized participantsThe 
sample size of the study accounts for the primary efficacy endpoint, PFS. PFS will be evaluated 
for treatment effect at the overall alpha level of 0.05 (two-sided), with 90% power. As of 17 
October 2019, enrollment was stopped. At total of 23 participants were randomized.
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Table 10.1-1:
Schedule of Statistical Analyses
Interim Analysis
Final Analysis
Conditions
At least 131 PFS events and 6 
months follow-up
At least 187 events
Expected timing
40 months (34 months + 6 months 
of follow-up)
45 months (34 months+ 11 months 
of follow-up)
Alpha level
Interim PFS analysis projected at 
0.0148 levela
Final PFS analysis projected at 
0.0455 level
a Using O’Brien and Fleming alpha spending function in case exact 131 PFS events are observed at the interim PFS 
analysis.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Randomized
Participants who had no post-randomization efficacy measure for the parameter being 
analyzed will be excluded. 
Safety
All treated participants who received at least 1 dose of study treatment. Participants will be 
included in the treatment group that they actually received
10.3
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the selection of 
participants to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. Below is a summary of planned statistical analyses of the primary and secondary 
endpoints.
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10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint, PFS based on investigator assessment, will be compared in two 
randomized armsvia a two-sided, log-rank test stratified by the same factors used in 
randomization. Participants who die without a reported progression 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 randomization date. A participant 
who initiates a subsequent anti-cancer therapy will be censored on the date of last tumor 
assessment prior or on the start date of their subsequent anti-cancer therapy. Sensitivity 
analyses will be performed using different PFS definitions to assess the robustness of the 
primary analysis. The PFS curve, median and PFS rate at 6, 12, 18, and 24 months for each 
randomized arm will be estimated using the Kaplan-Meier product-limit method. Two sided, 
95% confidence intervals for median PFS will be computed by Brookmeyer and Crowley 
method. A two-sided, 95% confidence interval for the PFS rates will be computed by 
Greenwood method. The hazard ratio (HR) and corresponding two-sided 100 * (1-α)% (α 
adjusted for the interim analysis) confidence interval will be estimated in a Cox proportional 
hazards model using randomized arm as a single covariate, stratified by the same factors used 
in randomization. 
Secondary
CRR/CMR based on investigator assessment will be compared in two randomized armsvia a 
two-sided, Cochran-Mantel-Haenszel test stratified by the same factors used in 
randomization. An estimate of the treatment odds ratio between the nivolumab + BV and BV 
arm along with corresponding two-sided 95% CIs and p-value will be presented. The estimate 
of the CRR/CMR and associated exact two-sided 95% CIs (by Clopper - Pearson method) 
will be presented for both arms.
ORR as defined as proportion of participants who achieved CR/CMR or PR/PMR before 
taking any subsequent anti-cancer therapy, will be computed in each treatment group along 
with the exact 95% CI using Clopper-Pearson method.
Duration of response (or complete response) in each treatment group will be estimated using 
KM product-limit method for participants who achieve PR or CR /CMR (or CR/CMR only). 
Median values along with two-sided 95% CI will be calculated.
The OS curves for each treatment group will be estimated using the Kaplan-Meier product-
limit method. Two-sided, 95% confidence intervals for median OS will be provided. For 
participants without documentation of death, OS will be censored on the last date the 
participant was known to be alive.When the primary endpoint, PFS, is statistically significant, 
the secondary endpoint CRR/CMR will be tested. The hierarchical testing procedure that 
ensures the study-wise type I error is controlled at 5% levels will be described in the SAP.
10.3.2
Safety Analyses
Safety analyses will be performed in all treated participants. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.03. All on-study AEs, treatment-related, AEs, SAEs and 
treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v4.03 criteria by 
system organ class and MedDRA preferred term. On-study lab parameters including hematology, 
chemistry, liver function, thyroid function, and renal function will be summarized using worst 
grade per NCI CTCAE v4.03 criteria.
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10.3.4
Interim Analyses 
As described in Section 10.1, an interim analysis of PFS assessed by BICR was to be performed 
after at least 131 PFS events (70% of total PFS events needed for final analysis) had occurred. It 
also required a minimum follow up of 6 months from the last patient first visit. This analysis was 
to be reviewed by the DMC while the Sponsor remained blinded. The estimated timing of this 
analysis was to be around 40 months after the start of randomization. The SAP will further describe 
the planned interim analyses.
 
 
.
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11
REFERENCES
1
Kuppers R, Klein U, Schwering I, et al: Identification of Hodgkin and Reed-Sternberg cell-
specific genes by gene expression profiling. J Clin Invest. 2003; 111:529-37.
2
National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in 
oncology. Available at http://www.nccn.org/professionals/physician_gls/f_guidenlines.asp. 
Accessed 27Feb2016.
3
Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD and 
MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup 
trial. J Clin Oncol. 2003; 21:607-14.
4
Sirohi B, Cunningham D, Powles R, et al: Long-term outcome of autologous stem-cell 
transplantation in relapsed or refractory Hodgkin's lymphoma. Ann Oncol. 2008; 19:1312-9.
 
6
Schreiber RD, Old LJ, Smyth MJ: Cancer immunoediting: integrating immunity’s roles in 
cancer suppression and promotion. Science. 2011; 331: 1565-70.
7
Pardoll D: Does the immune system see tumors as foreign or self? Annu Rev Immunol. 2003; 
21:807-39.
12 Schmitz N, Pfistner B, Sextro M, et al: Aggressive conventional chemotherapy compared with 
high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed 
chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002; 359:2065-71.
13 M. C: Management of Hodgkin Lymphoma in Relapse after Autologous Stem Cell Transplant. 
ASH Education Book. 2008; 326-333.
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14 von Tresckow B, Muller H, Eichenauer DA, et al: Outcome and risk factors of patients with 
Hodgkin Lymphoma who relapse or progress after autologous stem cell transplant. Leuk 
Lymphoma. 2014; 55:1922-4.
15 Chen R, Gopal AK, Smith SE, et al: Five-year survival and durability results of brentuximab 
vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016; 128:1562-6.
16 Bartlett NL, Chen R, Fanale MA, et al: Retreatment with brentuximab vedotin in patients with 
CD30-positive hematologic malignancies. J Hematol Oncol. 2014; 7:24.
18 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
19 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
20 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
21 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000; 192(7): 1027-34.
22 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
23 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20.
24 Younes A, Gopal AK, Smith SE, et al: Results of a pivotal phase II study of brentuximab 
vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 
2012;30:2183-9.
25 Gardai SJE A, Law CL. Brentuximab vedotin-mediated immunogenic cell death. Clin Cancer 
Res Annual Meeting Abstract. 2015.
26 Nivolumab Investigator Brochure, current version.
27 Das R, Verma R, Sznol M, et al: Combination therapy with anti-CTLA-4 and anti-PD-1 leads 
to distinct immunologic changes in vivo. J Immunol. 2015;194:950-9.
28 Rezvani K, Brody JD, Kohrt HE, et al: Cancer vaccines and T cell therapy. Biol Blood Marrow 
Transplant. 2013; 19:S97-S101.
29 Wang RF. The role of MHC class II-restricted tumor antigens and CD4+ T-cells in antitumor 
immunity. Trends Immunol. 2001;22:269-76.
30 Opdivo Prescribing Information. Opdivo US Prescribing Information for Opdivo. Last 
updated: 14-Apr-2016. Princeton, NJ: Bristol-Myers Squibb Company.
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31 Summary of Product Characteristics for Opdivo (nivolumab). http://www. ema.europa.eu. 
Accessed: 20-May-2016.
32 Brentuximab 
vedotin 
Summary 
of 
Product 
Characteristics. 
At: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002455/WC500135055.pdf. Last accessed 22 Sep 2016.
35 Adcetris
(Brentuximab 
Vedotin) 
Prescribing 
Information. 
At: 
http://www.seagensecure.com/assets/pdfs/ADCETRIS-brentuximab-vedotin-Prescribing-
Information.pdf?gclid=CPS-laD7ns8CFYEehgodf5IH-g.Last accessed: 20 Sep 2016
36 Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, Staging 
and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification. J Clin Oncol. 2014;32:3059-3067.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ADC
anti-drug conjugate
AE
adverse event
AIDS
Acquired Immuno-Deficiency Syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
BICR
Blinded Independent Central Review
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
BV
Brentuximab Vedotin
C
Celsius
Ca
calcium
Cavgss
average steady state concentration
CFR
Code of Federal Regulations 
cHL
classical Hodgkin lymphoma
CI
confidence interval
Cl
chloride
CL
clearance
CLss
steady state clearance
Cmaxss
maximum concentration at steady state
Cminss
minimum concentration at steady state
CMR
complete metabolic response
CMV
cytomegalovirus 
CR
complete response (remission)
CRF
case report form, paper or electronic
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Term
Definition
CrCL
creatinine clearance
CRR
complete response rate
CT
computed tomography
CTLA
cytotoxic T-lymphocyte associated (protein)
CV
coefficient of variation
DILI
drug-induced liver injury
dL
deci-liter
DLCO
Diffusing capacity of the lung for carbon monoxide
DSMC
Data Safety Monitoring Committee
DOCR
duration of complete response
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eg
exempli gratia (for example)
ELISA
enzyme-linked immunosorbent assay
EOI
end of infusion
EOT
end of treatment
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
FFPE
formalin-fixed paraffin-embedded
FSH
follicle stimulating hormone
FU
Follow-up
g
gram
G-CSF
granulocyte colony stimulating factor
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Term
Definition
GFR
glomerular filtration rate
GM-CSF
granulocyte macrophage colony stimulating factor
h
hour
HBV
hepatitis B virus
HBV sAG
hepatitis B virus surface antigen
HCV
hepatitis C virus
Hep B-
hepatitis B
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HL
Hodgkin lymphoma
HR
hazard ratio
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
immunogenic cell death
ICH
International Council on Harmonisation
ICOS
Inducible T-cell Costimulator
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
interferon
IHC
immunohistochemistry
IMP/IP
investigational medicinal product / investigational product
I-O
Immuno-oncology
IPS
International Prognostic Score
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IUD
intrauterine device
IV
intravenous
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Term
Definition
K
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
LDi
longest diameter
mg
milligram
Mg
magnesium
min
minute
mL
milliliter
MMAE
monomethyl auristatin E
MRI
magnetic resonance imaging
MST
medical safety team
D
Maximum Tolerated Dose
N
number of subjects or observations
Na
sodium
NCI
National Cancer Institute
NE
not evaluable
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PD-1
programmed death 1 (receptor)
PD-L1/PD-L2
programmed death ligand 1/2
PET
positron emission tomography
PFS
progression-free survival
PFT
pulmonary function test
PK
pharmacokinetics
PMD
progressive metabolic disease
PML
progressive multifocal leukoencephalopathy
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Term
Definition
PMR
partial metabolic response
PPD
perpendicular diameter
PPK
population pharmacokinetics
PR
partial response (remission)
Q2W
once every 2 weeks
Q3W
once every 3 weeks
QoL
Quality of Life
RBC
red blood cell
RCC
renal cell carcinoma
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCT
stem cell transplant
SD
standard deviation
SDi
shortest diameter
SMD
stable metabolic disease
SmPC
Summary of Product Characteristics
t1/2
Half life
T3
triiodothyronine
T4
thyroxine
TBili
total bilirubin
TIL
tumor-infiltrating lymphocyte
TSH
thyroid stimulating hormone
ULN
upper limit of normal
USPI
United States Package Insert
V
visit
Vss
volume of distribution at steady state
W
week
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Term
Definition
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Good Clinical Practice (GCP)

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)

applicable local requirements
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee 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). 
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, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee 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.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:

IRB/IEC for

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
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 participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study

Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant'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 participant records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
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refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original.
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each 
participant, including unique participant 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 
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If
Then

dates and initials of person responsible for 
Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
Sourced by site, and not supplied by BMS or its 
vendors (examples include IP sourced from the sites 
stock or commercial supply, or a specialty pharmacy)
The investigator or designee accepts responsibility for 
documenting traceability and study drug integrity in 
accordance with requirements applicable under law and 
the SOPs/standards of the sourcing pharmacy.
These records should include:

label identification number or batch number 

amount dispensed to and returned by each 
participant, including unique participant identifiers

dates and initials of person responsible for 
Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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 Sponsor or designee 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 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 
Sponsor or designee.
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, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
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Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee 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. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee 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 Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) 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, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
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If..
Then
Study treatments supplied by BMS 
(including its vendors
Any unused study treatments supplied by BMS can only be 
destroyed after being inspected and reconciled by the responsible 
Study Monitor unless study treatments containers must be 
immediately destroyed as required for safety, or to meet local 
regulations (eg, cytotoxics or biologics).
If study treatments will be returned, the return will be arranged by 
the responsible Study Monitor.
Study treatments sourced by site, not 
supplied by BMS (or its vendors) 
(examples include study treatments 
sourced from the sites stock or commercial 
supply, or a specialty pharmacy)
It is the investigator’s or designee’s responsibility to dispose of all 
containers according to the institutional guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

External Principal Investigator designated at protocol development
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National Coordinating Investigator 

Study Steering Committee chair or their designee

Participant recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee 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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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation participant 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.
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening (defined as an event in which the participant 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)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result in admission 
(unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into the study. 
Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status and requires no 
medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies to oncology 
protocols)
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 
participant 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 9.2.7 for the definition of potential DILI.) 
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Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to assess all adverse 
events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and the AE.
Not related: There is not a reasonable causal relationship between study drug administration and the 
AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Follow-up of AEs and SAEs
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.) 
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.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE

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 (EDC), electronic submission is the required 
method for reporting. In the event the electronic system is unavailable for transmission, paper forms must be 
used and submitted immediately. When paper forms are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state 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.
Note: 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.
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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
Two of the highly effective methods of contraception listed below are required during study 
duration and until the end of relevant systemic exposure, defined as approximately 6 months after
the end of study treatment.
Local laws and regulations may require use of alternative and/or additional contraception methods.
See the current prescribing information/country-specific label/SmPC for brentuximab vedotin 
pregnancy/contraception information.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
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
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant
systemic exposure defined as 7 months after the end of nivolumab or brentuximab vedotin 
treatment.
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
Female partners of males participating in the study to consider use of effective methods of
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
nivolumab or brentuximab vedotin treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of nivolumab or brentuximab vedotin
treatment.

Refrain from donating sperm for the duration of the study treatment and until 7 months after
the end of nivolumab or brentuximab vedotin treatment.
See the current prescribing information/country-specific label/SmPC for brentuximab vedotin 
pregnancy/contraception information.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 5
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 6
LUGANO 2014 CLASSIFICATION FOR INITIAL EVALUATION, 
STAGING, AND RESPONSE FOR HODGKIN LYMPHOMA
Table 1:
Revised Criteria for Response Assessment
Reference: Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, Staging, and 
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol 
2014;32:3059-3067.
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APPENDIX 7
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 8
HASENCLEVER SCORE (INTERNATIONAL PROGNOSIS 
SCORE)
Composite score determined by assigning 1 point for each of the following factors;

Age 45 yrs

Serum albumin < 40 g/L

Disease Stage 4

Gender is male

Hemoglobin level < 105 g/L

White Blood Cells 15G/L

Lymphocytes < 0.6 G/L or < 8% of White Blood Cells
Reference: Hasenclever D and Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic 
Factors Project on Advanced Hodgkin's Disease. N Engl J Med. 1998;339:1506-14.
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APPENDIX 9
ACUTE GVHD GRADING AND STAGING
Table 1:
Extent of Organ Involvement
Stage
Skin
Liver
Gut
1
Rash on < 25% of skina
Bilirubin 2 - 3 mg/dLb  
Diarrhea > 500 mL/dayc or 
persistent nausead      
2 
Rash on 25 - 50% of skin 
Bilirubin 3 - 6 mg/dL 
Diarrhea > 1000 mL/day 
3 
Rash on > 50% of skin 
Bilirubin 6 - 15 mg/dL 
Diarrhea > 1500 mL/day 
4 
Generalized erythroderma with 
bullous formation 
Bilirubin >15 mg/dL 
Severe abdominal pain with or 
without ileus 
Gradee
I 
Stage 1 - 2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
--
Stage 2 - 3 or 
Stages 2 - 4 
IVf   
Stage 4 
Stage 4 
--
a Use “Rules of Nines” (Table 2) or burn chart to determine extent of rash.
b Range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin has been 
documented.
c Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body surface 
area. Downgrade one stage if an additional cause of diarrhea has been documented.
d Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
e Criteria for grading given as minimum degree of organ involvement required to confer that grade.
f Grade IV may also include lesser organ involvement with an extreme decrease in performance status.
Table 2:
Percent Body Surfaces
Body Area
Percent
Total Percentage
Each Arm 
9%
18%
Each Leg 
18%
36%
Chest & Abdomen 
18%
18%
Back 
18%
18%
Head 
9%
9%
Pubis 
1%
1%
Ref.: Przepiorka et al. Bone Marrow Transplant 1995;15(6):825.
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Stage of Chronic GVHD
Limited: Localized skin involvement resembling localized scleroderma with or without liver 
involvement; no other organ involvement.
Extensive: Generalized skin and/or multiple organ involvement.
Ref. Sullivan KM, Blood 1981;57:267.
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