Conditions: Hodgkin Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 294
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B \& C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants.

Detailed description:

Arms:
arm 1: Cohort (A, B, C): Nivolumab: Specified dose on specified days

Cohort (D): Nivolumab: Specified dose on specified days + Doxorubicin: Specified dose on specified days + Vinblastine: Specified dose on specified days + Dacarbazine: Specified dose on specified days

Interventions: intervention 1: Nivolumab intervention 2: Doxorubicin intervention 3: Vinblastine intervention 4: Dacarbazine
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days

Protocol document:
Prot_002.pdf: 
 
 
Official Title of Study: 
Non-Comparative, Multi-Cohort, Single Arm, Open-Label, Phase 2 Study of Nivolumab 
(BMS-936558) in classical Hodgkin Lymphoma (cHL) Subjects 
(CheckMate 205: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 205) 
 
Protocol: CA209-205 
 
NCT Number: NCT02181738 
 
Document Date (Date in which document was last revised): 22-Aug-2019 




Clinical Protocol
CA209205
BMS-936558
nivolumab
Revised Protocol No: 04c
Date: 22-Aug-2019
2
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No: 04c
Date: 22-Aug-2019
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Document
Date of Issue
Summary of Change
biopsy was performed. Those results can be confirmed later.
•
Immunotherapeutic agents produce atypical clinical response patterns, 
which are not usually observed in conventional chemotherapy. Two 
distinct non-conventional patterns have been reported: 1) a reduction in 
total tumor burden despite of the appearance of new lesion(s), and 2) 
responses after a transit increase in total tumor burden in an initial 
phase, followed by subsequent tumor shrinkage. Therefore, it is 
important to avoid premature discontinuation of the study drug as 
nivolumab might induce non-conventional response patterns in some 
patients. Under the current discontinuation criteria (Section 3.5), 
subjects must stop the study drug when investigator assessment 
determines disease progression using the 2007 IWG criteria. The change 
in this amendment will permit the subjects to continue on the study drug 
beyond investigator-assessed disease progression in certain cases.
•
Exclusion criteria of history of severe hypersensitivity reaction to any 
monoclonal antibody is reworded to allow for subjects who experienced 
Grade 3 – 4 infusion-related reaction with the first dose of rituximab, 
but who were able to receive subsequent rituximab without recurrence 
of Grade 3 or 4 infusion-related reaction to be eligible.
•
A clarification note is being added with regard to disease response 
evaluation.
•
A section is introducing guidelines for assessment and initial 
management of tumor lysis syndrome.
•
A few editorial or administrative corrections.
Original 
Protocol
25-Apr-2014
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 04C:
The purpose of this revision is to allow subjects in Cohorts A, B, and C to have access to a more 
convenient dosing schedule, 480 mg (flat dose) every 4 weeks, based on feedback from 
investigators. Also, to simplify the dosing regimen, those subjects that prefer to remain on an every 
2-week dosing schedule, a switch to 240 mg (flat dose) will be required.
Revisions apply to all participants currently enrolled.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04C
Section Number & Title
Description of Change
Brief Rationale
Synopsis;
1.4.3.5, Nivolumab Monotherapy Clinical 
Pharmacology Summary;
3.1.1, Study Design and Duration for Cohorts 
A, B, and C;
4.5, Selection and Timing of Dose for Each 
Subject;
Table 5.1.1-2, On-Treatment Assessments for 
Cohorts A, B, and C
Table 5.1.1-5, Re-Initiation of Treatment 
Assessments for Cohort C Subjects
•
Subjects will switch from a dose of 
3 mg/kg every 2 weeks to a flat 
dose of 480 mg every 4 weeks or a 
flat dose of 240 mg every 2 weeks 
by IV infusion over 30 minutes. 
•
Subjects must sign an informed 
consent document prior to 
switching the dosing schedule.
To align with 
recommended dosing 
in nivolumab label.
1.1.2.2, Justification for Doses in Cohorts A, 
B, and C
Section added for justification of new 
doses/dosing frequencies.
To align with the 
current nivolumab IB.
Table 4-1, Study Drugs for CA209205 -
Treatment Period
4.3, Storage and Dispensing
Detailed text around packaging and 
storing conditions made more general 
and pharmacy manual is referenced.
To allow for change in 
dosing.
Table 5.1.1-3, Follow-Up Assessments for 
Cohorts A, B, and C
Table 5.5-1, Sampling Schedule for Cohorts 
A, B, and C
Collection of pharmacokinetic and 
immunogenicity samples at follow-up 
visits were removed.
To align with current 
nivolumab protocol 
standards, as 
immunogenicity and 
PK is already well-
characterized in many 
subjects across 
multiple tumor types.
Appendix 1, Nivolumab Management 
Algorithms
New Myocarditis Adverse Event 
Management Algorithm was added.
To align with current 
nivolumab standards.
All
•
Minor formatting and 
typographical corrections.
•
“Patients” changed to “subjects” 
when referring to study 
participants.
To improve readability 
and understanding.
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SYNOPSIS
Clinical Protocol CA209205
Protocol Title: Non-Comparative, Multi-Cohort, Single Arm, Open-Label, Phase 2 Study of Nivolumab 
(BMS-936558) in classical Hodgkin Lymphoma (cHL) Subjects
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Nivolumab (BMS-936558) administered IV over 60 minutes at 3 mg/kg (Cohorts A, B and C) or flat 
dose 240 mg over 30 minutes IV infusion (Cohort D) every 2 weeks until progression or unacceptable toxicity. In 
revised protocol 04c, subjects in Cohorts A, B, and C will switch to IV infusion over 30 minutes of nivolumab 
480 mg flat dose every 4 weeks or 240 mg flat dose every 2 weeks until progression or unacceptable toxicity.
Study Phase: 2b
Research Hypothesis:
Cohorts A, B, and C: Treatment with nivolumab will lead to clinical benefit, as demonstrated by a clinically 
meaningful objective response rate, including durable responses with substantial magnitude of tumor burden 
reduction in the heavily treated cHL subjects.
Cohort D: A new regimen, consisting of nivolumab monotherapy followed by the combination of nivolumab and 
chemotherapy (AVD; a combination of doxorubicin, vinblastine and dacarbazine), will be safe and tolerable in 
previously untreated cHL subjects with newly diagnosed advanced stage (Stage IIB, III and IV) disease.
Primary Objective:
Cohorts A, B, and C: To assess the clinical benefit of nivolumab, as measured by objective response rate (ORR) 
based on independent radiologic review committee (IRRC) assessment, and defined as proportion of subjects 
achieving either a partial remission (PR) or complete remission (CR) according to the revised International Working 
Group criteria for Malignant Lymphoma (2007 IWG criteria).
Cohort D: To assess the overall safety and tolerability of nivolumab monotherapy (flat dose 240 mg), followed by 
the combination of nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) chemotherapy in previously 
untreated cHL subjects who are newly diagnosed with advanced stage (Stage IIB, III and IV) disease , as measured 
by the proportion of subjects who experienced at least one treatment-related Grade 3 - 5 AEs with an onset date after 
or on the first dose date and no later than 30 days after the last study dose date, among subjects receiving at least one 
dose of study treatment.
Secondary Objectives: 
Cohorts A, B, and C
•
To assess the duration of objective response (DOR) based on IRRC assessments
•
To assess the CR rate and the duration of CR based on IRRC assessment
•
To assess the PR rate and the duration of PR based on IRRC assessment
•
To assess the ORR and DOR, based on investigator assessments.
Cohort D
•
To evaluate the safety and tolerability of nivolumab monotherapy during the monotherapy phase 
•
To evaluate the safety and tolerability of nivolumab in combination with AVD during the combination phase 
•
To evaluate the treatment discontinuation rate of the study therapy during the monotherapy phase, combination 
phase, and overall (the entire course of study treatment consisting of both phases)
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•
To assess the clinical activity of study therapy, as measured by the CR rate at the planned end of therapy, based 
on IRRC assessments.
Exploratory Objectives: 
Cohorts A, B, and C
•
To assess the progression free survival (PFS) based on IRRC assessment
•
To assess the overall survival (OS)
•
To assess the overall safety and tolerability of nivolumab, as measured by incidence and severity of adverse 
events, serious adverse events, and specific laboratory abnormalities
•
To investigate the association between biomarkers in the peripheral blood and tumor tissue, such as PD-L1 
expression, with safety and efficacy measures
•
To characterize pharmacokinetics of nivolumab and explore exposure-response relationships
•
To characterize the immunogenicity of nivolumab monotherapy
•
To evaluate both generic health-related quality of life as assessed by the EQ-5D and cancer specific quality of 
life as assessed by the EORTC QLQ-C30
•
To evaluate the pharmacodynamic activity of nivolumab monotherapy in the peripheral blood and tumor tissue 
as measured by flow cytometry, immunohistochemistry, soluble factor analysis, and gene expression 
(microarray technology, quantitative RT-PCR).
•
For Cohort C, to evaluate risk-benefit of discontinuation schedule of the study drug for the subjects who have 
persistent CR for 1 year.
Cohort D
•
To evaluate IRRC-assessed OR rate, and investigator-assessed CR and OR rates at the planned end of therapy
•
To evaluate the CR rate and OR rate at the planned end of Nivolumab monotherapy based on IRRC assessment 
and based on investigators assessment
•
To evaluate the CR rate and OR rate at the planned end of two combocycles based on IRRC assessment and 
based on investigators assessment
•
To evaluate the PFS based on IRRC assessment and based on investigators’ assessment
•
To assess the OS
•
To assess the duration of objective response (DOR) and duration of complete response based on IRRC 
assessment and based on investigators assessment
•
To investigate the association between biomarkers in the peripheral blood and tumor tissue, such as PD-L1 
expression, with safety and efficacy measures
•
To characterize pharmacokinetics of nivolumab and explore exposure-response relationships
•
To characterize the immunogenicity of nivolumab 
•
To evaluate the change from baseline of pulmonary function after treatment
•
To evaluate generic health-related quality of life as assessed by the EQ-5D
•
To evaluate the pharmacodynamic activity of nivolumab monotherapy in the peripheral blood and tumor tissue 
as measured by flow cytometry, immunohistochemistry (IHT), soluble factor analysis, and gene expression 
(microarray technology, quantitative reverse transcription polymerase chain reaction (RT-PCR).
Study Design:
Cohorts A, B, and C
This is a non-comparative, parallel cohort, single-arm Phase 2 study in cHL subjects ≥18 years old who failed 
autologous stem cell transplant (ASCT). Subjects can be brentuximab vedotin-naïve (Cohort A), or can have prior
brentuximab vedotin treatment as a salvage therapy after failure of ASCT (Cohort B). In addition to Cohorts A and 
B, a third cohort (Cohort C) is being added to the study with broader eligibility criteria. Subjects with a treatment 
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history of brentuximab vedotin before first ASCT will not be eligible, except in Cohort C. The original protocol 
requires nivolumab dosing 3 mg/kg every 2 weeks. Approximately 220 subjects with failure after ASCT will be 
treated with nivolumab 3 mg/kg IV infusion over 60 minutes every 2 weeks until disease progression or 
unacceptable toxicity, consisting of approximately 60 subjects for Cohorts A and B respectively, and approximately 
100 subjects for Cohort C. In revised protocol 04c, subjects will switch to IV infusion over 30 minutes of 
nivolumab 480 mg flat dose every 4 weeks (Q4W) or 240 mg flat dose every 2 weeks (Q2W). For those subjects 
receiving a 480 mg flat dose Q4W, a cycle will be a 28-dosing period. For those subjects receiving a 240 mg flat 
dose Q2W, a cycle will be a 14-day dosing period. Subjects will be independently enrolled for each cohort. If one of 
these cohorts complete enrollment earlier, the other cohorts will remain open until complete accrual is reached. 
Once a new dosing regimen has been selected for the subject, either flat dose 280 mg Q2W or flat dose 480 mg 
Q4W, the dosing regimen will remain in effect until the end of treatment and not change. Primary analysis will be 
performed separately for each cohort (ie, at separate time points) upon completion of a pre-specified amount of 
follow-up after last patient first treatment (LPFT). All analyses will be performed separately for each cohort upon 
completion of follow-up for the primary endpoint in each cohort. In addition safety analyses will be performed on
combined cohorts.
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first dose. Subjects may 
be dosed no less than 12 days from the previous dose during every 2-week cycle. For every 4-week dosing cycle, 
subjects may be dosed within a ± 3-day window.
Cohort D
Cohort D is a non-comparative single-arm cohort in subjects ≥18 years old who have newly diagnosed, previously 
untreated cHL with advanced stage (Stage IIB, III and IV) disease. Cohort D consists of approximately 50 subjects.
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first dose. Subjects will 
be enrolled independently from other cohorts. 
Treatment for Cohort D consists of two phases: monotherapy and combination phases. Subjects will be treated with 
four doses of nivolumab flat dose 240 mg IV every 2 weeks (two months of monotherapy phase), followed by 
twelve doses of the combination of AVD chemotherapy and nivolumab flat dose 240 mg IV for 6 cycles (six months 
of combination phase). The primary analysis for Cohort D will be conducted when all treated subjects from Cohort 
D have completed Follow-up visit 1 and end-of-therapy response assessment. All analyses for Cohort D will be 
performed separately from other cohorts.
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Study Population:
Cohorts A, B, and C
Male and female, ages 18 and above, with cHL after failure of ASCT and who are naïve to brentuximab vedotin 
(Cohort A), who had prior brentuximab vedotin treatment after failure of ASCT (Cohort B) or who had prior 
brentuximab vedotin treatment before and/or after failure of ASCT (Cohort C) will be eligible to participate in the 
study. Other key inclusion criteria include ECOG PS 0-1, biopsy confirmation of cHL prior to initiation of study 
drug (See protocol Sections 3.3.1 and 3.3.2 for full list of criteria).
Cohort D
Male and female, ages 18 and above, with newly diagnosed, previously untreated cHL lymphoma (Stage IIB, III and 
IV) will be eligible to participate in the study. Other key inclusion criteria include ECOG PS 0 - 1, biopsy 
confirmation of cHL prior to initiation of study drug (See protocol Sections 3.3.1 and 3.3.2 for full list of criteria).
Study Drug: includes Investigational [Medicinal] Products (IP/IMP) as listed:
Study Drug for CA209205
Medication 
Potency 
IP/Non-IP 
BMS-936558-01 Solution for 
Injection (Nivolumab)
100 mg (10 mg/mL)
IP
Dacarbazine Powder for IV 
Solution
200 mg
IP
Doxorubicin Powder for 
Solution for Injection
50 mg
IP
Vinblastine Solution for 
Injection
10 mg (1 mg/mL)
IP
Study Assessments:
Cohorts A, B, and C:
The primary endpoint is ORR as determined by an IRRC according to the revised International Working Group 
Criteria for Malignant Lymphoma. Subjects will be assessed for response by imaging (CT or MRI) beginning at 
Week 9 (± 7 days) after the start of therapy and then at Weeks 17, 25, 37 and 49 during the first year of treatment,
then every 16 weeks (± 14 days) for the second year of treatment up to Week 97, continuing every 26 weeks (± 21 
days) beyond Week 97 for the third year or beyond treatment, until disease progression is documented. A FDG-PET 
scan is required at screening, Weeks 17 and 25 in all subjects, and at Week 49 for subjects who do not have two 
consecutive negative FDG-PET scans after Week 1 and prior to Week 49, and to confirm CR.
Cohort C subjects who have persistent CR for one year will discontinue study treatment and have a specific 
follow-up schedule. Should those subjects relapse, they will have the possibility to re-initiate treatment.
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be summarized by binomial response rates and their corresponding two-sided 95% exact confidence intervals using 
the Clopper-Pearson method. The null hypothesis will be rejected if the 2-sided 95% CI lower bound is greater than 
20%. DOR will be summarized for subjects who achieve PR or CR using the Kaplan-Meier product-limit method. 
Median values of DOR along with two-sided 95% CIs and range will also be calculated.
Cohort D
Analysis of Cohort D will be performed separately from Cohorts A, B and C. 
Safety analyses will be performed in all treated subjects from cohort D. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0. All on-study AEs, drug-related, AEs, SAEs and drug-related SAEs will be 
tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ class and MedDRA preferred term. 
On-study lab parameters including hematology, chemistry, liver function, thyroid function, and renal function will 
be summarized using worst grade per NCI CTCAE v4.0 criteria.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 04C: .................................. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04C ...................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Scientific Rationale .................................................................................. 
1.1.2 Study Design Rationale for Cohorts A, B, and C ..................................... 
1.1.2.1 Rationale for Cohort C ................................................................... 
1.1.2.2 Justification for Doses in Cohorts A, B, and C ............................... 
1.1.3 Study Design Rationale for Cohort D ...................................................... 
1.1.3.1 Summary Information for AVD ....................................................... 
1.2 Research Hypothesis ......................................................................................... 
1.2.1 Cohorts A, B, and C ................................................................................. 
1.2.2 Cohort D .................................................................................................. 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.1.1 Cohorts A, B, and C ........................................................................ 
1.3.1.2 Cohort D ......................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.3.2.1 Cohorts A, B, and C ........................................................................ 
1.3.2.2 Cohort D ......................................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.3.3.1 Cohorts A, B, and C ........................................................................ 
1.3.3.2 Cohort D ......................................................................................... 
1.4 Product Development Background ................................................................... 
1.4.1 Nivolumab Mechanism of Action ............................................................. 
1.4.2 PD-1 Expression in Classical Hodgkin Lymphoma ................................. 
1.4.3 Summary of Results for Nivolumab Program .......................................... 
1.4.3.1 Summary of Nivolumab Monotherapy Safety in Solid Tumors ....... 
1.4.3.2 Nivolumab Monotherapy Safety in Phase 1 Study for Hematologic 
Malignancies Including cHL ................................................................. 
1.4.3.3 Nivolumab Monotherapy Clinical Activity in Solid Tumors ........... 
1.4.3.4 Nivolumab Monotherapy Clinical Activity in Hematologic 
Malignancies Including cHL ................................................................. 
1.4.3.5 Nivolumab Monotherapy Clinical Pharmacology Summary .......... 
1.4.4 Rationale for Exploratory Studies of Tumor PD-L1 Expression as a 
Potential Predictive Biomarker in HL ........................................................ 
1.4.5 Rationale and Aims for Biomarker Assessments ..................................... 
1.4.6 Rationale for Quality of Life Evaluation ................................................. 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
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2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Study Design and Duration for Cohorts A, B, and C .............................. 
3.1.2 Study Design and Duration Cohort D ..................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.2.1 Permitted Therapy .......................................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Follow up ............................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Antiemetic Premedications ...................................................................... 
4.5.2 Dose Delay Criteria ................................................................................. 
4.5.2.1 Nivolumab Dose Delay Criteria ..................................................... 
4.5.2.2 Management Algorithms for Immuno-Oncology Agents ................ 
4.5.2.3 AVD Dose Delay Criteria (Only for Cohort D) .............................. 
4.5.3 Doses Reductions and Escalations .......................................................... 
4.5.4 Criteria to Resume Nivolumab Dosing .................................................... 
4.5.5 Nivolumab Discontinuation Criteria ....................................................... 
4.5.5.1 Discontinuation of Nivolumab Monotherapy During Monotherapy 
Phase of Cohort D ................................................................................ 
4.5.5.2 Discontinuation of Nivolumab from the Combination Therapy 
During Combination Phase for Cohort D ............................................ 
4.5.6 Treatment of Nivolumab Related Infusion Reactions .............................. 
4.5.7 Treatment Beyond Disease Progression .................................................. 
4.5.7.1 Circumstances in which Post-progression Treatment is Permitted 
4.5.7.2 Assessment Schedule for the Subjects with Post-progression 
Treatment .............................................................................................. 
4.5.7.3 Discontinuation due to “Further Progression” ............................. 
4.5.7.4 Radiographic Assessment for the Subjects who Discontinue Study 
Drug during Post-progression Treatment ............................................ 
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4.5.8 Re-Initiation of Study Therapy for Cohort C subjects ............................. 
4.5.9 Guidelines for Assessment and Initial Management of Tumor Lysis 
Syndrome.....................................................................................................
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Time and Events Schedule for Cohorts A, B, and C ................................ 
5.1.2 Time and Events Schedule for Cohort D.................................................. 
5.1.3 Retesting During Screening ..................................................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Safety Assessments for Cohorts A, B, and C ............................................ 
5.3.2 Safety Assessments for Cohort D ............................................................. 
5.3.3 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Radiographic Assessments ....................................................................... 
5.4.1.1 Radiographic Assessments for Cohorts A, B, and C ....................... 
5.4.1.2 Radiographic Assessments for Cohort D ........................................ 
5.4.2 Assessment of Overall Tumor Burden and Measurable Disease ............. 
5.4.2.1 Measurable Lesions ........................................................................ 
5.4.2.2 Non-Measurable Lesions ................................................................ 
5.4.3 Specifications by Method of Assessment .................................................. 
5.4.3.1 Measurement of Lesions ................................................................. 
5.4.3.2 Method of Assessment ..................................................................... 
5.4.3.3 CT or MRI Scan .............................................................................. 
5.4.3.4 Clinical Lesions .............................................................................. 
5.4.3.5 FDG-PET scan................................................................................ 
5.4.4 Baseline Documentation of “Target” and “Non-Target” Lesions.......... 
5.4.4.1 Target Lesions ................................................................................. 
5.4.4.2 Non-Target Lesions ......................................................................... 
5.4.5 Bone Marrow Assessments ...................................................................... 
5.4.6 Disease Response Evaluation .................................................................. 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetic Sample Analysis ........................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
5.8.1 Immunogenicity Assessments ................................................................... 
5.9 Results of Central Assessments ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
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6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Cohorts A, B, and C ................................................................................. 
8.3.1.1 Primary Endpoint(s) for Cohorts A, B, and C ................................ 
8.3.1.2 Secondary Endpoint(s) for Cohorts A, B, and C ............................. 
8.3.1.3 Exploratory Endpoint(s) for Cohorts A, B, and C .......................... 
8.3.2 Cohort D .................................................................................................. 
8.3.2.1 Primary Endpoints for Cohort D .................................................... 
8.3.2.2 Secondary Endpoints for Cohort D ................................................ 
8.3.2.3 Exploratory Endpoints for Cohort D .............................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Complete Response, Partial Response and Objective Response 
Rates ...................................................................................................... 
8.4.2.2 Duration of Response ...................................................................... 
8.4.2.3 Progression Free Survival and Overall Survival ............................ 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.6.1 EQ-5D ............................................................................................. 
8.4.6.2 EORTC QLQ-C30 ........................................................................... 
8.4.7 Other Analyses ......................................................................................... 
8.4.7.1 Immunogenicity Analysis ................................................................ 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
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9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ................................................................................................................. 
APPENDIX 2 INTERNATIONAL WORKING GROUP CRITERIA FOR 
MALIGNANT LYMPHOMA ................................................................................ 
APPENDIX 3 HASENCLEVER-INDEX FOR HODGKIN’S DISEASE ALSO 
KNOWN AS INTERNATIONAL PROGNOSTIC SCORE (IPS) ........................ 
APPENDIX 4 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 5 ACUTE GVHD GRADING AND STAGING ..................................... 
APPENDIX 6 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
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1
INTRODUCTION AND STUDY RATIONALE
Hodgkin lymphoma (HL) 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. 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. In cHL, four subgroups are identified: nodular sclerosis (75% 
to 80% of cases), mixed cellularity, lymphocyte depletion, and lymphocyte rich.2 Importantly, 
Epstein-Barr (EB) virus may play both an etiologic and pathogenetic role in about 40% of cHL 
(usually in mixed cellularity and lymphocyte depleted HL), where three predominant viral 
proteins are typically expressed potentially contributing to dysregulated HL growth.3
In 2013, the National Cancer Institute estimated that 9,290 men and women would be diagnosed 
with HL and 1,180 would die of HL.4 The prevalence of HL in the US in 2013 was estimated to 
be 181,928. 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.
The treatment of limited-stage HL has improved significantly since the adoption of combined 
modality therapy, with treatment failure occurring in approximately 10% of patients.5 However, 
approximately 30% of patients presenting with newly diagnosed HL have advanced stage disease 
(Stages IIB - IV). Improvements in the use of combined chemotherapy and radiotherapy in 
advanced stage newly diagnosed HL have resulted in durable remission rates of approximately 
60% to 80%.6However, there continues to be a significant opportunity for improvement in 
treatment of HL, including the frontline setting for patients with advanced-stage disease.6,7,8
Although multiagent chemotherapy regimens such as doxorubicin, bleomycin, vinblastine, and 
dacarbazine (ABVD) have been established as standard initial therapy for advanced-stage 
cHL,9,10,11 an Eastern Cooperative Oncology Group (ECOG) study showed ABVD regimen 
provided 71% and 67% 3-year and 5-year failure-free survival rates, respectively.12 This is 
particularly important considering young patient population,13 and when compared to the 
excellent long-term disease control for limited-stage cHL (over 90%).5
More intensified regimen such as escalated bleomycin, etoposide, Adriamycin (doxorubicin), 
cyclophosphamide, Oncovin (vincristine), procarbazine, and prednisone (BEACOPP)
demonstrated an improvement in disease control.14 However this intensive approach was 
associated with a greater frequency of initial toxicities,14 treatment-related mortality,15 and 
long-term toxicities, including higher incidences of secondary acute myeloid leukemia and 
myelodysplastic syndrome (MDS),14 and anticipated infertility.16 A more recent randomized 
Phase 3 study directly comparing ABVD with BEACOPP failed to show a significant difference 
in overall survival (OS) despite statistically higher progression free survival (PFS) for the 
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BEACOPP arm.15 The results from these first-line studies indicate the challenges to improve the 
outcomes for advanced-stage cHL.
A substantial fraction of patients with HL are not cured; up to 10% of patients with advanced 
stage HL will not achieve an initial remission, and 30% of responding patients subsequently 
relapse.7,8 The standard of care for patients with relapsed and refractory HL is intensive salvage 
chemotherapy followed by autologous stem cell transplant (ASCT), which can produce 
long-term remissions in approximately 50% of patients. Unfortunately, the remaining 50% of 
ASCT patients do not experience long-term disease control with median overall survival of 
approximately 27 months.17 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.18 Several small clinical studies have examined various 
agents in the ASCT relapsed HL population with uniformly poor results. Therefore, the 
therapeutic options for these patients remain very limited.
Figure 1-1:
Current Treatment Flow for Advanced Stage HL (Stages IIB - IV)
More recently, other novel approaches have been investigated in an effort to improve the 
outcome for HL patients failing ASCT. The malignant Reed-Sternberg cells of classical HL are 
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characterized by the expression of CD30, a member of the tumor necrosis factor superfamily, 
whose expression is restricted to a subset of activated B-cells, T-cells, and eosinophils.19
Brentuximab vedotin (Adcentrix, SGN-35) is an antibody drug conjugate (ADC) comprising an 
anti-CD30 monoclonal antibody conjugated by a protease cleavable linker to the potent 
antimicrotubule disrupting agent, monoethyl auristatin E (MMAE). Binding of the ADC to CD30 
on the cell surface initiates internalization of the ADC-CD30 complex, followed by lysosomal 
proteolytic cleavage with the resultant release of MMAE, disruption of the microtubule network, 
and apoptotic cell death.20,21
In a Phase 1 study brentuximab vedotin was studied in 45 patients with relapsed or refractory 
CD30 lymphomas where the maximum tolerated dose (MTD) was determined to be 1.8 mg/kg 
every 3 weeks.22 Treatment was reasonably well tolerated with the most common adverse events 
(AEs) being fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. Because 
a substantial proportion of patients achieved objective responses, brentuximab vedotin was 
subsequently evaluated in a Phase 2 trial in a larger homogeneous population of HL patients who 
had relapsed or had refractory disease after ASCT.23 In this open-label Phase 2 study, 102 were 
patients treated up to a maximum of 16 cycles. Although the overall response rate (ORR) was 
75% with complete remissions (CR) in 34% and partial remission (PR) in 41% of patients, 
median progression free survival (PFS) and overall survival (OS) were 5.6 months and 
22.4 months for all patients. The median duration of response for patients who achieved a CR 
(n = 35) and a PR (n = 41) was 21.7 and 5.1 months, respectively. A recent update with longer 
follow up of the original patient population (median observation time 32.7 months) has shown 
that 14 patients remain in remission, with 9 patients who have not started a new anti-cancer 
therapy and 5 patients who received ASCT after brentuximab vedotin treatment.24 Despite the 
encouraging high response rate obtained with brentuximab vedotin, long-term disease control 
remains challenging since only a small proportion of patients can maintain complete responses. 
Additionally, in the Phase 2 trial, 21% of patients discontinued treatment due to AEs, most 
commonly peripheral sensory and peripheral motor neuropathies. Tolerability may also be of 
increased concern in patients > 60 years, where higher rates of anemia and peripheral neuropathy 
have been reported.25
Clearly for the relatively young and otherwise fit HL population who has relapsed after ASCT, 
there still remains a compelling unmet need for improved salvage therapy. Despite the high 
initial rate of OR obtained with brentuximab vedotin after ASCT failure, relapse for most 
patients occurs after a relatively short disease free interval. Unfortunately, for the population of 
HL patients who have failed both ASCT and brentuximab vedotin salvage therapy, there 
currently is no uniform approach to their treatment, underscoring the need for novel approaches 
to improve treatment outcomes for this group of patients as well.
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1.1
Study Rationale
1.1.1
Scientific Rationale
Immunotherapeutic approaches for the treatment of HL are well-established components of 
current treatment paradigms for these diseases.22,26,27,28 T cell checkpoint regulators such as 
programmed death-1 receptor (PD-1, CD279) and CTLA-4 (CD152) are cell surface molecules 
that, when engaged by their cognate ligands, induce signaling cascades down-regulating T cell 
activation and proliferation. Several models have been proposed to explain these activities, 
including the breaking of immune tolerance to tumor cell antigens by evasion of physiological 
T cell checkpoint controls. Other mutually non-exclusive models propose that PD-1 antagonists 
like nivolumab reverse the exhausted/arrested T cell phenotype by activating tumor reactive 
T cells in lymphoid organs and in the periphery, allowing for enhanced trafficking of tumor 
adjacent T cells into the tumor.29
Nivolumab is a fully human, IgG4 (κ) isotype mAb that binds PD-1 on activated immune cells 
and disrupts engagement of the receptor with its ligands PD-L1(B7-H1/CD274) and PD-L2 
(B7-DC/CD273), thereby abrogating inhibitory signals and augmenting the host antitumor 
response. In early clinical trials, nivolumab monotherapy has demonstrated activity in several 
tumor types, including melanoma, renal cell cancer, and non-small cell lung cancer (NSCLC).30
Additionally, in an ongoing Phase 1 study in subjects with relapsed hematologic malignancies 
(CA209039), nivolumab has demonstrated preliminary activity in subjects with HL, follicular 
lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). In general, nivolumab has been 
well tolerated to date, with a favorable safety profile relative to anticipated toxicities based on an 
immunostimulatory mechanism of action.31
Expression of PD-L1 by malignant lymphoma cells and by other cells in the tumor 
microenvironment including infiltrating T cells, dendritic cells, and monocytes, has the potential 
to interact with tumor specific T cells that express PD-1. The interaction of PD-1 on tumor 
specific cytotoxic T cells with its ligands PD-L1 and PD-L2 causes a decrease in the ability of 
these cells to proliferate and exert cytotoxic effects, increases their apoptotic rate and alters the 
functional characteristics of the cells to produce a tolerogenic and/or exhausted phenotype.32,33
This study will evaluate the effects of PD-1 blockade by nivolumab in subjects with cHL.
1.1.2
Study Design Rationale for Cohorts A, B, and C
A single-arm study design was chosen because there is no appropriate, fully-approved active 
comparator for relapsed third-line or later cHL subjects failing ASCT. Although brentuximab 
vedotin may be an effective treatment option for this patient population, its regulatory approval 
is provisional: accelerated approval in the US and the conditional approval in EU. As recently 
reported, long-term disease control has been observed in a very limited patient population; it is 
still uncertain whether patients are curable with this approach. Thus, this population still has 
limited therapeutic options, representing a substantial unmet medical need.
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A parallel cohort approach was selected because the target population of cHL failing ASCT 
requires clear distinction based upon prior brentuximab vedotin treatment. This study design will 
test nivolumab in parallel treatment groups; brentuximab vedotin- naïve subjects (Cohort A) who 
have failed ASCT, or those who received brentuximab vedotin treatment as salvage following 
failure of ASCT (Cohort B). Cohort A or Cohort B represents the subjects who require the third 
or fourth line of therapy (in Figure 1-1). The two cohorts will enroll independently and will be 
analyzed separately. A third Cohort (Cohort C) is being added. This new cohort will start to 
enroll after completion of Cohort B enrollment. Analysis will be also conducted independently 
for Cohort C.
1.1.2.1
Rationale for Cohort C
Cohort C will provide an extended assessment of the benefit-risk for this study drug in advanced 
stage cHL patients in a larger patient population. Approximately 100 subjects treated from 
Cohort C will assist in the identification and characterization of less common safety events as 
well as further confirmation of the activity initially observed in Cohort B. 
Importantly, Cohort C will also provide initial data concerning whether discontinuation of 
nivolumab monotherapy is safe in subjects who have remained in CR for one year on nivolumab. 
Most currently ongoing nivolumab Phase 2 and Phase 3 studies for solid tumor and hematologic 
malignancies permit treatment until disease progression or unacceptable toxicity. Because 
nivolumab is generally tolerable, some subjects who have achieved CR may remain on study 
therapy indefinitely unless disease progression occurs. It will be helpful to answer whether these 
subjects can safely stop treatment at some point in order to avoid unnecessary exposure to study 
drug, and can experience similar benefit. To address this scientific question, a discontinuation 
schedule will be examined in Cohort C. Subjects who have persistent CR for one year on study 
drug will discontinue the study drug. If 15 to 20% of the subjects from Cohort C achieve CR and 
maintain their CR for one year, the discontinuation schedule will be assessed on approximately 
15 to 20 subjects. To ensure that subjects can safely discontinue study therapy, regular follow-up 
observational visits will be conducted after treatment discontinuation for up to two years. 
Furthermore, re-initiation of study therapy will be permitted for those subjects relapsing within 
two years of study drug discontinuation. This discontinuation schedule will provide important 
information as to whether the subjects who have attained good disease control can safely 
discontinue study drug without increasing risk of relapse.
In addition, plasma samples will be collected in Cohort C subjects for, but not limited to, the 
determination of Minimal Residual Disease (MRD) for molecular monitoring of the disease.
1.1.2.2
Justification for Doses in Cohorts A, B, and C
The benefit-risk profiles of nivolumab 240 mg every 2 weeks (Q2W) and 480 mg every 4 weeks 
(Q4W) are expected to be comparable to 3 mg/kg Q2W. This assessment is based on a 
comprehensive characterization of nivolumab PK, safety, efficacy, and exposure-response (E-R)
relationships across indications. Given that nivolumab has linear PK over a dose range of 0.1 to 
10 mg/kg across multiple tumor types, the 240 mg Q2W regimen was selected based on the 
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approximate median body weight of 80 kg for subjects treated in nivolumab clinical trials. The 
480 mg Q4W regimen was selected as it translates to a doubling of the 240 mg flat dose given 
Q2W. With reduced dosing frequency from Q2W to Q4W, the average nivolumab exposure with 
480 mg Q4W is expected to be comparable to that from 3 mg/kg Q2W or 240 mg Q2W.
Using a previously developed population pharmacokinetic (PPK) model that incorporated time-
varying CL, nivolumab exposures were estimated in advanced melanoma, NSCLC, advanced 
RCC, SCCHN, cHL, and UC subjects for nivolumab 240 mg Q2W and 480 mg Q4W dosing.
The geometric means of key summary measures of exposure achieved with nivolumab 240 mg 
Q2W including peak (Cmax), time-averaged (Cavg) and trough (Cmin) concentrations after the 
first dose or at steady-state were similar (<6% difference) to the corresponding exposures 
achieved with nivolumab 3 mg/kg Q2W. The magnitude of the difference is not expected to be 
clinically significant.
In comparing nivolumab 480 mg Q4W to 3 mg/kg Q2W, the geometric mean time-averaged 
concentration over the first 28 days (Cavgd28) was approximately 27% higher with 480 mg 
Q4W, whereas the geometric mean steady-state time-averaged concentration (Cavgss) for both 
dosing regimens was similar. Nivolumab geometric mean trough concentrations at Day 28 
(Cmind28) and at steady-state (Cminss) were 22% and 16% lower, respectively, with 480 mg 
Q4W dosing. Conversely, geometric mean peak nivolumab concentrations after the first dose 
(Cmax1) and at steady-state (Cmaxss) were 111% and 43.4% higher, respectively, with 480 mg 
Q4W dosing. 
Extensive E-R analyses were conducted for OS, OR, and tumor growth dynamics to bridge 
efficacy of nivolumab 240 mg Q2W and 480 mg Q4W with the clinically evaluated 3 mg/kg 
Q2W dosing regimen. The primary exposure measure used in the analyses was Cavgd28 because 
it represents the relevant drug concentration over the entire duration of earlier dosing intervals 
from Q2W and Q4W regimens. The hazard ratios with nivolumab 240 mg Q2W or 480 mg Q4W 
were predicted to be similar to 3 mg/kg Q2W across multiple tumor types (melanoma, RCC, SQ 
and NSQ NSCLC). There were no differences in predicted response rate with nivolumab 240 mg 
Q2W or 480 mg Q4W compared to 3 mg/kg Q2W. There was also no apparent relationship 
between Cavgd28 and individual estimates of tumor growth rate.
To evaluate safety, the exposure margin of nivolumab 240 mg Q2W and 480 mg Q4W relative to 
the safe and well-tolerated dose of 10 mg/kg Q2W was determined. In addition, extensive E-R 
analyses for AE-DC/D, AE-Grade 3+, and Grade 2+ immune-mediated adverse events (AE-IM 
Grade 2+) were conducted with pooled safety data across multiple tumor types (melanoma, 
RCC, SQ NSCLC, NSQ NSCLC, SCCHN, cHL, and UC). Exposure margins with 240 mg Q2W 
or 480 mg Q4W were below that achieved with nivolumab 10 mg/kg Q2W indicating that these 
dosing regimens are expected to be safe and tolerable. In addition, the risk of AE-DC/D, AE-
Grade 3+, and AE-IM Grade 2+ was not significantly associated with Cavgd28 or Cmax1 in the 
E-R analyses.
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1.1.3
Study Design Rationale for Cohort D
Cohort D will investigate the overall safety and tolerability of nivolumab monotherapy (240 mg 
flat dose) followed by nivolumab (240 mg flat dose) in combination with chemotherapy 
(doxorubicin, vinblastine, and dacarbazine: AVD where A stands for Adriamycin, which is the 
trade name of doxorubicin) in subjects who are newly diagnosed, previously untreated cHL with 
advanced stage (Stage IIB, III and IV) disease. The first segment of the tested regimen in this 
cohort will consist of 4 doses of nivolumab monotherapy on a 2-week schedule. The second 
segment of the regimen will consist of 6 cycles (12 doses) of nivolumab in combination with 
three chemotherapy drugs (doxorubicin, vinblastine, and dacarbazine: AVD) which are 
frequently used as standard-of-care for newly diagnosed cHL. 
As explained in more detail below, a nivolumab-based regimen has the potential to improve 
long-term clinical outcome due to its capacity to reduce tumor burden and induce durable 
response as a single agent, in addition to its tolerable safety profile.
Rationale for Nivolumab Monotherapy
This study will evaluate nivolumab monotherapy (four doses) as the first component of the tested 
regimen in first line cHL subjects with advanced stage disease based on the following 
considerations. 
First, nivolumab monotherapy in CA209039 significantly reduced tumor burden in the first 
16 weeks (Figure 1.4.3.4-1), where 39.1% of heavily pretreated subjects with cHL were able to 
achieve an overall response within the first 8 weeks of nivolumab monotherapy, and 65.2% were 
able to achieve an overall response (CR or PR) within the first 16 weeks (Table 1.1.3-1). This 
indicates that nivolumab monotherapy can potentially be utilized as induction therapy for newly 
diagnosed cHL, given that monotherapy generated high response rate (87%) and the remaining 
subjects (13%) had stable disease. The earliest progression noted in the HL cohort was observed 
at 15 weeks. It is reasonable to presume that the durability of response will be similar between 
newly diagnosed cHL patients and heavily pre-treated cHL patients.
Table 1.1.3-1:
Cumulative Response Rate in cHL Subjects Treated with 
Nivolumab Monotherapy (CA209039)
Time from the First Dose
Respondersa with Overall 
Response (CR or PR)
N
Cumulative Response Rate
% (95% CI)
8 weeks
9
39.1 (22.6, 61.7)
16 weeks
15
65.2 (46.3, 83.4)
24 weeks
16
69.6 (50.7, 86.5)
48 weeks
19
82.6 (65.0, 94.6)
cHL = classical Hodgkin lymphoma; CR = complete remission; PR = partial remission
a Twenty out of the 23 subjects with cHL achieved overall response
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Second, nivolumab monotherapy generates durable responses in heavily pretreated cHL subjects. 
Out of 20 responders in the Phase 1 study (CA209039), the median duration of response in the 
14 subjects who did not proceed to stem cell transplant (SCT) was over 14 months (57.0 weeks; 
range: 23.3 - 76.3+ weeks).34 This is in contrast to the relative short durability of response 
(6.7 months 95% CI: 3.6 - 14.8), which was reported for 76 responders in a similar population 
who were treated with brentuximab vedotin monotherapy35. Again, there is no reason to consider 
that durability of response will be different in newly diagnosed cHL subjects from that observed 
in heavily treated cHL subjects.
Third, treatment with immune modulating therapy early in the disease course and prior to 
immunosuppressive/myelosuppressive effects of chemotherapy may be advantageous for 
therapies that require a host's ability to mount an initial immune response. Chemotherapies 
suppress myelopoiesis, and decrease the number of red blood cells, platelets, and lymphocytes 
(including T-lymphocytes) in the peripheral circulation. By lowering the overall number of 
T-lymphocytes, a checkpoint inhibitor such as nivolumab will have fewer effector cells for 
potential lessened downstream anti-tumor activity during the combination therapy period. 
Fourth, introduction of nivolumab would provide an opportunity to spare patients from toxicity 
associated with certain chemotherapy in the future. Due to the significant reduction of tumor 
burden by nivolumab monotherapy observed in the Phase 1 study, a nivolumab-incorporated 
regimen might reduce the number of required cycles of multiagent chemotherapy while 
maintaining long-term disease control in future studies. This would be beneficial for young 
patients to avoid late adverse effects of traditional chemotherapy (eg, secondary malignancies, 
cardiovascular disease, or pulmonary dysfunction)36,37 While nivolumab monotherapy in newly 
diagnosed advanced stage cHL in the front line setting is investigational, it was already 
investigated in two randomized phase III trials (CA209066 and CA209067) in the treatment 
naive setting in a different tumor, melanoma.38,39 These results indicated favorable safety profile 
of nivolumab monotherapy as a front line therapy in untreated melanoma patients. For example, 
treatment-related adverse events of grade 3 or 4 in the nivolumab-treated subjects were reported 
as 11.7% and 16.3%, respectively.38,39 Hence, nivolumab safety profile permits study of a 
relatively short monotherapy course prior to addition of proven chemotherapeutic regimen.
Lastly, the Phase 1 study (CA209039) showed a favorable safety profile for nivolumab 
monotherapy in heavily treated cHL subjects. Drug-related Grade 3 adverse events were reported 
in five subjects out of 23 (22%), whereas there were no drug-related Grade 4 or 5 adverse events. 
Only two subjects (9%) of 23 heavily treated subjects discontinued the drug due to toxicity. 
Discontinuation was reported at 39.6 weeks and at 40 weeks from first dose of nivolumab due to 
MDS and thrombocytopenia in one subject, and due to pancreatitis in the other subject, 
respectively. None of the cHL subjects discontinued nivolumab monotherapy due to toxicity 
before 39.6 weeks. This safety profile for the cHL cohort did not differ significantly compared to 
that for other tumor types, where over 8,000 subjects have been treated with nivolumab 
monotherapy.
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Rationale for Nivolumab in Combination with AVD 
This study will also evaluate nivolumab used in combination with AVD as the second segment 
of the proposed regimen. As shown in Table 1.1.3-1, responses continue to accumulate with 
longer nivolumab exposure. For example, nivolumab monotherapy continued to be effective 
beyond the first 16 weeks of therapy since the cumulative response rate continued to increase up 
to 82.6% response rate at 48 weeks from the first dose. Therefore, longer exposure with 
nivolumab maximizes its clinical benefits. However, multiagent chemotherapy which has been 
proven to generate long-term disease control is likely to still be needed to maximize treatment 
effect and ensure the opportunity for long term benefit in advanced stage cHL. 
ABVD is one of the most frequently used cHL regimens, where long-term clinical outcomes 
have been proved in randomized studies.40,41 However, bleomycin is considered as the least 
effective drug among the four drugs.42,43,44 A recent prospective study from the UK randomized 
952 subjects who had negative PET scans after two cycles of ABVD.44 The omission of 
bleomycin from the last four cycles resulted in no significant difference of PFS or OS. PFS at 
3 years was 85.5 % for the patients who continued ABVD vs. 84.5% for the patients who 
switched to AVD. OS at 3 years was 97.0 % for ABVD who continued ABVD vs. 97.5% for the 
patients who switched to AVD. The CR and unconfirmed CR rates are also similar 65 % for 
ABVD who continued ABVD vs. 69 % for the patients who switched to AVD. Importantly, the 
most serious toxicity associated with ABVD is bleomycin-related pulmonary toxicity, which was 
observed in 18% (25 of 141) of the patients from a Mayo Clinic series.43 When patients 
eliminated bleomycin during the ABVD cycles, there was no impact on CR rates, PFS, or 
OS.42,43 This analysis suggests that bleomycin has a limited role in the ABVD regimen, and 
omitting bleomycin is reasonable in the appropriate context.
Importantly, nivolumab could have the potential for overlapping toxicity with bleomycin. 
Nivolumab has been associated with immune-mediated pneumonitis. The incidence of 
pneumonitis, including interstitial lung disease, is relatively low (3.4% in unresectable or 
metastatic melanoma patients and 6% in metastatic squamous non-small cell lung cancer 
patients), whereas fatal immune-mediated pneumonitis has occurred in 0.7% (5/691) of patients 
receiving single agent nivolumab.45 On the other hand, bleomycin could cause pulmonary 
toxicity in 15 - 18%43,46 of all subjects where the majority was treated with ABVD. The 
mortality rate from bleomycin pulmonary toxicity was reported as 3.0 to 4.2% in all 
bleomycin-treated patients, and 24% in patients who developed the pulmonary syndrome.43,47
When brentuximab vedotin was combined with ABVD in a Phase 1 study, unexpected 
pulmonary toxicity was observed in 44% (11/25) of subjects with two fatal cases due this 
event.48 This study was amended by omitting bleomycin, and reported no subsequent pulmonary 
toxic effect when brentuximab vedotin was combined with AVD. Consequently, if nivolumab is 
combined with bleomycin-included multiagent chemotherapy, there is the potential of additive 
toxicity similar to what was observed when brentuximab vedotin was added to ABVD. Hence, in 
order to minimize potential toxicity with potentially superior efficacy, nivolumab will be 
included without bleomycin.
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While, there are no clinical or nonclinical data of the addition of nivolumab to the AVD regimen 
or individual components, the addition of nivolumab to other conventional chemotherapy 
regimens does not seem to increase the toxicity from other drugs.49,50 Nivolumab was evaluated
with concomitant administration of three different combinations (gemcitabine and cisplatin, 
pemetrexed and cisplatin, and paclitaxel or carboplatin) in subjects with an advanced non-small 
cell lung cancer.49,50 No dose-limiting toxicities (DLTs) were observed during the DLT period 
(the first 6 weeks) of nivolumab treatment in combination with platinum-based doublet 
chemotherapy. The frequencies of the most common treatment-related AEs were similar to those 
observed with platinum-based doublet chemotherapy alone, indicating a safety profile similar to 
that of individual chemotherapeutic agents. Additionally, drug-drug interaction between 
nivolumab and other chemotherapeutic agents is not expected. It is not likely that other drugs 
will affect the PK of nivolumab because nivolumab is an IgG4 monoclonal antibody, which is 
eliminated by non-specific catabolism (often by reticuloendothelial system proteases); this 
elimination process is not known to be inhibited or induced by specific drugs. Nivolumab is also 
unlikely to impact the PK of other companion drugs when used in combination regimens. 
A Phase 1 study in metastatic clear cell renal cell carcinoma (CA209009) demonstrated that 
nivolumab at all dose levels (0.3, 2, and 10 mg/kg) did not modulate cytokine levels (IL6, IL2, 
and IL10). Because no change in cytokine level was observed, nivolumab is not considered to 
mediate CYP induction, and has no or low potential for modulating CYP enzymes, and thereby a 
low risk of interaction with other drugs. Thus, combined toxicities from nivolumab and AVD are 
unlikely to be observed, whereas there are appropriate safety guards in place within this protocol 
to detect and manage any unanticipated toxicity from the combination (Section 7). 
In conclusion, it will be clinically important to understand the safety and tolerability of 
nivolumab monotherapy in newly diagnosed cHL population. Additionally, the safety and 
tolerability of the nivolumab-AVD combination should be evaluated. Overall, this new regimen, 
consisting of two temporal components (nivolumab monotherapy followed by nivolumab and 
AVD), may improve clinical outcomes newly diagnosed advanced stage cHL.
Rationale for Nivolumab Flat Dose and 30 Minutes Infusion in Cohort D 
The nivolumab dose of 240 mg every 2 weeks (Q2W) 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.
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no 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 the proportional with increasing weight, indicating that mg/kg 
dosing represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK 
model previously developed using data from NSCLC subjects has recently been updated, using 
data from 1544 subjects from 7 studies investigating nivolumab in the treatment of melanoma, 
NSCLC, and RCC. In this dataset, the median (minimum - maximum) weight was 77 kg 
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(35 kg - 160 kg) and thus, an approximately equivalent dose of 3 mg/kg for an 80 kg subject, 
nivolumab 240 mg Q2W was selected for future studies. To predict relevant summary exposures 
of nivolumab 240 mg Q2W, the PPK model was used to simulate virtual trials, each consisting of 
two arms, nivolumab 3 mg/kg Q2W and 240 mg Q2W. In the simulations, the simulated patient 
populations consisted of subjects randomly sampled from aforementioned pooled database of 
cancer patients. Because no differences in PK were noted across ethnicities and tumor types, 
these simulated melanoma and NSCLC data will be applicable to patients with other tumor 
types. The simulated measure of exposure of interest, time-averaged concentrations (Cavgss) for 
240 mg Q2W are predicted to be similar for all subjects in reference to 80 kg subjects receiving 
3 mg/kg Q2W. 
Nivolumab is safe and well tolerated up to 10 mg/kg Q2W dose level. Adverse events have been 
broadly consistent across tumor types following monotherapy and have not demonstrated clear 
dose-response or exposure-response relationships. Additionally, the simulated median and 95th 
prediction interval of nivolumab summary exposures across body weight range (35 - 160 kg) are 
predicted to be maintained below the corresponding observed highest exposure experienced in 
nivolumab ie, 95th percentile following nivolumab 10 mg/kg Q2W from clinical study 
CA209003. Thus, while subjects in the lower body weight ranges would have greater exposures 
than 80 kg subjects, the exposures are predicted to be within the range of observed exposures at 
doses (up to 10 mg/kg Q2W) used in the nivolumab clinical program, and are not considered to 
put subjects at increased risk. For subjects with greater body weights, the simulated ranges of 
exposures are also not expected to affect efficacy, because the exposures predicted following 
administration of a 240 mg Q2W are on the flat part of the exposure-response curves for 
previously investigated tumors, melanoma and NSCLC. Given the similarity of nivolumab PK 
across tumor types and the similar exposures predicted following administration of 240 mg flat 
dose compared to 3 mg/kg, it is expected that the safety and efficacy profile of nivolumab 
240 mg Q2W will be similar to that of nivolumab 3 mg/kg Q2W. Therefore, a flat dose of 
nivolumab 240 mg every 2 weeks will be used in cohort D.
Long infusion times place a burden on patients and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30 minutes duration in 
subjects will diminish the burden provided there is 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 
subjects 
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. Reduced infusion time is currently under 
investigation in study CA209038, an exploratory study of the biologic effects of Nivolumab and 
Nivolumab in combination with Ipilimumab treatment in subjects with advanced melanoma.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across nivolumab clinical studies. A change in safety profile is not anticipated with 30-minute 
infusion of nivolumab.
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1.1.3.1
Summary Information for AVD
Summary information for the individual agents in the chemotherapy combination AVD is 
provided below. Refer to the local product information for each product for more details.
Doxorubicin (Adriamycin)
Doxorubicin is an antitumor anthracycline antibiotic. Doxorubicin intercalates between adjoining 
nucleotide pairs in the DNA helix, and inhibits DNA and RNA synthesis. The terminal half-life 
of doxorubicin is 20 to 48 hours. Doxorubicin is used for Hodgkin’s lymphoma. AEs associated 
with doxorubicin include myocardial toxicity which is manifested in its most severe form by 
potentially fatal congestive heart failure. Myocardial toxicity may occur either during 
therapy or months to years after termination of therapy. Therefore, monitoring for 
potential cardiotoxicity is important. Secondary acute myelogenous leukemia (AML) or MDS 
have been reported in patients treated with doxorubicin. Severe local tissue necrosis will occur if 
there is extravasation during administration. Other reported adverse effects include, but are not 
limited to, hematologic (myelosuppression), hepatic (increased aspartate aminotransferase 
[AST], alanine aminotrasferase [ALT], alkaline phosphatase, and bilirubin), dermatologic 
(alopecia, red streaks along the injected vein), gastrointestinal (anorexia, nausea, vomiting, 
diarrhea, mucositis, dysphagia), other cardiovascular (electrocardiogram [ECG] change, 
arrhythmias), neurologic (peripheral neurotoxicity in the form of local-regional sensory and/or 
motor disturbances), ocular events (conjunctivitis, keratitis, lacrimation), and hypersensitivity 
(fever, chills, and urticaria, and anaphylaxis).51
Vinblastine (Vinblastine Sulphate)
Vinblastine is a vinca alkaloid, which binds to tubulin, a protein that forms microtubules. The 
mechanism of action is disruption of mitotic spindle assembly through the interaction with 
tubulin. The terminal half-live of vinblastine is 24.8 hours. AEs associated with vinblastine 
include severe hypomotility with constipation or ileus. Therefore, assessment for 
constipation and auscultate abdomen for bowel sounds will be important. Acute shortness of 
breath and severe bronchospasm have been reported following the administration of vinca 
alkaloids. Other reported adverse effects include, but are not limited to, hematologic 
(myelosuppression), dermatologic (alopecia, skin vesiculation,), gastrointestinal (nausea, 
vomiting abdominal pain, cramps, diarrhea, mucositis, gastrointestinal hemorrhage), 
cardiovascular (hypertension, myocardial infarction, angina pectoris and transient abnormalities 
of ECG, Raynaud's phenomenon), and neurologic events (peripheral neuropathy, loss of deep 
tendon reflexes, paresthesias, paralysis, autonomic neuropathy such as paralytic ileus, urinary 
retention, orthostasis, vocal cord paralysis, myalgias, headache, convulsions, depression, 
dizziness, malaise), jaw pain, and the syndrome of inappropriate secretion of antidiuretic 
hormone.52
Dacarbazine (DTIC)
Although the exact mode of action is unknown, dacarbazine hypothetically works by alkylation, 
inhibition of DNA synthesis as a purine analogue and interaction with sulfhydryl (SH) groups in 
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proteins. The terminal half-life of dacarbazine is 5 hours. Dacarbazine is used to treat Hodgkin’s 
lymphoma. AEs associated with dacarbazine include hematologic (myelosuppression), 
dermatologic (alopecia, facial flushing, extravasation with pain), gastrointestinal (nausea, 
vomiting, diarrhea), hepatic (increased AST, ALT, hepatic vein thrombosis, hepatocellular 
necrosis), renal (increased serum creatinine, blood urea nitrogen [BUN]), neurologic (facial 
flushing paresthesia) events, influenza-like syndrome (with fever, malaise, myalgia) and 
anaphylaxis.53
1.2
Research Hypothesis 
1.2.1
Cohorts A, B, and C
Treatment with nivolumab will lead to clinical benefit, as demonstrated by a clinically 
meaningful objective response rate, including durable responses with substantial magnitude of 
tumor burden reduction in the heavily treated cHL subjects.
1.2.2
Cohort D
A new regimen, consisting of nivolumab monotherapy followed by the combination of 
nivolumab and chemotherapy (AVD; a combination of doxorubicin, vinblastine and 
dacarbazine), will be safe and tolerable in previously untreated cHL subjects with newly 
diagnosed advanced stage (Stage IIB, III and IV) disease.
1.3
Objectives(s)
1.3.1
Primary Objective
1.3.1.1
Cohorts A, B, and C
To assess the clinical benefit of nivolumab, as measured by objective response rate (ORR) based 
on independent radiologic review committee (IRRC) assessment, and defined as proportion of 
subjects achieving either a PR or CR according to the revised International Working Group 
criteria for Malignant Lymphoma (2007 IWG criteria), see Appendix 2.
1.3.1.2
Cohort D
To assess the overall safety and tolerability of nivolumab monotherapy (flat dose 240 mg), 
followed by the combination of nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) 
chemotherapy in previously untreated cHL subjects who are newly diagnosed with advanced 
stage (Stage IIB, III and IV) disease , as measured by the proportion of subjects who experienced 
at least one treatment-related Grade 3 - 5 AEs with an onset date after or on the first dose date 
and no later than 30 days after the last study dose date, among subjects receiving at least one 
dose of study treatment.
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1.3.2
Secondary Objectives
1.3.2.1
Cohorts A, B, and C
•
To assess the duration of objective response (DOR) based on IRRC assessments
•
To assess the CR rate and the duration of CR based on IRRC assessment
•
To assess the PR rate and the duration of PR based on IRRC assessment
•
To assess the ORR and DOR, based on investigator assessments.
1.3.2.2
Cohort D
•
To evaluate the safety and tolerability of nivolumab monotherapy during the monotherapy 
phase 
•
To evaluate the safety and tolerability of nivolumab in combination with AVD during the 
combination phase 
•
To evaluate the treatment discontinuation rate of the study therapy during the monotherapy 
phase, combination phase, and overall (the entire course of study treatment consisting of both 
phases)
•
To assess the clinical activity of study therapy, as measured by the CR rate at the planned end 
of therapy, based on IRRC assessments.
1.3.3
Exploratory Objectives
1.3.3.1
Cohorts A, B, and C
•
To assess the PFS based on IRRC assessment
•
To assess the OS
•
To assess the overall safety and tolerability of nivolumab, as measured by incidence and 
severity of AEs, serious adverse events, and specific laboratory abnormalities
•
To investigate the association between biomarkers in the peripheral blood and tumor tissue, 
such as PD-L1 expression, with safety and efficacy measures
•
To characterize pharmacokinetics of nivolumab and explore E-R relationships
•
To characterize the immunogenicity of nivolumab monotherapy
•
To evaluate both generic health-related quality of life as assessed by the EQ-5D and cancer 
specific quality of life as assessed by the European Organisation for Research and Treatment 
of Cancer (EORTC) quality of life questionnaire (QLQ)-C30
•
To evaluate the pharmacodynamic activity of nivolumab monotherapy in the peripheral 
blood and tumor tissue as measured by flow cytometry, immunohistochemistry (IHT), 
soluble factor analysis, and gene expression (microarray technology, quantitative reverse 
transcription polymerase chain reaction (RT-PCR).
•
For Cohort C, to evaluate risk-benefit of discontinuation schedule of the study drug for the 
subjects who have persistent CR for 1 year.
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1.3.3.2
Cohort D
•
To evaluate IRRC-assessed OR rate, and investigator-assessed CR and OR rates at the 
planned end of therapy
•
To evaluate the CR rate and OR rate at the planned end of Nivolumab monotherapy based on 
IRRC assessment and based on investigators assessment
•
To evaluate the CR rate and OR rate at the planned end of two combocycles based on IRRC 
assessment and based on investigators assessment
•
To evaluate the PFS based on IRRC assessment and based on investigators’ assessment
•
To assess the duration of objective response (DOR) and duration of complete response based 
on IRRC assessment and based on investigators assessment
•
To assess the OS
•
To investigate the association between biomarkers in the peripheral blood and tumor tissue, 
such as PD-L1 expression, with safety and efficacy measures
•
To characterize pharmacokinetics of nivolumab and explore E-R relationships
•
To characterize the immunogenicity of nivolumab 
•
To evaluate the change from baseline of pulmonary function after treatment
•
To evaluate generic health-related quality of life as assessed by the EQ-5D
•
To evaluate the pharmacodynamic activity of nivolumab monotherapy in the peripheral 
blood and tumor tissue as measured by flow cytometry, immunohistochemistry (IHT), 
soluble factor analysis, and gene expression (microarray technology, quantitative reverse 
transcription polymerase chain reaction (RT-PCR).
1.4
Product Development Background
Nivolumab is in clinical development for the treatment of subjects with solid tumors and 
hematological malignancies. In addition to study CA209205, studies to be conducted in the 
hematologic malignancies program will assess the efficacy and safety of nivolumab in subjects 
with DLBCL who have relapsed following high dose chemotherapy ASCT or after failure of at 
least two prior multi-agent chemotherapy regimens in ASCT ineligible subjects (CA209139) and 
in subjects with relapsed or refractory FL (CA209140).
1.4.1
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. This 
functions by aborting the emergence of tumors as they arise and/or causing tumor shrinkage 
where it is present. Meanwhile, tumor progression may depend upon acquisition of traits that 
allow cancer cells to evade immune surveillance and an effective immune response.54 This 
evasion may occur by exploiting any of the checkpoints that control the regulatory immune 
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response, including display of antigens and control of co-stimulatory pathways that affect the 
proliferation of cells involved in immunity. 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, either directly by stimulation of immune cells by antibodies directed to receptors on 
T and B cells or indirectly by cytokine manipulation. T-cell stimulation is a complex process 
involving the integration of numerous positive, as well as negative, costimulatory signals in 
addition to antigen recognition by the T-cell receptor.55 Collectively, these signals govern the 
balance between T-cell activation and tolerance to antigens.54
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a 
member of the CD28 family of T-cell costimulatory receptors that also includes CD28, CTLA-4, 
ICOS, and BTLA.55 PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine 
inhibitory motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif 
(ITSM). Two ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and PD-L2 
(B7-DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon 
binding to PD-1 in both murine and human systems.56,57 PD-1 delivers a negative signal by the 
recruitment of SHP-2 to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic 
region.58,59 PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells.60
Further evidence for a negative regulatory role for PD-1 comes from studies of PD-1 deficient 
mice. PD-1-deficient mice develop various autoimmune phenotypes, including dilated 
cardiomyopathy, a lupus-like syndrome with arthritis and nephritis, and accelerated diabetes 
mellitus.61,62,63 The emergence of these autoimmune phenotypes is dependent upon the genetic 
background of the mouse strain and many of these phenotypes emerge at different times and 
show variable penetrance. In addition to the phenotypes of null mutations, PD-1 inhibition by 
antibody-mediated blockade in several murine models has been found to play a role in the 
development of autoimmune diseases such as encephalomyelitis, graft-versus-host disease, and 
type I diabetes.64,65 Taken together, these 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.
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal 
antibodies (mAbs) can enhance the anti-tumor immune response and result in tumor rejection. 
Antitumor activity by PD-1 blockade functions in PD-L1-positive tumors as well as in tumors 
that are negative for the expression of PD-L1.66,67,68,69,70,71 This suggests that host mechanisms 
(ie, expression of PD-L1 on antigen-presenting cells) limit the antitumor response. Consequently, 
both PD-L1 positive and negative tumors may be targeted using this approach. In humans, 
constitutive PD-L1 expression is normally limited to macrophage-lineage cells, although 
expression of PD-L1 can be induced on other hematologic cells as well, including activated 
T cells. However, aberrant expression of PD-L1 by tumor cells has been reported in a number of 
human malignancies.72,73,74,75,76,77,78 PD-L1 expressed by tumor cells, including FL and 
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DLBCL, has been shown to enhance apoptosis of activated tumor-specific T cells in vitro.59,79,80
Moreover, the expression of PD L1 may protect the tumor cells from the induction of apoptosis 
by effector T cells.81 Retrospective analyses of several human tumor types suggest that tumor 
over-expression (as measured by IHC) of PD-L1 may permit immune evasion by tumors. 
Blockade of the PD 1 pathway by nivolumab was studied using the mixed lymphocyte reaction 
(MLR). PD-1 blockade resulted in a reproducible enhancement of both proliferation and
interferon-gamma (IFN-γ) release in the MLR.82 The effect of nivolumab on antigen-specific 
recall response was investigated using a CMV-restimulation assay with human peripheral blood 
mononuclear cells (PBMCs), and was evaluated by ELISA. These data indicated that nivolumab, 
versus an isotype-matched control antibody, augmented IFN-γ secretion from CMV-specific 
memory T-cells in a dose-dependent manner. PD-1 blockade by nivolumab is therefore 
considered a promising immunotherapeutic option. 
1.4.2
PD-1 Expression in Classical Hodgkin Lymphoma
PD-L1 is expressed on the malignant cells in patients with a variety of hematologic malignancies 
including patients with HL, primary mediastinal B cell lymphoma, T cell lymphomas, multiple 
myeloma, and acute leukemias. Membranous staining of cHL tumors indicated that 82% of the 
cases showed ≥5% positive malignant cells.80
Although cHLs have an extensive polymorphous inflammatory infiltrate, there is little evidence 
of an effective host anti-tumor immune response. In fact, recent studies indicate that Hodgkin RS 
cells produce certain molecules that limit the efficacy of T-cell mediated anti-tumor immune 
responses.83,84 By integrating high-resolution copy number data with transcriptional profiles, the 
immunoregulatory genes, PD-L1 and PD-L2, were found to be key targets of the 9p24.1 
amplification in cHL cell lines and primary tumors.85 PD-1 ligand gene amplification was 
associated with increased protein expression in primary cHLs using quantitative 
immunohistochemical methods.85 In additional recent studies, EBV infection was found to be 
another mechanism of upregulating PD-L1.86,87 These findings suggest that targeting the 
PD-1-PD-L1/PD-L2 axis could have therapeutic implications in cHL patients.
1.4.3
Summary of Results for Nivolumab Program
1.4.3.1
Summary of Nivolumab Monotherapy Safety in Solid Tumors
Nivolumab is well tolerated based upon experience in approximately 1,500 subjects (as of 
21-Jul-2013) treated with nivolumab as a monotherapy or in combination with other therapeutic 
agents. Special attention is given to unique AEs which are referred to as “Select AEs” in the 
BMS-936558 (nivolumab) Investigator Brochure (IB) and as described below. 
An ongoing Phase 1 study (CA209003) has enrolled 306 subjects with advanced solid tumors 
including melanoma, renal cell carcinoma (RCC), and NSCLC has provided the most mature 
safety data from nivolumab monotherapy. Subjects received nivolumab at doses of 0.1, 0.3, 1, 3 
or 10 mg/kg intravenously every 2 weeks. No MTD was identified. Drug-related AEs of any 
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grade occurred in 72.4% of subjects. The most frequent drug-related AEs included fatigue 
(25.7%), rash (13.5%), diarrhea (11.8%), and pruritis (10.2%). Grade 3 or 4 drug-related AEs 
were observed in 14.8% of subjects. The most common Grade 3 or 4 drug-related AEs occurring 
in 1% of subjects were: fatigue (1.6%), lymphopenia (1.3%), abdominal pain (1%), diarrhea 
(1%), hypophosphatemia (1%) and pneumonitis (1%). 
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, have not typically been 
observed with cytotoxic agents. Select AEs have been categorized into seven 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 drug 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 IB and in Appendix 1 of the protocol.].
1.4.3.2
Nivolumab Monotherapy Safety in Phase 1 Study for Hematologic 
Malignancies Including cHL
Preliminary safety data from an ongoing Phase 1 study for subjects with a variety of hematologic 
malignancies (CA209039) suggested that the safety for these malignancies seems similar to that 
for solid tumors. As of 27-Feb-2014, data were available for 103 subjects, including 23 subjects 
with cHL. Treatment with nivolumab in subjects with hematological malignancies has been well 
tolerated and toxicities have been generally manageable. There was 1 DLT (Dose Limiting 
Toxicity) at the 1 mg/kg dose level in a subject with multiple myeloma who experienced Grade 3 
pneumonia and Grade 3 pneumonitis. There was 1 DLT at the 3 mg/kg dose level in a subject
with small lymphocytic lymphoma who experienced Grade 3 hypereosinophilia and Grade 3 
diplopia. The MTD was not reached. All of the subjects with HL were treated at a dose of 
3 mg/kg of nivolumab.
Adverse events were reported in 91 of 103 (88.3%) subjects and Grade 3 - 4 events in 
40 (38.8%) subjects. Related AEs were reported in 63 (61.2%) subjects. Those that occurred in 
more than 5% of subjects included: fatigue (12.6%), rash (10.7%), diarrhea (8.7%), pneumonitis 
(8.7%), pyrexia (7.8%), and pruritus (7.8%). Related Grade 3 - 4 events were reported in 
16 (15.5%) subjects; the most common of which was leukopenia that occurred in 3 (2.9%) 
subjects. Sixteen (15.5%) subjects discontinued therapy due to AEs, 7 of which were related to 
study therapy. A total of 18 (17.5%) subjects died: 14 due to disease, 3 due to other causes, and 1 
due to drug toxicity. Drug-related pneumonitis was observed in 9 subjects (8.7%): B-cell 
lymphoma (n = 5), T-cell lymphoma (n = 2), multiple myeloma (n = 1), and HL (n = 1). 
Six subjects had Grade 1 or 2 pneumonitis; 2 had Grade 4; one patient with small lymphocytic 
lymphoma suffered from Grade 5. In the CA209039 study, pneumonitis is slightly higher than 
that seen in the nivolumab studies in total and that now includes approximately 1,500 subjects.
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The safety experience focusing on the 23 subjects in the HL cohort did not differ significantly 
compared to that for all 103 subjects with other hematologic malignancies on the CA209039 
study. AEs were reported in 21 (91.3%) subjects and Grade 3 - 4 events in 10 (43.5%) subjects. 
Related serious adverse events (SAEs) were reported in 2 (8.7%) subjects. With the exception of 
myelodysplastic syndrome (MDS), the other related high grade events did not require treatment 
and resolved spontaneously at the next visit. Related AEs were reported in 16 (69.6%) subjects. 
Those that occurred in more than 2 (> 5%) subjects included: rash (17.4%), fatigue (13.0%), 
pyrexia (13.0%), diarrhea (13.0%), nausea (13.0%), decreased platelet count (13.0%), cough 
(8.7%), hypothyroidism (8.7%), ALT increased (8.7%), and AST increased (8.7%). Related 
Grade 3 events were reported in 4 (17.4%) subjects and included and low platelets (described in 
detail below), lipase increase, decreased lymphocytes and decreased leukocytes. 
Drug-related pneumonitis was reported in one patient from 23 subjects with cHL. This patient
had decreased leukocytes which resulted in discontinuation of the therapy. One month later, the 
patient underwent BCNU (carmustine), etoposide, cytarabine and melphalan (BEAM) 
conditioning and ASCT. The patient subsequently developed Grade 3 caecitis, mucositis, and 
pneumonitis, all considered possibly related to prior therapy with nivolumab. 
One patient discontinued therapy due to Grade 3 MDS. This patient had received BEAM 
conditioning, ASCT in 2008, and received 7 systemic treatment regimens including doxorubicin 
(adriamycin), bleomycin, vinblastine, dacarbazine (ABVD), ifosfamide, carboplatin, etoposide 
(ICE), brentuximab from 2007 to 2012. Although it was unclear if MDS was due to prior 
chemotherapy or prior ASCT, the possibility that it could have been due to nivolumab could not 
be excluded. 
Six subjects elected to stop therapy with a best response of CR or PR to pursue transplant 
options, including 1 patient who died of graft-versus-host-disease (GVHD) that was not related 
to nivolumab therapy.
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials, including CA209039 and the HL cohort.
Adverse Event Management Algorithms
Because of the potential for clinically meaningful nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for suspected 
pulmonary toxicity, gastrointestinal, hepatic toxicity, endocrinopathy, skin toxicity, neurological 
toxicity and renal toxicity. 
The algorithms recommended for utilization in CA209205 are contained in the nivolumab 
(BMS-936558) IB and in Appendix 1 of the protocol.
1.4.3.3
Nivolumab Monotherapy Clinical Activity in Solid Tumors
The clinical activity of nivolumab monotherapy has been observed in subjects with melanoma, 
RCC, and NSCLC in a Phase 1 study (CA209003), and in two subjects with colorectal cancer in 
other Phase 1 studies (MDX1106-01, ONO-4538-01). 
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In a Phase 1 study (CA209003, N = 306), nivolumab monotherapy demonstrated clinical activity 
in a variety of solid tumor types across a range of doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 
3 mg/kg, 10 mg/kg). A response of either CR or PR, as determined by investigator assessed 
tumor evaluations based on modified RECIST 1.0, has been reported at all dose levels. Among 
107 subjects with advanced melanoma, the ORR was 33 (31%) whereas progression-free 
survival rate (PFSR) at 24 week was 44% (95% confidence interval (CI): 34 - 54 weeks). Among 
129 subjects with advanced NSCLC, the ORR was 22 (17%) where as PFSR at 24 week was 
34% (95% CI: 25 - 42 weeks). Among 34 subjects with advanced RCC, the ORR was 10 (29%) 
where as PFSR at 24 weeks was 59% (95% CI: 42 - 75 weeks). The nivolumab IB includes 
details of clinical efficacy data from this study as well as additional solid tumor studies.
1.4.3.4
Nivolumab Monotherapy Clinical Activity in Hematologic Malignancies 
Including cHL
Nivolumab monotherapy clinical activity (at either the 1 mg/kg or 3 mg/kg dose levels) has been 
observed in heavily pretreated NHL and cHL subjects in an ongoing Phase 1 study for subjects
with a variety of hematologic malignancies (CA209039). Three of nine subjects (33%) with 
relapsed or refractory DLBCL treated have experienced an OR (2 PR and 1 CR), with the current 
response duration ranging between 12 to 24 weeks. Two of eight subjects (25%) with relapsed or 
refractory FL have experienced an OR (1 PR and 1 CR), with the current response duration 
ranging between 12 to 54 weeks.
Preliminary data has shown clinical activity in 23 subjects with cHL (average age: 35 year old; 
range 20 - 54). The Phase 1 study defined ORR as the proportion of subjects whose best overall 
response is either investigators-assessed CR or PR. The ORR in the cHL cohort is 87% (20 out 
of 23 subjects) with a CR rate of 26% (6 out of 23 subjects). Fifteen out of 23 subjects (65%) 
received brentuximab as salvage therapy after failure of ASCT. In this subset of subjects, the 
ORR is 87% (13 out 15 subjects); CR in 2 and PR in 13. Five subjects are brentuximab-naive
consisting of three without previous ASCT and two with previous ASCT. Two of the three 
without prior ASCT achieved CR, whereas both subjects with ASCT attained CR. Six subjects
elected to stop therapy with a best response of CR or PR to pursue allogeneic SCT options. One 
heavily treated patient stopped nivolumab therapy due to development of MDS; this patient had a 
best overall response (BOR) of PR. Two subjects came off study due to progressive disease 
(SD of 8 and 16 weeks then PD). All other subjects continue on study. Table 1.4.3.4-1
summarizes the preliminary investigator assessed efficacy data as of 27-Feb-2014.
Table 1.4.3.4-1:
Investigator Assessed Clinical Response in Study CA209039
Total
(N = 23)
Auto Failure
Bren Failure
(n = 15)
Auto Naive 
Bren Failure
(n = 3)
Bren Naive
(n = 5)
Best Overall Response (%)
CRa
6 (26.1)
2 (13.3)
0 
4 (80.0)
PR
14 (60.9)
11 (73.3)
3 (100)
0 
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In horizontal lines denote 50% decrease (threshold for PR) and no change. Subjects with baseline 
and at least one post-baseline assessment are presented.
In summary, nivolumab monotherapy reduced tumor burden in subjects with advanced stage 
cHL including in both brentuximab vedotin-naïve subjects who had failed prior ASCT, as well as 
in subjects who had failed both previous ASCT and brentuximab vedotin treatment. Prolonged 
DOR (CR and PR) has also been observed.
1.4.3.5
Nivolumab Monotherapy Clinical Pharmacology Summary
Single-dose pharmacokinetics (PK) of nivolumab were evaluated in 39 subjects with multiple 
tumor types in study MDX1106-01 in the dose range of 0.3 to 10 mg/kg. The median Tmax 
across single doses ranged from 1.6 to 3 hours with individual values ranging from 0.9 to 
7 hours. The PK of nivolumab was linear in the range of 0.3 to 10 mg/kg with dose proportional 
increases in Cmax and AUC(INF) and low to moderate inter-subject variability observed at each 
dose level (ie, coefficient of variation ranging from 7 to 45%). Geometric mean clearance after a 
single intravenous (IV) dose ranged from 0.13 to 0.19 mL/h/kg, while mean volume of 
distribution (Vz) varied from 83 to 113 mL/kg across doses. The mean terminal half-life of 
nivolumab is 17 to 25 days, which is consistent with the half-life of endogenous IgG4, indicating 
that the elimination mechanism of nivolumab may be similar to IgG4. Both elimination and 
distribution of nivolumab appear to be independent of dose in the dose range studied.
A preliminary PPK model was developed using data from 350 subjects from MDX1106-01, 
MDX1106-02 and CA209003. Clearance of nivolumab was found to be similar in all tumor 
types studied and is independent of dose range studied (0.1 to 10 mg/kg). Body weight 
normalized dosing produces approximately uniform trough concentrations over a wide range of 
body weights, and hence is appropriate for future clinical trials of nivolumab. 
The dose and schedule selected for evaluation in this study, 3 mg/kg every 2 weeks (Q2W), has 
been evaluated in solid tumors in the ongoing CA209003 study. Nivolumab was adequately 
tolerated up to 10 mg/kg, the highest dose level tested, and no MTD was identified. Anti-tumor 
activity was observed at dose levels ranging from 1 to 10 mg/kg in melanoma, NSCLC, and 
RCC, as well as at dose levels of 0.1 and 0.3 mg/kg in melanoma. The antitumor activity of 
nivolumab tended to increase with dose, as did the incidence of SAEs. The anti-tumor activity of 
BMS-936558 nivolumab in RCC was investigated at dose levels 1 and 10 mg/kg, with the higher 
activity observed at 10 mg/kg. The observed anti-tumor activity in melanoma, and NSCLC was 
highest at 3 mg/kg, suggesting that anti-tumor activity approaches a plateau at dose levels of 
3 mg/kg and above. The ongoing CA209039 study in hematologic malignancies includes 2 dose 
levels: 1 mg/kg and 3 mg/kg Q2W. The 3 mg/kg dose level has been shown to be adequately 
tolerable and has been expanded in select tumor types for further evaluation. Objective responses 
have been observed at both dose levels in study CA209039. Based upon the totality of available 
data across the program, a dose of 3 mg/kg Q2W is selected as the dose anticipated to maximize 
the benefit-risk ratio.
For revised protocol 04c, subjects in Cohorts A, B, and C will switch to being administered 
nivolumab as a 480 mg IV flat dose Q4W or a 240 mg IV flat dose Q2W (see also Section 3.1).
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Refer to the current BMS-936558 (nivolumab) IB for full details on the clinical pharmacology 
aspects of nivolumab.
1.4.4
Rationale for Exploratory Studies of Tumor PD-L1 Expression as a 
Potential Predictive Biomarker in HL
Aberrant expression of PD-L1 protein by tumor cells (retrospectively detected by IHC) has been 
reported in a number of human malignancies, including cHL.80 Elevated PD-L1 expression has 
been proposed to enhance immune evasion; this notion is supported by separate studies 
demonstrating that PD-L1 expressed by tumor cells enhances apoptosis of activated tumor-
specific T cells in vitro and that the expression of PD-L1 protects tumor cells from the induction 
of apoptosis by effector T cells.30 In vitro, anti-PD-L1 blocking antibody boosts proliferation and 
IFN-γ secretion by allogeneic T cells responding to DLBCL cells and in autologous cultures of 
primary DLBCL, PD-L1 blockade enhanced secretion of inflammatory cytokines IFN-γ, 
granulocyte macrophage colony-stimulating factor, IL-1, IL-6, IL-8, IL-13, TNF-α, and 
macrophage inflammatory protein-1α.
Preliminary data indicate PD-L1 protein expression in solid tumors may correlate with 
nivolumab clinical activity. Of 38 evaluable melanoma pre-treatment biopsies, 17 were PD-L1+ 
(45% positivity rate) and 7/17 of these PD-L1+ subjects had an OR (41%). Clinical activity of 
nivolumab was also seen in the PD-L1 negative population, however, at a much lower rate 
(3/21; 14%). This data suggests that, in melanoma, PD-L1 expression on tumor cells may 
correlate with clinical activity. Additional analysis is underway to further evaluate this 
hypothesis in solid tumors.
In order to more thoroughly assess the role of PD-L1 protein expression as a predictive 
biomarker in hematological malignancies, available archival or recent tumor tissue will be 
collected from all consenting subjects in this study, and PD-L1 expression will be tested 
retrospectively. Analyses to assess the association of PD-L1 and efficacy measures will be 
conducted.
1.4.5
Rationale and Aims for Biomarker Assessments
The biological basis of nivolumab in the treatment of oncological disease is to modulate the 
immune system to both generate and restore a durable anti-tumor response leading to clearance 
of tumor. The nivolumab clinical data supports the hypothesis that inhibition of the PD-1 
pathway results in rejection of tumor by the host immune system.
The precise mechanisms by which nivolumab exerts its anti-tumor activity is unclear, however, 
particular cell types, such as effector T cells and regulatory T cells are critical for the anti-tumor 
response. 
Therefore, the major hypotheses that will be addressed are: 
•
Does expression of PD-L1 on tumor cells prior to therapy correlate with clinical efficacy to 
monotherapy or study therapy?
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•
Does the mutational status of tumor cells or tumor infectivity (ie EBV status) correlate with 
clinical efficacy to monotherapy?
•
Can we define distinct pharmacodynamic markers of monotherapy in the peripheral 
compartment?
•
How does nivolumab alter the activating and negative costimulatory molecules on immune 
cells in the periphery and at the tumor site? Are their distinct mechanisms of resistance to 
nivolumab or study therapy?
•
Is the intratumoral or peripheral T cell repertoire predictive of response to nivolumab?
•
Does the composition and phenotype of the tumor microenvironment, at baseline, or 
on-treatment, correlate with clinical efficacy?
1.4.6
Rationale for Quality of Life Evaluation
Outcomes research data including health-related quality of life and patient reported symptom 
burden provide a more complete understanding of the impact of treatment by incorporating the 
patients’ perspective. These data offer insights into the patient experience that may not be 
captured through physician reporting. Generic health-related quality of life scales provide data 
necessary in calculating utility values for health economic models. The EQ-5D will be collected 
in order to assess the impact of nivolumab on generic health-related quality of life and the data 
will be used for populating health economic models most notably, cost effectiveness analysis. 
The EORTC QLQ-C30 will be collected in cohort A, B and C subjects in order to assess cancer 
specific health-related quality of life. The combination of the generic scale for general health 
status and economic evaluation and the cancer specific scale will provide a robust outcomes 
research package.
1.5
Overall Risk/Benefit Assessment
Patients with cHL who failed ASCT represent an area of substantial unmet medical need. The 
clinical activity of nivolumab (ORR: 87%, 20 out of 23 subjects) observed to date in heavily 
pretreated subjects with cHL suggests the potential for improved clinical outcomes for this 
patient population. Meanwhile, nivolumab also has the potential for clinically relevant unique 
AEs potentially caused by an inflammatory mechanism. These include pulmonary toxicity, 
hepatotoxicity, diarrhea/colitis, endocrinopathies, and nephrotoxicity. To date, these unique AEs 
have been manageable with frequent monitoring, prompt diagnosis, and initiation of 
corticosteroids, dose interruption, and adequate supportive care. Together the data suggest a 
positive benefit-risk potential, supporting a Phase 2 study to further assess the safety and efficacy 
of nivolumab in subjects with cHL in advanced stage.
Approximately 70% of patients with cHL with advanced-stage disease can expect long-term 
disease control. Nevertheless, the remaining 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. Compared to the high probability (> 90%) of long-term disease control for limited-stage 
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cHL, there remains substantial room for improvement in disease outcome for advanced-stage 
patients. Furthermore, where possible, these relatively young patients should avoid intensified 
chemotherapy (such as a preparative regimen for ASCT) because of concerns regarding 
long-term chemotherapy-related toxicities. Therefore, it is critical to improve long-term disease 
control by an improved first line therapy. A nivolumab-based first line regimen may have the 
potential to substantially improve long-term clinical outcomes due to its capacity to effectively 
and safely reduce tumor burden and induce durable response, as well as its favorable safety 
profile. Thus, it is reasonable to evaluate a new nivolumab-based regimen together with standard 
of care chemotherapy in newly diagnosed, previously untreated cHL with advanced stage as a 
pilot study. 
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the IB or product labeling 
information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
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must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
3.1.1
Study Design and Duration for Cohorts A, B, and C
This is a non-comparative, multi-cohort, single-arm Phase 2 study in cHL subjects ≥18 years old 
who failed ASCT. Subjects may be brentuximab vedotin-naïve (Cohort A), or may have had 
prior brentuximab vedotin treatment as a salvage therapy after failure of ASCT (Cohort B). In 
addition to Cohorts A and B, a third cohort (Cohort C) is being added to the study with broader 
eligibility criteria. Subjects with a treatment history of brentuximab vedotin before first ASCT 
will not be eligible, except in Cohort C. 
The original protocol requires nivolumab dosing 3 mg/kg Q2W. Approximately 220 subjects 
with failure after ASCT will be treated with nivolumab 3 mg/kg IV infusion over 60 minutes 
every 2 weeks until disease progression or unacceptable toxicity; Cohorts A and B consist of 
approximately 60 subjects each and Cohort C will treat approximately 100 subjects. 
In revised protocol 04c, subjects will switch to IV infusion over 30 minutes of nivolumab 480 
mg flat dose Q4W or 240 mg flat dose Q2W. For those subjects receiving a 480 mg flat dose 
Q4W, a cycle will be a 28-dosing period. For those subjects receiving a 240 mg flat dose Q2W, a 
cycle will be a 14-day dosing period.
Subjects will be independently enrolled for each cohort. When one cohort completes enrollment, 
the other cohort will remain open until its complete accrual is reached. Primary analysis will be 
performed separately for each cohort (ie, at separate time points) upon completion of a pre-
specified amount of follow-up (Table 8.3.1.1-1) after last patient first treatment (LPFT). All 
analyses will be performed separately for each cohort upon completion of follow-up for the 
primary endpoint in each cohort. In addition, safety analyses will be performed on combined 
cohorts.
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first 
dose. Subjects may be dosed no less than 12 days from the previous dose during every 2-week
cycle. For every 4-week dosing cycle, subjects may be dosed within a ± 3-day window.
The study design schematic is presented in Figure 3.1.1-1.
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Figure 3.1.1-1:
Study Design Schematic for Cohorts A, B, and C
Radiographical tumor assessments by computed tomography (CT) (preferred) or magnetic 
resonance imaging (MRI) will begin at screening, then at Week 9 (± 7 days) after the start of 
therapy and will continue at Weeks 17, 25, 37 and 49 for the first year of treatment. 
CT (preferred) or MRI will continue every 16 weeks (± 14 days) for the second year of 
treatment. CT (preferred) or MRI will be performed every 26 weeks (± 21 days) for the third 
year or beyond of treatment. [18F]-fluorodeoxyglucose positron emission tomography 
(FDG-PET) scan will be required in all subjects at screening and at Weeks 17 and 25 (± 7 days). 
Additionally, a FDG-PET scan at Week 49 (± 7 days) is required for subjects who do not have 
two consecutive negative FDG-PET scans after Week 1 and prior to Week 49. FDG-PET scan 
will also be required for confirmation of radiographic CR after initiation of the study drug at 
other time points when FDG-PET is not otherwise scheduled; this FDG-PET scan should be 
performed within 4 weeks of the CT scan. Tumor assessments will follow the above schedule 
until disease progression is documented or until the subject initiates a preparative regimen for 
allogeneic SCT or ASCT, whichever occurs earlier. If the subject discontinues treatment prior to 
disease progression, tumor assessment will continue in the follow-up phase. In rare cases, disease 
progression is clinically determined by investigators although disease progression does not meet 
2007 IWG criteria. In these cases, tumor assessment will not be required if clinical disease 
progression is documented and if investigators discontinue the study drug. If the subject 
discontinues study therapy by proceeding to allogeneic SCT or ASCT, they will not undergo 
IRRC radiographic assessments described here, but will be followed with a specific schedule 
(see Section 5.4).
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Revised Protocol 04c Update:
Subjects receiving nivolumab every 2 weeks at 3 mg/kg will switch to receive either a flat dose 
of 480 mg Q4W or a flat dose of 240 mg Q2W. Subjects may be dosed no less than 12 days from 
the previous dose during every 2-week cycle. For every 4-week dosing cycle, subjects may be 
dosed within a ± 3-day window.
Subjects must sign an informed consent document prior to switching dosing schedule.
Once a new dosing regimen has been selected for the subject, either flat dose 240 mg Q2W or 
flat dose 480 mg Q4W, the dosing regimen will remain in effect until end of treatment and not 
change.
Screening for Cohorts A, B, and C:
•
Begins by signing the informed consent form (ICF)
•
Subject is enrolled using the Interactive Voice Response System (IVRS) to obtain a subject 
ID
•
Confirm that documentation of cHL after failure of ASCT or after failure of ASCT and 
brentuximab vedotin is present in the subject’s medical record;
•
Submission of tumor tissue (formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or 
10 unstained slides) from a biopsy performed during screening is mandatory. If this is not 
possible, the following exceptions are allowed:
−
Subjects who do not have any accessible lesions which can be safely biopsied, or
−
Subjects who have archival tissue from a previous tumor biopsy that can be used for 
PD-L1 expression analysis. These subjects must submit archival tissue from the most 
recent tumor biopsy if archival tissues are available from tumor biopsies at multiple time
points. While submission of archival tissue from the most recent tumor biopsy is 
mandatory, archival tissue from other tumor biopsy is strongly encouraged. For example, 
subjects who must submit archival tissue from a tumor biopsy at relapse may optionally 
also submit archival tissue for tumor biopsy at initial diagnosis as well.
Note: For these exceptions, the reason must be clearly documented in the medical record 
AND the BMS Medical Monitor must be contacted. Subjects may initiate the study drug 
before the outcome of PD-L1 expression status become available.
−
Biopsy samples should be excisional, incisional or core needle.
•
For Cohorts A and B, confirm that a bone marrow biopsy/aspirate was performed within 
90 days prior to enrolment and is documented in the subject’s medical record;
−
If a bone marrow biopsy/aspirate was not performed within 90 days prior enrolment, a 
bone marrow biopsy/aspirate must be performed during the screening period.
−
If a bone marrow biopsy/aspirate needs to be performed during the screening period, 
submission of an aspirate sample for biomarker analyses is mandatory as per Table 5.1.1-
1
−
Subjects may start the study drug before bone marrow biopsy results become available; 
results of a bone marrow biopsy must be documented in the subject’s medical record 
when becoming available.
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•
Bone marrow biopsy/aspirate is optional for Cohort C. If the procedure is done during 
screening, an aspirate sample can be optionally submitted for biomarker analyses.
•
The Hasenclever-Index for Hodgkin’s disease also known as International Prognostic Score 
(IPS) at initial diagnosis must be reported in the eCRF. (See Appendix 3.)
Baseline assessments should be performed within 28 days of first dose of study drug, according 
to Table 5.1.1-1
•
Subject is assessed for study eligibility within the required timeframe found in Table 5.1.1-1.
•
The screening phase either ends with confirmation of full eligibility and treatment of the 
subject or with the confirmation that the subject is a screen failure.
Treatment for Cohorts A, B, and C:
•
Treatment begins with the call to the IVRS to obtain vial assignments. A negative pregnancy 
test should be documented within 24 hours prior to first dose of investigational product. 
Subsequently, women of childbearing potential (WOCBP) must have a pregnancy test every 
4 weeks (± 7 days) regardless of dosing schedule.
•
The subject should receive the dose of study medication within 1 day of vial assignment.
•
Subjects may be dosed no less than 12 days from the previous dose during every 2-week 
cycle. For every 4-week dosing cycle, subjects may be dosed within a ± 3-day window.
Doses given after the 3-day window are considered dose delays. A maximum delay of 42 
days between doses is allowed.
•
All vital signs starting after Cycle 1 will be collected within 72 hours prior to dosing.
•
Extended on-study local laboratory assessments should be done within 72 hours prior to 
dosing from Cycle 1 through Cycle 5 and every alternate dose thereafter (Cycles 7, 9, 11, 13, 
etc.). Limited on-study local laboratory assessment should be done within 72 hours prior to 
dosing beginning at Cycle 6 and every alternate dose thereafter (Cycles 8, 10, 12, 14, etc.).
•
AE assessments should be documented at each clinic visit.
•
Biomarker, PK and immunogenicity samples will be done according to the schedules in 
Sections 5.5 and 5.6.
•
Subjects should receive nivolumab at a flat dose of either 240 mg Q2W or flat dose of 480 
mg Q4W as an IV infusion over 30 minutes on Day 1 of each treatment cycle until disease 
progression or discontinuation due to toxicity, withdrawal of study consent, or the study 
ends. Study drug dosing may be delayed for toxicity (see Section 4.5.2).
•
On-treatment CT (preferred) or MRI will begin at Week 9 (± 7 days) after the start of therapy 
and then will occur at Weeks 17, 25, 37 and 49 during the first year of treatment, then every 
16 weeks (± 14 days) for the second year of treatment up to Week 97, continuing every 26 
weeks (± 21 days) beyond Week 97 for the third year or beyond treatment, until disease 
progression is documented. On-treatment FDG-PET scan will be required in all subjects at 
Weeks 17 and 25 (± 7 days). The FDG-PET scan performed on Week 49 will be required 
only for those subjects who do not have two consecutive negative FDG-PET scans after 
Week 1 and prior to Week 49.
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•
Screening/Baseline and all subsequent scans will be submitted to an IRRC, once the subject 
has been enrolled and throughout the study period.
•
Quality of Life (QoL) tools must be completed at Treatment Day 1 prior to the first dose of 
study drug. Following that, QoL tools will be completed according to the schedule in Table 
5.1.1-2 and Table 5.1.1-3.
•
The presence or absence of B symptoms will be assessed during treatment.
−
On Cycle 1 Day 1, presence of B symptoms is defined as:
a) Unexplained weight loss of more than 10% during the last 6 months, or
b) Unexplained, persistent, recurrent fever with temperatures above 38 degree Celsius 
during the previous month, or 
c) Recurrent drenching night sweats during the previous month. 
−
For subsequent assessments after Cycle 1 Day 1 (see Table 5.1.1-2), the presence of 
B symptoms is defined as:
a) Unexplained weight loss of more than 10% during the last 6 months from the current 
assessment, or
b) Unexplained, persistent, recurrent fever with temperatures above 38 degree Celsius 
since the last assessment, or 
c) Recurrent drenching night sweats since the last assessment.
•
This phase ends when the subject is discontinued from study therapy. For a complete list of 
reasons for treatment discontinuation, refer to Sections 3.5 and 4.5.5.
Follow-up for Cohorts A, B, and C:
•
Begins when the decision to discontinue a subject from study therapy is made (no further 
treatment with study drug).
•
All treated subjects will have two follow-up visits for safety. Follow-up visit 1 (X01), 
35 days (± 7 days) from the last dose of study therapy and Follow-up visit 2 (X02), 80 days 
(± 7 days) from X01. After X02, subjects will be followed every 3 months for ongoing 
drug-related AEs until resolved, return to baseline or deemed irreversible, or until lost to 
follow-up or withdrawal of study consent.
•
PK and immunogenicity samples will be collected at the first two follow-up visits. 
•
Subjects who discontinue study therapy for reasons other than disease progression or 
allogeneic SCT or ASCT will continue to have radiographic assessments at the intervals 
described in the Treatment Phase until disease progression, lost to follow-up, or withdrawal 
of study consent. In rare cases, disease progression is clinically determined by investigators 
although disease progression does not meet 2007 IWG criteria. In these cases, tumor 
assessment will not be required thereafter if clinical disease progression is documented and if 
investigators discontinue the study drug.
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•
Confirmation of CR by CT (preferred) or MRI is based on investigators’ assessment
•
Investigators must confirm that there are no clinical findings indicating disease progression 
before discontinuation.
•
The last dose of study therapy must be administered within 21 days of the date first on-study 
CR was observed plus one year.
After discontinuation, subjects will enter the FU/Observational phase as described in
Figure 3.1.1-4.
Figure 3.1.1-4:
FU/Observational Phase of Cohort C Subjects Who Have Reached 
One Year CR
•
CT (preferred) or MRI will be required at the time of the first observation follow-up visit: 
6 months (± 14 days) from last dose. 
•
CT (preferred) or MRI will be conducted when clinically indicated. 
•
FU/Observational visits occur every 3 months (± 14 days) in the first year from the last dose 
of study drug: 01 (6 months), 02 (9 months), and 03 (12 months). 
•
Thereafter, FU/Observational visits occur every 4 months (± 21 days) in the second year 
from the last dose of study drug: 04 (16 months), 05 (20 months), and 06 (24 months).
•
Targeted physical examination and laboratory tests will be conducted during those 
FU/Observational visits (01 - 06), see Table 5.1.1-4.
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•
Subjects will also be followed every 3 months for ongoing drug-related AEs until resolved, 
return to baseline or deemed irreversible, or until lost to follow-up or withdrawal of study 
consent.
•
PK and immunogenicity samples will not be collected after X02
•
QoL tools (EQ-5D and EORTC QLQ-C30) will be completed at X01, X02 and during 
FU/Observational visits, then EQ-5D only during survival follow-up.
•
For subjects who proceed to allogeneic SCT or ASCT during FU/Observational phase, tumor 
assessment by the investigator will be required after allogeneic SCT or ASCT as described in
Section 5.4. 
•
For the subjects who proceed to allogeneic SCT, acute and chronic GVHD documentation 
will also be simultaneously collected as described in Section 5.3.
•
FU/Observational phase will end after two years from the last dose of study therapy.
•
If, despite absence of relapse, subjects do not continue in the FU/Observational phase before 
reaching 2 years from the last dose, the reason for the discontinuation from this phase must 
be documented in the subject’s medical records and entered on the appropriate CRF page. If 
the subject did not withdraw consent, subject will continue to be followed for survival.
•
After completion of FU/Observational visits, subjects will be followed every 3 months for 
survival, until death, lost to follow-up or withdrawal of study consent. 
Re-initiation of Treatment (Cohort C Only):
•
Re- initiation of study treatment is allowed when subjects who discontinued study therapy 
due to persistent one year CR have relapsed within two years from last dose. Re-initiation of 
treatment will not be permitted after completion of the FU/observational visits.
•
Treatment must be re-initiated within 28 days after documented relapse which meets 2007 
IWG criteria
•
The same procedures described in the on-treatment phase will performed for the subjects 
who re- initiate study treatment except for the following:
−
QoL tools (EQ-5D and EORTC QLQ-C30) will not be competed after Re-initiation of 
Treatment. 
•
Subjects who achieved second on-study CR after re-initiation of treatment do not have to 
discontinue the study drug when second on-study CR persists for 1 year.
3.1.2
Study Design and Duration Cohort D
Cohort D is a non-comparative single-arm cohort in subjects ≥18 years old who are newly 
diagnosed, previously untreated cHL with advanced stage (Stage IIB, III and IV) 
Treatment for Cohort D consists of two phases: monotherapy and combination phases. Subjects 
will be treated with four doses of nivolumab flat dose 240 mg IV every 2 weeks (monotherapy 
phase), followed by twelve doses of the combination of AVD chemotherapy and nivolumab flat 
dose 240 mg IV for 6 cycles (combination phase). The primary analysis for Cohort D will be 
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(Section 4.5.5), or subjects who meet dose delay criteria (Section 4.5.2) and the dose delay is > 4 
weeks from previous dose are allowed to discontinue monotherapy phase and enter combination 
phase when the criteria are met as described in Table 3.1.2-1.
The combination phase (approximately 22 weeks) begins from the first dose of the combination 
therapy. The first dose of combination therapy should be dosed no less than 12 days and no more 
than 17 days after the last dose of nivolumab monotherapy. The combination therapy is 
administration of nivolumab (flat dose 240 mg) and AVD (Adriamycin/ doxorubicin 25 mg/m2, 
vinblastine 6 mg/m2, dacarbazine 375 mg/m2) on the same day. Use of AVD only (without 
nivolumab) is permitted as an alternative regimen only when the conditions are met as described 
in Table 3.1.2-1. Each 28-day dosing period will constitute a Combocycle: two doses of the 
combination therapy per cycle, except for Combocycle 6, which will only be a 15-day cycle. 
The combination therapy is administered every 2 weeks for 12 doses (two doses, Dose 1 on 
Day 1 and Dose 2 on Day 15, of each Combocycle x 6 cycles). The combination phase will end 
at Dose 2 (Day 15) of Combocycle 6. Thereafter, subjects will enter the Follow-up 
(FU)/Observational phase. Subjects who discontinue combination treatment before completing 
Combocycle 6 Dose 2 (Day 15) and who have not started subsequent anti-lymphoma therapy 
will also enter the FU/Observational phase.
Table 3.1.2-1:
Selection of Combination Therapy for Cohort D
During Monotherapy Phase
Regimen to be Used During Combination Phase
Subjects who have completed all 4 doses of nivolumab 
monotherapy (4 monotherapy doses)a,b
The combination of nivolumab and AVD
Subjects who have discontinued monotherapy before 
completing four doses of nivolumab because Nivolumab 
Discontinuation criteria (Section 4.5.5) are met
AVD
Subjects who have discontinued monotherapy before 
completing four doses of nivolumab because Nivolumab 
Delay Criteria (Section 4.5.2.1) are met, and the dose delay 
was > 4 weeks from a previous dose
AVD
Subjects who discontinued nivolumab monotherapy due to
disease progression meeting 2007 IWG criteria based on 
investigators’ assessment (but have not met safety criteria 
for discontinuation)
The combination of nivolumab and AVD or AVD 
alone
a If a subject subsequently meets Criteria to Resume Nivolumab Dosing (Section 4.5.4), the combination of 
nivolumab and AVD can be used
b Subjects who underwent treatment beyond progression during the Monotherapy phase can use the combination of 
nivolumab and AVD if all 4 doses of nivolumab monotherapy are completed
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For Cohort D, radiographical tumor assessments by CT (preferred) or MRI, and FDG-PET scans 
will be required at screening. Mandatory radiographical tumor assessments during the treatment 
are as follows:
•
Post-Monotherapy dose 4 assessments: FDG-PET scan and CT (preferred) or MRI after 
Monotherapy dose 4 and before entering the Combination phase. 
•
Post-Combocycle 2 assessments: FDG-PET scan* and CT (preferred) or MRI after 
Combocycle 2 and before Combocycle 3.
*Interim FDG-PET scans are optional if a previous scheduled or unscheduled FDG-PET scan 
after the first dose of nivolumab monotherapy was negative based on investigator’s 
assessment.
The end-of-therapy radiographic tumor assessments should be done at 9 weeks (± 14 days) 
from the last treatment). End-of-therapy FDG-PET, and CT (preferred) or MRI scans are 
mandatory in all subjects. When end-of-therapy FDG-PET scans are positive based on 
investigator’s assessment, tumor biopsy for FDG-avid lesion is strongly encouraged whenever 
possible. Bone marrow assessment is not required for CR determination as FDG-PET can be 
used in lieu of bone marrow aspirate/ biopsy.
After the end-of-therapy radiographic tumor assessments, no FDG-PET scan is required unless 
clinically indicated. CT (preferred) or MRI scans should be conducted at 39 weeks (± 21 days), 
65 weeks (± 21 days), and 104 weeks (± 21 days) from the last dose for the subjects who enter 
the FU/Observational phase. Thereafter, no radiographic tumor assessment is required.
Treatment beyond investigator-assessed progression is permitted in the circumstances specified 
in Section 4.5.7
Study Duration for Cohort D
Analysis of the primary endpoints will take place after the last patient for Cohort D completes 
Follow-up visit 1 and the end-of-therapy response assessment. Additional survival analysis will 
be conducted for up to five years from the last dose of study treatment.
For most subjects, this study will consist of four phases: screening, monotherapy phase, 
combination phase, and FU/Observational phase (max. 2 years). After two years in the 
FU/Observational phase, if no relapse is observed, those Cohort D subjects will enter the survival 
follow-up phase for up to five years from the last dose of study treatment.
Screening for Cohort D
•
Begins by signing the ICF
•
Subject is enrolled using the IVRS to obtain a subject ID
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•
Confirm that documentation of cHL newly diagnosed, previously untreated, advanced stage 
(Stage IIB, III and IV) by Cotswold modified Ann Arbor staging88 is present in the subject’s 
medical record; documentation of cHL histology by a local pathological laboratory is 
sufficient for subject to start the first dose. Histology of cHL will be confirmed later by a 
central pathological laboratory.
•
Submission of tumor tissue (FFPE tumor tissue block or at minimum 15 unstained slides, 
preferably 20) from a biopsy performed during screening is mandatory. Alternatively, 
submission of tumor tissue from a biopsy performed within 90 days prior to enrollment is 
allowed. A central laboratory will confirm the pathology, but subjects can proceed to the 
study drug with documentation of cHL by a local pathology laboratory.
•
Bone marrow biopsy/aspirate is not required for Cohort D. An aspirate sample does not need 
to be submitted if conducted as a standard of care.
•
The Hasenclever-Index for Hodgkin’s disease also known as International Prognostic Score 
(IPS) must be reported in the source documents and collected in the eCRF. (See Appendix 3)
•
Evaluation for pulmonary and cardiac functions will be required.
Baseline assessments should be performed within 28 days of first dose of study drug, according 
to Table 5.1.2-1. 
•
Subject is assessed for study eligibility within the required timeframe found in Table 5.1.2-1
•
The screening phase either ends with confirmation of full eligibility and treatment of the 
subject or with the confirmation that the subject is a screen failure.
Treatment During the Monotherapy Phase for Cohort D
•
Treatment begins with the call to the IVRS to obtain vial assignments. A negative pregnancy 
test should be documented within 24 hours prior to first dose of investigational product. 
Subsequently, women of childbearing potential (WOCBP) must have a pregnancy test every 
4 weeks (± 7 days) regardless of dosing schedule.
•
The subject should receive the dose of study medication within 1 day of vial assignment.
•
Subjects may be dosed no less than 12 days between doses and no more than 3 days after the 
scheduled dosing date. Dose given after the 3-day window is considered a dose delay. 
A maximum delay of 6 weeks between doses is allowed, except as specified in Section 4.5.5. 
When the dose delay is > 4 weeks from a previous nivolumab dose for subjects in the 
monotherapy phase, discontinuing the monotherapy phase and entering the combination 
phase is allowed after consultation with the medical monitor.
•
All vital signs starting after Monotherapy dose 1 will be collected within 72 hours prior to 
dosing.
•
Extended on-study local laboratory assessments should be done within 72 hours prior to 
monotherapy dose 1 through monotherapy dose 4. Extended on-study local laboratory 
assessment is also required on day 8 of after monotherapy dose 1.
•
AE assessments should be documented at each clinic visit.
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•
Biomarker, PK and immunogenicity samples will be done according to the schedules in
Sections 5.5 and 5.6.
•
Nivolumab monotherapy (flat dose 240 mg) is administered as an IV infusion over 30
minutes on Treatment Day 1 of each Monotherapy dose. The planned total dose is four doses 
of nivolumab flat dose 240 mg every two weeks. The monotherapy will continue until 
completing four doses, or until disease progression, discontinuation due to toxicity, with 
withdrawal of study consent, or the study ends. Nivolumab dosing may be delayed for 
toxicity (Section 4.5.2). When the dose delay is > 4 weeks from a previous nivolumab dose, 
discontinuing the monotherapy phase and entering the combination phase is allowed after
consultation with the medical monitor.
•
When subjects meet nivolumab Treatment Discontinuation Criteria (Section 4.5.5), subjects 
must terminate the monotherapy phase, and may enter the combination phase.
•
When subjects meet nivolumab Dose Delay Criteria (Section 4.5.2) for more than 4 weeks 
from a previous dose, subjects may opt to terminate the monotherapy phase, and enter the 
combination phase.
•
Post-Monotherapy Dose 4: FDG-PET scan and CT (preferred) or MRI scans will also be 
required after Monotherapy Dose 4 and before entering Combination phase. 
•
Screening/Baseline and all subsequent scans will be submitted to an IRRC, once the subject 
has been enrolled and while on study.
•
QoL tools must be completed at Treatment Day 1 prior to the first dose of nivolumab. 
Following that, QoL tools will be completed according to the schedule in Table 5.1.2-2 and 
Table 5.1.2-3
•
The presence or absence of B symptoms will be assessed during treatment.
−
On the day of Monotherapy dose 1, presence of B symptoms is defined as:
a) Unexplained weight loss of more than 10% during the last 6 months, or 
b) Unexplained, persistent, recurrent fever with temperatures above 38 degree Celsius 
during the previous month, or 
c) Recurrent drenching night sweats during the previous month. 
•
For subsequent assessments after Monotherapy dose 1 (Table 5.1.2-2 and Table 5.1.2-3), the 
presence of B symptoms is defined as:
a) Unexplained weight loss of more than 10% during the last 6 months from the current 
assessment, or
b) Unexplained, persistent, recurrent fever with temperatures above 38 degree Celsius 
since the last assessment, or 
c) Recurrent drenching night sweats since the last assessment.
•
The monotherapy phase ends when the subject starts combination therapy.
•
Subjects who were treated with at least one dose of nivolumab, and who discontinue 
nivolumab monotherapy by meeting discontinuation criteria (Section 4.5.5) and choose not to 
enter the combination phase will require two follow-up visits for safety: Follow-up visit 1, 
35 days (± 7 days) from the last dose of nivolumab and Follow-up visit 2, 80 days (± 7 days) 
from Follow-up visit1. These subjects will enter survival follow-up (every 6 months) after 
Follow-up visit 2. FU/Observational visits starting at visit 03 (26 weeks) will not be required 
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for these subjects. The end-of-therapy radiographic tumor assessments will not be required 
for these subjects.
Selection of Combination Therapy during Combination phase (See Table 3.1.2-1):
•
Subjects who have completed all four doses of nivolumab monotherapy must use 
Nivolumab-AVD as a combination regimen. 
−
After entering Combination phase, the combination regimen can be changed to AVD if 
subjects meet Nivolumab Delay Criteria 
(Section 4.5.2.1) or Nivolumab 
Discontinuation Criteria (Section 4.5.5).
•
Subjects who have discontinued monotherapy before completing four doses of nivolumab 
due to Nivolumab Discontinuation criteria (Section 4.5.5) must use AVD as a combination 
regimen for all six Combocycles. 
•
Subjects who have discontinued monotherapy before completing four doses of nivolumab 
due to Nivolumab Delay Criteria (Section 4.5.5), and due to the dose delay > 4 weeks from 
a previous dose must use AVD as a combination regimen until subjects meet Criteria to 
Resume Nivolumab Dosing (Section 4.5.4). 
−
If subjects meet Criteria to Resume Nivolumab Dosing (Section 4.5.4) before or at the
first dose of the combination therapy, Nivolumab-AVD should be used. AVD may be 
optionally used based on investigator’s judgment.
−
Nivolumab-AVD can be used later once subjects meet Criteria to Resume Nivolumab 
Dosing (Section 4.5.4). Based on investigator s’ judgment, continuing AVD through 
the end of Combocycle 6 is also acceptable.
Treatment During Combination Phase for Cohort D:
•
The subject should receive the dose of study medication within 1 day of vial assignment.
•
All vital signs starting after Combocycle 1 will be collected within 72 hours prior to dosing. 
•
Combination phase (approximately 22 weeks) begins from the first dose of the combination 
therapy (Dose 1 of Combocycle). 
•
Dose 1 of Combocycle 1 will be administered with AVD (Adriamycin/doxorubicin 
25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) with or without nivolumab (flat 
dose 240 mg) on Day 1 of Combocycle 1. AVD only (without nivolumab) is permitted as an 
alternative regimen only when the conditions are met as described above and in Table 3.1.2-
1.
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Table 3.1.2-2:
Combocycle 1 - 6
Drug
Dose
Each Combocycle
Dose 1 (Day 1)
Dose 2 (Day 15)
Nivolumab
Flat dose 240 mg
X
X
Doxorubicin (Adriamycin)
25 mg/m2
X
X
Vinblastine
6 mg/m2
X
X
Dacarbazine
375 mg/m2
X
X
Note 1: Nivolumab should be administered first before AVD administrations when Nivolumab-AVD is the 
combination therapy
Note 2: AVD without nivolumab is permitted as an alternative regimen only when the conditions are met as 
described above and in Table 3.1.2-1. 
•
The combination therapy (nivolumab-AVD or AVD only) should be administered as Dose 1 
on Day1 and as Dose 2 on Day 15 of each Combocycle. Each 28-day dosing period will 
constitute a Combocycle: two doses of the combination therapy per cycle, except for 
Combocycle 6, which will only be a 15-day cycle. Combination phase will end at Dose 2 
(Day 15) of Combocycle 6. Thereafter, subjects will enter the FU/Observational phase. 
Subjects who discontinue combination treatment before completing Combocycle 6 Dose 2 
(Day 15) will also enter the FU/Observational phase. For subjects who started subsequent 
anti-lymphoma therapy (systemic chemotherapy and/or radiotherapy), FU/Observational 
visits and the end-of-therapy radiographic tumor assessments will no longer be necessary. 
These subjects will enter survival follow-up (every 6 months) once subsequent anti-
lymphoma therapy begin.
•
The combination therapy should be administered every 2 weeks for 12 doses (two doses per 
Combocycle). If this is not feasible, subjects may be dosed no less than 12 days between 
doses and no more than 3 days after the scheduled dosing date. A dose given after the 3 day 
window is considered a dose delay. Dosing delay or dose reduction (except for nivolumab) is 
allowed for toxicity. See Sections 4.5.2 and 4.5.3.
•
Nivolumab should be administered first before AVD administration when Nivolumab-AVD 
is the combination therapy. 
•
Administration method and sequence of each component of AVD (doxorubicin, vinblastine, 
and dacarbazine) will be according to local and institutional standards. Dosing calculations 
should be based on the body surface area (BSA) and calculated using the body weight of first 
dose of the combination phase. However, if the subject’s weight later changes by > 10% 
from the previous weight used to calculate BSA, then BSA should be recalculated and AVD 
dose corrected accordingly. All doses should be rounded to the nearest milligram. 
•
Extended on-study local laboratory assessments should be done within 72 hours prior to 
dosing at each Dose 1 (Day1) of Combocycle 1-6, and Dose 2 (Day 15) of Combocycle 1
•
Limited on-study local laboratory assessment should be done within 72 hours prior to dosing 
at each Dose 2 (Day15) of Combocycle 2 through Combocycle 6. 
•
AE assessments should be documented at each clinic visit.
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•
Biomarker, PK and immunogenicity samples will be done according to the schedules in
Sections 5.5 and 5.6.
•
Post-Combocycle 2 FDG-PET and CT (preferred) or MRI scans should be performed after 
Combocycle 2 and before Combocycle 3. This interim FDG-PET scan is optional if a 
previous scheduled or unscheduled FDG-PET scan after the first dose of nivolumab 
monotherapy was negative based on investigator’s assessment.
•
The end-of-therapy radiographic assessments should be done at 9 weeks (± 14 days) from the 
last treatment). End-of-therapy FDG-PET, and CT (preferred) or MRI scans are mandatory 
for all subjects. When end-of-therapy FDG-PET scan are positive based on investigator’s 
assessment, tumor biopsy for FDG-avid lesion is strongly encouraged whenever possible.
•
QoL tools will be completed according to the schedule in Table 5.1.2-2 and Table 5.1.2-3.
•
The presence or absence of B symptoms will be assessed during treatment in the same way as 
described for monotherapy phase.
•
The combination phase ends when the subject completes Dose 2 (Day 15) of Combocycle 6, 
or when the subject is discontinued from study therapy. Thereafter, subjects will enter the 
FU/Observational phase. 
•
Subjects with documented evidence of disease progression meeting 2007 IWG criteria during 
the Combination phase are not eligible for any further treatment on the study. 
•
Subjects who discontinued combination therapy (Nivolumab-AVD or AVD) before 
completing a total of 12 doses with combination therapy will require two follow-up visits for 
safety: Follow-up visit 1, 35 days (± 7 days) from the last dose of study therapy and 
Follow-up visit 2, 80 days (± 7 days) from Follow-up visit1. The end-of-therapy radiographic 
tumor assessments and FU/Observational visits starting at visit 3 (26 weeks) will be required 
for these subjects. However, once subjects start subsequent anti-lymphoma therapy (systemic 
chemotherapy and/or radiotherapy), FU/Observational visits and the end-of-therapy 
radiographic tumor assessments will be no longer necessary. These subjects will enter 
survival follow-up (every 6 months) once subsequent anti-lymphoma therapy begins. Safety 
Follow-up visit1 and Safety Follow-up visit 2 are required for all subjects.
•
For a complete list of reasons for treatment discontinuation, refer to Sections 3.5 and 4.5.5.
Follow-up (FU)/Observational Phase
•
Begins when the subject completes Dose 2 (Day 15) of Combocycle 6, or when the decision 
to discontinue a subject from study therapy is made (no further treatment with study drug).
•
After discontinuation, subjects will enter the FU/Observational phase as described in Figure 
3.1.2-2.
•
All treated subjects will have two follow-up visits for safety. Safety Follow-up visit 1, 
35 days (± 7 days) from the last dose of study therapy, and Safety Follow-up visit 2, 80 days 
(± 7 days) from Safety Follow-up visit1. 
•
A pulmonary function test is required for the subjects who have completed Dose 2 (Day 15) 
of Combocycle 6 during Follow-up visit 1. The test can be conducted 35 days (± 14 days) 
from the last dose of study therapy.
•
PK and immunogenicity samples will be collected at the first two safety follow-up visits.
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•
The end-of-therapy radiographic tumor assessments will be conducted at 9 weeks 
(± 14 days) from the last dose, which is between Safety Follow-up visit 1 and Safety 
Follow-up visit 2. FDG-PET and CT (preferred) or MRI scans are mandatory for all subjects 
unless previous evidence of disease progression meeting 2007 IWG criteria is documented. 
When end-of-therapy FDG-PET scan are positive based on investigator’s assessment, tumor 
biopsy for FDG-avid lesion is strongly encouraged whenever possible. Submission of tumor 
biopsy specimen for biomarker analysis is encouraged.
•
After Safety Follow-up visit 2, subjects will be followed every 3 months for ongoing drug-
related AEs until resolved, return to baseline or deemed irreversible, or until lost to follow-up 
or withdrawal of study consent.
•
QoL tools (EQ-5D) will be completed at Safety Follow-up visit 1 and Safety Follow-up visit 
2, during FU/Observational visits, and during survival follow-up according to the schedule in
Table 5.1.2-4
•
PK and immunogenicity samples will not be collected after Follow-up visit 2
•
FU/Observational visits occur every 3 months (± 21 days) in the first two years from the last 
dose of study treatment: 03 (26 weeks), 04 (39 weeks), 05 (52 weeks), 06 (65 weeks), 07 
(78 weeks), 08 (91weeks), and 09 (104 weeks).
•
The radiographic tumor assessments, are required at visit 04 (39 weeks), 06 (65 weeks), and 
09 (104 weeks). Only CT (preferred) or MRI is required. Thereafter, no radiographic tumor 
assessment is required. FDG-PET and CT (preferred) or MRI can be conducted when 
clinically indicated. All scans for radiographic tumor assessments will be collected and be 
evaluated by IRRC.
•
Targeted physical examination will be conducted during the safety follow-up visits 1 &2 and 
during FU/Observational visits (03 - 11), see Table 5.1.2-4. Laboratory tests will be 
performed during safety follow-up visits 1 &2.
•
Subjects who have disease progression or relapse during the FU/Observational phase may 
end the FU/Observational phase, and enter survival follow-up (every 6 months) once subjects 
start subsequent anti-lymphoma therapy (systemic chemotherapy and/or radiotherapy). 
Safety Follow-up visit 1 and Safety Follow-up visit 2 will still be required if these were not 
completed yet.
•
For subjects who have disease progression and undergo other anti-lymphoma treatment, 
information on these anti-lymphoma therapies will be collected as much as possible along 
with survival status. Investigators will make telephone contacts with the subject’s current 
physician to obtain disease status and document the status if subject is being followed by 
another physician.
•
If, despite absence of relapse, subjects do not continue in the FU/Observational phase before 
reaching three years from the last dose, the reason for the discontinuation from this phase 
must be documented in the subject’s medical records and entered on the appropriate CRF 
page. If the subject did not withdraw consent, subject will continue to be followed for 
survival.
•
After completion of FU/Observational visits, subjects will be followed every 6 months for 
survival for up to 5 years from the last study treatment, until death, lost to follow-up, or 
withdrawal of study consent. 
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Figure 3.1.2-2:
Treatment and Follow-up Phase for Cohort D
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3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug for the subjects in Cohorts A, B, and C. Study drug 
will be provided via an extension of the study, a rollover study requiring approval by responsible 
health authority and ethics committee or through another mechanism at the discretion of BMS. 
BMS reserves the right to terminate access to BMS supplied study drug if any of the following 
occur: a) the marketing application is rejected by responsible health authority; b) the study is 
terminated due to safety concerns; c) the subject can obtain medication from a government 
sponsored or private health program; or d) therapeutic alternatives become available in the local 
market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol-related procedures that are not part of normal 
subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study.
2. Target Population
a) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1, see 
Appendix 4.
b) For Cohorts A, B, and C, subjects must have received prior high-dose conditioning 
chemotherapy followed by ASCT as a part of salvage therapy for cHL:
i)
Cohort A: Subjects who are naïve to brentuximab vedotin- treatment and who meet 
one of the following criteria according to the 2007 IWG criteria:
(1) Documented absence of CR after 90 days from stem cell infusion for the most 
recent ASCT; or, 
(2) Documented relapsed disease (after CR) or disease progression (after PR or SD) 
ii) Cohort B: Subjects who failed treatment with brentuximab vedotin which was 
administered following failure of ASCT, and who meet one of the following criteria 
according to the 2007 IWG criteria:
(1) Documented failure to achieve at least PR after the most recent treatment; or, 
(2) Documented relapse disease (after CR) or disease progression (after PR or SD)
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iii) Cohort C: Subjects who failed ASCT and who have received prior treatment* with 
brentuximab vedotin at any time point, and who meet one of the following criteria 
according to the 2007 IWG criteria:
(1) Documented absence of CR after 90 days from stem cell infusion for the most 
recent ASCT; or,
(2) Documented failure to achieve at least PR after the most recent chemotherapy or 
radiation therapy; or,
(3) Documented relapse disease (after CR) or disease progression (after PR or SD)
*This includes brentuximab vedotin treatment as an initial therapy or salvage therapy 
before ASCT, and/or brentuximab vedotin treatment after ASCT (eg, salvage and 
maintenance therapy after ASCT)
c) Must have at least one lesion that is > 15 mm (1.5 cm) in the longest diameter on cross-
sectional imaging and measureable in two perpendicular dimensions on CT (or MRI) and 
FDG avid by PET.
d) Biopsy confirmation of cHL prior to the initiation of study drug. cHL should be 
pathologically confirmed by standard immunohistochemical or flow cytometric 
techniques.
e) Subject re-enrollment: This study permits the re-enrollment of a subject who has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-consented.
f)
For Cohort D, subjects must have newly diagnosed, previously untreated cHL lymphoma 
(except for corticosteroid use) 
g) For Cohort D, subjects must be Stage IIB, III and IV by Cotswold modified Ann Arbor 
staging88
i)
If Stage IIB, subjects must have B symptoms and either bulky disease or extranodal 
disease:
(1) bulky disease, defined as one or more of the following:
(a) a node or nodal mass >10 cm)
(b) a mediastinal mass with the maximum width is ≥1/3 of the internal transverse 
diameter of the thorax at the level of T5/6 
(2) extranodal disease
3. Age and Reproductive Status 
a) Males and Females, ≥18 years of age.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding.
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception from the time of enrollment for the duration of treatment with 
nivolumab plus 5 half-lives of study drug plus 30 days (duration of ovulatory cycle) for a 
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total of 5 months post treatment completion. Only for Cohort D, after a total of 23 weeks 
elapses from the last dose of nivolumab, WOCBP subjects must agree to follow 
instructions for method(s) of contraception for the duration of treatment with AVD plus 
5 half-lives of AVD plus 30 days (duration of ovulatory cycle) for a total of 6 weeks from 
the last dose of AVD when AVD only is used as combination therapy. Doxorubicin, 
vinblastine, and dacarbazine are teratogenic.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives 
of study drug plus 90 days (duration of sperm turnover) for a total of 7 months 
post-treatment completion. Only for Cohort D, after a total of 31 weeks elapses from the 
last dose of nivolumab, men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment with AVD plus 
5 half-lives of AVD plus 90 days (duration of ovulatory cycle) for a total of 15 weeks 
from the last dose of AVD when AVD only is used as combination therapy. Doxorubicin, 
vinblastine, and dacarbazine are teratogenic. In addition, male subjects must be willing to 
refrain from sperm donation during this time.
f)
Azospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. One of the highly effective methods of 
contraception listed below is required during study duration and until the end of relevant 
systemic exposure, defined as 5 months after the end of study treatment. Local laws and 
regulations may require use of alternative and/or additional contraception methods.
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
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 
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants, transdermal, 
and intrauterine hormone-releasing system (IUS)c
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•
Intrauterine devices (IUDs)c
•
Bilateral tubal ligation 
•
Vasectomized partner
−
NOTE: 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
−
NOTE: 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.
−
WOCBP subjects who choose complete abstinence must continue to have 
pregnancy tests as specified per protocol.
−
Acceptable alternate methods of highly effective contraception must be discussed 
in the event that the subject 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.
UNACCEPTABLE METHODS OF CONTRACEPTION
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal sponge with spermicide
•
Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously.
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus)
•
Spermicide only
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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 study treatment.
•
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 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 study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
4. Physical and Laboratory Test Finding
a) Screening laboratory values must meet the following criteria and should be obtained 
within 14 days prior to first dose:
i)
Absolute neutrophil Count ≥750/μL (no WBC growth factors for prior 14 days).
ii) Platelets ≥50 x103/μL (no platelet transfusions for prior 14 days).
iii) Hemoglobin ≥8.5 g/dL (no RBC transfusions for prior 7 days).
iv) Serum creatinine ≤1.5 x Upper limit of normal (ULN) or creatinine clearance (CrCl) 
≥40 mL/min (measured using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
v) AST/ALT ≤3 x ULN.
vi) Total bilirubin ≤1.5 x ULN (except subjects with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL).
b) For Cohorts A, B, and C, subjects with a prior history of chemotherapy-induced or 
radiation-induced pulmonary toxicity require confirmation of diffusing capacity of the 
lung for carbon monoxide (DLCO) over 60% (adjusted for hemoglobin) by a pulmonary 
function test prior to study enrollment.
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c) For Cohort D, subjects require confirmation of diffusing capacity of the lung for carbon 
monoxide (DLCO) over 60% (adjusted for hemoglobin) by a pulmonary function test 
during screening.
d) For Cohort D, subjects require left ventricular ejection fraction over 50% at rest by 
echocardiography or over 55% by isotopic measurement during screening.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Known central nervous system lymphoma.
b) Subjects with nodular lymphocyte-predominant HL.
2. Medical History and Concurrent Diseases
a) Subjects with active interstitial pneumonitis.
b) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
c) Prior malignancy active within the previous 3 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial 
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
d) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll.
e) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease. Only for Cohort D, prior treatment with corticosteroids for cHL are 
acceptable.
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection.
b) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody with the 
following exception: subjects who experienced Grade 3 or 4 infusion-related reaction 
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with the first dose of rituximab, but who were able to receive subsequent rituximab 
without recurrence of Grade 3 or 4 infusion-related reaction are eligible.
5. Prohibited Treatments and/or Therapies
a) Prior treatment history with brentuximab vedotin administered before first ASCT, for 
Cohorts A and B.
b) ASCT ≤90 days prior to first dose of study drug.
c) Prior chemotherapy within 4 weeks, nitrosureas within 6 weeks, therapeutic anticancer 
antibodies within 4 weeks, radio- or toxin immunoconjugates (excluding brentuximab 
vedotin) within 10 weeks and brentuximab vedotin within 4 weeks or major surgery 
within 2 weeks prior to first dose of study drug.
d) Carmustine BCNU) ≥600 mg/m² received as part of the pre-transplant conditioning 
regimen.
e) Prior radiation therapy within 3 weeks, or chest radiation ≤24 weeks prior to first dose of 
the study drug.
f)
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).
g) Prior allogeneic SCT.
h) For Cohort D, prior treatment for cHL (prior use of corticosteroid is acceptable).
i)
For Cohort D, planned post-treatment consolidative radiotherapy.
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is 
required)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, women under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.*
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*Women treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal:
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:
•
Immunosuppressive agents (except to treat a drug-related AE).
•
Systemic corticosteroids > 10 mg daily prednisone equivalent (except as stated in 
Section 3.3.2 or to treat a drug-related AE), except for Cohort D. 
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose.
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy, or standard or investigational agents for 
treatment of cancer), except for Cohort D. Protocol defined chemotherapy (doxorubicin, 
vinblastine, and dacarbazine) is permitted in Cohort D.
Supportive care for disease-related symptoms may be offered to all subjects on the trial.
3.4.2
Other Restrictions and Precautions
3.4.2.1
Permitted Therapy
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
Concomitant medications are recorded at baseline and throughout the treatment phase of the 
study in the appropriate section of the case report form (CRF). All medications (prescriptions or 
over the counter medications) continued at the start of the study or started during the study and 
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different from the study drug must be documented in the concomitant therapy section of the 
CRF.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Disease progression as determined by investigator assessment following the guidelines given 
in Section 5.4.6 with the exception described in Section 4.5.7.
•
Subject’s request to stop study treatment
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Additional protocol-specific reasons for discontinuation (See Section 4.5.5).
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 subject becomes pregnant 
during a clinical trial, the study drug must be discontinued immediately. In most cases, the study 
drug will be permanently discontinued in an appropriate manner (eg, dose tapering if necessary 
for subject safety). Please call the BMS Medical Monitor within 24 hours of awareness of the 
pregnancy. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Follow up
For Cohorts A, B, and C, ORR and DOR are key endpoints of the study. For all cohorts, post 
study drug follow-up is of critical importance and is essential to preserve subject safety and the 
integrity of the study. Subjects who discontinue study drug must continue to be followed for 
collection of outcome and/or survival follow-up data as required and in line with Section 5 until 
death, withdrawal of consent, lost to follow-up, or the conclusion of the study.
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In addition, for Cohorts A, B, and C, subjects who discontinue study therapy by proceeding to 
allogeneic SCT or ASCT will require tumor assessment (CR or non-CR) by the investigators 
according to the 2007 IWG criteria on Day 100, at 6 months, 1 year and every year thereafter 
from the date of stem cell infusion until the first non-CR after SCT is documented (see 
Section 5.4). For the subjects who discontinue study therapy by proceeding to allogeneic SCT, 
documentation of acute and chronic GVHD will be simultaneously collected (see Section 5.3).
For Cohort D, if subjects have disease progression during study treatment, or have relapse 
disease after the end of study treatment, limited information of anti-lymphoma salvage treatment 
will be collected along with survival status Table 5.1.2-4.
BMS may request that survival data be collected on all treated subjects outside of the protocol 
window (section 5.1). At the time of this request, each subject will be contacted to determine 
their survival status unless the subject has withdrawn consent for all contacts or is lost to follow 
up.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor-
retained third-party representative to assist site staff with obtaining subject’s contact information 
or other public vital status data necessary to complete the follow-up portion of the study. The site 
staff and representative will consult publicly available sources, such as public health registries 
and databases, in order to obtain updated contact information. If after all attempts, the subject
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remains lost to follow-up, then the last known alive date as determined by the investigator should 
be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes Investigational [Medicinal] Product (IP/IMP):
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Table 4-1:
Study Drugs for CA209205 - Treatment Period
Product Description / 
Class and Dosage Form
Potency/Route 
of 
Administration
IP/Non-IMP
Blinded or Open-
Label
Packaging/Appearance
Storage Conditions
(per label)
Nivolumab (BMS-936558-01)
Solution for Injectiona
100 mg
(10 mg/mL)
IP
Open-label
Vial or various packaging 
configurations
Refer to the label on container 
and/or pharmacy manual.
Dacarbazine Powder for IV 
Solutionb
200 mg 
200 mg per vial
Open-label
10 vials per carton/
Open-label
White to pale yellow 
powder
Do not store above 25° C. 
Protect from light.
Doxorubicin Powder for Solution 
for Injectionb
50 mg
(2 mg/mL)
25 mL per vial/
Open-label
1 vial per carton/
Open-label
Red, compact unit or 
fragment with a porous 
appearance
Store at 15° to 25 °C.
Vinblastine (Sulphate) Solution 
for Injectionb
10 mg
(1 mg/mL)
10 mL per vial/ 
Open-label
2 vials per carton/
Open-label
A clear, colorless pale to 
yellow solution
2° to 8°C. 
Protect from light.
a Product may be labeled as either “BMS-936558” or “Nivolumab”.
b 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 this. Locally sourced marketed product utilized for this study should be stored in accordance with the package insert, 
summary of product characteristics (SmPC), or equivalent document.
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and 
permitted by local regulations.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: 
•
BMS-936558 (nivolumab) for Cohorts A, B, C, and D
•
Dacarbazine for Cohort D
•
Doxorubicin for Cohort D
•
Vinblastine for Cohort D.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
Not applicable for this study.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
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.
Please refer to the current version of the IB and/or pharmacy reference sheets/pharmacy manual
for complete storage, handling, dispensing, and infusion information for BMS-936558 
(nivolumab).
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For details on prepared drug storage and use time of nivolumab under room temperature/light 
and refrigeration, please refer to the BMS-936558 (nivolumab) IB section for “Recommended 
Storage and Use Conditions” and/or pharmacy reference sheets/pharmacy manual. 
At the end of the infusion, flush the line with a sufficient quantity of normal saline or 5% 
dextrose.
For Cohort D, for the drugs used during the combination phase (AVD), refer to SmPC or USPI.
4.4
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by calling an IVRS to obtain the subject number. Every 
subject that signs the informed consent form must be assigned a subject number in IVRS. 
Specific instructions for using IVRS will be provided to the investigational site in a separate 
document. 
The investigator (or designee) will register the subject for enrollment by following the 
enrollment procedures established by BMS. The following information is required for 
enrollment:
•
Date of informed consent
•
Date of birth
•
Gender at birth
•
Prior Brentuximab vedotin exposure (Cohorts A, B, and C, only).
•
Prior anti-lymphoma treatment history (Cohort D).
4.5
Selection and Timing of Dose for Each Subject
Cohorts A, B and C eligible subjects will receive nivolumab at either a 480 mg IV flat dose Q4W 
or a 240 mg IV flat dose Q2W. Subjects should receive nivolumab 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. There will be no dose escalations or reductions of 
nivolumab allowed. Once a new dosing regimen has been selected for the subject, either flat dose 
240 mg Q2W or flat dose 480 mg Q4W, the dosing regimen will remain in effect until the end of 
treatment and not change. For subjects being treated with nivolumab at 3 mg/kg every 2 weeks 
who switch dosing to every 4 weeks at 480 mg flat dose, the first dose of nivolumab at 480 mg 
should be administered 2 weeks after the last 3 mg/kg Q2W dose. Cohorts A, B, and C subjects 
should be carefully monitored for infusion reactions during nivolumab administration. If an acute 
infusion reaction is noted, subjects should be managed according to Section 4.5.6.
Cohort D subjects will receive nivolumab at a flat dose of 240 mg as a 30-minute IV infusion 
every 2 weeks. Subjects must be treated within one day after study drug vial assignment. There 
will be no dose escalations or reductions of nivolumab allowed. Subjects should be carefully 
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monitored for infusion reactions during nivolumab administration. If an acute infusion reaction is 
noted, subjects should be managed according to Section 4.5.6.
There are no premedications recommended for nivolumab on the first cycle.
Cohorts A, B, and C subjects may be dosed no less than 12 days from the previous dose during 
every 2-week cycle. Doses given after the 3-day window are considered dose delays. 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed.
For every 4-week dosing cycle, Cohorts A, B, and C subjects may be dosed within a ± 3-day 
window. Cohorts A, B, and C subjects receiving nivolumab every 4 weeks may be allowed to 
interrupt longer delay after discussion and written approval by the BMS Medical Monitor, in 
subjects with expected clinical benefit as per investigator assessment and after resolution of any 
AE leading to dosing interruption with stable performance status.
For Cohorts A, B, and C, tumor assessments by CT or MRI should continue as per protocol 
even if dosing is delayed.
For Cohort D, tumor assessment by CT, MRI, FDG-PET should be conducted based on 
cycles, not weeks.
Subjects will be monitored continuously for AEs while on study. Treatment modifications 
(eg, dose delay or discontinuation) will be based on specific laboratory and AE criteria.
4.5.1
Antiemetic Premedications
Antiemetic premedications should not be routinely administered prior to dosing of nivolumab 
monotherapy. For Cohort D, antiemetic premedications during combination therapy is according 
to local or institutional standards. Corticosteroid use for antiemesis is permitted for the entire 
study for Cohort D. 
4.5.2
Dose Delay Criteria
4.5.2.1
Nivolumab Dose Delay Criteria
Dose delay criteria apply for all drug-related AEs. Nivolumab must be delayed until treatment
can resume (see Section 4.5.4). For Cohort D, these criteria apply both for the Monotherapy and 
Combination phases. During the Combination phase, only nivolumab must be delayed if the AE 
is considered to be nivolumab-related, whereas AVD can be dosed at the planned schedule per 
the protocol.
Nivolumab administration should be delayed for the following:
•
Any Grade ≥2 non-skin, drug-related AE, with the following exceptions:
−
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay
•
Any Grade 3 skin, drug-related AE
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•
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or lipase:
−
Grade 3 lymphopenia or leukopenia does not require dose delay.
−
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥2 toxicity.
−
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
4.5.2.2
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 immuno-oncology 
agent in this protocol. Early recognition and management of AEs associated with 
immuno-oncology agents may mitigate severe toxicity. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathies
•
Skin
•
Neurological.
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the algorithms. 
These algorithms are found in the Nivolumab IB and in Appendix 1 of this protocol. Discussions 
with the BMS Medical Monitor on how to apply these algorithms are strongly encouraged. The 
guidance provided in these algorithms should not replace the Investigator’s medical judgment 
but should complement it.
4.5.2.3
AVD Dose Delay Criteria (Only for Cohort D)
This rule applies to subjects in Cohort D during the combination phase. When an investigator 
judges that dose is delayed > 21 days from a previous dose due to an AVD-related AE, the BMS 
medical monitor should be contacted. 
•
If neutrophils < 1,500/mm3 (≥Grade 1) on the day of drug administration, treatment 
(Nivolumab-AVD or AVD) can be delayed until normalization of the values. G-CSF is 
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permitted for leucopenia or neutropenia. Prophylactic use of G-CSF is also permitted for 
subsequent treatment.
•
If platelets are < 75,000/mm3 (≥Grade 1) on the day of drug administration, treatment can be 
delayed until normalization of the values.
When the causality of AE resulting in a dose delay > 21 days from a previous dose is not 
determined due to either nivolumab or AVD from the Nivolumab-AVD regimen, the BMS 
medical monitor should be contacted.
4.5.3
Doses Reductions and Escalations
In all cohorts, dose reductions and escalations of nivolumab are not permitted.
Only for Cohort D: omitting only nivolumab from Nivolumab-AVD is permitted during the
combination phase. When an investigator judges that a dose is delayed > 21 days from a previous 
dose due to a nivolumab-related AE, the BMS medical monitor must be contacted. Subjects who 
meet Nivolumab Delay Criteria (Section 4.5.2.1) may eliminate nivolumab and use only AVD 
for the subsequent combination treatment after the BMS medical monitor is consulted. If the 
subject subsequently meets Criteria to Resume Nivolumab Dosing (Section 4.5.4), the regimen 
may be changed back to Nivolumab-AVD, after the BMS medical monitor is consulted again. 
Dose interruption of nivolumab > 6 weeks during combination phase is permitted. Skipped 
nivolumab doses will not be compensated. 
Only for Cohort D: each component of AVD should reduce its dose when subjects are treated 
with AVD or Nivolumab-AVD during combination phase, as follows:
•
If ≥Grade 3 febrile neutropenia is observed, the dose of doxorubicin and vinblastine can be 
reduced by up to 50% reduction for subsequent treatment. 
•
If plasma bilirubin concentration is between 1.2 - 3.0 mg/dL, the dose of doxorubicin and 
vinblastine can be reduced by 50%.
•
If plasma bilirubin concentration is > 3.0 - 5.0 mg/dL, the dose of doxorubicin and 
vinblastine can be reduced by 75%.
•
If ≥Grade 2 peripheral motor neuropathy, or/and if ≥Grade 3 peripheral sensory neuropathy 
is observed, the dose of vinblastine can be reduced by up to 50% reduction for subsequent 
treatment.
When AVD is delayed, nivolumab should also be delayed.
The BMS medical monitor should be contacted when dose is reduced regardless of the causality.
4.5.4
Criteria to Resume Nivolumab Dosing
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue 
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•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity 
•
Subjects with baseline AST/ALT or total bilirubin in the Grade 1 toxicity range who require 
dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin
•
Subjects with combined Grade 2 AST/ALT AND
total bilirubin values meeting 
discontinuation parameters (Section 4.5.5) should have treatment permanently discontinued
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
If the criterion to resume treatment is met, the subject should restart treatment at the next 
scheduled time point per protocol.
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.5.5.
For Cohort D, these criteria apply both for the monotherapy and combination phases. During the 
combination phase, when only nivolumab is delayed due to nivolumab-related AE, nivolumab 
can be resumed in combination with AVD if these resuming criteria are met. Withholding dose 
of nivolumab for > 6 weeks during the combination phase is permitted.
4.5.5
Nivolumab Discontinuation Criteria
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment 
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days, with the following exceptions for 
drug-related laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, and infusion reactions:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation
−
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with clinically 
significant bleeding requires discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:
•
AST or ALT > 5-10 x ULN for > 2 weeks
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•
AST or ALT > 10 x ULN
•
Total bilirubin > 5 x ULN
•
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related AE or laboratory abnormality, except for the following events 
which do not require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset
−
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations, or radiographic signs of pancreatitis. It is recommended to consult with 
the BMS Medical Monitor for Grade 4 amylase or lipase abnormalities
−
Grade 4 drug-related endocrinopathy AEs such as adrenal insufficiency, ACTH 
(Adrenocorticotropic Hormone) deficiency, hyper- or hypothyroidosis, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (steroids, thyroid hormones) or glucose controlling agents, respectively, may 
not require discontinuation after discussion with and approval from the BMS Medical 
Monitor
•
Any dosing delay lasting > 6 weeks from the previous dose with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting 
> 6 weeks, the BMS medical monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is delayed. 
−
Dosing delays > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS medical monitor. Prior to re-initiating treatment in a subject with a 
dosing delay lasting > 6 weeks, the BMS medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed.
−
Withholding dosing for > 6 weeks during combination phase (only for Cohort D).
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
•
Disease progression as determined by investigator assessment following the guidelines given 
in Section 5.4.6 with the exception described in Section 4.5.7. For Cohort D, subjects who 
discontinued nivolumab monotherapy due to 2007 IWG criteria-met disease progression 
based on investigators’ assessment during the Monotherapy phase are allowed to enter the 
Combination phase when AVD is used as a combination therapy. For Cohort D, subjects who 
had 2007 IWG criteria-met disease progression based on investigators’ assessment and who 
had treatment beyond progression during the Monotherapy phase are allowed to use 
Nivolumab-AVD combination therapy during the Combination phase.
•
Subject who initiated the preparative regimen for allogeneic SCT or ASCT after the first dose 
of nivolumab treatment.
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•
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).
•
Cohort C subjects who have persistent CR for 1 year will discontinue the study drug when 
CR is confirmed by CT (preferred) or MRI. Please refer to section 3.1.
For Cohort D, these criteria apply both for monotherapy and combination phases. 
During monotherapy phase, subjects who meet Nivolumab Delay Criteria (Section 4.5.2) may 
enter the combination phase when nivolumab monotherapy requires dose delay > 4 weeks from a 
previous dose after the BMS medical monitor is consulted.
During combination phase, if nivolumab meet one of these discontinuation criteria due to 
nivolumab-related AE, nivolumab must be permanently discontinued, whereas AVD can be 
dosed as planned.
4.5.5.1
Discontinuation of Nivolumab Monotherapy During Monotherapy Phase 
of Cohort D
Subjects who meet Nivolumab Discontinuation Criteria (Section 4.5.5) may enter the 
combination phase if AVD only (without nivolumab) is used as the combination therapy. The 
BMS medical monitor should be contacted before starting AVD. These subjects are not allowed 
to use the combination of nivolumab and AVD (See Table 3.1.2-1). 
When nivolumab monotherapy dose delays are > 4 weeks from a previous dose, the BMS 
medical monitor should be contacted. Withholding dosing of nivolumab monotherapy is 
permitted up to 6 weeks. However, based on the investigator’s judgment, subjects who meet 
Nivolumab Delay Criteria (Section 4.5.2.1) may also enter the combination phase if nivolumab 
monotherapy dose delay > 4 weeks from a previous dose after the BMS medical monitor is 
consulted.
•
If subjects meet Criteria to Resume Nivolumab Dosing (Section 4.5.4) before or when they 
enter combination phase, the combination of nivolumab and AVD should be used. However, 
based on investigators’ judgment, AVD only (without nivolumab) may be used (See Table 
3.1.2-1).
•
If subjects do not meet Criteria to Resume Nivolumab Dosing (Section 4.5.4) when they 
enter combination phase, AVD only (without nivolumab) must be used. If subjects 
subsequently meet Criteria to Resume Nivolumab Dosing (Section 4.5.4), the regimen may 
switch from AVD only to the combination of nivolumab and AVD, after the BMS medical 
monitor is consulted. For example, a subject who has started Combocycle 1 with AVD only 
may start using the combination of nivolumab and AVD from Combocycle 4 after discussion 
with the BMS medical monitor. Based on investigator s’ judgment, continuing AVD only
through the end of Combocycle 6 is also acceptable (See Table 3.1.2-1). 
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4.5.5.2
Discontinuation of Nivolumab from the Combination Therapy During 
Combination Phase for Cohort D
Subjects who 
meet Nivolumab Discontinuation 
Criteria (Section 4.5.5) due to a 
nivolumab-related AE must eliminate nivolumab, and must use AVD only for the subsequent 
combination treatment after the BMS medical monitor is consulted. The use of nivolumab as a 
part of the combination is no longer allowed (See Table 3.1.2-1).
4.5.6
Treatment of Nivolumab Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce an infusion or hypersensitivity reaction. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, 
hypo- or hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an 
SAE if criteria are met. Infusion reactions should be graded according to National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) 
guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds 
promptly 
to 
symptomatic 
treatment 
[eg, 
antihistamines, 
non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤24 hours).
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, 
restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor subject closely. If symptoms recur then no further nivolumab will be administered 
at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
subject until resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 
325 to 1000 mg (acetaminophen) should be administered at least 30 minutes before additional 
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nivolumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or ventilatory 
support indicated).
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat 
the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly 
for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed. Subject should be monitored until the investigator is comfortable that 
the symptoms will not recur. Nivolumab will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms. In the case of late-occurring hypersensitivity 
symptoms (eg, appearance of a localized or generalized pruritis within 1 week after treatment), 
symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids).
4.5.7
Treatment Beyond Disease Progression
4.5.7.1
Circumstances in which Post-progression Treatment is Permitted
Subjects meeting progression defined by relapsed disease (after CR) or progressive disease (after 
PR, SD) per 2007 IWG criteria may continue receiving study medication beyond investigator-
assessed progression as long as they meet the following criteria:
•
Investigator-assessed clinical benefit and do not have rapid disease progression 
•
Stable performance status 
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression 
•
Subjects will be re-consented with an informed consent document describing any reasonably 
foreseeable risks or discomfort and other alternative treatment options 
•
Tolerance of study drug. 
The decision to continue treatment beyond investigator-assessed progression should be discussed 
with the BMS Medical Monitor and documented in the study records. Subjects for Cohorts A, B, 
and C should continue to meet all other study protocol eligibility criteria. Treatment beyond 
disease progression is permitted for subjects in Cohort D only during the monotherapy phase. 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.
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4.5.7.2
Assessment Schedule for the Subjects with Post-progression 
Treatment
The subject should continue to receive monitoring according to the On-Treatment Assessments 
on Table 5.1.1-2 except for FDG-PET scans. Radiographic assessment by CT (preferred) or MRI 
described in Section 5.4.1 and Table 5.4.1.1-1 are required when subjects continue 
post-progression treatment. FDG-PET scans are not mandated after investigator-assessed 
progression.
4.5.7.3
Discontinuation due to “Further Progression”
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). 
•
Further progression is evaluated by a subsequent CT or MRI which is performed at least 
8 weeks from previous CT or MRI.
•
The tumor burden volume from time of initial progression should be used as the reference 
baseline for comparison with the post-progression assessment.
•
New lesions are considered measurable at the time of initial progression if the long axis is 
more than 15 mm regardless of the short axis. If a lymph node has a long axis of 11 to 
15 mm, it should only be considered measurable if its short axis is more than 10 mm.
•
Any new lesion considered non-measurable at the time of or after initial progression may 
become measurable and therefore included in the tumor burden determination.
4.5.7.4
Radiographic Assessment for the Subjects who Discontinue Study 
Drug during Post-progression Treatment
When subjects stop post-progression treatment, no additional radiographic assessment will be 
required and they will continue in the follow-up phase of the study (see Section 5.1). The 
subjects who proceed to allogeneic SCT or ASCT will be followed with specific schedule (see 
Section 5.4).
4.5.8
Re-Initiation of Study Therapy for Cohort C subjects
As described in Section 4.5.5, subjects in Cohort C will discontinue study therapy after 
maintaining CR for one year. If subjects relapse within 2 years from last dose, subjects may 
reinitiate study therapy. Relapse must meet 2007 IWG criteria based on investigators’ 
assessment, and must be clearly documented in the medical record AND the BMS Medical 
Monitor must be contacted. Re-initiation of treatment after relapse is not mandatory, should a 
subject chose not to re-initiate treatment, this subject will continue to be followed every three 
months for survival.
Subjects re-initiating study therapy should continue to meet eligibility criteria at the time study 
drug resumes. FDG-PET is not mandated if FDG-avid disease was previously proved. 
Pulmonary function test is not required if DLCO was previously over 60% (adjusted for 
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
hemoglobin) at initial enrollment and if no drug-related pulmonary toxicity was reported during 
the study therapy. Re-initiation of study therapy is not allowed for subjects who proceeded to 
ASCT or allogeneic SCT, and for subjects who initiated other anti-neoplastic therapy after study 
drug discontinuation. Re-initiation of treatment procedures are described in Table 5.1.1-5.
When subjects achieve second on-study CR by re-initiation of study drug, subjects do not have to 
discontinue the study drug when second on-study CR persists for 1 year.
Additional safety and efficacy summaries will be presented for those subjects who reinitiated 
study therapy.
4.5.9
Guidelines for Assessment and Initial Management of Tumor Lysis 
Syndrome
The possibility of tumor lysis syndrome cannot be ruled out for the subjects with lymphoma. 
Therefore, adequate management such as hydration and/or the use of allopurinol is 
recommended in the subjects who have risk factor of potential tumor lysis syndrome, for 
example the subjects with high tumor burden, reflected by high serum LDH levels, or bulky 
disease, or those with preexisting renal failure.
4.6
Blinding/Unblinding
Not applicable.
4.7
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and CRF.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
Revised Protocol No: 04c
Date: 22-Aug-2019
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nivolumab
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
5.1.1
Time and Events Schedule for Cohorts A, B, and C
Table 5.1.1-1:
Screening Procedural Outline for Cohorts A, B, and C (CA209205)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed 
prior to first dose
Medical History
X
Prior Systemic Therapy
X
Safety Assessments
Physical Examination
X
Physical Measurements
X
Include Height, Weight, and ECOG performance Status
Hasenclever-Index for Hodgkin's Disease also known as
IPS at Initial Diagnosis
X
Composite score, see Appendix 3.
Vital Signs and Oxygen saturation
X
Temperature, BP, HR, and O2 saturation by pulse oximetry (at rest and after 
exertion). 
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 
14 days prior to first dose.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
Table 5.1.1-1:
Screening Procedural Outline for Cohorts A, B, and C (CA209205)
Procedure
Screening
Visita
Notes
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), 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)
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment
CT or MRI of Chest, Abdomen, Pelvis, and any other 
known sites of disease (eg neck)
FDG-PET scan
X
Must be performed within 28 days prior to first dose.
Additional sites of known or suspected disease (eg neck) should be imaged at 
the screening visit and at subsequent on-study assessments. 
FDG-PET scan required at screening.
Bone Marrow Biopsy/Aspirate (Submission of aspirate 
sample is mandatory for biomarker analyses for subjects 
who have a bone marrow aspirate performed during 
screening.) for Cohorts A and B, optional for Cohort C.
X
See Table 5.6-1 of Biomarker Sampling Schedule.
Collection of tumor tissue 
X
Submission of tumor tissue (FFPE tumor tissue block or 10 unstained slides) 
from a biopsy performed during screening is mandatory. If this is not possible, 
the following exceptions are allowed:
Subjects who do not have any accessible lesions, or
Subjects who have archival tissue from a previous tumor biopsy that can be 
used for PD-L1 expression analysis. These subjects must submit archival tissue 
from the most recent tumor biopsy if archival tissues are available from tumor 
biopsies at multiple time points. While submission of archival tissue from the 
most recent tumor biopsy is mandatory, archival tissue from other tumor biopsy 
is strongly encouraged. For example, subjects who mandatorily submit archival 
tissue from a tumor biopsy at relapse may optionally submit archival tissue for 
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-1:
Screening Procedural Outline for Cohorts A, B, and C (CA209205)
Procedure
Screening
Visita
Notes
tumor biopsy at initial diagnosis.
Note: For these exceptions, the reason must be clearly documented in the 
medical record AND the BMS Medical Monitor must be contacted. Subjects 
may initiate the study drug before the outcomes of PD-L1 expression status 
become available.
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
Phone calls must be made to IVRS as follows:
For subject cohort and number assignment at the time informed consent is 
obtained.
Prior to dosing for study drug vial assignment (call should be made within 1 day 
prior to dosing).
a Within 28 days prior to first dose
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
Table 5.1.1-2:
On-Treatment Assessments for Cohorts A, B, and C (CA209205)
Procedure
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 8 
(C1D8)
Each Cycle 
(240 mg Q2W 
or 480 mg 
Q4W a) on 
Day 1
Notes
Dosing cycle = 240 mg Q2W
or 480 mg Q4W
Safety Assessments
Targeted Physical Examination
X
X
Lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), and abdominal organs (eg, spleen, 
liver)
Vital Signs and Oxygen Saturation
X
X
X
Temperature, BP, HR, O2 saturation by pulse oximetry at rest and 
after exertion (also monitor amount of supplemental oxygen if 
applicable) prior to dosing and at any time a subject has any new or 
worsening respiratory symptoms
Physical Measurements
X
X
X
Includes Weight and ECOG performance status
Adverse Events Assessment
---------- Continuously ----------
Assessed using NCI CTCAE v. 4.0.
Review of Concomitant Medications
X
X
X
Laboratory Tests
X
X
X
Extended on-study local laboratory assessments should be done 
within 72 hours prior to dosing from Cycle 1 through Cycle 5 and 
every alternate dose thereafter (Cycles 7, 9, 11, 13, etc.) and include: 
CBC with differential, BUN or serum urea level, serum creatinine, 
sodium, potassium, calcium, magnesium, chloride, amylase, lipase, 
glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH.
Limited on-study local laboratory assessment should be done within 
72 hours prior to dosing beginning at Cycle 6 and every alternate 
dose thereafter (Cycles 8, 10, 12, 14, etc.) and include: CBC with 
differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase) 
and creatinine.
Thyroid Function Testing
See note
TSH (reflex to free T3 and free T4 if abnormal result) to be 
performed every 6 weeks (± 7 days) 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 
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-2:
On-Treatment Assessments for Cohorts A, B, and C (CA209205)
Procedure
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 8 
(C1D8)
Each Cycle 
(240 mg Q2W 
or 480 mg 
Q4W a) on 
Day 1
Notes
Dosing cycle = 240 mg Q2W
or 480 mg Q4W
once every 4 weeks (± 7 days) regardless of dosing schedule.
Efficacy Assessments
Radiographic Tumor Assessment
CT or MRI of Chest, Abdomen, Pelvis, and 
any other known sites of disease
FDG-PET Scan
See note
See Table 5.4.1.1-1 and Table 5.4.1.1-2 of CT or MRI and FDG-PET 
scan schedule and also Section 4.5.7.2 in case of treatment beyond 
progression.
Bone Marrow Aspirate and Biopsy
See note 
See note
For Cohorts A and B: Bone Marrow Aspirate and Biopsy is required
to confirm any CR in subjects with lymphoma involvement in bone 
marrow at study entry.
For Cohort C, Bone Marrow Aspirate and Biopsy is optional. If it is 
done, Bone Marrow Aspirate sample can be optionally submitted for 
biomarker analysis.
See Table 5.6-1 of Biomarker Sampling Schedule.
Additional Exploratory Biomarker Testing
Serum
Whole Blood
Tumor Biopsy
See note
See note
See Table 5.6-1 of Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See note
See Table 5.5-1 of PK and Immunogenicity Sampling
Immunogenicity samples
See note
See Table 5.5-1 of PK and Immunogenicity Sampling
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-2:
On-Treatment Assessments for Cohorts A, B, and C (CA209205)
Procedure
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 8 
(C1D8)
Each Cycle 
(240 mg Q2W 
or 480 mg 
Q4W a) on 
Day 1
Notes
Dosing cycle = 240 mg Q2W
or 480 mg Q4W
Outcomes Research Assessments
EORTC QLQ-C30 & EQ-5D
X
See note
Assessments to be collected every 4 cycles for the first 17 cycles;
Day 1 (prior to dosing) of Cycles 5, 9, 13, 17
every 6 cycles thereafter;
Day 1 (prior to dosing) of Cycles 23, 29, 35+.
B Symptoms
X
See note
Assessments to be collected every 4 cycles for the first 17 cycles; 
Day 1 (prior to dosing) of Cycles 5, 9, 13, 17. Every 6 cycles 
thereafter; Day 1 (prior to dosing) of Cycles 23, 29, 35+, and when 
subjects achieve first PR or first CR after initiation of the study drug. 
If subjects with previous PR attain CR, B symptoms should be 
collected again at CR.
Clinical Drug Supplies
Administer Study Drug
X
X
IVRS should be called within 1 day prior to study drug 
administration to receive vial assignment.
a Per revised protocol 04c, subjects will switch to 480 mg flat dose Q4W or 240 mg flat dose Q2W as an IV infusion over 30 minutes. Subjects must sign an 
informed consent document prior to switching the dosing schedule.
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-3:
Follow-Up Assessments for Cohorts A, B, and C (CA209205)
Procedure
X, Follow-Up,a
Visits 1 and 2
S, Survival Follow-Up 
Visitsb
Notes
Safety Assessments
Targeted Physical Examination
X
Lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), and abdominal organs (eg, 
spleen, liver).
To assess for potential late emergent study drug-related issues
Adverse Events Assessment
X
X
NSAEs and SAEs must be collected up to 100 days after study 
drug discontinuation. SAEs related to any later protocol-specified 
procedure must be collected.
Laboratory Tests
X
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)
Pregnancy Test
X
Serum or urine (WOCBP only)
GVHD Assessments
See note
See note
Only for subjects who discontinued study therapy by proceeding 
to allogeneic SCT. To be assessed on Day 100, at 6 months, at 
1 year and every one year thereafter from the date of stem cell 
infusion until the first non-CR after SCT is documented.
See Section 5.3.
Efficacy Assessments
Radiographic Tumor Assessment
CT or MRI 
FDG-PET Scan
See note
See note
See Table 5.4.1.1-1 and Table 5.4.1.1-2 for CT or MRI and 
FDG-PET scan schedule and also Section 4.5.7.4 for those 
subjects who discontinue study drug after treatment beyond 
progression.
Tumor Assessment by the Investigator 
(CR or non-CR)
See note
See note
Only for subjects who discontinued study therapy by proceeding 
to allogeneic SCT or ASCT. To be assessed on Day 100, at 
6 months, at 1 year and every one year thereafter from the date of 
stem cell infusion until the first non-CR after SCT is 
documented. 
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-3:
Follow-Up Assessments for Cohorts A, B, and C (CA209205)
Procedure
X, Follow-Up,a
Visits 1 and 2
S, Survival Follow-Up 
Visitsb
Notes
See Section 5.4
Outcomes Research Assessments
EORTC QLQ-C30
X
EQ-5D
X
X
EQ-5D during the survival follow-up will be assessed during a 
clinic visit or via a phone contact
Exploratory Biomarker Testing
Serum
See note
Collection of these biomarker samples at time of progression is 
optional.
See Table 5.6-1of Biomarker Sampling Schedule.
Whole Blood 
Tumor Biopsy 
Bone Marrow Aspirate 
Subject Status
Survival Status
X
X
Survival follow-up, every 3 months after X02 may be 
accomplished by visit or phone contact to update survival 
information and assess subsequent anti-cancer therapy.
a X visits occur as follows: X01 = 35 days ± 7 days from last dose, X02 = 80 days ± 7 days from X01
b S, Survival visits continue every 3 months after X visit
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-4:
Follow-Up Assessments for Cohort C Subjects who Discontinued due to CR (CA209205) or After Re-
Initiation of Nivolumab
Procedure
X, 
Follow-
Up, 
Visits 1 
and 2a
FU/Observational 
visitsb
S, Survival 
Follow-Up 
Visitsc
Notes
Safety Assessments
Targeted Physical Examination
X
X
Lymph node areas (eg, submandibular, cervical, 
supraclavicular, axillary, or inguinal lymph node), and 
abdominal organs (eg, spleen, liver)
Adverse Events Assessment
See notes
NSAEs and SAEs must be collected during X01, X02 and 
FU/Observational visits for a maximum of 2 years and a 
minimum of 100 days after last dose. After, only SAEs 
related to study procedures must be collected.
Laboratory Tests
X
X
During X01 and X02 visits: CBC with differential, BUN 
or serum urea level, serum creatinine, sodium, potassium, 
calcium, magnesium, chloride, glucose, AST, ALT, total 
bilirubin, alkaline phosphatase, LDH.
During observation follow-up visits, after X02: CBC with 
differential, BUN or serum urea level, serum creatinine, 
AST, ALT, total bilirubin
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result)
Pregnancy Test for WOCBP
X
Serum or urine (WOCBP only).
GVHD Assessments
See 
note
See note
See note
Only for subjects who proceed to allogeneic SCT. To be 
assessed on Day 100, at 6 months, at 1 year and every 1
year thereafter from the date of stem cell infusion until 
the first non-CR after SCT is documented.
See Section 5.3
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-4:
Follow-Up Assessments for Cohort C Subjects who Discontinued due to CR (CA209205) or After Re-
Initiation of Nivolumab
Procedure
X, 
Follow-
Up, 
Visits 1 
and 2a
FU/Observational 
visitsb
S, Survival 
Follow-Up 
Visitsc
Notes
Efficacy Assessments
Radiographic Tumor Assessment
CT or MRI of Chest, Abdomen, Pelvis, and 
any other known sites of disease
See note
CT (preferred) or MRI to be performed at time of first 
FU/Observational visit, 6 months (± 14 days) after study 
drug discontinuation, and if clinically indicated.
Tumor Assessment by the Investigator (CR 
or non-CR)
See 
note
See note
See note
Only for subjects who proceed to allogeneic SCT or 
ASCT. To be assessed on Day 100, at 6 months, at 1 year 
and every 1 year thereafter from the date of stem cell 
infusion until the first non-CR after SCT is
Outcomes Research Assessments
EORTC QLQ-C30
X
X
EQ-5D
X
X
X
EQ-5D during the survival follow-up will be assessed 
during a clinic visit or via a phone contact
Pharmacokinetic/Immunogenicity Assessments
PK samples
X
Immunogenicity samples
X
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-4:
Follow-Up Assessments for Cohort C Subjects who Discontinued due to CR (CA209205) or After Re-
Initiation of Nivolumab
Procedure
X, 
Follow-
Up, 
Visits 1 
and 2a
FU/Observational 
visitsb
S, Survival 
Follow-Up 
Visitsc
Notes
Exploratory Biomarker Testing
Serum
See 
note
See note
See note
Collection of Biomarker samples at time of progression is 
optional.
See Table 5.6-1 of Biomarker Sampling Schedule.
Whole Blood
Tumor Biopsy
Bone Marrow Aspirate
Subject Status
Survival Status
X
X
X
Survival follow-up, every 3 months after observation 
follow-up may be accomplished by visit or phone contact 
to update survival information and assess subsequent anti-
cancer therapy.
a X visits occur as follows: X01 = 35 days ± 7 days from last dose, X02 = 80 days ± 7 days from X01
b First FU/Observational visit must occur 6 months (± 14 days) after study drug discontinuation, then at Month 9 (± 14 days), 12 (± 14 days), 16 (± 21 days), 
20 (± 21 days), and 24 (± 21 days)
c S, Survival visits continue every 3 months after last FU/Observational visits
Revised Protocol No: 04c
Date: 22-Aug-2019
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Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-5:
Re-Initiation of Treatment Assessments for Cohort C subjects (CA209205)
Procedure
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 8 
(C1D8)
Each Cycle 
(240 mg Q2W 
or 480 mg 
Q4Wa) on 
Day 1
Notes
Dosing cycle = 240 mg Q2W
or 480 mg Q4W
Safety Assessments
Targeted Physical Examination
X
X
Lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), and abdominal organs (eg, spleen, 
liver)
Vital Signs and Oxygen Saturation
X
X
X
Temperature, BP, HR, O2 saturation by pulse oximetry at rest and 
after exertion (also monitor amount of supplemental oxygen if 
applicable) prior to dosing and at any time a subject has any new or 
worsening respiratory symptoms
Physical Measurements
X
X
X
Includes Weight and ECOG performance status
Adverse Events Assessment
---------- Continuously ----------
Assessed using NCI CTCAE v. 4.0.
Review of Concomitant Medications
X
X
X
Laboratory Tests
X
X
X
Extended on-study local laboratory assessments should be done 
within 72 hours prior to dosing from Cycle 1 through Cycle 5 and 
every alternate dose thereafter (Cycles 7, 9, 11, 13, etc.) and include: 
CBC with differential, BUN or serum urea level, serum creatinine, 
sodium, potassium, calcium, magnesium, chloride, amylase, lipase, 
glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH.
Limited on-study local laboratory assessment should be done within 
72 hours prior to dosing beginning at Cycle 6 and every alternate 
dose thereafter (Cycles 8, 10, 12, 14, etc.) and include: CBC with 
differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase) 
and creatinine.
Thyroid Function Testing
See note
TSH (reflex to free T3 and free T4 if abnormal result) to be 
performed every 6 weeks (± 7 days) 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 
Revised Protocol No: 04c
Date: 22-Aug-2019
98
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930105741
3.0
v


Clinical Protocol
CA209205
BMS-936558
nivolumab
Table 5.1.1-5:
Re-Initiation of Treatment Assessments for Cohort C subjects (CA209205)
Procedure
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 8 
(C1D8)
Each Cycle 
(240 mg Q2W 
or 480 mg 
Q4Wa) on 
Day 1
Notes
Dosing cycle = 240 mg Q2W
or 480 mg Q4W
once every 4 weeks (± 7 days) regardless of dosing schedule.
Efficacy Assessments
Radiographic Tumor Assessment
CT or MRI of Chest, Abdomen, Pelvis, and 
any other known sites of disease
FDG-PET Scan
See note
See Table 5.4.1.1-1 and Table 5.4.1.1-2 of CT or MRI and FDG-PET 
scan schedule and also Section 4.5.7.2 in case of treatment beyond 
progression.
Bone Marrow Aspirate and Biopsy
See note 
See note
Bone Marrow Aspirate and Biopsy is optional. If it is done, Bone 
Marrow Aspirate sample can be optionally submitted for biomarker 
analysis.
See Table 5.6-1 of Biomarker Sampling Schedule.
B Symptoms
X
See note
Assessments to be collected every 4 cycles for the first 17 cycles; 
Day 1 (prior to dosing) of Cycles 5, 9, 13, 17. Every 6 cycles 
thereafter; Day 1 (prior to dosing) of Cycles 23, 29, 35+, and when 
subjects achieve first PR or first CR after re-initiation of the study 
drug. If subjects with previous PR attain CR, B symptoms should be 
collected again at CR.
Additional Exploratory Biomarker Testing
Serum
Whole Blood
Tumor Biopsy
See note
See note
See Table 5.6-1 of Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See note
See Table 5.5-1 of PK and Immunogenicity Sampling
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Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
Table 5.1.1-5:
Re-Initiation of Treatment Assessments for Cohort C subjects (CA209205)
Procedure
Cycle 1 
Day 1 
(C1D1)
Cycle 1 
Day 8 
(C1D8)
Each Cycle 
(240 mg Q2W 
or 480 mg 
Q4Wa) on 
Day 1
Notes
Dosing cycle = 240 mg Q2W
or 480 mg Q4W
Immunogenicity samples
See note
See Table 5.5-1 of PK and Immunogenicity Sampling
Clinical Drug Supplies
Administer Study Drug
X
X
IVRS should be called within 1 day prior to study drug 
administration to receive vial assignment.
a Per revised protocol 04c, subjects will switch to 480 mg flat dose Q4W or 240 mg flat dose Q2W as an IV infusion over 30 minutes. Subjects must sign an 
informed consent document prior to switching the dosing schedule.
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
5.1.2
Time and Events Schedule for Cohort D
Table 5.1.2-1:
Screening Procedural Outline Cohort D (CA209205)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed 
prior to first dose
Medical History
X
Prior Systemic Therapy
X
Safety Assessments
Physical Examination
X
Physical Measurements
X
Include Height, Weight, and ECOG performance Status
Hasenclever-Index for Hodgkin's Disease also known as
IPS at Initial Diagnosis
X
Composite score, see Appendix 3.
Vital Signs and Oxygen saturation
X
Temperature, BP, HR, and O2 saturation by pulse oximetry (at rest and after 
exertion). 
Assessment of Signs and Symptoms
X
After obtaining Informed Consent, assess all signs and symptoms within 
14 days prior to first dose.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Laboratory Tests
X
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), 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.
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BMS-936558
nivolumab
Table 5.1.2-1:
Screening Procedural Outline Cohort D (CA209205)
Procedure
Screening
Visita
Notes
Pregnancy Test
X
For WOCBP only (serum or urine)
Pulmonary function test 
X
To confirm that the diffusing capacity of the lung for carbon monoxide (DLCO) 
is over 60% (adjusted for hemoglobin)
ECG
X
Cardiac function test 
X
To confirm left ventricular ejection fraction is over 50% at rest by 
echocardiography or over 55% by isotopic measurement
Efficacy/Biomarker Assessments
Radiographic Tumor Assessment
CT or MRI of Chest, Abdomen, Pelvis, and any other 
known sites of disease (eg neck)
FDG-PET scan
X
Must be performed within 28 days prior to first dose.
Additional sites of known or suspected disease (eg neck) should be imaged at 
the screening visit and at subsequent on-study assessments. 
FDG-PET scan required at screening.
Collection of tumor tissue 
X
Submission of tumor tissue (FFPE tumor tissue block or a minimum of 
15 unstained slides, preferably 20) from a biopsy performed during screening is 
mandatory. Alternatively, submission of tumor tissue from a biopsy performed 
within 90 days prior to enrollment is allowed.
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
Phone calls must be made to IVRS as follows:
For subject cohort and number assignment at the time informed consent is 
obtained.
Prior to dosing for study drug vial assignment (call should be made within 1 day 
prior to dosing).
a Within 28 days prior to first dose
Revised Protocol No: 04c
Date: 22-Aug-2019
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BMS-936558
nivolumab
Table 5.1.2-2:
On-Treatment Assessments During Monotherapy Phase for Cohort D (CA209205)
Procedure
Monoth
erapy 
Dose 1 
(Day 1)
Day 8 
(after 
monot
herapy 
dose 1)
Each 
Monotherapy 
Dosing (Every 
2 Weeks)
Notes
Safety Assessments
Targeted Physical Examination
X
X
Lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), and abdominal organs (eg, spleen, 
liver)
Vital Signs and Oxygen Saturation
X
X
X
Temperature, BP, HR, O2 saturation by pulse oximetry at rest and 
after exertion (also monitor amount of supplemental oxygen if 
applicable) prior to dosing and at any time a subject has any new or 
worsening respiratory symptoms
Physical Measurements
X
X
X
Includes Weight and ECOG performance status
Adverse Events Assessment
---------- Continuously ----------
Assessed using NCI CTCAE v. 4.0.
Review of Concomitant Medications
X
X
X
Laboratory Tests
X
X
X
Extended on-study local laboratory assessments include CBC with 
differential, BUN or serum urea level, serum creatinine, sodium, 
potassium, calcium, magnesium, chloride, amylase, lipase, glucose, 
AST, ALT, total bilirubin, alkaline phosphatase, LDH.
Extended on-treatment local laboratory assessments should be 
done within 72 hours prior to dosing for: 
−
Monotherapy dose 1 through Monotherapy dose 4
Extended on-treatment local laboratory assessments should also 
be done on Day 8 after Monotherapy dose 1 
Thyroid Function Testing
See note
TSH (reflex to free T3 and free T4 if abnormal result) to be 
performed every 6 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.
Revised Protocol No: 04c
Date: 22-Aug-2019
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BMS-936558
nivolumab
Table 5.1.2-2:
On-Treatment Assessments During Monotherapy Phase for Cohort D (CA209205)
Procedure
Monoth
erapy 
Dose 1 
(Day 1)
Day 8 
(after 
monot
herapy 
dose 1)
Each 
Monotherapy 
Dosing (Every 
2 Weeks)
Notes
Efficacy Assessments
Radiographic Tumor Assessment
CT or MRI of Chest, Abdomen, Pelvis, and 
any other known sites of disease
FDG-PET Scan
See note
See Table 5.4.1.2-1 and Table 5.4.1.2-2 of CT or MRI and FDG-PET 
scan schedule and also Section 4.5.7.2 in case of treatment beyond 
progression.
Additional Exploratory Biomarker Testing
Serum
Whole Blood
Tumor Biopsy
See note
See note
See Table 5.6-2 of Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See note
See Table 5.5-2 of PK and Immunogenicity Sampling
Immunogenicity samples
See note
See Table 5.5-2 of PK and Immunogenicity Sampling
Outcomes Research Assessments
EQ-5D
X
Assessment to be collected on Day 1 (prior to dosing)
B Symptoms
X
Assessment to be collected on Day 1
Clinical Drug Supplies
Administer Study Drug
X
X
IVRS should be called within 1 day prior to study drug 
administration to receive vial assignment.
Revised Protocol No: 04c
Date: 22-Aug-2019
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BMS-936558
nivolumab
Table 5.1.2-3:
On-Treatment Assessments During Combination Phase for Cohort D (CA209205)
Procedure
Dose 1 of
each 
Combo 
cycle 
(Day 1)
Dose 2 
(Day 15) 
of 
Combo 
cycle 1
Dose 2 
(Day 15) 
Beginning
Combocycle 2 
through 
Combocycle 6
Notes
Safety Assessments
Targeted Physical Examination
X
X
Lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), and abdominal organs (eg, spleen, 
liver)
Vital Signs and Oxygen Saturation
X
X
X
Temperature, BP, HR, O2 saturation by pulse oximetry at rest and 
after exertion (also monitor amount of supplemental oxygen if 
applicable) prior to dosing and at any time a subject has any new or 
worsening respiratory symptoms
Physical Measurements
X
X
X
Includes Weight and ECOG performance status
Adverse Events Assessment
---------- Continuously ----------
Assessed using NCI CTCAE v. 4.0.
Review of Concomitant Medications
X
X
X
Laboratory Tests
X
X
X
Extended on-study local laboratory assessments include CBC with 
differential, BUN or serum urea level, serum creatinine, sodium, 
potassium, calcium, magnesium, chloride, amylase, lipase, glucose, 
AST, ALT, total bilirubin, alkaline phosphatase, LDH.
Extended on-treatment local laboratory assessments should be 
done within 72 hours prior to dosing for: 
−
Dose 1 (Day 1) of Combocycle 1 through Combocycle 6
−
Dose 2 (Day 15) of Combocycle 1
Limited on-study local laboratory assessments includes CBC 
with differential, LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase) and creatinine
−
Limited on-treatment local laboratory assessments should 
be done within 72 hours prior to dosing for Dose 2 (Day 15) 
of Combocycle 2 through Combocycle 6.
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
Table 5.1.2-3:
On-Treatment Assessments During Combination Phase for Cohort D (CA209205)
Procedure
Dose 1 of
each 
Combo 
cycle 
(Day 1)
Dose 2 
(Day 15) 
of 
Combo 
cycle 1
Dose 2 
(Day 15) 
Beginning
Combocycle 2 
through 
Combocycle 6
Notes
Thyroid Function Testing
See note
TSH (reflex to free T3 and free T4 if abnormal result) to be 
performed every 6 weeks (± 7 days) 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
CT or MRI of Chest, Abdomen, Pelvis, and 
any other known sites of disease
FDG-PET Scan
See note
See Table 5.4.1.2-1 and Table 5.4.1.2-2 of CT or MRI and FDG-PET 
scan schedule and also Section 4.5.7.2 in case of treatment beyond 
progression.
Additional Exploratory Biomarker Testing
Serum
Whole Blood
Tumor Biopsy
See note
See note
See Table 5.6-2 of Biomarker Sampling Schedule
PK and Immunogenicity Assessments
PK samples
See note
See Table 5.5-2 of PK and Immunogenicity Sampling
Immunogenicity samples
See note
See Table 5.5-2 of PK and Immunogenicity Sampling
Outcomes Research Assessments
EQ-5D
X
See note
Assessment to be collected on Day 1 Combocycle 1 (prior to dosing),
on Day 1 of Combocycle 3, and on Day 1 of Combocyle 5 during the 
Combination phase.
B Symptoms
X
See note
Assessments to be collected Day 1 (prior to dosing) of 
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
Table 5.1.2-3:
On-Treatment Assessments During Combination Phase for Cohort D (CA209205)
Procedure
Dose 1 of
each 
Combo 
cycle 
(Day 1)
Dose 2 
(Day 15) 
of 
Combo 
cycle 1
Dose 2 
(Day 15) 
Beginning
Combocycle 2 
through 
Combocycle 6
Notes
Combocycle 1, 3, and 5.
Clinical Drug Supplies
Administer Study Drug
X
X
X
IVRS should be called within 1 day prior to study drug 
administration to receive vial assignment.
Revised Protocol No: 04c
Date: 22-Aug-2019
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BMS-936558
nivolumab
Table 5.1.2-4:
Follow-Up Assessments for Cohort D (CA209205)
Procedure
X, Follow-Up,a
Visits 1 and 2
FU/ 
Observational 
visitsb
S, Survival 
Follow-Up 
Visitsc
Notes
Safety Assessments
Targeted Physical Examination
X
X
Lymph node areas (eg, submandibular, cervical, supraclavicular, 
axillary, or inguinal lymph node), and abdominal organs (eg, 
spleen, liver).
Adverse Events Assessment
See Notes
NSAEs and SAEs must be collected during Follow-up visit 1 
and Follow-up visit 2. Thereafter, SAEs related to any later 
protocol-specified procedure must be collected.
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.
Pulmonary Function Test
X
Test to be conducted 35 days (± 14 days) from the last dose of 
study therapy.
Thyroid Function Testing
X
TSH (reflex to free T3 and free T4 if abnormal result)
Pregnancy Test
X
Serum or urine (WOCBP only)
Efficacy Assessments
End-of-therapy radiographic tumor 
assessments:
FDG-PET 
CT or MRI of Chest, Abdomen, Pelvis, 
and any other known sites of disease
See note
FDG-PET and CT (preferred) or MRI will be conducted at 
9 weeks (± 14 days) from the last dose, which is between 
Follow-up visit 1 and Follow-up visit 2.
Radiographic Tumor Assessment 
End-of-therapy radiographic tumor 
assessments 
CT or MRI of Chest, Abdomen, Pelvis, 
and any other known sites of disease
See note
CT (preferred) or MRI is required at visit 04 (39 weeks from the 
last dose), 06 (65 weeks from the last dose), and 09 (104 weeks 
from the last dose).
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
Table 5.1.2-4:
Follow-Up Assessments for Cohort D (CA209205)
Procedure
X, Follow-Up,a
Visits 1 and 2
FU/ 
Observational 
visitsb
S, Survival 
Follow-Up 
Visitsc
Notes
Subsequent therapy information
See note
See note
See note
Only for subjects who have disease progression and undergo 
other anti-lymphoma treatment
Outcomes Research Assessments
EQ-5D
X
X
X
EQ-5D during the survival follow-up will be assessed during a 
clinic visit or via a phone contact
B Symptoms
X
To be collected only at Follow-up visit 1
Pharmacokinetic/Immunogenicity Assessments
PK Samples
X
See Table 5.5-2 of PK and Immunogenicity Sampling
Immunogenicity samples
X
See Table 5.5-2 of PK and Immunogenicity Sampling
Exploratory Biomarker Testing
Serum
See note
See note
See note
Collection of Biomarker samples at time of progression is 
optional.
See Table 5.6-2 of Biomarker Sampling Schedule.
Whole Blood 
Tumor Biopsy 
Subject Status
Survival Status & subsequent anti-
lymphoma therapies
X
X
X
Survival follow-up, every 6 months after observation follow-up 
may be accomplished by visit or phone contact to update 
survival information and assess subsequent anti-cancer therapy
a Follow-up visit 1 occurs 35 days ± 7 days from last dose and Follow-up visit 2 occurs 80 days ± 7 days from Follow-up visit.
b First FU/Observational visits (visit 03) will occur 26 weeks (± 21 days) after the last dose of study treatment, then approximately every 3 months (± 21 days): 
visit 04 (39 weeks), visit 05 (52 weeks), visit 06 (65 weeks), visit 07 (78 weeks), visit 08 (91weeks), and visit 09 (104 weeks).
c S, Survival visits continue every 6 months after last FU/Observational visits. Please note that this frequency is different from Cohorts A, B, and C.
Revised Protocol No: 04c
Date: 22-Aug-2019
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BMS-936558
nivolumab
5.1.3
Retesting During Screening
Retesting of laboratory parameters and/or other assessments within any single Screening will be 
permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1.1-1 and Table 5.1.2-1, 
Screening Procedural Outline may be repeated in an effort to find all possible well-qualified 
subjects. Consultation with the Medical Monitor may be needed to identify whether repeat 
testing of any particular parameter is clinically relevant.
5.2
Study Materials
The following materials will be provided at study start:
•
NCI CTCAE version 4.0
•
Nivolumab IB
•
Pharmacy Binder
•
Laboratory manuals for collection and handling of blood (including PKs, biomarker and 
immunogenicity) and tissue specimens
•
Site manual for operation of IVRS, including enrollment worksheet
•
Manual for entry of local laboratory data
•
Serious Adverse Events (or eSAE) case report forms
•
EORTC QLQ-C30 and EQ-5D questionnaires
•
Pregnancy Surveillance Forms
•
CA209205 Imaging Manual.
5.3
Safety Assessments
5.3.1
Safety Assessments for Cohorts A, B, and C
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, BP, HR, 
temperature and oxygen saturation by pulse oximetry at rest and after exertion and should be 
performed within 28 days prior to first dose as described in Table 5.1.1-1 notes. Baseline signs 
and symptoms are those that are assessed within 14 days prior to first dose. Concomitant 
medications will be collected from within 14 days prior to first dose through the study treatment 
period. Additionally, medications which are used to treat AEs that are late emergent will be 
captured beyond the last dose for study treatment.
Baseline local laboratory assessments should be done within 14 days prior to first dose to 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), uric acid, 
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, P, LDH, glucose, albumin, amylase, 
lipase, urinalysis, TSH, and Hep B and C testing (HBV sAg, HCV Ab or HCV RNA) (see Table 
5.1.1-1). Pregnancy testing for WOCBP (done locally) must be performed at baseline (within 
28 days prior to first dose) and repeated within 24 hours prior to the initial administration of 
study drug, then every 4 weeks (± 7 days) regardless of dosing schedule.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase (Follow-up 
visits X01 and X02, Table 5.1.1-3) toxicity assessments should be done in person. Once subjects 
reach the survival follow-up phase either in person or documented telephone calls to assess the 
subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
Performance status and body weight should be assessed at each on study visit prior to nivolumab 
dosing and at Cycle 1 Day 8. Vital signs should also be taken as per institutional standard of care 
prior to, during, and after dosing. Oxygen saturation by pulse oximetry at rest and after exertion 
should be assessed at each on-study visit prior to nivolumab dosing. The start and stop time of 
the nivolumab infusion should be documented. Physical examinations are to be performed as 
clinically indicated. If there are any new or worsening clinically significant changes since the last 
exam, report changes on the appropriate non-serious or serious adverse event page.
On treatment local laboratory assessments should be done within 72 hours prior to dosing;
•
Extended on-treatment local laboratory assessments: Cycle 1 through Cycle 5 and every 
alternate dose thereafter (Cycle 7, 9, 11, 13, etc) and include: CBC with differential, BUN or 
serum urea level, serum creatinine, sodium, potassium, calcium, magnesium, chloride, 
amylase, lipase, glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH.
•
Limited on-study treatment laboratory assessment: beginning at Cycle 6 and every 
alternate dose thereafter (Cycle 8, 10, 12, 14, etc) and include: CBC with differential, LFTs 
(ALT, AST, total bilirubin, alkaline phosphatase) and creatinine.
In addition, TSH (with reflexive Free T4 and Free T3) should be performed every 6 weeks 
(± 7 days) from first dose regardless of dosing schedule.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug-related toxicities resolve, return to baseline or are deemed irreversible.
Oxygen saturation by pulse oximetry should be obtained prior to each dose of nivolumab and at 
any time a subject has any new or worsening respiratory symptoms. A reading at rest and on 
exertion should be obtained at each time point. The extent of the exertion should be based on the 
judgment of the investigator, but should remain consistent for each individual subject throughout 
the study. If the subject’s status changes, the investigator can alter the extent of exertion based on 
their medical judgment. If a subject shows changes on pulse oximetry or other pulmonary-related 
Revised Protocol No: 04c
Date: 22-Aug-2019
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nivolumab
signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) consistent with possible pulmonary 
adverse events, the subject should be immediately evaluated to rule out pulmonary toxicity. An 
algorithm for the management of suspected pulmonary toxicity can be found in the BMS-936558 
(nivolumab) IB.
Some of the previously referred to assessments may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
For subjects who discontinue study therapy by proceeding to allogeneic SCT, documentation 
of acute and chronic GVHD will be captured on Day 100, at 6 months, 1 year and every 
year thereafter from the date of stem cell infusion until the first non-CR after SCT is 
documented [Appendix 5]. Investigators will make telephone contact with the subject’s 
hematologist /oncologist /transplant physician to obtain this information if the subject is 
being followed by another physician.
When Cohort C subjects discontinue study therapy due to persistent one year CR, they will enter 
the Follow-up Phase. Targeted physical examination and laboratory tests will be conducted 
during FU/Observational visits (Table 5.1.1-4). NSAEs and SAEs must be collected during the 
safety follow-up visits (X01 and X02) and FU/Observational visits for a maximum of 2 years 
and minimum of 100 days after last dose, after, only SAEs related to study procedures must be 
collected. These assessments should be done in person. Once subjects complete the 
FU/Observational phase and reach the survival follow-up phase, either in person or documented 
telephone calls to assess the subject’s status are acceptable. In the event of study drug 
re-initiation after relapse, subjects will have safety assessments as described in Table 5.1.1-5.
5.3.2
Safety Assessments for Cohort D
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, BP, HR, 
temperature and oxygen saturation by pulse oximetry at rest and after exertion and should be 
performed within 28 days prior to first dose as described in Table 5.1.2-1 notes. Baseline signs 
and symptoms are those that are assessed within 14 days prior to first dose. Concomitant 
medications will be collected from within 14 days prior to first dose through the study treatment 
period. Additionally, medications which are used to treat AEs that are late emergent will be 
captured beyond the last dose for study treatment.
Only for Cohort D, evaluation for pulmonary functions test will be required during screening and 
at the end of therapy. Evaluation of cardiac function by echocardiography or nuclear medicine 
scan, and ECG will be required during screening.
Baseline local laboratory assessments should be done within 14 days prior to first dose to 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), uric acid, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, P, LDH, glucose, albumin, amylase, 
Revised Protocol No: 04c
Date: 22-Aug-2019
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CA209205
BMS-936558
nivolumab
lipase, urinalysis, TSH, and Hep B and C testing (HBV sAg, HCV Ab or HCV RNA) (see Table 
5.1.2-1). Pregnancy testing for WOCBP (done locally) must be performed at baseline (within 
28 days prior to first dose) and repeated within 24 hours prior to the initial administration of 
study drug, then every 4 weeks (± 7 days) regardless of dosing schedule.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase (Follow-up 
visits 01 and 02, Table 5.1.2-4) toxicity assessments should be done in person. Once subjects 
reach the survival follow-up phase either in person or documented telephone calls to assess the 
subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
Performance status and body weight should be assessed at each on study visit prior to nivolumab 
dosing and also on Day 8 after monotherapy dose 1. Vital signs should also be taken as per 
institutional standard of care prior to, during, and after dosing. Oxygen saturation by pulse 
oximetry at rest and after exertion should be assessed at each on-study visit prior to nivolumab 
dosing. The start and stop time of the nivolumab infusion should be documented. Physical 
examinations are to be performed as clinically indicated. If there are any new or worsening 
clinically significant changes since the last exam, report changes on the appropriate non-serious 
or serious adverse event page.
On treatment local laboratory assessments should be done within 72 hours prior to dosing.
•
Extended on-treatment local laboratory assessments: CBC with differential, BUN or 
serum urea level, serum creatinine, sodium, potassium, calcium, magnesium, chloride, 
amylase, lipase, glucose, AST, ALT, total bilirubin, alkaline phosphatase, LDH.
Extended on-treatment local laboratory assessments are required at the following time points: 
−
Monotherapy dose 1 through monotherapy dose 4
−
Day 8 after monotherapy dose 1
−
Dose 1 (Day 1) of Combocycle 1 through Combocycle 6
−
Dose 2 (Day 15) of Combocycle 1
•
Limited on-study treatment laboratory assessment: CBC with differential, LFTs (ALT, 
AST, total bilirubin, alkaline phosphatase) and creatinine.
Limited on-treatment local laboratory assessments are required at the following time points:
−
Dose 2 (Day 15) of Combocycle 2 through Combocycle 6
In addition, TSH (with reflexive Free T4 and Free T3) should be performed every 6 weeks 
(± 7 days) from first dose regardless of dosing schedule.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug-related toxicities resolve, return to baseline or are deemed irreversible.
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Oxygen saturation by pulse oximetry should be obtained prior to each dose of nivolumab and at 
any time a subject has any new or worsening respiratory symptoms. A reading at rest and on 
exertion should be obtained at each time point. The extent of the exertion should be based on the 
judgment of the investigator, but should remain consistent for each individual subject throughout 
the study. If the patient’s subject’s status changes, the investigator can alter the extent of exertion 
based on their medical judgment. If a subject shows changes on pulse oximetry or other 
pulmonary-related signs (eg, hypoxia, fever) or symptoms (eg, dyspnea, cough) consistent with 
possible pulmonary adverse events, the subject should be immediately evaluated to rule out 
pulmonary toxicity. An algorithm for the management of suspected pulmonary toxicity can be 
found in the BMS-936558 (nivolumab) IB.
Some of the previously referred to assessments may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
Cohort D, subject who completes Dose 2 (Day 15) of Combocycle 6, or subject who is 
discontinued from study therapy during the combination phase, enter FU/observational phase. 
Targeted physical examination will be conducted during Safety follow-up visits 1 &2 and 
FU/Observational visits (Table 5.1.2-4), laboratory tests will be performed during Safety follow-
up visits 1 &2.
Laboratory Assessment after Completion of Treatment: 
•
During Safety Follow up 01 and 02 visits: 
CBC with differential, BUN or serum urea level, serum creatinine, sodium, potassium, 
calcium, magnesium, chloride, glucose, AST, ALT, total bilirubin, alkaline phosphatase, 
LDH.
NSAEs and SAEs must be collected during the Safety Follow-up visits 1 and 2. All SAEs that 
occur during the screening period and within 100 days of discontinuation of dosing must be 
collected. If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (eg, a follow-up skin biopsy). The investigator should report any SAE that occurs after 
these time periods and that is believed to be related to study drug or protocol-specified 
procedure.
5.3.3
Imaging Assessment for the Study
Images will be submitted to an imaging corelab for central review. Sites will be trained prior to 
scanning the first study subject. Image acquisition guidelines and submission process will be 
outlined in the CA209205 Imaging Manual to be provided by the corelab.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
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5.4
Efficacy Assessments
For Cohorts A, B, and C, the primary efficacy assessment is ORR, defined as a subject achieving 
either a PR or CR according to the revised International Working Group Criteria for Malignant 
Lymphoma (Appendix 2).
For Cohort D, efficacy assessment is conducted according to 2007 IWG criteria (Appendix 2).
Additional assessments, for example, Deauville scoring, may also be performed.
The primary efficacy assessment, along with the secondary endpoints of DOR, complete and 
partial remission rates and durations will be based on IRRC assessments. Assessment of ORR, 
based on investigator assessments, will be examined as a secondary endpoint. Sites are required 
to send all on-study disease assessments to the IRRC for review.
For Cohorts A, B, and C, once subjects discontinue study therapy by proceeding to 
allogeneic SCT or ASCT, they will not undergo IRRC- radiographic assessments as 
described in Table 5.4.1.1-1 and Table 5.4.1.1-2. Instead, they will be evaluated using the 
following schedule. Tumor assessment (CR or non-CR) will be assessed by the 
investigator according to the 2007 IWG criteria and will be required on Day 100, at 
6 months, 1 year and every year thereafter from the date of stem cell infusion until the 
first non-CR after SCT is documented. Investigators will make telephone contacts with the 
subject’s referring hematologist/oncologist/transplant physician to obtain CR or non-CR 
status and document the status if subject is being followed by another physician.
For Cohort C subjects, relapse after discontinuation of study therapy due to persistent one year 
CR will be determined by 2007 IWG criteria. 
5.4.1
Radiographic Assessments
5.4.1.1
Radiographic Assessments for Cohorts A, B, and C
Radiographic study evaluations will take place in accordance with the flow charts in Section 5.1
and Table 5.4.1.1-1 and Table 5.4.1.1-2. Baseline assessments should be performed within 
28 days prior to the first dose, utilizing CT (preferred) or MRI. In addition to chest, abdomen, 
and pelvis, all known sites of disease should be assessed at baseline. A baseline FDG-PET scan 
is required at screening.
On-study assessments should include chest, abdomen, and pelvis, and all known sites of disease 
(eg neck) and should use the same imaging method as used at baseline.
Subjects will be evaluated for tumor responses by CT (preferred) or MRI at Week 9 (± 7 days) 
after the start of therapy and then at Weeks 17, 25, 37 and 49 during the first year of treatment,
then every 16 weeks (± 14 days) up to Week 97, continuing every 26 weeks (± 21 days) beyond 
Week 97, until disease progression is documented, or until the subject initiates a preparative 
regimen for allogeneic SCT or ASCT, whichever occurs earlier. On-treatment FDG-PET scan 
will be required for all subjects at Weeks 17 and 25 (± 7 days). Additionally, a FDG-PET scan at 
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Week 49 (± 7 days) is required for subjects who do not have two consecutive negative FDG-PET 
scans after Week 1 and prior to Week 49. FDG-PET scan will also be required for confirmation 
of radiographic CR after initiation of the study drug at other time points where FDG-PET is not 
otherwise scheduled; this FDG-PET scan should be performed within 4 weeks of a CT scan.
Tumor assessments for ongoing study treatment decisions will be completed by the investigator 
using 2007 IWG criteria (Appendix 2).
Table 5.4.1.1-1:
Schedule of CT or MRI Tumor Assessments for Cohorts A, B, and 
C
Time On Study
Assessment 
Frequency
Assessment Week
(Day 1 of Week Shown)
Assessment Window
Baseline
Once
Screening
Within 28 days prior to 
first dosea
Until Week 49
-
9, 17, 25, 37, 49
± 7 days
Between Week 50 and Week 97
Every 16 weeks
65, 81, 97
± 14 days
Beyond Week 97
Every 26 weeks
123, 149, 175+
± 21 days
Cohort C subjects, 1 year after 
first CR confirmation
Once
-
± 14 daysb
a For Cohort C subjects who re-initiate treatment, the CT scan used to confirm relapse will serve as new baseline 
scan, study drug should then be re-initiated within 28 days
b Not required if a scheduled CT or MRI was performed within 8 weeks of the date of first confirmed CR plus 
1 year
Note: Once subjects discontinue study therapy by proceeding to allogeneic SCT or ASCT, they will not undergo 
IRRC radiographic assessments described here, but will be followed with specific schedule (see Section 5.4).
Table 5.4.1.1-2:
Schedule of FDG-PET Tumor Assessments for Cohorts A, B, and C
Assessment Week
(Day 1 of Week Shown)
Assessment Window
All subjects
Screening
Within 28 days prior to first 
dose
All subjects 
17
± 7 days
All subjects
25
± 7 days
Subjects who do not have two consecutive 
negative FDG-PET scans after Week 1 and prior 
to Week 49 
49
± 7 days
Confirmation of the first CR after initiation of the 
study drug
Other time points
Within 4 weeks of CT
Note: Once subjects discontinue study therapy by proceeding to allogeneic SCT or ASCT, they will not undergo 
IRRC radiographic assessments described here but will be followed with specific schedule (see Section 5.4).
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When Cohort C subjects discontinue study therapy due to persistent one year CR, CT (preferred) 
or MRI will be required for CR confirmation as described in Table 5.4.1.1-1. These subjects will 
then require CT (preferred) or MRI at the time of the first FU/Observational visit: 6 months 
(± 14 days) from last dose of study drug, or if clinically indicated (ie clinical evidence of 
relapse). 
Relapse will be determined using 2007 IWG criteria, the CT (preferred) or MRI used for relapse 
assessment will serve as new baseline in case of re-initiation of study drug. A new set of target 
and non-target lesions will be defined and subsequent response assessment during re-initiation of 
treatment will be based on this new set. 
5.4.1.2
Radiographic Assessments for Cohort D
Radiographic study evaluations will take place in accordance with the flow charts in Section 5.1,
Table 5.4.1.2-1 and Table 5.4.1.2-2 and as shown in Figure 5.4.1.2-1. Baseline assessments 
should be performed prior to the first dose, utilizing CT (preferred) or MRI. In addition to chest, 
abdomen, and pelvis, all known sites of disease should be assessed at baseline. A baseline 
FDG-PET scan is also required at screening.
On-study assessments should include chest, abdomen, and pelvis, and all known sites of disease 
(eg, neck) and should use the same imaging method as used at baseline. Tumor assessments for 
ongoing study treatment decisions will be completed by the investigator using 2007 IWG criteria 
(Appendix 2).
The first scheduled on-treatment radiographic assessments are FDG-PET scans and CT 
(preferred) or MRI after Monotherapy dose 4. FDG-PET scans should be scheduled at least 
4 days before the start of Combocycle 1 (4 days excluding the day of subsequent cycle). CT 
(preferred) or MRI can be performed anytime between the monotherapy Dose 4 and first 
Combocycle dose.
The subjects who have early discontinuation of nivolumab during monotherapy phase and who 
enter combination phase will require the following end-of-monotherapy radiographic 
assessments before starting the combination treatment. 
•
CT (preferred) or MRI will be required if previous assessment was conducted > 4 weeks ago.
•
FDG-PET scan will be required if previous assessment was conducted > 4 weeks ago.
The second scheduled on-treatment radiographic assessments are post-Combocycle 2 FDG-PET 
scan, and CT (preferred) or MRI after Combocycle 2 and before Combocycle 3. This interim 
FDG-PET scan is optional if a previous scheduled or unscheduled FDG-PET scan after the first 
dose was negative based on investigator’s assessment. This interim PET study should be 
scheduled at least 4 days before the start of Combocycle 3 (4 days excluding the day of 
subsequent cycle). CT (preferred) or MRI can be performed anytime after Combocycle 2 and 
before Combocycle 3.
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The end-of-therapy radiographic assessments should be conducted at 9 weeks (± 14 days) from 
the last dose, which is between Follow-up visit 1 and Follow-up visit 2. End-of-therapy 
FDG-PET, and CT (preferred) or MRI scans are mandatory for all subjects. When 
end-of-therapy FDG-PET scans are positive based on investigator’s assessment, tumor biopsy for 
an FDG-avid lesion is strongly encouraged whenever possible. Tumor biopsy for an FDG-avid 
lesion in other situation is also permitted if clinically indicated 
After the end-of-therapy radiographic assessments, CT (preferred) or MRI are required at visit 04 
(39 weeks from the last dose), visit 06 (65 weeks from the last dose), and visit 09 (104 weeks 
from the last dose), during the first two years from the last dose (Table 5.4.1.2-1). Thereafter, no 
radiographic tumor assessment will be required.
Additional FDG-PET and CT (preferred) or MRI can be conducted when clinically indicated. All 
scans for radiographic tumor assessments while on study will be collected and be evaluated by 
IRRC.
Figure 5.4.1.2-1:
Cohort D - Radiographic Assessment Schedule (Treatment Phase)
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Table 5.4.1.2-1:
Schedule of CT (or MRI) Tumor Assessment for Cohort D
Time point
Population
Assessment timing 
Assessment Window
Baseline
All subjects
Screening
Within 28 days prior to 
first dose
End-of-monotherapy assessments
when four nivolumab monotherapy 
doses are not completeda
Only subjects 
who have early 
discontinuation of 
nivolumab 
monotherapy 
during 
monotherapy 
phase and who 
enter combination 
phase
at the end of 
monotherapy
anytime between the 
last monotherapy dose 
and first Combocycle 
dose
Post-Monotherapy dose 4
assessments
All subjects who 
completed 4
doses of 
nivolumab 
monotherapy
after monotherapy dose 4
and before entering 
combination phase
anytime between the 
monotherapy dose 4 and 
first Combocycle dose
Post-Combocycle 2 assessments
All subjects who 
have completed 
Combocycle 2
after Combocycle 2 and 
before Combocycle 3
anytime between
Combocycle 2 and 
Combocycle 3
End-of-therapy radiographic 
assessments
All subjects
9 weeks from the last 
dose, which is between 
Follow-up visit 1 and 
Follow-up visit 2.
± 14 days
FU/Observational visit 04 (39 
weeks)
All subjects
39 weeks from the last 
dose
± 21 days
FU/Observational visit 06 (65 
weeks)
All subjects
65 weeks from the last 
dose
± 21 days
FU/Observational visit 09 
(104 weeks)
All subjects
104 weeks from the last 
dose
± 21 days
a CT (preferred) or MRI will be required if previous assessment was conducted > 4 weeks ago. 
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Table 5.4.1.2-2:
Schedule of FDG-PET Tumor Assessments for Cohort D
Time point
Population
Assessment timing 
Assessment Window
Baseline
All subjects
Screening
Within 28 days prior to first 
dose
End-of-monotherapy 
assessments when four
nivolumab monotherapy 
doses are not completed.a
Only subjects who have 
not completed 4 dose of
nivolumab monotherapy, 
and who enter 
Combination phase
at the end of 
monotherapy
anytime between the last 
monotherapy dose and first 
Combocycle dose. Preferably 
at least 10 days after last 
monotherapy dose
Post-Monotherapy dose 4
assessments
All subjects who 
completed 4 doses of 
nivolumab monotherapy
after monotherapy 
dose 4 and before 
entering 
Combination phase
After monotherapy Dose 4 
and at least 4 days prior to 
first Combocycle dose 
(4 days excluding the day of 
subsequent cycle)
Post-Combocycle 2 
assessmentsb
All subjects who have 
completed Combocycle 2
after Combocycle 2 
and before 
Combocycle 3
At least 4 days before the 
start of Combocycle 3 
(4 days excluding the day of 
subsequent cycle).
End-of-therapy radiographic 
assessments
All subjects
nine weeks from 
the last dose, which 
is between Follow-
up visit 1 and 
Follow-up visit 2.
± 14 days
a FDG-PET scan will be required if a previous assessment was conducted > 4 weeks ago.
b Post-Combocycle 2 PET scan is optional if previous PET was negative
5.4.2
Assessment of Overall Tumor Burden and Measurable Disease
To serially evaluate tumor response to therapy, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable tumor lesion. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows in Sections 5.4.2.1 and 5.4.2.2.
5.4.2.1
Measurable Lesions
Measurable lesions must be accurately measured in at least two perpendicular dimensions based 
on 2007 IWG criteria.89 The following lesions should be considered as measurable lesions.
•
Lesion(s) with the long axis > 15 mm regardless of the short axis, and 
•
Lesion(s) with the long axis 11 - 15 mm and with short axis > 10 mm.
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Please note that, to be eligible for this study, a subject must have at least one lesion that is 
> 15 mm (1.5 cm) in the longest diameter on cross-sectional imaging and measureable in two 
perpendicular dimensions on CT (or MRI). Refer to inclusion criteria Section 3.3.1.
If possible, nodes or masses should be from disparate regions of the body and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
5.4.2.2
Non-Measurable Lesions
All other lesions, including small lymph nodes (longest diameter < 10 mm) as well as truly non-
measurable lesions.
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.
5.4.3
Specifications by Method of Assessment
5.4.3.1
Measurement of Lesions
All measurements should be recorded in mm. All baseline evaluations should be performed as 
close as possible to the treatment start and never more than 28 days before the beginning of 
treatment.
5.4.3.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical 
5.4.3.3
CT or MRI Scan
CT or MRI is the best currently available and reproducible method to measure lesions selected 
for response assessment. Measurability of lesions on CT or MRI scan is based on the assumption 
that CT or MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
Note on PET/CT scans: Combined modality scanning such as with PET/CT is increasingly used 
in clinical care. Low dose or attenuation correction CT portions of a combined PET/CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for anatomically 
based measurements. However, if a site can document that the CT performed as part of a 
PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the 
CT portion of the PET/CT can be used for measurements.
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5.4.3.4
Clinical Lesions
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers. As previously noted, when lesions can be evaluated both by 
clinical exam and imaging, imaging evaluation should be undertaken since it is more objective 
and may also be reviewed by the IRRC.
5.4.3.5
FDG-PET scan
For Cohorts A, B, and C, a baseline FDG-PET scan is required for each treated subject at 
screening (within 28 days prior to first dose) and at Weeks 17 and 25 (± 7 days). Additionally, a 
FDG-PET scan at Week 49 (± 7 days) is required for subjects who do not have two consecutive 
negative FDG-PET scans after Week 1 and prior to Week 49. FDG-PET scan will also be 
required for confirmation of radiographic CR after initiation of the study drug at other time
points where FDG-PET is not otherwise scheduled; this FDG-PET scan should be performed 
within 4 weeks of a CT scan.
For Cohort D, a baseline FDG-PET scan is required for each treated subject at screening (within 
28 days prior to first dose). Two interim FDG-PET scans are planned: post-monotherapy dose 4
and post-Combocycle 2. The interim FDG-PET scan post-monotherapy dose 4 is required for 
each treated subject while the interim FDG-PET scan post-Combocycle 2 is optional if a 
previous scheduled or unscheduled FDG-PET scan after the first dose was negative based on the 
investigator’s assessment. These interim PET studies should be scheduled at least 4 days before 
the start of the subsequent cycle (4 days excluding the day of subsequent cycle). The end-of-
therapy FDG-PET should be conducted 9 weeks (± 14 days) from the last study treatment.
5.4.4
Baseline Documentation of “Target” and “Non-Target” Lesions
5.4.4.1
Target Lesions
At baseline, up to 6 of the largest dominant nodes or nodal masses meeting the criteria for 
measurable lesions given in Section 5.4.2.1 should be identified as target lesions and their 
measurements recorded.
Target lesions should be selected according to the definitions of abnormal lesion in 2007 IWG 
criteria.
•
Lesion(s) with the long axis > 15 mm regardless of the short axis, or
•
Lesion(s) with the long axis 11 to 15 mm and with short axis > 10 mm.
Other measurable lesions will be designated as non-target lesions.
A sum of the product of the diameters (SPD) will be calculated for all target lesions and recorded 
as the baseline SPD. The baseline SPD will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.
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5.4.4.2
Non-Target Lesions
All other lesions (or sites of disease) including non-measurable lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
multiple liver nodules’).
5.4.5
Bone Marrow Assessments
To determine the extent of disease involvement of the bone marrow, a bone marrow 
biopsy/aspirate performed at screening or within 90 days prior to enrolment must be 
documented. Subjects may start the study drug before bone marrow biopsy results become 
available; results must be documented in the subject’s medical record when becoming available.
If a bone marrow biopsy/aspirate needs to be performed during the screening period, an aspirate 
sample for biomarker analyses as per Table 5.6-1 must be submitted.
For subjects with marrow involvement at screening, a bone marrow biopsy and aspirate will be 
required to confirm a CR, and submission of bone marrow aspirate samples is mandatory as 
detailed in Table 5.6-1. 
For Cohorts C and D, FDG-PET at baseline can be used in lieu of a bone marrow biopsy/ 
aspirate. No evidence of FDG-avid disease in the bone marrow will be required to confirm CR 
for all subjects regardless of FDG-PET results in the bone marrow at baseline.
5.4.6
Disease Response Evaluation
The determination of disease response to study treatment will be made using 2007 IWG criteria 
(Appendix 2).
For Cohorts C and D, bone marrow assessment will be based on 2014 Lugano classification in 
which FDG-PET can be used in lieu of bone marrow aspirate/ biopsy.90
The 2007 IWG criteria define relapsed disease or progressive disease based largely on the 
evaluation of nodal masses, spleen/liver, and bone marrow (Appendix 2). The criteria also 
stipulate that disease that is only assessable but not measureable (eg, pleural effusion or bone 
lesion) will be recorded as “present” or “absent”, unless such an assessable abnormality, noted 
by imaging studies or physical examination, is confirmed to be histologically negative. For 
purposes of protocol-defined disease progression, the appearance of new sites of assessable but 
not measureable disease while on treatment meets protocol criteria for disease progression if 
histological results are documented (eg, the presence of lymphoma cells in a pleural effusion or 
spinal fluid).
Immunotherapeutic agents produce atypical clinical response patterns which are not usually 
observed in conventional chemotherapy. Two distinct non-conventional patterns have been 
reported: a reduction in total tumor burden despite of the appearance of new lesion(s), and 
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responses after a transit increase in total tumor burden in an initial phase, followed by subsequent 
tumor shrinkage.91 These two patterns have also been recognized in the subjects who were 
treated with nivolumab monotherapy in the CA209039 Phase 1 study (Figure 1.4.3.4-1).
Therefore, appearance of new lesions during nivolumab monotherapy may not necessarily 
indicate true disease progression although this should be reported as disease progression 
according to 2007 IWG criteria for all four cohorts in this study.
5.5
Pharmacokinetic Assessments
Samples for pharmacokinetic and immunogenicity assessments will be collected for all subjects 
receiving nivolumab. Table 5.5-1
lists the sampling schedule to be followed for 
pharmacokinetics and immunogenicity for Cohorts A, B, and C. Table 5.5-2 lists the sampling 
schedule to be followed for pharmacokinetics and immunogenicity for Cohort D. All time points 
are relative to the start of nivolumab infusion. All on-treatment PK time points are intended to 
align with days on which nivolumab is administered. If it is known that a dose is going to be 
delayed, then the predose sample should be collected just prior to the delayed dose. However, if 
a predose sample is collected, but the dose is subsequently delayed, an additional predose sample 
should not be collected. Further details of blood collection and processing will be provided in the 
procedure manual.
Table 5.5-1:
Sampling Schedule for Cohorts A, B, and C
Study Daya
Event 
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour: Min
Nivolumab PK
Blood Sample
Nivolumab 
Immunogenicity 
Sample
Cycle 1 Day 1
predosea
00:00
X
X
Cycle 3 Day 1
predosea
00:00
X
X
Cycle 7 Day 1
predosea
00:00
X
X
Cycle 13 Day 1
predosea
00:00
X
X
Day 1 of every 12th 
cycle up to Cycle 49
predosea
00:00
X
X
a Predose samples should be taken just prior to the start of Nivolumab infusion (preferably within 30 minutes, 
however predose collection up to 4 hours before study drug administration would be acceptable). If the infusion is 
delayed and a predose sample was already collected, there is no need to collect an additional predose sample.
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Table 5.5-2:
Sampling Schedule for Cohort D
Study Day
Event
Time (Relative to 
Start of Nivolumab 
Infusion)
Hour: Min
Nivolumab PK
Blood Sample
Nivolumab 
Immunogenicity 
Sample
Monotherapy Dose 1
Predoseb
00:00
X
X
Monotherapy Dose 3
Predoseb
00:00
X
X
Combocycle 1 Day 1a
Predoseb
00:00
X
X
Combocycle 4 Day 1
Predoseb
00:00
X
X
First 2 Follow-up 
Visits FU1 & FU2
X
X
a For subjects who discontinue nivolumab monotherapy before the end of monotherapy dose 4, blood samples for 
nivolumab will be collected at the start of combination cycle.
b Predose samples should be taken just prior to the start of Nivolumab infusion (preferably within 30 minutes, 
however predose collection up to 4 hours before study drug administration would be acceptable). If the infusion is 
delayed and a predose sample was already collected, there is no need to collect an additional predose sample.
5.5.1
Pharmacokinetic Sample Analysis
Serum samples will be analyzed for nivolumab concentrations by a validated method. In 
addition, selected samples may be analyzed by an exploratory analytical method that measures 
nivolumab for technology exploration purposes; exploratory results will not be reported.
5.6
Biomarker Assessments
Peripheral blood and tumor tissue will be collected prior to therapy and at selected time points on 
treatment as outlined in Table 5.6-1 for Cohorts A, B, and C and Table 5.6-2 for Cohort D, 
unless restricted by local requirements. 
Tumor Biopsy
Minimum of 1 FFPE tumor tissue block (preferred) OR minimum of 10 FFPE unstained sections 
are required for assessment of PD-L1 status and other biomarker evaluations. For Cohort D, a 
minimum of 15 unstained slides, preferably 20, is required.
Tumor samples obtained from bone metastases are not considered acceptable for PD-L1 testing 
because the PD-L1 assay does not include a decalcification step. For any cases where the only 
tumor tissue available is from a bone metastasis lesion, please discuss further with the study 
Medical Monitor.
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Exploratory Analysis for Tumor Biopsy during Nivolumab Monotherapy in Cohort D
(Optional)
In order to assess the immune response to nivolumab therapy, patients will undergo tumor 
biopsies during screening and, optionally, at any time during the monotherapy phase (ideally, 
approximately 3 weeks following the initiation of nivolumab monotherapy) if the procedure is 
deemed as safe by investigators. Tumor biopsies can be either excisional, incisional, or core 
needle. Excisional or incisional biopsies are encouraged whenever possible. In addition to 
preparing a FFPE tumor tissue block or 15 unstained slides per standard protocols, the 
remaining tumor biopsy specimen should be sent en bloc in media on ice. Please refer to 
laboratory manual for the shipping address and procedural details. Viable tumor cell suspensions 
will be prepared for comprehensive CyTOF analysis and single cell RNAseq. The receiving 
laboratory should be contacted on the day before the planned biopsy procedure regarding the 
planned shipment. Please note that submission of tumor tissue (FFPE tumor tissue block or a 
minimum of 15 unstained slides, preferably 20, per standard protocols) from a biopsy performed 
during screening, or within 90 days prior to enrollment is still mandatory for all subjects of 
Cohort D.
Bone Marrow Aspirates
For Cohorts A and B, samples from bone marrow aspirates performed at screening and during 
CR evaluation (only for subjects who had marrow involvement at study entry) must be submitted 
for biomarker assessment. These will be utilized to assess the phenotypic and functional status of 
immune cells and tumor cells.
In all cohorts, for subjects who had bone marrow biopsies performed at any time during therapy, 
if clinically indicated, submission of the bone marrow aspirates is strongly encouraged.
Bone marrow aspirates will be obtained using institutional standards for these procedures.
A schedule of biomarkers evaluations is provided in Table 5.6-1.
Soluble Biomarkers
Soluble factors, such as cytokines, chemokines, soluble receptors, and antibodies to tumor 
antigens will be characterized and quantified by immunoassays in serum. Analyses may include, 
but not necessarily be limited to, soluble CD25, soluble PD-1, soluble LAG-3, and CXCL-9.
Collected serum samples will also be used for the assessment of tumor antigen-specific 
responses elicited following treatment with study therapy to explore which antitumor antibodies 
are most associated with clinical response. Antibody levels to cancer test antigens will be 
assessed by multiplex assays and enzyme-linked immunosorbent assay (ELISA).
Immunophenotyping of PBMC and Bone Marrow Aspirates
The proportion of specific lymphocyte subsets and expression levels of T cell co-stimulatory 
markers in PBMC preparations will be quantified by flow cytometry. Analyses may include, but 
not necessarily be limited to, the proportion of T, B, and NK cells, proportion of memory and 
effector T cell subsets, and expression levels of PD-1, PD-L1, PD-L2, ICOS, and Ki67.
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Ex vivo Functional Assays
To explore whether nivolumab will restore T cell activation and function, PBMCs will be 
isolated and cryopreserved. Assays of the functional status of effector T cells will be performed, 
including but not limited to, assays for IFN-γ and CD107.
Peripheral Blood Gene Expression
The expression level of genes and miRNA related to response to nivolumab monotherapy will be 
quantified molecular methods such as Affymetrix by microarray and/or quantitative RT-PCR 
analysis in whole blood samples. Analysis may include, but not necessarily be limited to, genes 
associated with immune-related pathways, such as T cell activation and antigen processing and 
presentation.
T cell Repertoire Analysis
Low diversity of the peripheral T cell compartment has been shown to correlate with poor OS in 
metastatic breast cancer. A standing theory in immuno-oncology suggests a diverse and activated 
immune environment is better adept at eradicating tumor compared to a skewed repertoire of 
naïve and tolerized T cells. In order to explore whether a diverse T cell repertoire is predictive of 
response to therapy, next generation, high-throughput, Deoxyribonucleic acid (DNA) sequencing 
will be performed on DNA isolated from peripheral blood and tumor tissue to quantitate the
composition of the T cell repertoire prior to, and during, monotherapy.
SNP Analysis
In order to identify potential polymorphisms associated with safety and efficacy of nivolumab, 
selected genes will be evaluated for single nucleotide polymorphisms (SNP). Analysis will be 
limited to sequence polymorphisms linked to genes associated with the PD-1/PD-L1 pathway 
and activated T cell phenotype, including PD-1, PD-L1, PD-L2, and CTLA-4. A blood sample 
will be obtained at Day 1, unless restricted by local requirements.
Tumor-Based Biomarker Measures
Tumor biopsy specimens will be obtained from consenting subjects prior to nivolumab to 
characterize immune cell populations and expression of selected tumor markers. Submission of 
tumor biopsy is mandatory for subjects with accessible lesions prior to therapy and on-treatment 
biopsy samples are optional.
Submission of tumor tissue from a biopsy performed during screening is mandatory for 
biomarker analysis. If this is not possible, archival tissue from a previous biopsy can be used.
For subjects who had tumor biopsies performed at any time during therapy, if clinically 
indicated, submission of the biopsy samples is strongly encouraged. 
Biopsy samples may be used for the following assessments:
Characterization of TILs and tumor antigens IHC will be used to assess the number and 
composition of immune infiltrates in order to define the immune cell subsets present within 
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FFPE tumor tissue before and after exposure to therapy. These IHC analyses will include, but not 
necessarily be limited to, the following markers: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2. 
Characterization of tumor genotype and phenotype
Gene mutations, chromosomal translocations, aberrant expressions, and epigenetic modifications 
within tumor cells will be characterized and explored by IHC and RNA/DNA analysis of tumor 
biopsies. Associations of altered tumor cell genetic structure with nivolumab efficacy will be 
performed.
Characterization of T cell repertoire
As described above, DNA sequencing will be performed on pre- and post treatment tumor tissue 
to assess the composition of the T cell repertoire. DNA will be isolated from either the FFPE 
tumor block or from RNAlater or equivalent preparations.
Gene expression profiling
Tumor biopsies that are collected in RNAlater or equivalent fixative will be examined for mRNA 
and miRNA gene expression by Affymetrix gene array technology and/or quantitative real-time 
polymerase chain reaction (qPCR) to detect expression of selected immune-related genes and 
regulatory pathways.
Complete instructions on the collection, processing, handling, and shipment of all samples 
described herein will be provided in a separate procedure manual at the time of study initiation.
Plasma samples
Plasma samples will be collected for subjects in Cohorts C and D for, but not limited to, the 
determination of Minimal Residual Disease (MRD). For this purpose, novel sequencing-based 
methods can detect circulating tumor DNA (ctDNA) in plasma isolated from whole blood of 
subjects with great sensitivity which opens new opportunities for molecular monitoring before, 
during, and after therapy. Beyond monitoring, ctDNA can also be used as a “liquid biopsy” to 
assess for molecular changes during the course of the therapy that may identify the emergence of 
treatment-resistant clones in the subjects at risk of relapse.
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Table 5.6-1:
CA209205 Biomarker Sampling Schedule for Cohorts A, B, and C
Collection Time
Serum
PBMC
Tumor 
Biopsy
Bone 
Marrow 
Biopsy
Bone 
Marrow 
Aspirate
Whole Blood
Plasma
(ctDNA)a
Study Dayb
Soluble 
Biomarker
Immuno-
phenotyping
Ex-vivo 
Functional
Gene 
Expression
SNP
Screening
Xc
Xd
X
X
Cycle 1 Day 1
X
X
X
X
X
Cycle 2 Day 1
X
X
X
Cycle 3 Day 1
X
X
X
Cycle 4 Day 1
X
X
X
X
Cycle 7 Day 1
X
X
X
Cycle 11 Day 1
X
Cycle 15 Day 1
X
Cycle 19 Day 1
X
Cycle 23 Day 1
X
Cycle 27 Day 1
X
Cycle 68 Day 1
X
Cycle 81 Day 1
X
CR Evaluation
X
X
Xe
Xe
X
X
X
During Treatment (when
clinically indicated)
Xf
Xf
Xf
At Study Drug Discontinuation
Xg
Safety FU X02
Xg
FU/Observational 1
Xg
FU/Observational 2
Xg
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Table 5.6-1:
CA209205 Biomarker Sampling Schedule for Cohorts A, B, and C
Collection Time
Serum
PBMC
Tumor 
Biopsy
Bone 
Marrow 
Biopsy
Bone 
Marrow 
Aspirate
Whole Blood
Plasma
(ctDNA)a
Study Dayb
Soluble 
Biomarker
Immuno-
phenotyping
Ex-vivo 
Functional
Gene 
Expression
SNP
FU/Observational 3
Xg
FU/Observational 4
Xg
FU/Observational 5
Xg
FU/Observational 6
Xg
Upon Progressionh
X 
(optional)
X
(optional)
X 
(optional)
X 
(optional)
X 
(optional)
X 
(optional)
X 
(strongly 
recom-
mended)
a Plasma (ctDNA) sample collection is only applicable to Cohort C subjects.
b On-treatment biomarker samples will be collected prior to administration of study drug and may be obtained ± 3 days of the indicated time (except for Cycle 1 
Day 1).
c Submission of tumor tissue from a biopsy performed during screening is mandatory (see the details in Section 3.1 and Table 5.1.1-1).
d For Cohorts A and B, extent of disease involvement in the bone marrow must be documented at screening based on the results of a bone marrow 
biopsy/aspirate performed within 90 days prior to enrolment or a bone marrow biopsy/aspirate performed during the screening period. If bone marrow 
biopsy/aspirate is performed during screening (after obtaining informed consent), submission of bone marrow aspirate is mandatory. Submission of bone 
marrow biopsy specimen is not required at any point in the study. For Cohort C, performing a bone marrow biopsy/aspirate is optional and submission of bone 
marrow aspirate, if performed, is optional.
e For Cohorts A and B, if the bone marrow was involved by lymphoma at baseline, a bone marrow biopsy and aspirate will be required to confirm a CR. 
Submission of bone marrow aspirate is mandatory in this case.
f All subjects may volunteer to undergo tumor and/or bone marrow biopsies at any time during therapy if clinically indicated. When tumor biopsy is performed, 
submission of tumor biopsy is strongly encouraged. When bone marrow biopsy is done, submission of bone marrow aspirate is strongly encouraged.
g Only for those Cohort C subjects who discontinued study drug due to persistent CR for one year.
h Sample submission upon progression is optional (except for plasma, which is strongly recommended) and can be taken ± 7 days at the discretion of the 
investigator.
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Table 5.6-2:
CA209205 Biomarker Sampling Schedule for Cohort D
Collection Timea
Serum
PBMC
Tumor Biopsy
Whole Blood
Plasma (ctDNA)
Study Day
Soluble Biomarker
Immuno-phenotyping
SNP
Screening
Xb
Monotherapy Dose 1
X
X
X
Monotherapy Dose 3
X
X
Tumor biopsy during 
monotherapy phase 
X (optional)c
Combocycle 1 Day 1
X
X
Combocycle 3 Day 1
X
X
Combocycle 5 Day 1
X
X
Tumor biopsy during 
combotherapy phase
X (optional)d
Safety Follow up 1 
X
X
X
Upon Progressione
X (optional)
X (optional)
X (optional)
a On-treatment biomarker samples will be collected prior to administration of study drug and may be obtained ± 3 days of the indicated time (except for 
Monocycle 1 Day 1).
b Submission of tumor tissue from a biopsy performed during screening is mandatory (see the details in Section 3.1.2 and Table 5.1.2-1).
c All subjects may volunteer to undergo tumor biopsies for exploratory analysis at any time during monotherapy phase if the procedure is deemed as safe by 
investigators. When tumor biopsy is performed, specimen of tumor biopsy should be submitted.
d All subjects may volunteer to undergo tumor biopsies at any time during therapy if clinically indicated. 
e All sample submission upon progression is optional up to 3 years from the last dose of study treatment at the discretion of the investigator.
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5.7
Outcomes Research Assessments
Outcomes research data including health-related quality of life and patient reported symptom 
burden provide a more complete understanding of the impact of treatment by incorporating the 
subjects’ perspective. These data offer insights into the patient experience that may not be 
captured through physician reporting. Generic health-related quality of life scales provide data 
necessary in calculating utility values for health economic models. The EQ-5D will be collected 
in order to assess the impact of nivolumab on generic health-related quality of life and the data 
will be used for populating health economic models most notably, cost effectiveness analysis. 
The EORTC QLQ-C30 will be collected in order to assess cancer specific health-related quality 
of life. The combination of the generic scale for general health status and economic evaluation 
and the cancer specific scale will provide a robust outcomes research package. 
The EORTC QLQ-C30 is one the most commonly used QoL instrument in oncology studies. The 
EORTC QLQ-C30 is a 30-item instrument comprising six functional scales (physical 
functioning, cognitive functioning, emotional functioning, role functioning, social functioning 
and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, 
dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Except for the 
overall health status and global quality of life items, responses for all items are 4-point 
categorical scales ranging from 1 (Not at all) to 4 (Very much). The overall health status/quality 
of life responses are 7-point Likert scales. 
General health status will be measured using the EQ-5D. The EQ-5D is a standardized 
instrument for use as a measure of self-reported general health status. The EQ-5D comprises 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety) and a visual 
analog rating scale (VAS). The utility data generated from the EQ-5D is recommended for and 
commonly used in cost effectiveness analysis.
All QoL assessments will be administered as outlined in Table 5.1.1-2, Table 5.1.1-3, Table 
5.1.1-4, Table 5.1.2-2, Table 5.1.2-3 and Table 5.1.2-4. EORTC-QLQ-C30 will be collected for 
Cohorts A, B, and C. EQ-5D will be collected for Cohorts A, B, C, and D.
Outcomes research data will not be collected for subjects who re-initiate study therapy (Cohort C 
subjects).
5.8
Other Assessments 
5.8.1
Immunogenicity Assessments
Serum samples collected at time points identified in Table 5.5-1 (Cohorts A, B, and C) and Table 
5.5-2 (Cohort D) will be analyzed by a validated immunoassay. Additional characterization (ie,
neutralizing antibodies) for any detected anti-drug antibodies (ADA) response to nivolumab may 
also be performed using a validated functional cell-based assay. All on-treatment 
immunogenicity assessment time points are intended to align with days on which nivolumab is 
administered. If it is known that a dose is going to be delayed, then the predose sample should be 
collected just prior to the delayed dose. However, if a predose sample is collected, but the dose is 
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subsequently delayed, an additional predose sample should not be collected. Selected serum 
samples may be analyzed by an exploratory method that measures anti-nivolumab antibodies for 
technology exploration purposes; exploratory results will not be reported. 
In addition, serum samples designated for PK or biomarker assessments may also be used for 
immunogenicity analysis if required (eg, if there is insufficient volume for complete 
immunogenicity assessment or to follow up on suspected immunogenicity-related AE).
5.9
Results of Central Assessments
The primary endpoint for Cohorts A, B, and C is ORR, as determined by the IRRC.
For Cohort D, OR and CR for secondary and exploratory endpoints are also determined by the 
IRRC.
Site will be informed of quality issues or needs for repeat scanning via queries from the corelab. 
Results of central Imaging analysis will not be returned to the site.
For Cohort D, histology of cHL will be confirmed later by a central pathological laboratory; 
subjects may start the first dose after cHL histology is confirmed by a local pathological 
laboratory.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
BMS 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.
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
•
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect 
•
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See 
Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)
−
elective surgery, planned prior to signing consent
−
admissions as per protocol for a planned medical/surgical procedure
−
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)
−
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
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−
admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
−
admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols).
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 100 days of discontinuation of dosing. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
For the Cohort C subjects who discontinue treatment after persistent one-year CR, SAEs will be 
collected for a maximum of two years and a minimum of 100 days after last dose during safety 
and FU/Observational visits. After, only study procedures-related SAEs will need to be reported 
and collected.
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not 
functioning. In this case, the paper forms are to be transmitted via email or confirmed facsimile 
(fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (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.
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SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, 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.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic).
All nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days following the 
last dose of study treatment.
For the Cohort C subjects who discontinue treatment after persistent one-year CR, NSAEs will 
be collected for a maximum of two years and a minimum of 100 days after last dose during 
safety and FU/Observational visits.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate. Paper forms are only intended as 
a back-up option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
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It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the BMS (or 
designee) Medical Monitor of this event and complete and forward a Pregnancy Surveillance 
Form to BMS (or designee) within 24 hours and in accordance with the SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug, after a thorough 
discussion of benefits and risk with the subject.
Protocol required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and where applicable, offspring information must be reported on the Pregnancy 
Surveillance form
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
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Potential drug induced liver injury is defined as: 
1. Aminotransaminases (AT) (ALT or AST) elevation > 3 times ULN
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
An IRRC will be utilized in this study for determination of IRRC-assessed endpoints such as 
ORR, CR rate, PR rate and associated durations. The IRRC will review all available tumor 
assessment scans for all treated subjects. Details of IRRC responsibilities and procedures will be 
specified in the IRRC charter.
The subjects’ 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 subjects
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 (MST) 
routinely reviews safety signals across the entire nivolumab program including combination 
studies with ipilimumab. 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. 
For Cohort D, when required, adjudicated events will be submitted to the DMC and Health 
Authorities for review on a specified timeframe in accordance with the adjudication 
documentation. In addition, safety conference calls with investigators and representatives of the 
sponsor will be held regularly until all subjects have entered the FU/observational phase or 
discontinued the study.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The planned sample size for this study will be approximately 270 treated subjects, placed into 
four cohorts of subjects: brentuximab vedotin-naïve (n = 60; Cohort A), treatment with 
brentuximab vedotin after failure of ASCT (n = 60; Cohort B), and treatment with brentuximab 
vedotin at any time point (n = 100; Cohort C), and first-line subjects (n = 50; Cohort D).
Cohorts A and B
The sample size from both cohorts was determined based on two considerations: the ability to 
produce a CI which would exclude an ORR of 20%, which is not considered clinically relevant
and provide sufficient information for a reliable understanding of the safety profile.23
Assuming the true ORR is 40%, each cohort has approximately 93% power to reject the null 
hypothesis that the true ORR is ≤20%, considering a 2-sided alpha of 5%. In addition, Table 
8.1-1 summarizes the 95% exact CI for the target ORRs ranging from 35% to 70% with sample 
size of 60. At observed ORR ≥35%, the lower bound of the 95% CI excludes 20%.
Table 8.1-1:
Observed ORR with Exact 95 % CI
ORR
95% Exact CI
35%
[23.1%-48.4%]
40%
[27.6%-53.5%]
50%
[36.8%-63.2%]
60%
[46.5%-72.4%]
70%
[56.8%-81.2%]
Cohort C
The sample size for Cohort C was empirically determined to support expanded assessment of the 
benefit-risk profile of nivolumab in cHL through observation of less common safety events. In 
particular, administration of nivolumab to 100 subjects provides 87% probability of observing at 
least one occurrence of any adverse event that would occur with 2% incidence in the population 
from which the sample is drawn. Benefit in this cohort will be measured by the ORR and DOR.
Cohort D
The sample size for Cohort D was empirically determined to provide sufficient information for 
understanding the safety profile and estimating the proportion of subjects who experience at least 
one treatment-related grade 3-5 adverse events. 
In a randomized study92 comparing ABVD and BEACOPP in previously untreated and 
unfavorable Hodgkin’s lymphoma, 43% of the subjects from the ABVD arm experienced at least 
one Grade 3 or 4 acute hematologic adverse event and 7% of subjects experienced at least one 
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acute non-hematologic adverse event in the ABVD arm. Table 8.1-2 summarizes the 95% exact 
CI for a range of incidence rates.
Table 8.1-2:
Observed Percentage of Subjects with Treatment-Related Grade 3 -
5 AE with Exact 95%CI
Observed Incidence rate
95% Exact CI
16%
[7.17% - 29.11% ]
26%
[14.63%   40.34%]
36%
[22.92%   50.81%]
46%
[31.81%  60.68%]
CI = confidence interval
Other considerations:
A discontinuation rate above 20% is not considered as acceptable because ABVD 
discontinuation rates due to any reasons (toxicity, disease progression or others) are consistently 
around 10% across previous clinical studies.12,15,93 Table 8.1-3 summarizes the 95% exact CI for 
a target discontinuation rate ranging from 8% to 14%. If 10% (Five out of 50 treated subjects) or 
fewer discontinue the treatment, the upper bound of the 95% CI will exclude 20%.
Table 8.1-3:
Observed Discontinuation Rate with 95% CI
Observed Discontinuation Rate
95% Exact CI
8%
[2.22%   19.23%]
10%
[3.33%  21.81%]
12%
[4.53%  24.31%]
14%
[5.82%  26.74%]
CI - confidence interval
8.2
Populations for Analyses
Within each cohort the following populations will be defined.
−
All Enrolled Subjects: All subjects who signed an informed consent form and were 
registered into the IVRS.
−
All Treated Subjects: All subjects who received at least one dose of nivolumab. This is 
the primary population for safety and efficacy analyses.
−
PK subjects: All subjects with available serum time-concentration data from subjects 
dosed with nivolumab
−
Immunogenicity Evaluable Subjects: All treated subjects with baseline and at least 
1 postbaseline immunogenicity assessment.
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8.3
Endpoints
8.3.1
Cohorts A, B, and C
8.3.1.1
Primary Endpoint(s) for Cohorts A, B, and C
The primary objective will be measured by the primary endpoint of IRRC-assessed ORR. It is 
defined as the number of subjects with a BOR of CR or PR, according to the 2007 IWG criteria, 
based on IRRC assessment, divided by the number of treated subjects. Only for Cohort C, 
FDG-PET can be used in lieu of bone marrow aspirate/ biopsy for bone marrow assessment. The 
BOR is defined as the best response designation recorded between the date of first dose and the 
date of initial objectively documented progression per the 2007 IWG criteria or the date of 
subsequent therapy, whichever occurs first. Allogeneic SCT and ASCT will be considered as 
subsequent anti-cancer therapy. For subjects without documented progression or subsequent 
therapy, all available response designations will contribute to the BOR determination. For 
purposes of analysis, if a subject receives one dose and discontinues the study without 
assessment or receives subsequent therapy prior to assessment, this subject will be counted in the 
denominator (as non-responder). Primary analysis will be performed separately for each cohort 
(ie, at separate time points) upon completion of a pre-specified amount of follow-up (Table 
8.3.1.1-1) after last patient first treatment (LPFT).
Table 8.3.1.1-1:
CA209205 Schedule of Analyses
Cohort
Follow-Up Requirement for Primary Endpoint Analysis
Cohort A
Primary ORR analysis after approximately 9 months minimum follow up in all Cohort A 
subjects
Cohort B
Primary ORR analysis after approximately 6 months minimum follow-up in all Cohort B 
subjects
Cohort C
Primary ORR analysis after approximately 6 months minimum follow-up in all Cohort C 
subjects
8.3.1.2
Secondary Endpoint(s) for Cohorts A, B, and C
Secondary endpoints will be analyzed at the same time as the primary endpoint.
Duration of Objective Response Based on IRRC Assessment
DOR is defined as the time from first response (CR or PR) to the date of initial objectively 
documented progression as determined using the 2007 IWG criteria or death due to any cause, 
whichever occurs first. For subjects who neither progress nor die, the DOR will be censored on 
the date of their last tumor assessment. Subjects who start subsequent therapy without a prior 
reported progression will be censored at the last tumor assessments prior to initiation of the 
subsequent anticancer therapy. This endpoint will only be evaluated in subjects with objective 
response of CR or PR.
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Complete Remission Rate and Duration Based on IRRC Assessment
The CR rate is defined as the number of subjects with a BOR of CR according to the 2007 IWG 
criteria, based on IRRC assessment, divided by the number of treated subjects. The duration of 
CR will only be evaluated in subjects with BOR of CR and is defined as the time from first 
documentation of CR (the date of first negative FDG-PET scan or the date of first documentation 
of no disease involvement in the bone marrow (if required), whichever occurs later) to the date 
of initial objectively documented progression as determined using the 2007 IWG criteria or death
due to any cause, whichever occurs first. Censoring will be applied as per DOR definition.
Partial Remission Rate and Duration Based on IRRC Assessment
The PR rate is defined as the number of subjects with a BOR of PR according to the 2007 IWG 
criteria, based on IRRC assessment, divided by the number of treated subjects. The duration of 
PR will only be evaluated in subjects with BOR of PR and is defined as the time from first 
documentation of PR to the date of initial objectively documented progression as determined 
using the 2007 IWG criteria or death due to any cause, whichever occurs first. Censoring will be 
applied as per DOR definition.
Objective Response Rate and Duration Based on Investigator Assessment
Investigator-assessed ORR and DOR are defined similarly as described for ORR and DOR per 
IRRC assessment above, but will be assessed per investigator.
8.3.1.3
Exploratory Endpoint(s) for Cohorts A, B, and C
Exploratory efficacy objectives will be measured by exploratory endpoints of PFS based on 
IRRC assessment and OS.
PFS is defined as the time from first dosing date to the date of the first documented progression 
using the 2007 IWG criteria, as determined by IRRC, or death due to any cause, whichever 
occurs first. Subjects who die without a reported progression will be considered to have 
progressed on the date of their death. Subjects who did not progress or die will be censored on 
the date of their last tumor assessment. Subjects who did not have any on study assessments and 
did not die will be censored on the first dosing date. Subjects who started any subsequent 
anti-cancer therapy without a prior reported progression will be censored at the last tumor 
assessment prior to initiation of the subsequent anti-cancer therapy.
OS is defined as the time from first dosing date to the date of death. For subjects without 
documentation of death, OS will be censored on the last date the subject was known to be alive.
The safety and tolerability objective will be measured by the incidence of adverse events, serious 
adverse events, deaths and laboratory abnormalities.
The PK samples collected will be used to determine summary measures of nivolumab exposure 
(see Section 8.4.4).
Other exploratory endpoints for pharmacodynamics, outcomes research and immunogenicity are 
discussed in detail in Sections 5.6, 5.7 and 5.8.
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For Cohort C, clinical course of the subjects who discontinued after persistent CR for 1 year will 
be evaluated in a descriptive fashion.
8.3.2
Cohort D
8.3.2.1
Primary Endpoints for Cohort D
The primary objective for Cohort D will be measured by the proportion of subjects who 
experienced at least one treatment-related Grade 3 - 5 AEs (per NCI CTCAE version 4.0 criteria, 
any PT term) with an onset date after or on the first dose date and no later than 30 days after the 
last study dose date, among subjects receiving at least one dose of study treatment.
8.3.2.2
Secondary Endpoints for Cohort D
•
The treatment discontinuation rate, defined by the number of subjects who were treated with 
fewer than 12 doses (2 doses per cycle x 6 cycles) of combination regimen 
(AVD ± nivolumab), divided by the number of subjects who have received at least one dose 
of nivolumab monotherapy. Discontinuation can be due to any reason including, but not 
limited to, drug-related toxicity, diseases progression, or death. The numerator includes 
subjects who discontinued nivolumab monotherapy and were unable to start combination 
regimen (AVD ± nivolumab), as a part of study, and subjects who discontinued nivolumab 
monotherapy and were treated with fewer than 12 doses of combination regimen 
(AVD ± nivolumab). The numerator does not include subjects who discontinued nivolumab 
monotherapy and were able to complete all 12 doses of the combination regimen 
(AVD ± nivolumab).
•
The treatment discontinuation rate of nivolumab monotherapy is equal
to one
minus the completion rate of nivolumab monotherapy phase. The completion rate of 
nivolumab monotherapy is defined as the number of subjects who have received four
nivolumab monotherapy doses, divided by the number of subjects who have received at least 
one dose of nivolumab monotherapy.
•
The treatment discontinuation rate of the Nivolumab-AVD combination therapy is equal to 
one minus the completion rate of Nivolumab-AVD combination therapy. The completion rate 
of Nivolumab-AVD combination therapy is defined as the number of subjects who have 
received 12 doses of Nivolumab-AVD therapy, divided by the number of subjects who
received at least one dose of Nivolumab-AVD therapy
•
The treatment discontinuation rate of combination therapy (AVD ± nivolumab) is equal to 
one minus the completion rate of combination therapy (AVD ± nivolumab). The completion 
rate of combination therapy (AVD ± nivolumab) is defined as the number of subjects who 
have received 12 doses of any combination therapy (AVD ± nivolumab), divided by the 
number of subjects who received at least one dose of any combination therapy 
(AVD ± nivolumab).
•
The proportion of subjects who experienced at least one treatment-related Grade 3 - 5 AEs 
during the monotherapy phase (per NCI CTCAE version 4.0 criteria, any PT term) with an 
onset date after or on the first dose date and before the first dose of combination therapy, or 
no later than 30 days after the last dose of Nivolumab monotherapy whatever comes first. 
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This proportion will be calculated among subjects receiving at least one dose of nivolumab 
monotherapy. 
•
The proportion of subjects who experienced at least one treatment-related Grade 3 - 5 AEs 
during the combination phase (per NCT CTCAE version 4.0 criteria, any PT term) with an 
onset date after or on the first dose of nivolumab combined with AVD and no later than 30 
days after the last dose of combination therapy. This proportion will be calculated among 
subjects receiving at least one dose of nivolumab combined with AVD.
•
The CR rate at the planned end of study therapy (IRRC-assessed) is defined as the number of 
subjects who are CR according to the 2007 IWG criteria at the planned end of study therapy 
radiographic tumor assessment, divided by the number of subjects who have received at least 
one dose of nivolumab monotherapy.
8.3.2.3
Exploratory Endpoints for Cohort D
•
The OR rate at the planned end of study therapy based on IRRC assessments, and the CR and 
OR rates based on investigator assessments, are defined as follows:
−
The CR rate at the planned end of study therapy (investigator-assessed) is defined as the 
number of subjects who are CR according to the 2007 IWG criteria at the planned end of 
study therapy radiographic tumor assessment, divided by the number of subjects who 
have received at least one dose of nivolumab monotherapy. 
−
The OR rate at the planned end of study therapy (IRRC-assessed or investigator-assessed) 
is defined as the number of subjects who have CR or PR according to the 2007 IWG 
criteria at the planned end of study therapy radiographic tumor assessment, divided by the 
number of subjects who have received at least one dose of nivolumab monotherapy. For 
purposes of analysis, if a subject receives one dose and discontinues the study without 
assessment or receives subsequent therapy prior to assessment, this subject will be 
counted in the denominator (as non-responder).
•
The CR and OR rates at the planned end of nivolumab monotherapy therapy based on IRRC 
assessments or based on investigator assessments, are defined as follows:
−
The CR rate at the planned end of nivolumab monotherapy (IRRC-assessed or 
investigator-assessed) is defined as the number of subjects who are CR according to the 
2007 IWG criteria at the planned end of nivolumab monotherapy radiographic tumor 
assessment, divided by the number of subjects who have received at least one dose of 
nivolumab monotherapy.
−
The OR rate at the planned end of nivolumab therapy (IRRC-assessed or investigator-
assessed) is defined as the number of subjects who have CR or PR according to the 2007 
IWG criteria at the planned end of nivolumab monotherapy radiographic tumor 
assessment, divided by the number of subjects who have received at least one dose of 
nivolumab monotherapy.
•
The CR and OR rates at the planned end of two Combocycles based on IRRC assessments or 
based on investigator assessments, are defined as followed:
−
The CR rate at the planned end of two Combocycles (IRRC-assessed or investigator-
assessed) is defined as the number of subjects who are CR according to the 2007 IWG 
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criteria at the planned end of two Combocycles radiographic tumor assessment, divided 
by the number of subjects who have received at least one dose of nivolumab 
monotherapy.
−
The OR rate at the planned end of two Combocycles (IRRC-assessed or investigator-
assessed) is defined as the number of subjects who are CR or PR according to the 2007 
IWG criteria at the planned end of two Combocycles radiographic tumor assessment, 
divided by the number of subjects who have received at least one dose of nivolumab 
monotherapy.
•
The PFS IRRC-assessed is defined as the time from first dosing date to the date of the first 
documented progression using the 2007 IWG criteria, as determined by IRRC or death due to 
any cause, whichever occurs first. Subjects who die without a reported progression will be
considered to have progressed on the date of their death. Subjects who did not progress or die 
will be censored on the date of their last tumor assessment. Subjects who did not have any on 
study assessments and did not die will be censored on the first dosing date. Subjects who 
initiate a subsequent anti-cancer therapy will contribute as an event to PFS analysis at the 
date of the start of their subsequent anti-cancer therapy.
•
The PFS investigator-assessed is defined similarly as for IRRC-assessed PFS.
•
OS is defined as the time from first dosing date to the date of death. For subjects without 
documentation of death, OS will be censored on the last date the subject was known to be 
alive.
•
The safety and tolerability objective will be measured by the incidence of adverse events, 
serious adverse events, deaths and laboratory abnormalities.
•
The nivolumab concentration data obtained in this study may be combined with data from 
other studies in the clinical development program to develop or refine a PPK model (see 
Section 8.4.4).
•
Other exploratory endpoints for pharmacodynamics, pulmonary function outcomes research 
and immunogenicity are discussed in detail in Sections 5.6, 5.7, and 5.8.
•
Other exploratory endpoints are discussed in details in the statistical analysis plan.
8.4
Analyses
All analyses will be performed separately for each cohort.
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline laboratory results will be summarized using descriptive statistics for 
all treated subjects.
8.4.2
Efficacy Analyses
8.4.2.1
Complete Response, Partial Response and Objective Response Rates
The IRRC-assessed and investigator-assessed CR, PR, and ORR will be summarized by binomial 
response rates and their corresponding two-sided 95% exact CI using the Clopper-Pearson 
method.
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For Cohorts A and B, the null hypothesis will be rejected if the 2-sided 95% CI lower bound for 
the ORR IRRC-assessed estimate is greater than 20%. This translates in observing at least 
19 responders out of 60 treated subjects.
8.4.2.2
Duration of Response
The IRRC-assessed DOR will be summarized by cohort for subjects who achieve PR or CR 
using the Kaplan-Meier (KM) product-limit method. Median values of DOR, along with 
two-sided 95% CIs (based on the log-log transformation) and range, will also be calculated. The 
same analysis will be performed for the duration of PR and CR, as well as DOR per investigator.
For Cohorts A and B, the IRRC-assessed CR and PR rates and investigator-assessed ORR will be 
summarized by binomial response rates and their corresponding two-sided 95% CI using the 
Clopper-Pearson method.
8.4.2.3
Progression Free Survival and Overall Survival
The IRRC-assessed and investigator-assessed PFS and OS will be summarized by the 
Kaplan-Meier product-limit method. Median values along with two-sided 95% CIs based on the 
log-log transformation, will be calculated. PFS and OS will be evaluated in all treated subjects.
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0. All on-study AEs, drug-related, AEs, SAEs and 
drug-related SAEs will be tabulated using worst grade per NCI CTCAE v4.0 criteria by system 
organ class and MedDRA preferred term. On-study lab parameters including hematology, 
chemistry, liver function, thyroid function, and renal function will be summarized using worst 
grade per NCI CTCAE v4.0 criteria.
In addition to separate analyses per cohort, safety analyses will be performed on combined 
cohorts for Cohorts A, B, and C.
For Cohort D, in addition to analyses described above, the treatment discontinuation rate, the 
treatment discontinuation rate of Nivolumab monotherapy, the treatment discontinuation rate of 
the Nivolumab-AVD combination therapy and the treatment discontinuation rate of combination 
therapy (AVD ± Nivolumab), as defined in Section 8.3.2.2, will be provided with exact 95%CI 
using the Clopper-Pearson method.
8.4.4
Pharmacokinetic Analyses
The nivolumab concentration data obtained in this study may be combined with data from other 
studies in the clinical development program to develop or refine a PPK model. This model may 
be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab and to 
determine measures of individual exposure (such as steady-state peak, trough, and time-averaged 
concentration). In addition, model determined exposures may be used for E-R analyses. Results 
of PPK and E-R analyses will be reported separately.
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8.4.5
Biomarker Analyses
Methodology for exploratory biomarker analyses will be described in the statistical analysis plan.
8.4.6
Outcomes Research Analyses
8.4.6.1
EQ-5D
Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
will be summarized using descriptive statistics (N, mean, standard deviation, median, first and 
third quartiles, minimum, maximum). Proportion of subjects reporting problems for the 5 EQ-5D 
dimensions at each assessment time point will be summarized by level of problem. Percentages 
will be based on number subjects assessed at assessment time point.
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression), health state (5 dimensions 
digits combined in a 5-digit number) and EQ-VAS will be provided.
8.4.6.2
EORTC QLQ-C30
The analysis of EORTC QLQ-C30 will be performed in all treated subjects who have an 
assessment at baseline and at least one subsequent assessment. The analysis will be conducted 
separately for Cohorts A, B, and C.
All scales and single items are scored on a categorical scale and linearly transformed to 0-to-100 
scales with higher scores for a functional scale representing higher levels of functioning, higher 
scores for the global health status/quality of life representing higher levels of global health 
status/quality of life, and higher scores for a symptom scale representing higher level of 
symptoms.
Baseline and change from baseline in EORTC QLQ-C30 global health status/QoL composite 
scale data and the remaining EORTC QLQ-C30 scale data will be summarized by time point 
using descriptive statistics for each cohort (N, mean, standard deviation, median, first and third 
quartiles, minimum, maximum). In addition, the percentage of subjects demonstrating a 
clinically meaningful deterioration (defined as a 10 point change from baseline) will be 
presented for each scale at each assessment time point. Percentages will be based on number 
subjects assessed at assessment time point.
8.4.7
Other Analyses 
8.4.7.1
Immunogenicity Analysis
Immunogenicity may be reported for ADA positive status (such as persistent positive, 
neutralizing positive, only last sample positive, baseline positive and other positive) and ADA 
negative status, relative to baseline. Effect of immunogenicity on safety, efficacy, biomarkers 
and PK may be explored. Additional details will be described in the SAP.
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8.5
Interim Analyses
Interim analyses may be conducted if it is necessary in order to make decisions regarding further 
development. Summaries and listings of efficacy and safety will be provided.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents.
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
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The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site. Records or logs must comply with 
applicable regulations and guidelines and should include:
•
amount received and placed in storage area
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•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the electronic SAE form and Pregnancy Surveillance form, respectively. If electronic SAE form 
is not available, a paper SAE form can be used.
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. For electronic CRFs, review and approval/signature is 
completed electronically through the BMS electronic data capture tool. The investigator must 
retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
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9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:
•
External Principal Investigator designated at protocol development
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the patient. This does not mean periodic abstinence (e.g., 
calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of 
contraception. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
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LIST OF ABBREVIATIONS
Term
Definition
ABVD
doxorubicin, bleomycin, vinblastine, and dacarbazine, where A stands for 
Adriamycin, which is the trade name of doxorubicin
ADA
Anti-drug antibodies
AE
adverse event
ADC
antibody drug conjugate
AEs
adverse events
AI
accumulation index
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ASCT
autologous stem cell transplant
AT
aminotransaminases
AVD
doxorubicin, vinblastine, and dacarbazine, where A stands for 
Adriamycin, which is the trade name of doxorubicin
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
β-HCG
beta-human chorionic gonadotrophin
BCNU
bis-chloroethylnitrosourea (Carmustine)
BEACOPP
bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, 
Oncovin (vincristine), procarbazine, and prednisone
BEAM
Carmustine, etoposide, cytarabine and melphalan
BID, bid
bis in die, twice daily
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BSA
Body surface area
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
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Term
Definition
CBC
complete blood count
CFR
Code of Federal Regulations 
cHL
“classic” HL
CI
confidence interval
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CR
complete remission
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an expected 
future dosing interval (eg, concentration at 24 hours, concentration at 12 
hours, etc.)
CT
Computed tomography
D/C
discontinue
DILI
drug induced liver injury
dL
deciliter
DLBCL
Diffuse Large B-Cell Lymphoma
DLCO
Diffusing capacity or Transfer factor of the lung for carbon monoxide
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DOR
duration of objective response
EA
extent of absorption
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
EB
Epstein-Barr
ELISA
enzyme-linked immunosorbent assay
EORTC
European Organisation for Research and Treatment of Cancer
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Term
Definition
E-R
exposure–response
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FDG-PET
[18F]-fluorodeoxyglucose positron emission tomography
FFPE
Formalin-fixed, paraffin-embedded 
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
FL
Follicular Lymphoma
FSH
follicle stimulating hormone
fT4
Free thyroxine
FU
Follow-up
fu
fraction of unbound drug
g
gram
G
Grade
GCP
Good Clinical Practice
GVHD
graft-versus-host-disease
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HL
Hodgkin lymphoma
HR
heart rate
hrs
Hours
HRT
hormone replacement therapy
IB
Investigator Brochure
ICE
ifosfamide, carboplatin, etoposide 
ICF
Informed Consent
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Term
Definition
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IPS
International Prognostic Score
IRB
Institutional Review Board
ID
Infectious Disease
I-O
Immuno-oncology
IRRC
independent radiologic review committee
ITIM
immunoreceptor tyrosine inhibitory motif
ITSM
immunoreceptor tyrosine-based switch motif 
IU
International Unit
IV
intravenous
IVRS
Interactive Voice Response Service 
IWG
International Working Group
K
slope of the terminal phase of the log concentration-time curve
KM
Kaplan-Meier
K+
potassium
kg
kilogram
L
liter
LDH
lactate dehydrogenase
LFT
Liver function tests
mAbs
monoclonal antibodies
MDS
Myelodysplastic syndrome
mg
milligram
mg/kg
Milligram per kilogram
Mg++
magnesium
min
minute
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Term
Definition
mL
milliliter
MLR
mixed lymphocyte reaction
MMAE
monoethyl auristatin E
mmHg
millimeters of mercury
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NCI CTCAE v4
National Cancer Institute Common Terminology Criteria for Adverse 
Event version 4
ng
nanogram
NSAE
Non-Serious Adverse Event 
NSCLC
non-small cell lung cancer
ORR
Objective Response Rate
OS
Overall survival
PBMCs
peripheral blood mononuclear cells
PD
pharmacodynamics
PFS
progression free survival
PFSR
progression-free survival rate
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PPK
population pharmacokinetic
PR
partial remission
Q2W
every 2 weeks
Q4W
every 4 weeks
QD, qd
quaque die, once daily
QLQ
Quality of Life Questionnaire
RBC
red blood cell
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Term
Definition
RCC
renal cell carcinoma
RNA
Ribonucleic acid
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SCT
stem cell transplant
SD
Stable Disease
SNP
single nucleotide polymorphisms
SOP
Standard Operating Procedures
SPD
sum of the product of the diameters
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
Tmax, TMAX
time of maximum observed concentration
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
VAS
visual analog rating scale
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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12
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Last 
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Vinblastine
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ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+I
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nivolumab
58 Chemnitz JM, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T 
cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 
2004;173(2):945-54.
59 Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation 
of the ZAP70/CD3zeta signalosome and downstream signaling to PKC-theta. FEBS Letters 
2004;574(1-3):37-41.
60 Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. 
Trends Immunol. 2001;22:265-8.
61 Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by 
disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 
1999;11:141-51.
62 Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 
receptor-deficient mice. Science. 2001;291:319-22.
63 Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are 
responsible for dilated cardiomyopathy in PD-1 deficient mice. Nat Med. 2003;9:1477-83.
64 Salama AD, Chitnis T, Imitola J, et al. Critical role of the programmed death-1 (PD-1) 
pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med. 
2003;198:71-8.
65 Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 
engagemet accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism. 
J Immunol. 2003;171:1272-7.
66 Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly 
immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 
2004;17:133-44.
67 Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from 
host immune system and tumor immunotherapy by PD-1 blockade. Proc Natl Acad Sci USA. 
2002;99:12293-7.
68 Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma. Cancer Res 2003;63:6501-5.
69 Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: 
a potential mechanism of immune evasion. Nat Med 2002;8:793-800.
70 Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal 
antibodies potentiates cancer therapeutic immunity. Cancer Res 2005;65:1089-96.
71 Blank C, Brown, I, Peterson AC, et al. PD-L1/B7-H1 inhibits the effector phase of tumor 
rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 2004;64:1140-45.
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72 Konishi J, Yamazaki K, Azuma M, et al. B7-H1 expression on non-small cell lung cancer 
and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin 
Cancer Res 2004;10:5094-100.
73 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma 
subjects: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad 
Sci USA 2004;101:7174-9.
74 Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 
and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 
2005;11:2947-53.
75 Tsushima F, Tanaka K, Otsuki N, et al. Predominant expression of B7-H1 and its 
immunoregulatory roles in oral squamous cell carcinoma. Oral Oncol. 2006;42:268-74.
76 Thompson RH, Weber, WS, Cheville JC, et al. B7-H1 glycoprotein blockade: a novel 
strategy to enhance immunotherapy in subjects with renal cell carcinoma. Urology 
2005;66:10-4.
77 Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and 
metastatic clear cell renal cell carcinoma. Cancer 2005;104:2084-91.
78 Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. 
Blood. 2008;111:3635-43.
79 Andorsky DJ, Yamada RE, Said J, et al. Programmed death ligand 1 is expressed by non-
hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 
2011 Jul 1;17(13):4232-44.
80 Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of 
aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 
2013;19(13):3462-73.
81 Non-Clinical Expedited Safety Report for Nivolumab (Ad Hoc CARES #54344.1). BMS; 
2013. Document Control No. 930067627 1.0.
82 Effect of MDX-1106 on CD4+ T cells during an allogeneic mixed lymphocyte reaction 
(MLR) (Medarex Study no. MDX-1106-026-R). Bristol-Myers Squibb Pharmaceutical 
Research Institute; 2006. Document Control No. 930046581.
83 Kuppers R. The biology of Hodgkin's lymphoma. Nat Rev Cancer 2009;9:15-27.
84 Juszczynski P, Ouyang J, Monti S, et al. The AP1-dependent secretion of galectin-1 by Reed 
Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci 
U S A 2007;104(32):13134-9.
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85 Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 
amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular 
sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma Blood 
2010;116(17):3268-77; PMCID: PMC2995356.
86 Green MR, Rodig SJ, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection 
induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: 
implications for targeted therapy. Clin Cancer Res 2012;18(6):1611-8.
87 Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of 
aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013:1-12.
88 Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the 
evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol. 
1989 Nov;7(11):1630-6. Erratum in: J Clin Oncol 1990 Sep;8(9):1602.
89 Cheson BD, Pfistner B, Juweld ME, et al. Revised Response Criteria for Malignant 
Lymphoma. J Clin Oncol 2007;25(5):579-586.
90 Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014 Aug 11.
91 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; 52(23): 
7412-7420.
92 Viviani S, Zinzani PL, Rambaldi A, et al. ABVD versus BEACOPP for Hodgkin’s 
lymphoma when high-dose salvage is planned. N Engl J Med 2011;365:203-12.
93 Federico M, Luminari S, Iannitto E, et al; HD2000 Gruppo Italianoper lo Studio dei Linfomi 
Trial. ABVD compared with BEACOPP compared with CEC forthe initial treatment of 
patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per 
lo Studio dei Linfomi Trial. J Clin Oncol. 2009;27(5):805-811.
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APPENDIX 1
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 2
INTERNATIONAL WORKING GROUP CRITERIA FOR
MALIGNANT LYMPHOMA
2007 IWG Response Criteria for Malignant Lymphoma
Response
Definition
Nodal masses
Spleen, Liver
Bone marrow
CR
Disappearance 
of all evidence 
of disease
(a) FDG-avid or PET positive prior 
to therapy; residual mass of any size 
permitted if PET negative
(b) Variably FDG-avid or PET 
negative; regression to normal size 
on CT
Not palpable, 
nodules 
disappeared
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology,
immunohistochemistry
should be negative
[Cohort C only] No 
evidence of FDG-avid 
disease in bone 
marrow
PR
Regression of 
measurable 
disease and no 
new sites
≥50% decrease in SPD of up to 6 
largest dominant masses (index 
lesions); no increase in size of other 
nodes (non-index lesions)
(a) FDG-avid or PET positive prior 
to therapy; one or more PET 
positive at previously involved site
(b) Variably FDG-avid or 
PET negative; regression 
on CT
≥50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified
SD
Failure to 
attain CR/PR 
or PD
(a) FDG-avid or PET positive prior 
to therapy; PET positive at prior 
sites of disease and no new sites on 
CT or PET
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT
N/A
N/A
Relapsed 
disease
or PD
Any new 
lesion or 
increase by 
≥50% of 
previously
involved sites 
from nadir
Appearance of a new lesion(s) > 1.5 
cm in any axis, ≥50% increase in 
SPD of more than one node (index 
lesions), or ≥50% increase in 
longest diameter of a previously 
identified node > 1 cm in short axis.
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy
> 50% increase 
from nadir in the 
SPD of any 
previous lesions
New or recurrent 
involvement
Key: CR = complete remission CT = computed tomography; FDG = [18F] fluorodeoxyglucose; IWG = International 
Working Group; NA = Not applicable; PD = progressive disease; PET = positron-emission tomography; PR = 
partial remission; SD = stable disease; SPD = sum of the product of the diameters.
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CR (Complete Remission)
The designation of CR requires the following:
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms, if present before therapy.
2. a.
Typically [18F] fluorodeoxyglucose (FDG)-avid lymphoma: in patients with no 
pretreatment positron emission tomography (PET) scan or when the PET scan was positive 
before therapy, a post-treatment residual mass of any size is permitted as long as it is PET 
negative.
b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on computed tomography (CT) scan to normal size (≤1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in their long axis and > 1.0 cm in their short axis before treatment 
must have decreased to ≤1.0 cm in their short axis after treatment.
3. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear. However, determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen 
may reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or 
causes other than lymphoma.
4. For cohort A and B, if the bone marrow was involved by lymphoma before treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). If the 
sample is indeterminate by morphology, it should be negative by immunohistochemistry. A 
sample that is negative by immunohistochemistry but demonstrates a small population of 
clonal lymphocytes by flow cytometry will be considered a CR until data become available 
demonstrating a clear difference in patient outcome.
5. For cohort C, no evidence of FDG-avid disease in bone marrow will be required in all 
patients in lieu of bone marrow aspirate/ biopsy.
PR (Partial Remission)
The designation of PR requires all of the following:
1. At least a 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the 
largest dominant nodes or nodal masses. These nodes or masses should be selected according 
to all of the following: they should be clearly measurable in at least 2 perpendicular 
dimensions; if possible they should be from disparate regions of the body; and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
2. No increase should be observed in the size of other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the 
greatest transverse diameter.
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4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present.
5. Bone marrow assessment is irrelevant for determination of a PR, if the sample was positive 
before treatment. However, if positive, the cell type should be specified (e.g., large-cell 
lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria but 
have persistent morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was achieved but with 
no bone marrow assessment after treatment, patients should be considered partial responders.
6. No new sites of disease should be observed.
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET should be positive in at least 
1 previously involved site.
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT criteria should be used. In patients 
with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated with 1 or at 
most 2 residual masses that have regressed by > 50% on CT; those with more than 2 residual 
lesions are unlikely to be PET negative and should be considered partial responders
SD (Stable Disease)
SD is defined as the following:
1. A patient is considered to have SD when he or she fails to attain the criteria needed for a CR 
or PR but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]).
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with no 
new areas of involvement on the post-treatment CT or PET scan.
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size of the 
previous lesions on the post-treatment CT scan.
PD: Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
Lymph nodes should be considered abnormal if the long axis is > 1.5 cm regardless of the short 
axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if 
its short axis is > 1.0. Lymph nodes ≤1.0 x ≤1.0 cm will not be considered abnormal for relapse 
or progressive disease.
1. Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, even if 
other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site 
should only be considered relapsed or PD after confirmation with other modalities. In 
patients with no prior history of pulmonary lymphoma, new lung nodules identified by CT 
are mostly benign. Thus, a therapeutic decision should not be made solely on the basis of the 
PET without histologic confirmation.
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2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be 
considered PD, a lymph node with a diameter of the short axis of < 1.0 cm must increase by 
≥50% and to a size of 1.5 x 1.5 cm or > 1.5 cm in the long axis.
3. At least a 50% increase in the longest diameter of any single previously identified node 
> 1 cm in its short axis.
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion 
was PET positive before therapy unless the lesion is too small to be detected with current 
PET systems (< 1.5 cm in its long axis by CT).
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, 
unless, while an abnormality is still noted by imaging studies or physical examination, it is found 
to be histologically negative.
In clinical trials where PET is unavailable to the vast majority of participants, or where PET is 
not deemed necessary or appropriate for use (e.g., a trial in patients with MALT lymphoma), 
response should be assessed as above, but only using CT scans. However, residual masses should 
not be assigned CRu status, but should be considered partial responses.
Reference: Cheson BD, Pfisner B, Juweid ME, et al. Revised Response Criteria for Malignant Lymphoma. Journal 
of Clinical Oncology 2007;25:579-586. 
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APPENDIX 3
HASENCLEVER-INDEX FOR HODGKIN’S DISEASE ALSO 
KNOWN AS INTERNATIONAL PROGNOSTIC SCORE (IPS)
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. NEJM 1998;339:1506-14.
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APPENDIX 4
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, e.g., 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, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 5
ACUTE GVHD GRADING AND STAGING
Table 1:
Extent of Organ Involvement
Stage
Skin
Liver
Gut
1
Rash on < 25% of skina
Bilirubin 2 - 3 mg/dLb  
Diarrhea > 500 mL/dayc or 
persistent nausead      
2 
Rash on 25 - 50% of skin 
Bilirubin 3 - 6 mg/dL 
Diarrhea > 1000 mL/day 
3 
Rash on > 50% of skin 
Bilirubin 6 - 15 mg/dL 
Diarrhea > 1500 mL/day 
4 
Generalized erythroderma with 
bullous formation 
Bilirubin >15 mg/dL 
Severe abdominal pain with or 
without ileus 
Gradee
I 
Stage 1 - 2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
--
Stage 2 - 3 or 
Stages 2 - 4 
IVf   
Stage 4 
Stage 4 
--
a Use “Rules of Nines” (Table 2) or burn chart to determine extent of rash.
b Range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin has been 
documented.
c Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body 
surface area. Downgrade one stage if an additional cause of diarrhea has been documented.
d Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
e Criteria for grading given as minimum degree of organ involvement required to confer that grade.
f Grade IV may also include lesser organ involvement with an extreme decrease in performance status.
Table 2:
Percent Body Surfaces
Body Area
Percent
Total Percentage
Each Arm 
9%
18%
Each Leg 
18%
36%
Chest & Abdomen 
18%
18%
Back 
18%
18%
Head 
9%
9%
Pubis 
1%
1%
Ref.: Przepiorka et al. Bone Marrow Transplant 1995;15(6):825.
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Stage of Chronic GVHD
Limited: Localized skin involvement resembling localized scleroderma with or without liver 
involvement; no other organ involvement.
Extensive: Generalized skin and/or multiple organ involvement.
Ref. Sullivan KM, Blood 1981;57:267.
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APPENDIX 6
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 04b, 14-Sep-2018
The purpose of this revision is to clarify language surrounding the timing of biomarker sample 
collection, specifically plasma ctDNA. Additional changes were made to align text with 
nivolumab program standards and to align text concerning contraception with the Investigator’s 
Brochure (IB) for nivolumab.
Revisions apply to all participants currently enrolled.
Summary of key changes of Revised Protocol 04b
Section Number & Title
Description of Change
Brief Rationale
Section 1.1.2.1, Rationale 
for Cohort C
Added rationale for why plasma samples will be 
collected (for molecular monitoring of the disease).
To clarify text.
Section 1.4.3.5, 
Nivolumab Monotherapy 
Clinical Pharmacology 
Summary
In reference to the current IB, “additional 
information” was changed to “full details on the 
clinical pharmacology aspects of nivolumab.”
To clarify text.
Figure 3.1.2-2: Treatment 
and Follow-up Phase for 
Cohort D
In top figure, the last bullet was corrected: 
“...survival visits continue every 3 months” was 
changed to 6 months.
To be consistent with the 
language in the Follow-up 
(FU)/Observational Phase 
subsection on the previous 
page.
Section 3.3.1, Inclusion 
Criteria: #3, Age and 
Reproductive Status
Changes to contraception wording. 
To align with IB for 
nivolumab.
Section 3.4.1, Prohibited 
and/or Restricted 
Treatments
Added 3rd bullet:
•
Any live/attenuated vaccine (eg, varicella, 
zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella [MMR]) during 
treatment and until 100 days post last dose.
To align with nivolumab 
program standards.
Table 5.1.1-4: Follow-Up 
Assessments for Cohort C 
Subjects who 
Discontinued due to CR 
(CA209205) or After Re-
Initiation of Nivolumab
Added “or After Re-Initiation of Nivolumab” to the
table title.
To clarify that follow-up 
assessments also apply to 
patients in Cohort C who 
discontinue after re-initiation 
of nivolumab.
Section 5.4, Efficacy 
Assessments
Sentence added to specify that for Cohort D, 
additional assessments, for example, Deauville 
scoring, may also be performed.
Since the predictive value of 
interim PET Deauville score 
in the prognosis of patients 
with Hodgkin’s lymphoma 
using I-O (Nivolumab-AVD) 
in a first-line setting is of 
limited value, as opposed to 
when chemotherapy is used, 
the predictive value of EOT 
PET Deauville score might 
be more helpful.
Revised Protocol No: 04c
Date: 22-Aug-2019
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Summary of key changes of Revised Protocol 04b
Section Number & Title
Description of Change
Brief Rationale
Table 5.5-1: Sampling 
Schedule for Cohorts A, 
B, and C
In the Day 1 of every 12th cycle row, instead of 
samples being collected until discontinuation of 
study treatment, text was changed to “up to Cycle 
49.”
PK/IMG sample collection 
beyond Cycle 49 from 
subjects randomized to 
Cohorts A, B, or C is not 
required. Samples collected 
from subjects beyond Cycle 
49 will not be used in 
PK/statistical analyses, 
tables, listings, or figures.
Section 5.6, Biomarker 
Assessments
In the last subsection, “Plasma samples,” text was 
added that describes “novel sequencing-based 
methods” that “can detect circulating tumor DNA 
(ctDNA).”
ctDNA opens new 
opportunities for molecular 
monitoring before, during, 
and after therapy. It can also 
be used as a “liquid biopsy” 
to assess for molecular 
changes during the course of 
the therapy that may identify 
the emergence of treatment-
resistant clones in the 
subjects at risk of relapse.
Table 5.6-1: CA209205 
Biomarker Sampling 
Schedule for Cohorts A, 
B, and C
•
“(ctDNA)” added after “Plasma” in last 
column heading and in table footnote a.
•
For plasma (ctDNA) collection times after 
Cycle 27, “Thereafter, every 6 cycles” was 
changed to “Cycle 68 Day 1” and “Cycle 81 Day 
1.”
•
Plasma (ctDNA) collection changed from 
“optional” to “strongly recommended” in the 
“Upon Progression” collection time row and in 
table footnote h.
•
To be consistent 
with changes made in 
Section 5.6.
•
Collection of 
plasma/ctDNA after C27 
was stopped since it is not 
expected that the 
emergence of any 
treatment resistance 
clones/mutations earlier 
than C68 will be 
identified. Plasma will be 
collected at C81 to 
confirm the presence 
and/or the selection of the 
mutations/clones at a later 
phase of the treatment 
course.
•
This time point is 
extremely important to 
identify emergence of 
therapy resistance clone; 
therefore, it has been 
specified as “strongly 
recommended.”
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Summary of key changes of Revised Protocol 04b
Section Number & Title
Description of Change
Brief Rationale
Table 5.6-2: CA209205 
Biomarker Sampling 
Schedule for Cohort D
“(ctDNA)” added after “Plasma” in last column 
heading.
To be consistent with 
changes made in Section 5.6.
All
Minor formatting and typographical corrections
Minor, therefore have not 
been summarized.
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SAP_001.pdf: 
Official Title:  NON-COMPARATIVE, MULTI-COHORT, SINGLE ARM, OPEN-LABEL, PHASE 2 
STUDY OF NIVOLUMAB (BMS-936558) IN CLASSICAL HODGKIN LYMPHOMA 
(CHL) SUBJECTS AFTER FAILURE OF AUTOLOGOUS STEM CELL TRANSPLANT 
(ASCT) 
NCT Number:  NCT02181738 
 
Document Date:  June 8, 2018  


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
NON-COMPARATIVE, MULTI-COHORT, SINGLE ARM, OPEN-LABEL, PHASE 2 
STUDY OF NIVOLUMAB (BMS-936558) IN CLASSICAL HODGKIN LYMPHOMA 
(CHL) SUBJECTS AFTER FAILURE OF AUTOLOGOUS STEM CELL TRANSPLANT 
(ASCT)
PROTOCOL(S) CA209205
VERSION # 3.1
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................6
LIST OF FIGURES ....................................................................................................................6
1
BACKGROUND AND RATIONALE......................................................................7
1.1
Cohorts A, B, and C..................................................................................................7
1.2
Cohort D...................................................................................................................7
2
STUDY DESCRIPTION ..........................................................................................9
2.1
Study Design ............................................................................................................9
2.1.1
Cohorts A, B and C...................................................................................................9
2.1.2
Cohort D ................................................................................................................11
2.2
Treatment Assignment............................................................................................14
2.3
Blinding and Unblinding.........................................................................................14
2.4
Protocol Amendments.............................................................................................14
2.5
Data Monitoring and Other External Committees ...................................................15
3
OBJECTIVES ........................................................................................................16
3.1
Primary...................................................................................................................16
3.1.1
Cohorts A, B and C.................................................................................................16
3.1.2
Cohort D ................................................................................................................16
3.2
Secondary...............................................................................................................16
3.2.1
Cohorts A, B and C.................................................................................................16
3.2.2
Cohort D ................................................................................................................16
3.3
Exploratory.............................................................................................................17
3.3.1
Cohorts A, B and C.................................................................................................17
3.3.2
Cohort D ................................................................................................................17
4
ENDPOINTS..........................................................................................................18
4.1
Primary Endpoint....................................................................................................18
4.1.1
Cohort A, B, C........................................................................................................18
4.1.2
Cohort D ................................................................................................................18
4.2
Secondary Endpoints ..............................................................................................18
4.2.1
Cohorts A, B and C.................................................................................................18
4.2.1.1
Duration of Objective Response Based on IRRC Assessment...................................18
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4.2.1.2
Complete Remission Rate and Duration Based on IRRC Assessment.......................19
4.2.1.3
Partial Remission Rate and Duration Based on IRRC Assessment ..........................19
4.2.1.4
Objective Response Rate and Duration Based on Investigator Assessment..............20
4.2.2
Cohort D ................................................................................................................20
4.2.2.1
Treatment discontinuation rate ...............................................................................20
4.2.2.2
Treatment-related Grade 3-5 AEs in each therapy phase ........................................20
4.2.2.3
Complete remission rate at the end of study therapy per IRRC................................21
4.3
Exploratory Endpoints............................................................................................21
4.3.1.1
Progression Free Survival based on IRRC Assessment ...........................................21
4.3.1.2
Overall Survival .....................................................................................................23
4.3.1.3
Safety and Tolerability............................................................................................23
4.3.1.4
Immune-Mediated Adverse Events ..........................................................................23
4.3.1.5
Pharmacokinetics ...................................................................................................24
4.3.1.6
Immunogenicity to Nivolumab ................................................................................24
4.3.1.7
Outcome Research..................................................................................................24
4.3.1.8
Biomarkers .............................................................................................................26
5
SAMPLE SIZE AND POWER...............................................................................27
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................28
6.1
Study Periods..........................................................................................................28
6.1.1
Baseline Period ......................................................................................................28
6.1.2
Post Baseline Period...............................................................................................29
6.2
Treatment Regimens...............................................................................................30
6.3
Populations for Analyses ........................................................................................30
6.3.1
Study Cohorts .........................................................................................................30
6.3.2
Analysis Populations ..............................................................................................30
7
STATISTICAL ANALYSES..................................................................................31
7.1
General Methods ....................................................................................................31
7.2
Study Conduct........................................................................................................31
7.2.1
Accrual...................................................................................................................31
7.2.2
Relevant Protocol Deviations..................................................................................31
7.2.2.1
Cohorts A, B and C.................................................................................................32
7.2.2.2
Cohort D ................................................................................................................32
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7.3
Study Population ....................................................................................................32
7.3.1
Subject Disposition.................................................................................................33
7.3.2
Demographics and Other Baseline Characteristics.................................................33
7.3.3
Medical History......................................................................................................34
7.3.4
Prior therapy (Cohorts A, B and C) ........................................................................34
7.3.5
Prior Therapy (Cohort D).......................................................................................35
7.3.6
Baseline Examinations............................................................................................35
7.4
Extent of Exposure .................................................................................................35
7.4.1
Administration of Study Therapy.............................................................................35
7.4.2
Modifications of Study Therapy ..............................................................................37
7.4.2.1
Dose delays ............................................................................................................37
7.4.2.2
Infusion Interruptions and Rate Changes................................................................37
7.4.2.3
Dose Reductions/Escalation....................................................................................38
7.4.3
Concomitant Medications.......................................................................................38
7.5
Efficacy..................................................................................................................38
7.5.1
Primary Endpoint of ORR (based on IRRC assessment) (Cohorts A, B and C)........38
7.5.1.1
ORR Subgroups......................................................................................................39
7.5.1.2
Sensitivity Analyses for ORR...................................................................................39
7.5.2
Secondary Endpoints ..............................................................................................40
7.5.2.1
Duration of Response Based on IRRC Assessment (Cohorts A, B and C).................40
7.5.2.2
Complete Remission Rate and Duration Based on IRRC Assessment (Cohorts 
A, B , C and D).......................................................................................................40
7.5.2.3
Partial Remission Rate and Duration Based on IRRC Assessment (Cohorts A, 
B and C).................................................................................................................40
7.5.2.4
Objective Response Rate and Duration Based on Investigator Assessment 
(Cohorts A, B and C) ..............................................................................................41
7.5.3
Exploratory Endpoints............................................................................................41
7.5.3.1
ORR and DoR per IRRC/per Investigator assessments (Cohort D)..........................41
7.5.3.2
Complete Remission Rate and Duration of CR Based on Investigator 
Assessment (Cohort D) ...........................................................................................41
7.5.3.3
Progression Free Survival based on IRRC Assessment (Cohorts A, B and C)..........41
7.5.3.4
Modified Progression Free Survival (Cohort D) .....................................................42
7.5.3.5
Overall Survival .....................................................................................................42
7.5.4
Other exploratory analyses.....................................................................................43
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7.5.4.1
Response Evaluation After Transplant (Cohorts A, B and C) ..................................43
7.5.4.2
Efficacy for Subjects Treated Beyond Progression (Cohorts A, B and C) ................43
7.6
Safety.....................................................................................................................44
7.6.1
Deaths ....................................................................................................................45
7.6.2
Serious Adverse Events...........................................................................................45
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................45
7.6.4
Adverse Events Leading to Dose Modification........................................................45
7.6.5
Adverse Events .......................................................................................................45
7.6.6
Select Adverse Events .............................................................................................45
7.6.7
Immune modulating medication..............................................................................46
7.6.8
Multiple Events.......................................................................................................46
7.6.9
Clinical laboratory evaluations...............................................................................46
7.6.10
Vital Signs and Pulse Oximetry...............................................................................46
7.6.11
Immunogenicity Analysis ........................................................................................46
7.6.12
Pregnancy ..............................................................................................................46
7.6.13
Clinical Safety Program (CSP)...............................................................................46
7.6.14
Adverse Events by Subgroup...................................................................................46
7.6.15
Immune-mediated Adverse Events Analysis.............................................................46
7.6.16
Other Events of Special Interest..............................................................................47
7.6.17
Safety of subjects who undergo subsequent Allogeneic Transplant (Cohorts 
A, B and C).............................................................................................................47
7.6.18
Other safety analyses..............................................................................................48
7.7
Pharmacokinetics....................................................................................................48
7.8
Biomarker Analyses ...............................................................................................48
7.8.1
PD-L1 Expression ..................................................................................................48
7.8.1.1
Descriptive Statistics of PD-L1 Expression and PD-L1 Status ................................48
7.8.1.2
Evaluation of Associations between PD-L1 Status and Efficacy Measures ..............49
7.9
Outcome Research Analyses...................................................................................49
7.9.1
EORTC-QLQ-C30 Questionnaire (Cohorts A, B and C) .........................................49
7.9.2
EQ-5D Questionnaire (Cohorts A, B, C and D) ......................................................50
8
CONVENTIONS....................................................................................................50
9
CONTENT OF REPORTS .....................................................................................51
10
DOCUMENT HISTORY........................................................................................51
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11
REFERENCES.......................................................................................................53
LIST OF TABLES
Table 2.1.2-1:
Selection of Combination Therapy for Cohort D.....................................13
Table 2.4-1:
Protocol Amendments ............................................................................14
Table 4.2.1.1-1:
Censoring Scheme for Primary and Sensitivity Analysis of DOR 
(Cohorts A, B and C)..............................................................................19
Table 4.3.1.1-1:
Censoring Scheme for analysis of PFS....................................................22
Table 4.3.1.7-1:
Time Windows for EORTC-QLQ-C30 Assessments...............................25
Table 5-1:
Observed ORR with Exact 95 % CI........................................................27
Table 5-2:
Observed Percentage of Subjects with Treatment-Related Grade 
3-5 AE with Exact 95%CI ......................................................................28
Table 5-3:
Observed Discontinuation Rate with 95% CI..........................................28
Table 6.1.2-1:
Primary On-Treatment Definition For Safety in Treated Subjects ...........29
Table 7.4.1-1:
Administration of study therapy: definition of parameters (Cohorts 
A, B, C)..................................................................................................36
Table 7.4.1-2:
Administration of study therapy: definition of parameters (Cohort 
D)...........................................................................................................36
Table 10-1:
Document History ..................................................................................51
LIST OF FIGURES
Figure 2.1.1-1:
Study Design Schematic (Cohorts A, B and C).......................................10
Figure 2.1.1-2:
CT or MRI and FDG-PET Scans Schedule (Cohorts A, B and C) ...........11
Figure 2.1.2-1:
Treatment Schedule for Cohort D...........................................................12
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Research Hypothesis:  
Cohorts A, B and C: Treatment with nivolumab will lead to clinical benefit, as demonstrated by a 
clinically meaningful objective response rate, including durable responses with substantial 
magnitude of tumor burden reduction in heavily treated cHL subjects.
Cohort D: A new regimen, consisting of nivolumab monotherapy followed by the combination of 
nivolumab and chemotherapy (AVD; a combination of doxorubicin, vinblastine and dacarbazine), 
will be safe and tolerable in previously untreated cHL subjects with newly diagnosed advanced 
stage (Stage IIB, III and IV) disease.
Schedule of Analyses:
Cohorts A, B and C: The objective response rate (ORR) based on independent radiologic review 
committee (IRRC) assessment is the primary endpoint of this study. Primary analysis will be 
performed separately for each cohort (i.e. at separate time points) upon completion of a pre-
specified amount of follow-up after last patient first treatment (LPFT) as follows:

Cohort A: Primary ORR analysis after 1 year minimum follow-up in all Cohort A subjects.

Cohort B: Primary ORR analysis after 6 months minimum follow-up in all Cohort B subjects.

Cohort C: Primary ORR analysis after 1 year minimum follow-up in all Cohort C subjects.
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In addition, safety analyses will be performed on combined cohorts. Additional survival analysis 
will be conducted for up to 5 years beyond analysis of the primary endpoint. Analysis schedules 
were chosen based on a median duration of response (6.7 months) and a median duration of CR 
(20.5 months) observed from a pivotal Ph 2 study testing brentuximab vedotin in a similar patient 
population2.
Cohort D: The primary analysis for Cohort D will be conducted when all treated patients for Cohort 
D have completed Follow-up visit 1 and end-of-therapy response assessment. All analyses for 
Cohort D will be performed separately from other cohorts.
2
STUDY DESCRIPTION
2.1
Study Design
2.1.1
Cohorts A, B and C
This is a non-comparative, parallel cohort, single-arm Phase 2 study in cHL subjects 18 years 
old who failed ASCT. Subjects may be brentuximab vedotin-naïve (Cohort A), or may have had 
prior brentuximab vedotin treatment as a salvage therapy after failure of ASCT (Cohort B). In 
addition to Cohorts A and B, a third cohort (Cohort C) allows subjects with broader eligibility 
criteria. Subjects with a treatment history of brentuximab vedotin before first ASCT will not be 
eligible, except in Cohort C. Approximately 320 subjects with failure after ASCT will be treated 
with nivolumab 3mg/kg IV every 2 weeks until disease progression or unacceptable toxicity; 
Cohorts A and B consist of approximately 60 subjects each, whereas approximately 200 subjects 
will be treated in Cohort C. Subjects will be independently enrolled for each cohort. When one
cohort completes enrollment, the other cohort will remain open until its complete accrual is 
reached.
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first 
dose. Each 14-day dosing period will constitute a cycle.
The study design schematic is presented in Figure 2.1.1-1.
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Figure 2.1.1-1:
Study Design Schematic (Cohorts A, B and C)
Radiographical tumor assessments by computed tomography (CT) (preferred) or magnetic 
resonance imaging (MRI) will begin at screening, then at Week 9 (7 days) after the start of 
therapy and will continue at Weeks 17, 25, 37 and 49 for the first year of treatment. CT (preferred) 
or MRI will continue every 16 weeks (14 days) for the second year of treatment. CT (preferred) 
or MRI will be performed every 26 weeks (21 days) for the third year or beyond of treatment. 
[18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scan will be required in all 
subjects at screening and at Weeks 17 and 25 (7 days). 
Additionally, a FDG-PET scan at Week 49 (7 days) is required for subjects who do not have two 
consecutive negative FDG-PET scans after Week 1 and prior to Week 49. FDG-PET scan will also 
be required for confirmation of radiographic CR after initiation of the study drug at other
timepoints when FDG-PET is not otherwise scheduled; this FDG-PET scan should be performed 
within 4 weeks of the CT scan. Tumor assessments will follow the above schedule until disease 
progression is documented or until the subject initiates a preparative regimen for allogeneic stem 
cell transplantation (SCT) or autologous stem cell transplant (ASCT), whichever occurs earlier. If 
the subject discontinues treatment prior to disease progression, tumor assessment will continue in 
the follow-up phase. 
Treatment
Follow -Up
Nivolumab
3mg/kg Q2wk
Failure
of ASCT
ASCT
Cohort A
N=60
Failure of 
Brentuximab
treatment
ASCT
Brentuximab
Treatment
Each cohort will be independentlyrecruited
Screening
CA209 -205 Study
Previous Treatment History
Nivolumab
3mg/kg Q2wk
ASCT
Brentuximab
Treatment
Brentuximab
Treatment
Nivolumab
3mg/kg Q2wk
(must discontinue after
persistent CR for one year)
And/Or
if 
relapse
Possibility to re-initiate treatment
Cohort B
N=60
Cohort C*
N=200
*Cohort C: Subjects who failed ASCT and who have received prior treatment with brentuximab vedotin at any timepoint. 
Patients may have brentuximab treatment only before ASCT and failure of ASCT. Patients may have failure of ASCT, and 
failure of post-ASCT brentuximab treatment. Or, patients may have brentuximab treatment before and after ASCT, and 
failure of brentuximab at enrollment.
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Figure 2.1.1-2:
CT or MRI and FDG-PET Scans Schedule (Cohorts A, B and C)
If the subject discontinues study therapy by proceeding to allogeneic SCT or ASCT, they will not 
undergo IRRC radiographic assessments described here. Instead, they will be evaluated using the 
following schedule. Tumor assessment (CR or non-CR) will be assessed by the investigator 
according to the 2007 IWG criteria and will be required on Day 100, at 6 months, 1 year and every 
year thereafter from the date of stem cell infusion until the first non-CR after SCT is documented. 
Investigators 
will 
make 
telephone 
contacts 
with 
the 
subject’s 
referring 
hematologist/oncologist/transplant physician to obtain CR or non-CR status and document the 
status if subject is being followed by another physician.
Nivolumab will be administered until unacceptable toxicity or disease progression which is 
defined by relapsed disease (after CR achieved during the study) or progressive disease (after PR, 
SD attained during the study) according to the 2007 IWG criteria. In addition, subjects in 
Cohort C are to discontinue treatment following a 1 year persistent CR, with the possibility to 
reinitiate therapy upon relapse.
Treatment beyond investigator-assessed progression is permitted in the circumstances specified in 
the protocol.
2.1.2
Cohort D
Cohort D is a non-comparative single-arm cohort in subjects 18 years old who are newly 
diagnosed, previously untreated cHL with advanced stage (Stage IIB, III and IV). Treatment for 
Cohort D consists of two phases: monotherapy and combination phases. Subjects will be treated 
with four doses of nivolumab flat dose 240mg IV every 2 weeks (monotherapy phase), followed 
by twelve doses of the combination of AVD chemotherapy (doxorubicin, vinblastine, and 
dacarbazine) (combination phase).
Subjects will undergo screening evaluations to determine eligibility within 28 days prior to first 
dose. Subjects will be enrolled independently from other cohorts.  
Cohort D consists of approximately 50 subjects.
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The study design schematic is presented in Figure 2.1.2-1.
Figure 2.1.2-1:
Treatment Schedule for Cohort D
Treatment consists of two phases: monotherapy phase (approximately 8 weeks) and Combination 
phase (approximately 22 weeks). The monotherapy phase begins from the first dose of nivolumab 
(flat dose 240mg) until the first dose of the combination therapy. Nivolumab monotherapy is 
administered every 2 weeks for four doses. After subjects complete all four doses of nivolumab 
monotherapy, they will enter the combination phase, and will be treated with the combination of 
AVD chemotherapy and nivolumab. As exceptions, before completing all four doses of nivolumab 
monotherapy, subjects who meet discontinuation criteria (Section 4.5.5 of the protocol), or 
subjects who meet dose delay criteria (Section 4.5.2 of the protocol) and the dose delay is > 4 
weeks from previous dose are allowed to discontinue monotherapy phase and enter combination 
phase when the criteria are met as described in Table 3.1.2-1 of the protocol.  
The combination phase (approximately 22 weeks) begins from the first dose of the combination 
therapy. The first dose of combination therapy should be dosed no less than 12 days and no more 
than 17 days after the last dose of nivolumab monotherapy. The combination therapy is 
administration of nivolumab (flat dose 240mg) and AVD (Adriamycin/ doxorubicin 25mg/m2, 
vinblastine 6mg/m2, dacarbazine 375mg/m2) on the same day. Use of AVD only (without 
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nivolumab) is permitted as an alternative regimen only when the conditions are met as described
in Table 3.1.2-1 of the protocol. Each 28-day dosing period will constitute a Combocycle: two 
doses of the combination therapy per cycle, except for Combocycle 6, which will only be a 15-day 
cycle. The combination therapy is administered every 2 weeks for 12 doses (two doses, Dose 1 on 
Day 1 and Dose 2 on Day 15, of each Combocycle x 6 cycles). The combination phase will end at 
Dose 2 (Day 15) of Combocycle 6. Thereafter, subjects will enter the Follow-up 
(FU)/Observational phase. Subjects who discontinue combination treatment before completing 
Combocycle 6 Dose 2 (Day 15) and who have not started subsequent anti-lymphoma therapy will 
also enter the FU/Observational phase.
Table 2.1.2-1:
Selection of Combination Therapy for Cohort D
During Monotherapy Phase
Regimen to be Used During Combination Phase
Subjects who have completed all 4 doses of nivolumab 
monotherapy (4 monotherapy doses)a,b
The combination of nivolumab and AVD
Subjects who have discontinued monotherapy before 
completing four doses of nivolumab because Nivolumab 
Discontinuation criteria (Section 4.5.5 of the protocol) are 
met
AVD
Subjects who have discontinued monotherapy before 
completing four doses of nivolumab because Nivolumab 
Delay Criteria (Section 4.5.2.1 of the protocol) are met, and 
the dose delay was > 4 weeks from a previous dose
AVD
Subjects who discontinued nivolumab monotherapy due to  
disease progression meeting  2007 IWG criteria based on 
investigators’ assessment (but have not met safety criteria 
for discontinuation)
The combination of nivolumab and AVD or AVD 
alone
a If a subject subsequently meets Criteria to Resume Nivolumab Dosing (Section 4.5.4 of the protocol), the 
combination of nivolumab and AVD can be used
b Subjects who underwent treatment beyond progression during the Monotherapy phase can use the combination of 
nivolumab and AVD if all 4 doses of nivolumab monotherapy are completed
For Cohort D, radiographical tumor assessments by CT (preferred) or MRI, and FDG-PET scans 
will be required at screening. Mandatory radiographical tumor assessments during the treatment 
are as follows:

Post-Monotherapy dose 4 assessments: FDG-PET scan and CT (preferred) or MRI after 
Monotherapy dose 4 and before entering the Combination phase. 

Post-Combocycle 2 assessments: FDG-PET scan* and CT (preferred) or MRI after 
Combocycle 2 and before Combocycle 3.
*Interim FDG-PET scans are optional if a previous scheduled or unscheduled FDG-PET scan 
after the first dose of nivolumab monotherapy was negative based on investigator’s assessment.
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The end-of-therapy radiographic tumor assessments should be done at 9 weeks (14 days) 
from the last treatment). End-of-therapy FDG-PET, and CT (preferred) or MRI scans are 
mandatory in all subjects. When end-of-therapy FDG-PET scans are positive based on 
investigator’s assessment, tumor biopsy for FDG-avid lesion is strongly encouraged whenever 
possible. Bone marrow assessment is not required for CR determination as FDG-PET can be used 
in lieu of bone marrow aspirate/ biopsy.
After the end-of-therapy radiographic tumor assessments, no FDG-PET scan is required unless 
clinically indicated. CT (preferred) or MRI scans should be conducted at 39 weeks (21 days), 65 
weeks (21 days), and 104 weeks (21 days) from the last dose for the subjects who enter the 
FU/Observational phase. Thereafter, no radiographic tumor assessment is required. Treatment 
beyond investigator-assessed progression is permitted in the circumstances specified in the 
protocol.
2.2
Treatment Assignment
After the subject’s initial eligibility is established and informed consent has been obtained, the
subject must be enrolled into the study by calling an interactive voice response system (IVRS) to
obtain the subject number. Every subject that signs the informed consent form must be assigned a 
subject number in IVRS. All enrolled subjects from Cohorts A, B or C who meet eligibility criteria 
will be treated with nivolumab at 3mg/kg IV every 2 weeks. All enrolled subjects from Cohort D 
who meet eligibility criteria will be treated with four doses of nivolumab 240mg IV every 2 weeks 
followed by 12 doses of Nivolumab 240mg combined with AVD (Adriamycin/ doxorubicin 
25mg/m2, vinblastine 6mg/m2, dacarbazine 375mg/m2) every 2 weeks. 
2.3
Blinding and Unblinding
Not applicable.
2.4
Protocol Amendments
This SAP incorporates the following protocol amendments.
 
 
 
 
 
 
 
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2.5
Data Monitoring and Other External Committees
An IRRC will be utilized in this study for determination of IRRC-assessed primary endpoints
(ORR), secondary endpoints (DOR, CR and PR rates and durations) endpoints and exploratory 
endpoints (PFS). The IRRC will review all available tumor assessment scans for all treated 
subjects. Details of IRRC responsibilities and procedures will be specified in the IRRC charter.
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3
OBJECTIVES
3.1
Primary
3.1.1
Cohorts A, B and C
To assess the clinical benefit of nivolumab, as measured by objective response rate (ORR) based 
on independent radiologic review committee (IRRC) assessment, and defined as proportion of 
subjects achieving either a partial remission (PR) or complete remission (CR) according to the 
revised International Working Group criteria for Malignant Lymphoma (2007 IWG criteria).
3.1.2
Cohort D
To assess the overall safety and tolerability of nivolumab monotherapy (flat dose 240 mg), 
followed by the combination of nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) 
chemotherapy in previously untreated cHL subjects who are newly diagnosed with advanced stage 
(Stage IIB, III and IV) disease , as measured by the proportion of subjects who experienced at least 
one treatment-related Grade 3-5 AEs with an onset date after or on the first dose date and no later 
than 30 days after the last study dose date, among subjects receiving at least one dose of study 
treatment.
3.2
Secondary
3.2.1
Cohorts A, B and C

To assess the duration of objective response (DOR) based on IRRC assessments

To assess the CR rate and the duration of CR based on IRRC assessment

To assess the PR rate and the duration of PR based on IRRC assessment

To assess the ORR and DOR based on investigator assessments
3.2.2
Cohort D

To evaluate the safety and tolerability of nivolumab monotherapy during the monotherapy 
phase 

To evaluate the safety and tolerability of nivolumab in combination with AVD during the 
combination phase 

To evaluate the treatment discontinuation rate of the study therapy during the monotherapy 
phase, combination phase, and overall (the entire course of study treatment consisting of both 
phases)

To assess the clinical activity of study therapy, as measured by the CR rate at the planned end
of therapy, based on IRRC assessments.
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4
ENDPOINTS
4.1
Primary Endpoint
4.1.1
Cohort A, B, C
The primary objective will be measured by the primary endpoint of ORR based on IRRC 
assessment. It is defined as the number of subjects with a Best Overall Response (BOR) of CR or 
PR, according to the 2007 IWG criteria, based on IRRC assessment, divided by the number of 
treated subjects. The BOR is defined as the best response designation recorded between the date 
of first dose and the date of initial objectively documented progression per the 2007 IWG criteria 
or the date of subsequent therapy, whichever occurs first. Allogeneic SCT and ASCT will be 
considered as subsequent anti-cancer therapy. For subjects without documented progression or 
subsequent therapy, all available response designations will contribute to the BOR determination. 
For subjects who continue treatment beyond progression, the BOR should be determined based on 
response designations recorded up to the time of the initial 2007 IWG defined progression. For 
purposes of analysis, if a subject receives one dose and discontinues the study without assessment 
or receives subsequent therapy prior to assessment, this subject will be counted in the denominator 
(as non-responder). 
Analysis of the primary endpoint of each Cohort will occur separately at least 1 year (Cohorts A 
and C) or 6 months (Cohort B) after last patient first treatment in each respective Cohort.
The objective response will be further characterized by the time to response (TTR). TTR is defined 
as the time from first dosing date to the date of the first response, based on IRRC assessment.
4.1.2
Cohort D
The primary objective for Cohort D will be measured by the proportion of subjects who 
experienced at least one treatment-related Grade 3 - 5 AEs (per NCI CTCAE version 4.0 criteria, 
any PT term) with an onset date after or on the first dose date and no later than 30 days after the 
last study dose date, among subjects receiving at least one dose of study treatment.
4.2
Secondary Endpoints
4.2.1
Cohorts A, B and C
4.2.1.1
Duration of Objective Response Based on IRRC Assessment
DOR is defined as the time from first response (CR or PR) to the date of initial objectively 
documented progression as determined using the 2007 IWG criteria or death due to any cause, 
whichever occurs first. For subjects who neither progress nor die, the DOR will be censored on 
the date of their last tumor assessment. Subjects who start subsequent therapy without a prior 
reported progression will be censored at the last tumor assessment prior to initiation of the 
subsequent anticancer therapy. Sensitivity analyses will be performed based on an alternate 
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censoring scheme to account for infrequent tumor assessments. See Table 4.2.1.1-1 for censoring 
details. This endpoint will only be evaluated in subjects with objective response of CR or PR.
Table 4.2.1.1-1:
Censoring Scheme for Primary and Sensitivity Analysis of DOR
(Cohorts A, B and C)
Situation
Primary
Sensitivity
No progression per response criteria, 
no death and no subsequent 
anticancer therapy
Censored on the date of last tumor 
assessment
Censored on the date of last visit 
date
No progression per response criteria, 
no death and with subsequent 
anticancer therapy
Censored on the date of last tumor 
assessment prior or on the date of  
initiation of the subsequent 
anticancer therapy
Censored on the date of last visit 
prior or on the date of initiation of 
the subsequent anticancer therapy
Progression per response criteria
without a subsequent anticancer 
therapy started
Event on the date of the first 
documented tumor progression per 
response criteria
Event on the date of the first 
documented tumor progression per 
response criteria
Subsequent anticancer therapy 
started without a reported 
progression per response criteria
Censored on date of last tumor 
assessment prior or on the date of 
initiation of the subsequent 
anticancer therapy
Censored on date of last visit prior 
or on the date of initiation of the 
subsequent anticancer therapy
Death without progression per 
response criteria and without 
subsequent anticancer therapy 
started
Event on the date of death
Event on the date of death
Censoring scheme for primary analysis of DOR aligns with censoring scheme for PFS analysis. 
Last visit is defined as the last date of dosing, tumor assessment or lab assessment, whichever occurs last.
4.2.1.2
Complete Remission Rate and Duration Based on IRRC Assessment
The CR rate is defined as the number of subjects with a BOR of CR according to the 2007 IWG 
criteria, based on IRRC assessment, divided by the number of treated subjects. The duration of CR 
will only be evaluated in subjects with BOR of CR and is defined as the time from first 
documentation of CR (the date of first negative FDG-PET scan or the date of first documentation 
of no disease involvement in the bone marrow (if required), whichever occurs later) to the date of 
initial objectively documented progression as determined using the 2007 IWG criteria or death due 
to any cause, whichever occurs first. Censoring will be applied as per DOR definition. This 
endpoint will be further characterized by the time to CR, defined as the time from first dosing date 
to the date of first documentation of CR.
4.2.1.3
Partial Remission Rate and Duration Based on IRRC Assessment
The PR rate is defined as the number of subjects with a BOR of PR according to the 2007 IWG 
criteria, based on IRRC assessment, divided by the number of treated subjects. The duration of PR 
will only be evaluated in subjects with BOR of PR and is defined as the time from first 
documentation of PR to the date of initial objectively documented progression as determined using 
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the 2007 IWG criteria or death due to any cause, whichever occurs first. Censoring will be applied 
as per DOR definition.
4.2.1.4
Objective Response Rate and Duration Based on Investigator 
Assessment
Investigator-assessed ORR and DOR are defined similarly as described for ORR and DOR per 
IRRC assessment above (Section 4.1), but will be assessed per investigator based on 2007 IWG 
criteria. It will be further characterized by TTR, time to CR and duration of CR.
4.2.2
Cohort D
4.2.2.1
Treatment discontinuation rate

The treatment discontinuation rate, defined by the number of subjects who were treated with 
fewer than 12 doses (2 doses per cycle x 6 cycles) of combination regimen 
(AVD ± nivolumab), divided by the number of subjects who have received at least one dose 
of nivolumab monotherapy. Discontinuation can be due to any reason including, but not limited 
to, drug-related toxicity, diseases progression, or death. The numerator includes subjects who 
discontinued nivolumab monotherapy and were unable to start combination regimen 
(AVD ± nivolumab), as a part of study, and subjects who discontinued nivolumab monotherapy 
and were treated with fewer than 12 doses of combination regimen (AVD ± nivolumab). The 
numerator does not include subjects who discontinued nivolumab monotherapy and were able 
to complete all 12 doses of the combination regimen (AVD ± nivolumab).

The treatment discontinuation rate of nivolumab monotherapy is equal to one 
minus the completion rate of nivolumab monotherapy phase. The completion rate of 
nivolumab monotherapy is defined as the number of subjects who have received four 
nivolumab monotherapy doses, divided by the number of subjects who have received at least 
one dose of nivolumab monotherapy.

The treatment discontinuation rate of the Nivolumab-AVD combination therapy is equal to 
one minus the completion rate of Nivolumab-AVD combination therapy. The completion rate 
of Nivolumab-AVD combination therapy is defined as the number of subjects who have 
received 12 doses of Nivolumab-AVD therapy, divided by the number of subjects who 
received at least one dose of Nivolumab-AVD therapy.

The treatment discontinuation rate of combination therapy (AVD ± nivolumab) is equal to one 
minus the completion rate of combination therapy (AVD ± nivolumab). The completion rate 
of combination therapy (AVD ± nivolumab) is defined as the number of subjects who have 
received 12 doses of any combination therapy (AVD ± nivolumab), divided by the number of 
subjects who received at least one dose of any combination therapy (AVD ± nivolumab).
4.2.2.2
Treatment-related Grade 3-5 AEs in each therapy phase

The proportion of subjects who experienced at least one treatment-related Grade 3-5 AEs 
during the monotherapy phase (per NCI CTCAE version 4.0 criteria, any PT term) with an 
onset date after or on the first dose date and before the first dose of combination therapy, or no 
later than 30 days after the last dose of Nivolumab monotherapy whatever comes first. This 
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proportion will be calculated among subjects receiving at least one dose of nivolumab 
monotherapy. 

The proportion of subjects who experienced at least one treatment-related Grade 3-5 AEs 
during the combination phase (per NCT CTCAE version 4.0 criteria, any PT term) with an 
onset date after or on the first dose of nivolumab combined with AVD and no later than 
30 days after the last dose of combination therapy. This proportion will be calculated among 
subjects receiving at least one dose of nivolumab combined with AVD.
4.2.2.3
Complete remission rate at the end of study therapy per IRRC

The CR rate at the planned end of study therapy (IRRC-assessed) is defined as the number of 
subjects who are CR according to the 2007 IWG criteria at the planned end of study therapy 
radiographic tumor assessment, divided by the number of subjects who have received at least 
one dose of nivolumab monotherapy.
For our main analysis on all treated subjects, the following definitions will be used to identify the 
planned response assessments:

The End of Monotherapy assessment is the first assessment performed on or after the last 
nivolumab monotherapy dose date (regardless of its dose number) and before or on the day of 
the first combination therapy dose date (if any). The End of Monotherapy assessment must be 
prior or on the first subsequent therapy date if any.

The After 2 combocycles assessment is the first assessment performed on or after dose 2 of 
combo cycle 2 and before or on the first dose of combo cycle 3. The After 2 combocycles 
assessment must be prior or on the first subsequent therapy date if any.

The End of Therapy assessment is the closest assessment to last dose date + 9 weeks which is
prior or on the first subsequent therapy date (if any) and which is within [last dose date + 2 
weeks; last dose date + 24 weeks]. 
 
 
 
 
 
 
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4.3.1.2
Overall Survival
Overall Survival (OS) is defined as the time from first dosing date to the date of death. A subject 
who has not died will be censored at last known date alive. The overall survival rate at time T is 
defined as the probability that a subject is alive at time T following first dosing date.
4.3.1.3
Safety and Tolerability
Safety will be analyzed through the incidence of deaths, adverse events, serious adverse events, 
adverse events leading to discontinuation, adverse events leading to dose delay, select adverse 
events and specific laboratory abnormalities (worst grade). Toxicities will be graded using the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. See details in the Core Safety SAP1.
For cohorts A, B and C, safety of subjects who undergo a subsequent allogeneic transplant will 
also be analyzed through cumulative incidence rate of transplant related deaths and acute gvhd.
Other transplant-related complications will also be reported. Subjects with missing worst acute 
gvhd grade will be imputed grade 4. Subjects with missing acute gvhd onset dates will be imputed 
to the first subsequent allogeneic transplant date.
For cohort D, safety of subjects will be analyzed per treatment phase (monotherapy phase, 
combination therapy phase) and overall. Change from baseline of pulmonary function after 
treatment will also be reported.
4.3.1.4 Immune-Mediated Adverse Events
In order to further characterize AEs of special clinical interest, analysis of immune-mediated AEs 
(imAEs) will be conducted. Immune-mediated AEs are specific events (or groups of PTs 
describing specific events) that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal 
dysfunction, rash, endocrine (adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis). The imAE categories and terms are defined by the Sponsor 
and the list that is the most current at the time of analysis will be used. This list will be based on 
the most current version of MedDRA at the time when database will be built. The final list used 
for the CSR will be included in an Appendix of the CSR.
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4.3.1.6
Immunogenicity to Nivolumab
Refer to Core Safety SAP1.
 
 
 
 
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
The planned sample size for this study will be approximately 270 treated subjects, placed into four
cohorts of subjects: brentuximab vedotin-naïve [n = 60; Cohort A], treatment with brentuximab 
vedotin after failure of ASCT [n = 60; Cohort B], treatment with brentuximab vedotin at any 
timepoint [n = 100; Cohort C] and first-line subjects [n = 50; Cohort D].
Cohorts A and B
The sample size from both cohorts was determined based on two considerations: the ability to 
produce a CI which would exclude an ORR of 20%, which is not considered clinically relevant
and provide sufficient information for a reliable understanding of the safety profile2.
Assuming the true ORR is 40%, each cohort has approximately 93% power to reject the null 
hypothesis that the true ORR is 20%, considering a 2-sided alpha of 5%. In addition, Table 5-1
summarizes the 95% exact CI for the target ORRs ranging from 35% to 70% with sample size of 
60. At observed ORR 35%, the lower bound of the 95% CI excludes 20%.
Table 5-1:
Observed ORR with Exact 95 % CI
ORR
95% Exact CI
35%
[23.1%-48.4%]
40%
[27.6%-53.5%]
50%
[36.8%-63.2%]
60%
[46.5%-72.4%]
70%
[56.8%-81.2%]
Cohort C
The sample size for Cohort C was empirically determined to support expanded assessment of the 
benefit-risk profile of nivolumab in cHL through observation of less common safety events. In 
particular, administration of nivolumab to 100 subjects provides 87% probability of observing at 
least one occurrence of any adverse event that would occur with 2% incidence in the population 
from which the sample is drawn. Benefit in this cohort will be measured by the ORR and DOR.
Cohort D
The sample size for Cohort D was empirically determined to provide sufficient information for 
understanding the safety profile and estimating the proportion of subjects who experience at least 
one treatment-related grade 3-5 adverse events. 
In a randomized study comparing ABVD and BEACOPP in previously untreated and unfavorable 
Hodgkin’s lymphoma, 43% of the subjects from the ABVD arm experienced at least one Grade 3 
or 4 acute hematologic adverse event and 7% of subjects experienced at least one acute non-
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hematologic adverse event in the ABVD arm. Table 5-2 summarizes the 95% exact CI for a range 
of incidence rates.
Table 5-2:
Observed Percentage of Subjects with Treatment-Related Grade 3-5 
AE with Exact 95%CI
Observed Incidence rate
95% Exact CI
16%
[7.17% - 29.11% ]
26%
[14.63%   40.34%]
36%
[22.92%   50.81%]
46%
[31.81%  60.68%]
CI = confidence interval
Other considerations:
A discontinuation rate above 20% is not considered as acceptable because ABVD discontinuation 
rates due to any reasons (toxicity, disease progression or others) are consistently around 10% 
across previous clinical studies. Table 5-3 summarizes the 95% exact CI for a target 
discontinuation rate ranging from 8% to 14%. If 10% (Five out of 50 treated subjects) or fewer 
discontinue the treatment, the upper bound of the 95% CI will exclude 20%.
Table 5-3:
Observed Discontinuation Rate with 95% CI
Observed Discontinuation Rate
95% Exact CI
8%
[2.22%   19.23%]
10%
[3.33%  21.81%]
12%
[4.53% 24.31%]
14%
[5.82%  26.74%]
CI - confidence interval
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Baseline Period
Baseline evaluations or events will be defined as evaluations or events that occur before the date 
and time of the first dose of study treatment.
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not 
collected, the following definitions will apply:

Pre-treatment AEs will be defined as AEs with an onset date prior to but not including the day 
of the first dose of study treatment
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
Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as 
evaluations with a date on or prior to the day of first dose of study treatment
If there are multiple valid assessments, the assessment that is closest to day (and time if collected) 
of the first dose of study treatment will be used as the baseline in the analyses. If multiple 
assessments are collected at the same date (and time if collected), the assessment with the latest 
database entry date (and time if collected) will considered as baseline.
6.1.2
Post Baseline Period
On-treatment AEs will be defined as AEs with an onset date-time on or after the date-time of the 
first dose of study treatment (or with an onset date on or after the day of first dose of study 
treatment if time is not collected or is missing). An AE will be counted as on-treatment if the event 
occurred within 30 days (or 100 days depending on analysis) of the last dose of study treatment as 
defined in Table 6.1.2-1. Specifically, re-initiation nivolumab therapy is excluded for the purpose 
of determining the last dose of nivolumab as part of the definition of on-treatment; separate safety 
analyses for re-initiation therapy may be performed. Refer to Core SAP1.
On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as
evaluations taken after the day (and time, if collected and not missing) of first dose of study 
treatment. An evaluation will be counted as on-treatment if it occurred within 30 days (or 100 days 
depending on analysis) of the last dose of study treatment. Refer to Core SAP1.
Table 6.1.2-1:
Primary On-Treatment Definition For Safety in Treated Subjects
Cohort
Option for Re-Initiation
On-Treatment Definition
Cohorts A and B
No
On or after first dose of nivolumab and within 30 
(or 100) days after last dose of nivolumab
Cohort C
Yes
On or after first dose of nivolumab and within 30 
(or 100) days after the last dose of nivolumab prior 
to re-initiation dosing
Cohort D
No
On or after first dose of nivolumab and within 30 
(or 100) days after last dose of nivolumab. 
For cohort D, the following phases will be considered

the monotherapy phase: from first nivolumab dose date to the first combination therapy dose 
date, or for subjects who do not enter the combination therapy phase  up to 30 (or 100) days 
after the last dose of nivolumab. All treated subjects will be considered.

the combination therapy phase: from the first combination therapy dose date up to 30 (or 100) 
days after the last study dose date. All subjects who received at least one dose in the 
combination therapy phase will be considered.

overall: from the first nivolumab dose date up to 30 (or 100 days depending on analysis) of the 
last dose of study treatment). All treated subjects will be considered.
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6.2
Treatment Regimens
All subjects from cohort A, B, C will be treated with nivolumab 3mg/kg and from cohort D will 
be treated with Nivolumab 240mg monotherapy followed by Nivolumab 240mg combined with 
AVD.
6.3
Populations for Analyses
6.3.1
Study Cohorts
Cohort A: Brentuximab vedotin- naïve subjects who have failed ASCT.
Cohort B: Subjects who received brentuximab vedotin treatment as salvage following failure of 
ASCT.
Cohort C: Subjects who have undergone ASCT and received brentuximab vedotin, in any 
treatment order.
Cohort D: Previously untreated cHL subjects. Cohorts will be determined as entered in CRF.
6.3.2
Analysis Populations
Within each cohort the following populations will be defined.

Enrolled subjects: All subjects who signed an informed consent form and were registered into 
the IVRS.

Treated subjects: All subjects who received at least one dose of nivolumab. This is the 
primary population for efficacy and safety.

Response evaluable subjects: All treated subjects who have baseline and at least one on-study 
evaluable tumor measurement.

Immunogenicity evaluable subjects: See Core SAP1.

PD-L1 per Dako tested subjects: All subjects who had a tumor tissue sample available for
assessment of PD-L1 expression.

PD-L1 per Dako evaluable subjects: All treated subjects with quantifiable baseline PD-L1 
expression

Outcomes Research subjects: All treated subjects who have an assessment at baseline (Visit 
1 assessment prior to administration of drug) and at least 1 subsequent assessment (for EORTC
QLQ-C30 and EQ-5D separately).(QLQ-C30 for Cohorts A, B and C only).

Nivolumab subjects treated beyond progression (Cohorts A, B and C): All subjects who 
received at least one dose of nivolumab after the date of initial progression per 2007 IWG 
criteria based on investigator assessment.

Persistent CR subjects (Cohort C only): All treated subjects in Cohort C who discontinue 
treatment following a CR of 1 year duration.

Treated Subjects who underwent a subsequent Allogeneic Transplant (Cohorts A, B and 
C): All subjects who received at least one dose of Nivolumab and who reported an allogeneic 
transplant date after first nivolumab dose.
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The following populations will also be defined for Cohort D:

Treated subjects with NAVD: All subjects who received at least one dose of nivolumab in the 
combination therapy phase.

Treated subjects with AVD only: All subjects who received at least one dose of AVD but no 
nivolumab in the combination therapy phase.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, the bulleted titles in the following subsections describe tabulations of 
discrete variables, by the frequency and proportion of subjects falling into each category. 
Percentages given in these tables will be rounded and, therefore, may not always sum to 100%. 
Continuous variables will be summarized using the mean, standard deviation, median, minimum 
and maximum values. If a missing category is not being presented in the data display, only those 
subjects with non-missing values for the parameter being assessed are included in the percentage 
calculation.
Time to event distribution (e.g. progression free survival, overall survival, time to response, and 
duration of response) will be estimated using Kaplan Meier techniques. When appropriate, the 
median along with the corresponding log-log transformed 95% CI will be estimated. Rates at fixed 
time points will be derived from the Kaplan Meier estimate and corresponding confidence interval 
will be derived based on Greenwood formula6 for variance derivation and on log-log 
transformation applied on the survivor function S(t) 7.
Confidence intervals for binomial proportions will be derived using the Clopper-Pearson method8.
All analyses will be performed separately for each cohort upon completion of follow-up for the 
primary endpoint in each cohort. In addition to separate analyses per cohort, safety analyses will
be performed on combined cohorts.
7.2
Study Conduct
7.2.1
Accrual
The following will be summarized on the enrolled population separately for each cohort and on 
the pooled population: 

Number of subjects accrued by country and investigational site

Number of subjects accrued by month
A by subject listing of accrual will be produced.
7.2.2
Relevant Protocol Deviations
The following programmable deviations will be considered as relevant protocol deviations. Non-
programmable relevant eligibility and on-treatment protocol deviations, as well as significant (both 
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programmable and non-programmable) eligibility and on-treatment protocol deviations will be 
reported through ClinSIGHT listings.
7.2.2.1
Cohorts A, B and C
At entrance:

Subjects without documented classical Hodgkin’s lymphoma

Subjects without prior ASCT

Subjects with prior brentuximab vedotin treatment (Cohort A only)

Subjects without prior brentuximab vedotin treatment (Cohorts B and C only)

Subjects with prior treatment history of brentuximab vedotin administered before first ASCT 
(Cohort B only)

Subjects without either measurable disease at baseline or FDG avid by PET

Subject with baseline ECOG >1
On-Study:

Any concurrent antineoplastic therapy (i.e., chemotherapy, immunotherapy, radiation therapy 
except for palliative radiation therapy, or standard or investigational agents for treatment of 
cancer).
A summary table will be produced separately for each cohort and pooled across cohorts in all 
treated subjects. A by subject listing will be produced.
7.2.2.2
Cohort D
At entrance:

Subjects without documented classical Hodgkin’s lymphoma

Subjects with prior treatment history for classical Hodgkin’s lymphoma

Subjects without either measurable disease at baseline or FDG avid by PET

Subject with baseline ECOG not in (0, 1)
On-Study:

Subjects with concurrent autologous or allogeneic transplant, systemic anti-cancer therapy or
non-palliative radiotherapy (curative or other).
7.3
Study Population
Except stated otherwise, analyses from this section will be produced separately for each cohort
and pooled across cohorts A, B and C.
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7.3.1
Subject Disposition
The total number of subjects enrolled (treated or not) will be presented along with the reason for 
not being treated.
Number of subjects who discontinued treatment along with corresponding reason will also be 
tabulated. For Cohort D, number of subjects who prematurely discontinue monotherapy treatment 
phase and enter combination therapy phase will also be presented.
7.3.2
Demographics and Other Baseline Characteristics
Descriptive statistics will be summarized the following baseline characteristics for all treated 
subjects. All baseline presentations will identify subjects with missing measurements. Listings will 
also be provided.

Age (descriptive statistics)

Age categories (< 65, 65 and < 75, 75 and < 85, 85, 75, 65, < 30, 30 and < 45, 45 
and < 60, 60)

Gender (male, female)

Race (white, black or african american, asian, american indian or alaska native, native hawaiian 
or other pacific islander, other)

Ethnicity (hispanic or latino, not hispanic or latino, nor reported)

Baseline ECOG Performance Status (0, 1)

Weight (descriptive statistics)

Time from initial disease diagnosis to first dose of nivolumab (< 1 year, 1 - < 2 year, 2 - < 3 
year, 3 - < 4 year, 4 - < 5 year, 5 year) 

Region (US/Canada, Europe, Rest of the World)

Smoking Status (Current\Former, Never Smoked, Unknown)

Disease stage at initial diagnosis (Stage I-II-III-IV)

International Prognostic Score (IPS) (0-2, 3 or higher) at initial diagnosis

Disease stage at study entry (Stage I-II-III-IV)

Specific B-symptoms at baseline (Fever, Night Sweats, Weight Loss) 

Bulky disease at baseline (Yes, No, Not Available)

Extra lymphatic involvement at baseline (Yes, No, Not Available)

Lymphoma involvement in bone marrow at baseline (Yes, No, Not Available)

All lesions (Investigator Tumor Assessments at Baseline): sites of diseases, number of disease 
sites per subject

Target Lesions (Investigator Tumor Assessments at Baseline): Presence of target lesions, site 
of target lesion, sum of product diameters of target lesions.
For Cohorts A, B and C:
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
Time from the initial diagnosis to first transplant (< 1 year, 1 - < 2 year, 2 - < 3 year, 3 - < 4 
year, 4 - < 5 year, 5 year)

Time from the most recent transplant to first dose of nivolumab (< 1 year, 1 - < 2 year, 2 - < 3 
year, 3 - < 4 year, 4 - < 5 year, 5 year)

Time from the most recent transplant to first subsequent treatment (< 6 months, 6 - < 12 
months, 12 months)

B-symptoms at initial diagnosis and at study entry (absent, present)
7.3.3
Medical History
General medical history will be listed by subject and pretreatment events will be tabulated.
7.3.4
Prior therapy (Cohorts A, B and C)
The following will be summarized:

Number of subjects by type of prior therapy received (excluding preparative regimen for 
ASCT): 
immunomodulatory 
derivatives 
(e.g. 
lenalidomide), 
other 
chemotherapy, 
immunotherapy by monoclonal antibodies (e.g. Rituximab, Brentuximab)

Number of subjects by type of regimen for first and second lines of therapy (e.g. ABVD, ICE, 
BEACOPP, Stanford V) 

Number of subjects by type of regimen received for preparation to ASCT (BEAM, CBV, 
Other) 

Number of prior systemic regimens received (1, 2,), excluding preparative regimen 
for ASCT 

Number of prior systemic regimens received (1, 2,), excluding preparative regimen 
for ASCT, for subjects who received brentuximab prior to ASCT only, received brentuximab 
after ASCT only, and received brentuximab both prior to and after ASCT), Cohort C only

Number of Prior Systemic Regimens by Administration Sequence of ASCT and brentuximab

Number of prior systemic regimens (1, 2,) received before ASCT and after ASCT, 
Cohort A only

Number of prior systemic regimens received (1, 2,) before ASCT, between ASCT 
and brentuximab and after brentuximab administration, Cohort B only

Number of prior systemic regimens received (1, 2,) before brentuximab, between 
brentuximab and ASCT, and after ASCT, Cohort C subjects who received brentuximab 
prior to ASCT only

Number of prior systemic regimens received (1, 2,) before ASCT, between ASCT 
and brentuximab, and after brentuximab administration, Cohort C subjects who had 
brentuximab only after ASCT

Best response to regimen before most recent ASCT

Disease Status at most recent ASCT

Best response to most recent ASCT

Best response to regimen post most recent ASCT
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
Best response to regimen post brentuximab (post most recent ASCT), Cohort B

Best response to regimen post most recent brentuximab but prior to most recent ASCT, Cohort 
C subjects who received brentuximab prior to ASCT only

Best response to regimen post most recent brentuximab, Cohort C subjects who had 
brentuximab only after ASCT

Best response to front line therapy for Cohort A subjects

Best response to most recent Brentuximab for Cohort B and C subjects

Time from completion of most recent prior regimen to treatment (< 3, 3 - 6, > 6 months)

Prior radiotherapy (yes or no)
Other Prior therapy:

Prior/current non-study medication classified by anatomic and therapeutic classes.
Medication will be reported using the generic name. A listing by subject will also be provided.
7.3.5
Prior Therapy (Cohort D)
Subjects are not expected to have received prior cHL anti-cancer therapy. Note that surgeries are 
not considered as prohibited prior therapies. A summary table and listing of prior therapies 
reported will be provided.
7.3.6
Baseline Examinations
Percentage of subjects with abnormal baseline physical examination will be tabulated by 
examination criteria.
7.4
Extent of Exposure
Analyses from this section will be produced separately for each cohort and pooled across cohorts
A, B and C. For cohort C, extent of exposure summary tables will exclude data collected in 
persistent CR subjects on or after the first date of re-initiation therapy. Listings will include all 
available exposure data.
7.4.1
Administration of Study Therapy
The following parameters will be summarized (descriptive statistics):

For each drug, relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 
70 - < 90%; 90 - < 110%; 110%. 

For each drug, number of doses received (summary statistics)
For cohort D, this will include

The number of subjects who received 1, 2, 3 or 4 doses of Nivolumab during the 
monotherapy period 
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
The number of subjects who received 1, ... 12 doses for each drug during the combination 
period

The number of subjects who received  12 doses of NAVD during the combination therapy
among subjects who have received at least one dose of NAVD

The number of subjects who received 12 doses of AVD with or without Nivolumab during 
the combination therapy among subjects who have received at least one dose of 
combination therapy (AVD with or without Nivolumab).

For each drug, cumulative dose 

Duration of treatment: duration of treatment will be presented using a Kaplan-Meier curve 
whereby the last dose date will be the event date for subjects who discontinued study therapy.  
Subjects who are still on study therapy will be censored on their last dose date.  Median 
duration of treatment and associated 95% CI will be provided.

A by-subject listing of dosing of study medication (record of study medication, infusion details, 
dose change) and a listing of batch number will be also provided.
Table 7.4.1-1:
Administration of study therapy: definition of parameters (Cohorts A, 
B, C)
nivolumab
Dosing schedule per protocol
3mg/kg every 2 weeks 
Dose
Dose (mg/kg) is defined as Total Dose administered (mg)/Most recent 
weight (kg). Dose administered in mg at each dosing date and weight are 
collected on the CRF.
Cumulative Dose
Cum dose (mg/kg) is sum of the doses (mg/kg) administered to a subject 
during the treatment period.
Relative dose intensity (%)
Cum dose (mg/kg) /[ (Last dose date - Start dose date + 14) x 3 / 14 ] x 100
Duration of treatment 
Last dose date - Start dose date +1
Table 7.4.1-2:
Administration of study therapy: definition of parameters (Cohort 
D)
Nivolumab
AVD
Dosing schedule per 
protocol
240mg every 2 weeks
A: adriamycin/doxorubicin 25mg/m2, 
V: vinblastine 6mg/m2, 
D: dacarbazine 375mg/m2
Dose
Dose (mg) is defined as Total Dose 
administered (mg). Dose administered in 
mg at each dosing date on the CRF
Dose (mg/m²) is defined as Total Dose 
administered (mg) / BSA. Dose 
administered in mg at each dosing date 
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Table 7.4.1-2:
Administration of study therapy: definition of parameters (Cohort 
D)
Nivolumab
AVD
and BSA (computed using bsl weight 
and bsl height) are collected on the CRF.
Dose (mg/kg) is defined as Total Dose 
administered (mg) /Weight. Dose 
adminstered in mg at each dosing date 
and weight (actual weight at each visit) 
are collected on the CRF
Cumulative Dose
Cum dose (mg) is sum of the doses (mg) 
administered to a participant during the 
treatment period.
Cum dose (mg/m², mg/kg) is sum of the 
doses (mg/m²) administered to a 
participant during the treatment period
Relative dose intensity 
(%)
Cum dose (mg) / [(Last dose date - Start 
dose date + 14) x 240 / 14] x 100
A: Cum dose (mg/m²) / [(Last dose date 
- Start dose date + 14) x 25 / 14] x 100
V: Cum dose (mg/m²) / [(Last dose date 
- Start dose date + 14) x 6 / 14] x 100
D: Cum dose (mg/m²) / [(Last dose date 
- Start dose date + 14) x 375 / 14] x 100
Duration of treatment
Last dose date - Start dose date +1
Last dose date - Start dose date +1
7.4.2
Modifications of Study Therapy
7.4.2.1
Dose delays
Treatment may be delayed for up to a maximum of 6 weeks from the last dose. A dose will be 
considered as actually delayed if the delay is exceeding 3 days (i.e., greater than or equal to 4 days 
from scheduled dosing date). Length of delay is defined as (duration of previous cycle in days -
14). Dose delays will be divided into following categories: 4 - < 8 days, 8 - < 15 days, 15 - < 43, 
43 days. Reason for dose delay will be retrieved from CRF dosing pages.
The following parameters will be summarized for each drug separately:

Number of subjects with at least one dose delayed, number of dose delayed per subject, Length 
of Delay and Reason for Dose Delay
7.4.2.2
Infusion Interruptions and Rate Changes
The following parameters will be summarized for each drug:

Number of subjects with at least one dose infusion interruption, number of infusion 
interruptions per subject and the reason for interruption.

Number of subjects with at least one IV infusion rate reduction, number of IV infusion rate 
reduction per subject and the reason for reduction
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7.4.2.3
Dose Reductions/Escalation
There will be no dose escalations or reductions of nivolumab allowed. 
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary.
For Cohort D, concomitant medication will be analyzed by treatment phase and overall.
The following summary tables will be provided: 

Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term).
A by-subject listing will accompany the table.
7.5
Efficacy
Analyses from this section will be produced separately for each cohort.
For persistent CR subjects, tumor assessments taken prior to progression/relapse (including during 
the observational follow-up period), and thus prior to re-initiation, will contribute towards BOR, 
time to objective response, duration of objective response and PFS following endpoint definitions. 
If persistent CR subjects re-initiate study therapy for progression/relapse, tumor assessments 
performed after re-initiation will be identified in efficacy listings but do not contribute towards 
these endpoints.
7.5.1
Primary Endpoint of ORR (based on IRRC assessment) (Cohorts A, B 
and C)
The ORR based on IRRC assessment (using 2007 revised International Working Group Criteria 
for Malignant Lymphoma criteria) will be summarized using all treated subjects by a binomial 
response rate. The Clopper-Pearson method8 will be used to estimate the two-sided 95% 
confidence interval. 
The null hypothesis will be rejected if the 2-sided 95% CI lower bound is greater than 20%. This 
translates in observing at least 19 responders out of 60 treated subjects.
BOR will be summarized by response category.
Summary statistics of time to objective response will be provided for subjects who achieve PR or 
CR, as assessed by the IRRC. CR requires confirmation by PET. To assess tumor response kinetics, 
time to response will also be analyzed using the KM methodology for all treated subjects. Kaplan-
Meier curve will represent the cumulative rate of response over time. For the non-responders, time 
to response will be censored at the maximum time to response + 1 day of all subjects in their 
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respective treatment group. Cumulative response rates will be tabulated for Week 9, Month 4, 6, 
8, 12 and 18.
7.5.1.1
ORR Subgroups

To assess consistency of ORR, IRRC-assessed ORR (primary analysis) will be summarized
for the following subgroups by cohort: Age (< 65, 65 and < 75, 75 and < 85, 85, 75, 
65, < 30, 30 and < 45, 45 and < 60, 60)

Region (US/Canada, Europe, Rest of the World).

Gender (Male, Female)

Race (white, black, Asian, and other)

Smoking status (yes, no)

ECOG (0, 1)

B-symptoms at initial diagnosis and at study entry (absent, present)Time from the initial 
diagnosis to transplant (< 1 year, 1 - < 2 year, 2 - < 3 year, 3 - < 4 year, 4 - < 5 year, 5 year)

Number of prior therapies (3, 4-6, 7) excluding preparative regimen 

Time from the most recent transplant to first subsequent treatment (< 6 months, 6 - < 12 
months, 12 months)

Categories including less than 5 subjects may be collapsed. Analyses of subgroups of less than 
5 subjects may not be provided.
7.5.1.2
Sensitivity Analyses for ORR

As sensitivity analysis, a summary of IRRC-assessed ORR based on response evaluable 
subjects instead of all treated subjects will also be presented. 

To assess concordance between IRRC (primary analysis) and investigator assessments, BOR 
will be cross-tabulated by assessment type (Investigator vs IRRC). Concordance Rate of 
Responders will be computed as the frequency with which Investigator and IRRC agree on 
classification of a subject as responder/non responder as a proportion of the total number of 
subjects assessed.
The following subject-level graphics will also be provided: 

For the responders only, time courses of the following events of interest will be graphically 
displayed (IRRC assessed): first tumor response, tumor progression, last dose received, 
subsequent hematopoietic stem cell transplant and death.

For response evaluable subjects, a waterfall plot showing the best reduction from baseline in 
target lesion based on IRRC assessment will be produced (excluding assessments after PD and 
assessments after start of subsequent anti-cancer therapy).

Plot of Individual Time course of Tumor Burden Change, per IRRC, for all treated subjects 
(spider plot)
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7.5.2
Secondary Endpoints
7.5.2.1
Duration of Response Based on IRRC Assessment (Cohorts A, B and C)
The DOR will be summarized by cohort for subjects who achieve PR or CR as determined by 
IRRC using KM product-limit method. Two-sided, 95% confidence intervals for median DOR will 
be constructed based on log-log transformation. Range of DOR will also be presented. Sensitivity 
analysis will be performed based on an alternate censoring scheme. In addition, the number of 
subjects with duration of response at least 3, 6, 12, 18 and 24 months will be presented.
7.5.2.2
Complete Remission Rate and Duration Based on IRRC Assessment
(Cohorts A, B , C and D)
Complete remission rate (CRR) based on IRRC assessment will be summarized by cohort by a 
binomial response rate and its corresponding two-sided 95% exact CIs using the Clopper-Pearson
method8.
To further characterize CRR, the duration of CR will be summarized by cohort for subjects who 
achieve CR as determined by IRRC using KM product-limit method. Two-sided, 95% confidence 
intervals for median duration of CR will be constructed based on log-log transformation. Range of 
duration of CR will also be presented. For Cohorts A, B and C, sensitivity analysis will be 
performed based on an alternate censoring scheme.
To assess tumor response kinetics, time to first CR will also be analyzed using the KM 
methodology for all treated subjects. Kaplan-Meier curve will represent the cumulative rate of CR 
over time. For the subjects who don’t achieve CR, time to CR will be censored at the maximum 
time to complete response + 1 day of all subjects in their respective treatment group.
For Cohort D, response assessment after the start of subsequent therapy will be censored for the 
main analysis. A second analysis will be performed to keep them in the analysis. Another analysis 
of the (complete) response rate at each planned timepoint (end of monotherapy, after two 
combination therapy cycles and end of therapy assessment) will be performed on all treated 
subjects with an evaluable response at the considered timepoint.
7.5.2.3
Partial Remission Rate and Duration Based on IRRC Assessment
(Cohorts A, B and C)
Partial remission rate (PRR) based on IRRC assessment will be summarized by cohort by a 
binomial response rate and its corresponding two-sided 95% exact CIs using the Clopper-Pearson8
method.
To further characterize PRR, the duration of PR will be summarized by cohort for subjects who 
achieve PR as determined by IRRC using KM product-limit method. Two-sided, 95% confidence 
intervals for median duration of PR will be constructed based on log-log transformation. Range of 
duration of PR will also be presented. Sensitivity analysis will be performed based on an alternate 
censoring scheme.
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7.5.2.4
Objective Response Rate and Duration Based on Investigator 
Assessment (Cohorts A, B and C)
Investigator-assessed ORR will be summarized by cohort by a binomial response rate and its 
corresponding two-sided 95% exact CIs using the Clopper-Pearson method8. 
The DOR based on investigator assessment will be summarized by cohort for subjects who achieve 
PR or CR as determined by investigator using KM product-limit method. Two-sided, 95% 
confidence intervals for median DOR will be constructed based on log-log transformation. Range 
of DOR will also be presented.
Time to CR and duration of CR based on investigator assessment will be summarized using the 
same method as for the IRRC assessment.
 
 
 
 
 
 
 
 
 
  
7.5.3.3
Progression Free Survival based on IRRC Assessment (Cohorts A, B 
and C)
PFS based on IRRC assessment will be summarized descriptively by cohort using the Kaplan-
Meier (KM) product-limit method. Median values of PFS, along with two-sided 95% CIs (based 
on the log-log transformation), will also be calculated.
The source of progression (death vs. progression) will be summarized.
The status of subjects who are censored in the PFS Kaplan-Meier analysis will be tabulated using 
following categories:

Received subsequent anti-cancer therapy (Stem Cell Transplant, other)

Still on-treatment
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
Progression-free in follow-up

Off-study: (lost to follow-up, withdrew consent, other).
KM curve of PFS will be generated. PFS rates per IRRC at 6 and 12 months will be estimated 
using KM estimates on the PFS curve. Associated two-sided 95% CIs will be calculated.
Subject listings of PFS will be produced.
7.5.3.4
Modified Progression Free Survival (Cohort D)
Modified PFS based on IRRC assessment/investigator assessments will be summarized 
descriptively using the Kaplan-Meier (KM) product-limit method. Median values of modified PFS, 
along with two-sided 95% CIs (based on the log-log transformation), will also be calculated.
The source of progression (death vs. progression vs start of subsequent therapy) will be 
summarized.
The status of subjects who are censored in the modified PFS Kaplan-Meier analysis will be 
tabulated using following categories:

Still on-treatment

Progression-free in follow-up

Off-study: (lost to follow-up, withdrew consent, other).
KM curve of modified PFS will be generated. ModifiedPFS rates at 6, 12,... months will be 
estimated using KM estimates on the modified PFS curve. Associated two-sided 95% CIs will be 
calculated.
By-subject listings of modified PFS will be produced.
7.5.3.5
Overall Survival
OS will be summarized by the Kaplan-Meier product-limit method. Median values of OS, along 
with two-sided 95% CIs (based on the log-log transformation), will be calculated. Survival rates 
at 6, 12, 18 and 24 months (minimum follow-up must be longer than timepoint to generate the 
rate) will also be estimated using KM estimates from the OS curve. The associated two-sided 
95% CIs will be calculated based on the log-log transformation. Additional follow-up may be up 
to 5 years and updated OS analysis may be performed. 
The status of subjects who are censored in the OS Kaplan-Meier analysis will be tabulated using 
the following categories:

On-study (on-treatment and not progressed, on-treatment progressed, in follow-up);

Off-study: (lost to follow-up, withdraw consent, etc.).
Subject Follow-up
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The extent of follow-up for survival defined as the time between first dose date and last known 
date alive (for subjects who are alive) or death date (for subjects who died) will be summarized 
descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum) 
for all treated subjects.
The currentness of follow-up for survival, defined as the time between last contact for overall 
survival (i.e., last known date alive or death date) and cutoff date (defined by last patient last visit 
date), will be summarized for all treated subjects. Subjects who died before cut-off date or subjects 
whose last known date alive is on or after data cut-off date will have currentness of follow-up set 
to zero. The currentness of follow-up will be categorized into the following categories: 0 day, 
1day-3 months, 3-6 months, 6-9 months, 9-12 months and months. 
Follow-Up Therapy
The following information pertaining to subsequent therapies will be summarized:
Number and percentage of subjects receiving subsequent therapies including:

Chemotherapy by drug name

Antibody by drug name (e.g. brentuximab) 

Immunotherapy by drug name (including anti-PD1 or anti-CTLA4 agents)

Other investigational agent by drug name

Hematopoietic stem cell transplantation (Allogeneic, Autologous)

Radiotherapy
A subject listing of follow-up therapy will be produced for subjects who had any subsequent
therapy.
 
 
 
 
 
7.5.4.2
Efficacy for Subjects Treated Beyond Progression (Cohorts A, B and C)
Individual time course of tumor burden change from baseline in target lesions, per investigator, 
will be generated for nivolumab subjects treated beyond progression (spider plot).
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By subject listing of efficacy and per timepoint tumor response per investigator will also be 
produced.
7.6
Safety
For Cohort A, B and C, all analyses from the Core Safety SAP1 will be produced separately for 
each cohort and on combined cohorts following the definition of on-treatment described in 
Table 6.1.2-1. Additional analyses examining the discontinuation schedule and subsequent 
potential re-initiation of therapy in persistent CR subjects may be performed. Listings will include 
all available data.
For Cohort D, all analyses from the Core Safety SAP will be produced for this cohort separately, 
for the monotherapy phase, combination phase and overall, except the following list of outputs 
which will not be produced:

Summary of Any Adverse Events That Required Immune Modulating Medication by Worst 
CTC Grade with Extended Follow-Up (Any Grade, Grade 3-4, Grade 5)

Summary of Late Emergent Drug-Related Adverse Events by Worst CTC Grade

Summary of Any Adverse Events by Worst CTC Grade (Any Grade, Grade 3-4, Grade 5) by 
Gender, Race, Age Category, Region

Summary of Drug-Related Adverse Events by Worst CTC Grade (Any Grade, Grade 3-4, 
Grade 5) by Gender, Race, Age Category, Region

Summary of Any Select Adverse Events by Worst CTC Grade with Extended Follow-Up

Summary of Any Drug-Related Select Adverse Events by Worst CTC Grade with Extended 
Follow-Up

Summary of Any Select Endocrine Adverse Events by Worst CTC Grade with Extended 
Follow-Up

Summary of Any Drug-Related Endocrine Select Adverse Events by Worst CTC Grade with 
Extended Follow-Up

Summary of Drug-Related Serious Select Adverse Events by Worst CTC Grade (Any Grade, 
Grade 3-4, Grade 5)

Summary of Time to Onset of Drug-Related Select Adverse Events by Category for Treated 
Subjects Who Experienced at Least One Drug-Related Select Adverse Event from the 
Category

Summary of Time to Onset of Drug-Related Select Endocrine Adverse Events by Subcategory
for Treated Subjects Who Experienced at Least One Drug-Related Select Adverse Event from 
the Subcategory

Summary of Time to Resolution of Drug-Related Select Adverse Events by Category for 
Treated Subjects Who Experienced at Least One Drug-Related Select Adverse Event from the 
Category

Summary of Time to Resolution of Drug-Related Select Adverse Events where Immune 
Modulating Medication Was Initiated by Category for Treated Subjects Who Experienced at 
Least One Drug-Related Select Adverse Event from the Category
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
Summary of Time to Resolution of Drug-Related Select Endocrine Adverse Events by 
Subcategory for Treated Subjects Who Experienced at Least One Drug-Related Select Adverse 
Event from the Subcategory

Summary of Time to Resolution of Drug-Related Select Endocrine Adverse Events where 
Immune Modulating Medication Was Initiated by Subcategory for Treated Subjects Who 
Experienced at Least One Drug-Related Select Adverse Event from the Subcategory

By Subject Listing of Time to Resolution for Longest Any Grade Immune-Mediated Adverse 
Event Cluster for Treated Subjects Who Experienced at Least One Immune-Mediated Adverse 
Event in the Category

By Subject Listing of Time to Resolution for Longest Grade 3-5 Immune-Mediated Adverse 
Event Cluster for Treated Subjects Who Experienced at Least One Grade 3-5 Immune-
Mediated Adverse Event in the Category
7.6.1
Deaths
See Core Safety SAP1
7.6.2
Serious Adverse Events
See Core Safety SAP1
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP1
7.6.4
Adverse Events Leading to Dose Modification
See Core Safety SAP1
7.6.5
Adverse Events
See Core Safety SAP1
7.6.6
Select Adverse Events 
See Core Safety SAP1with the exception that most of the analyses of select adverse events will be 
limited to the 30 days safety windows and will not be repeated with the 100 days safety windows. 
Plots of time to onset of select adverse events and tables of rates by timepoint of select adverse 
events will not be produced. Summary of any select, drug-related select, select endocrine, drug-
related select endocrine AE by worst CTC grade will be produced. Summary of any select, drug-
related select, select endocrine and drug-related select endocrine AE leading to discontinuation by 
worst CTC grade will also be produced.
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7.6.7
Immune modulating medication 
See Core Safety SAP1
7.6.8
Multiple Events
See Core Safety SAP1
7.6.9
Clinical laboratory evaluations
See Core Safety SAP1
7.6.10
Vital Signs and Pulse Oximetry
See Core Safety SAP1
7.6.11
Immunogenicity Analysis
See Core Safety SAP1
7.6.12
Pregnancy
By-subject listing of pregnancy tests results will be provided 
7.6.13
Clinical Safety Program (CSP)
See Core Safety SAP1
7.6.14
Adverse Events by Subgroup
See Core Safety SAP1
7.6.15 Immune-mediated Adverse Events Analysis
IMAE analyses will include events, regardless of causality, occurring within 100 days of the last 
dose. These analyses are limited to subjects who received immunosuppressive medication for 
treatment of the event, with the exception of endocrine events (hypothyroidism/thyroiditis, 
hyperthyroidism, hypophysitis, diabetes mellitus, adrenal insufficiency), which will be included 
in the analysis regardless of treatment since these events are often managed without 
immunosuppression.
IMAEs, serious IMAEs, IMAEs leading to discontinuation, and IMAEs leading to dose delay or 
reduction will be summarized by worst CTC grade and presented by IMAE Category/PT. 
Time to onset, time to resolution, time to resolution with completion of immunosuppressive 
medication will be defined and summarized by IMAE category in the same manner as for select 
AEs (see Section 7.6.6 ) except that, other than for the endocrine category, the longest duration of 
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IMAEs has to be associated with the use of an immune-modulating medication. Time to Resolution 
for Longest Any Grade or Grade 3-5 IMAE cluster per subject will be listed.
Use of immune-modulating medications for IMAE management will be summarized by IMAE 
category in a similar manner as for the select AEs (see Section 7.6.7).
IMAE rechallenge will be also summarized.
7.6.16 Other Events of Special Interest
In addition to select AE and immune-mediated AE, categories of other events of special interest 
(OESI) have been defined (i.e. myasthenic syndrome, Guillain-Barre syndrome, demyelination, 
pancreatitis, uveitis, encephalitis events). Worst CTC grade of any and drug-related OESI (both 
safety windows) will be summarized along with the time to onset and resolution. In addition, worst 
CTC grade of serious OESI and OESI leading to discontinuation will be summarized (both safety 
windows). Lastly, OESI occurring within 100 days of the last dose in subjects who received 
immunosuppressive medication for treatment of the events will be tabulated by worst CTC grade 
and the time to onset and resolution will be provided.
7.6.17
Safety of subjects who undergo subsequent Allogeneic Transplant
(Cohorts A, B and C)
Summary of baseline characteristics for subjects who undergo subsequent Allogeneic Transplant 
will be provided by cohort and overall (age, age categorisation, gender, race, ethnicity, number of 
prior systemic cancer therapies). 
Summary of Allogeneic Transplant characteristics will be also provided by cohort and overall 
(Number of Nivolumab doses prior subsequent allogeneic transplant, Time between last 
nivolumab dose and allogeneic transplant, transplant source, donor type and relationship, type of 
preparative stem cells regimen).
The extent of post allogeneic transplant (time from allogeneic transplant to last known alive date 
or death), will be summarized for each cohort and overall. Number and percentage of subjects with 
at least 100 days, 6 months and 1 year extent of post-allogeneic transplant follow-up will be 
provided. 
The incidence of subjects who progress post allogeneic transplant, the incidence of transplant 
related deaths, acute gvhd (any grade, grade 2-4, grade 3-4) or other potential complications will 
be summarized by cohort and overall. The time from transplant to these events will be summarized 
as well. Cumulative incidence rate will be plotted for cohort A+B+C. A multivariate Cox model 
analysis may be performed on cohort A+B+C to model the occurrence of transplant related deaths, 
acute gvhd grade 2-4, acute gvhd 3-4 with a set of covariates which may include a set of relevant 
factors such as age at the time of transplant, number of therapies prior Nivolumab, number of 
nivolumab doses, time from last nivolumab dose to allogeneic transplant, transplant source, donor 
type and relationship or other transplant characteristics. As post-transplant disease progression can 
be seen as a competing risk to transplant-related death or acute gvhd, competing risk modeling 
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methods such as Fine-Clay model may be used instead of the Cox model if competing risks are 
observed.
By-subject listings of transplant-related characteristics, transplant-related complications and 
extent of post-transplant follow-up will also be provided. 
7.6.18
Other safety analyses
For cohort D, a by-subject listing of electrocardiograms results and pulmonary functions data will 
be provided. A summary table of the change from baseline in pulmonary functions (such as 
percentage of the predicted forced expiratory volume in one second (FEV1), percentage of the 
predicted forced vital capacity (FVC) and the percentage of the predicted ratio of FEV1/FVC) after 
study therapy will also be provided.
 
 
 
 
 
 
 
 
 
 
 
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8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates:
For missing and partial adverse event onset dates, imputation will be performed using the Adverse 
Event Domain Requirements Specification9. Missing and partial Non-Study Medication Domain 
dates will be imputed using the derivation algorithm described in BMS Non-Study Medication 
Domain Requirements Specification10.
For death dates, the following conventions will be used for imputing partial dates:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known alive date and the maximum will be 
considered as the death date.

If the month or the year is missing, the death date will be imputed as the last known alive date 

If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known alive date
For date of progression, the following conventions will be used for imputing partial dates:

If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day.

If the day and month are missing or a date is completely missing, it will be considered as 
missing.

In case, the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
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For other partial/missing dates, the following conventions will be used:

If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day.

If both the day and the month are missing, “July 1” will be used to replace the missing 
information.

If a date is completely missing, it will be considered as missing.
The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days.
Duration (e.g. time from first diagnosis to first dosing date, duration response, and time to 
response) will be calculated as follows:
Duration = (Last date - first date + 1)
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
9
CONTENT OF REPORTS
All analyses described in this SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables and listings.
 
 
 
 
 
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Table 10-1:
Document History
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