Clinical trial NCT02572167
Conditions: Hodgkin Lymphoma
Keywords: Monomethyl auristatin E Antigens, CD30 Antibody-Drug Conjugate Antibodies, Monoclonal Immunotherapy Autologous stem cell transplant
Sponsor: Seagen Inc.
Start date: 2015-10-31; Completion date: 2021-10-21
Enrollment: 93 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the safety profile and antitumor activity of brentuximab vedotin administered in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma (HL)

Detailed description:
This study will examine the safety profile and antitumor activity when brentuximab vedotin is combined with nivolumab. Patients will be treated for up to four 21-day cycles with brentuximab vedotin 1.8 mg/kg and nivolumab 3 mg/kg.

There will be 3 parts to this study. In Part 1, the safety of combination treatment will be evaluated by a Safety Monitoring Committee (SMC) prior to expansion of enrollment to evaluate treatment effect in Part 2. Part 2 of the study will further characterize the safety and antitumor activity of brentuximab vedotin combined with nivolumab by enrolling patients at the recommended dose schedule determined in Part 1. Part 3 of the study will evaluate the safety and antitumor activity of combination treatment administered at an alternate dosing schedule determined by cumulative safety and activity data from Parts 1 and 2.

Arms: arm 1: Brentuximab vedotin plus nivolumab
Interventions: intervention 1: brentuximab vedotin intervention 2: nivolumab
Intervention descriptions: intervention 1: 1.8 mg/kg by intravenous (IV) infusion for up to 4 cycles intervention 2: 3 mg/kg by intravenous (IV) infusion for up to 4 cycles

Protocol documents:
Prot_002.pdf: 


Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
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PROTOCOL SYNOPSIS 
Protocol Number 
SGN35-025 
Version 
Amendment 4; 23 Jan 2017 
Phase 
1/2 
Product Name 
Brentuximab vedotin; nivolumab 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
A phase 1/2 study evaluating brentuximab vedotin in combination with nivolumab in patients with relapsed or 
refractory Hodgkin lymphoma after failure of frontline therapy 
Study Objectives 
Primary: 
● To assess the safety profile of brentuximab vedotin administered in combination with nivolumab in patients 
with relapsed or refractory Hodgkin lymphoma (HL) 
● To assess the antitumor activity of brentuximab vedotin administered in combination with nivolumab in 
patients with relapsed or refractory HL 
Secondary: 
● To assess the objective response rate (ORR) 
● To assess the duration of complete response (CR) and objective response (OR) 
● To assess progression-free survival (PFS) after autologous stem cell transplant (ASCT) 
Additional: 
● To assess overall survival (OS) 
● To compare the CR rate in patients who relapsed after frontline therapy with the CR rate in patients who 
were refractory to frontline therapy 
● To assess the feasibility of stem cell mobilization and collection after treatment with brentuximab vedotin 
in combination with nivolumab 
● To assess PFS 
● To assess pharmacokinetics and incidence of antitherapeutic antibodies (ATA) against each study drug 
given in combination 
● To assess tumor amplification and expression of programmed death-ligand 1/programmed death-ligand 2 
(PD-L1/PD-L2) and relationship to response 
● To assess tumor microenvironment and peripheral immune status 
● To compare safety and efficacy of treatment with staggered versus same-day dosing schemes 
● To compare biomarker data obtained with staggered versus same-day dosing schemes 
● To explore efficacy in patients who previously received brentuximab vedotin 
Study Population 
Key eligibility criteria include adult (aged ≥18 years) patients with relapsed or refractory HL following failure 
of standard frontline chemotherapy for the treatment of classical HL.  Patients must have an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0 or 1 and qualifying baseline laboratory data.  
Patients are excluded if they were previously treated with immuno-oncology agents or previously received an 
autologous or allogeneic stem cell transplant.  Patients with documented history of a cerebral vascular event, 
history of another invasive malignancy that has not been in remission for at least 3 years, or history of 
progressive multifocal leukoencephalopathy (PML) are also excluded.  There will be 3 parts in this study; each 
part will be enrolled sequentially.  For Parts 1 and 2, patients previously treated with brentuximab vedotin are 


Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
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Seattle Genetics, Inc. - Confidential 
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excluded; for Part 3, patients who were treated with brentuximab vedotin are eligible under the following 
conditions: 1) patient's HL was not primary refractory to a brentuximab vedotin-containing regimen in first line, 
i.e., patient achieved a CR to a brentuximab vedotin-containing regimen and did not progress within 3 months 
of the last dose of brentuximab vedotin; and 2) brentuximab vedotin was not discontinued due to unacceptable 
toxicity. 
Number of Planned Patients 
Approximately 92 patients will be enrolled in this study. 
Study Design 
This is a phase 1/2, open-label, multicenter study designed to evaluate the safety and antitumor activity of 
brentuximab vedotin treatment combined with nivolumab. 
Patients will be treated for up to four 21-day cycles.  In Parts 1 and 2, the first dose of brentuximab vedotin 
1.8 mg/kg will be given on Cycle 1 Day 1. The first dose of nivolumab 3 mg/kg will be given on Cycle 1 Day 8. 
For Cycle 2 and all subsequent cycles, brentuximab vedotin 1.8 mg/kg followed by nivolumab 3 mg/kg will be 
given on Day 1.  In Part 3, both brentuximab vedotin 1.8 mg/kg and nivolumab 3 mg/kg will be administered on 
Day 1 of all Cycles.  For patients in Part 3 who were previously treated with brentuximab vedotin and had a 
dose reduction, dose assignment must be discussed with the medical monitor. 
Patients in Parts 1 and 2 with radiographic evidence of progressive disease (PD) at the Cycle 2 response 
assessment are not eligible for further treatment on the study.  All other patients are eligible to continue 
treatment on study through Cycle 4.  After completion of the end-of-treatment (EOT) response assessments, 
patients are eligible to undergo ASCT.  It is recommended that hematopoietic stem cells (HSC) be mobilized 
and collected after Cycle 4.  However, stem cell collection may occur in prior cycles after discussion with the 
medical monitor.  If patients have an unacceptable toxicity that is attributable to only one agent, as determined 
by the investigator, they will be eligible to continue on the treatment protocol through Cycle 4 with the tolerated 
drug as a single agent. 
Patients in Part 3 with confirmed, unequivocal PD at the Cycle 2 response assessment are not eligible for further 
treatment and will proceed to the EOT visit.  Patients with stable disease (SD) or better at the Cycle 2 response 
assessment may continue on treatment through Cycle 4.  Patients with an indeterminate response (IR), as 
defined by the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC; Appendix D) (Cheson 
2016), also may continue on treatment through Cycle 4.  After completion of the EOT response assessment, 
patients are eligible to undergo ASCT.  It is recommended that HSC be mobilized and collected after Cycle 4.  
However, stem cell collection may occur in prior cycles after discussion with the medical monitor.  If patients 
have an unacceptable toxicity that is attributable to only one agent, as determined by the investigator, they will 
be eligible to continue on the treatment protocol through Cycle 4 with the tolerated drug as a single agent. 
The safety of combination treatment in Part 1 will be evaluated by a Safety Monitoring Committee (SMC) prior 
to expansion of enrollment in Part 2 to evaluate treatment effect.  In Part 1, after 6 patients have been followed 
through the end of the dose-limiting toxicity (DLT) period, or at the point that 2 or more patients experience a 
DLT, whichever comes first, the SMC will review all available data and make a recommendation for one of the 
following: 
1. To proceed to Part 2 of the study, expanding enrollment with additional patients treated with the study 
drugs at the doses and schedule determined to be safe in Part 1 of the study; 
2. To repeat Part 1 of the study and treat up to 6 additional patients at the same drug doses and schedule 
previously tested or with any of the following modifications that may include, but are not limited to: 
a. 
Dose reduction of brentuximab vedotin to 1.2 mg/kg and/or nivolumab to 1 mg/kg; of note, doses may 
not be increased above 1.8 mg/kg brentuximab vedotin or 3 mg/kg nivolumab 
b. Administration of combination treatment on Day 1 of every cycle 


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3. To close the study to additional enrollment. 
For the purpose of this study, DLTs are defined as any study drug-related toxicity (brentuximab vedotin or 
nivolumab) that requires either a dose reduction or delay of more than 7 days of either study drug in Cycle 2 or 
delays the Cycle 3 Day 1 administration of combined treatment by more than 7 days.  The DLT-evaluation 
period consists of the first cycle of therapy through the Cycle 3 Day 1 administration of combined treatment. 
Part 2 of the study will further characterize safety and evaluate the antitumor activity of brentuximab vedotin 
combined with nivolumab in patients who have failed standard frontline chemotherapy by enrolling 
approximately 50 additional patients at the recommended dose schedule determined in Part 1. 
Part 3 of the study will further characterize safety and efficacy of the study drug combination administered as 
same-day dosing in all cycles by enrolling approximately 30 additional patients with relapsed or refractory HL 
at the recommended doses as followed in Part 2. 
Test Product, Dose, and Mode of Administration 
Brentuximab vedotin 
Parts 1, 2, and 3: 1.8 mg/kg or 1.2 mg/kg will be administered every 3 weeks via outpatient intravenous (IV) 
infusion on Day 1 of each cycle, as determined by the SMC in Part 1. 
Nivolumab 
Parts 1 and 2 (Staggered Dosing): 3 mg/kg or 1 mg/kg will be administered every 3 weeks via outpatient IV 
infusion on Day 8 of Cycle 1 and Day 1 of each subsequent cycle or on Day 1 of each cycle, as determined by 
the SMC in Part 1. 
Part 3 (Same-day Dosing): 3 mg/kg will be administered every 3 weeks via outpatient IV infusion following 
each brentuximab vedotin dose on Day 1 of all treatment cycles. 
Duration of Treatment 
Planned treatment duration is 4 cycles (12 weeks). 
Efficacy Assessments 
Lymphoma response and progression will be assessed by investigators using the Lugano Classification Revised 
Staging System for malignant lymphoma (Cheson 2014).  Dedicated CT scans of chest, neck, abdomen, and 
pelvis will be conducted at Cycle 2 response assessments. CT and PET scans will be performed at baseline, at 
EOT, prior to ASCT, and during long-term follow-up.  PET will be performed with CT scans until the patient is 
in complete metabolic response (CmR) by PET.  For patients in Part 3, investigators will conduct response 
assessments using the Lugano criteria with the incorporation of the Lymphoma Response to 
Immunomodulatory Therapy Criteria (Cheson 2016). 
Cycle-2 CT scans of diagnostic quality will be performed 15 to 21 days after dosing to assess for progression of 
disease.  The window for performing CT/PET scans at the EOT assessment for patients in Parts 1 and 2 is 23 to 
37 days post last dose of study drug, but for patients in Part 3, the window for performing CT/PET scans at the 
EOT assessment is 15 to 30 days post last dose of study drug.  Pre-ASCT scans may be waived for patients who 
have a scan performed within 6 weeks prior.  Long-term follow-up assessments will be performed at the 
following timepoints post-ASCT (or post-EOT for patients who do not undergo ASCT): 100 days and then 6, 9, 
12, 18, 24, 30, and 36 months, and then per institutional standard thereafter.  A final safety visit will be 
performed 100 days after the last dose of nivolumab and after the EOT visit to assess for potential immune-
mediated adverse events (AEs).  Patients will be followed according to this schedule until withdrawal of 
consent, death, or study closure, whichever occurs first. 
Pharmacokinetic and Immunogenicity Assessments 
Serum concentrations of brentuximab vedotin and nivolumab, and plasma concentrations of MMAE 
(unconjugated) will be measured.  ATA against brentuximab vedotin and ATA against nivolumab will also be 
assessed. 


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Biomarker Assessments 
Blood and tumor samples will be collected for measurement of potential biomarkers. 
Safety Assessments 
Safety assessments will include the surveillance and recording of AEs, physical examination findings, pulse 
oximetry tests, and laboratory tests. 
Statistical Methods 
Safety and efficacy analyses will be summarized with descriptive statistics.  Frequencies and percentages will 
be used when presenting categorical variables.  The primary efficacy endpoint of CR rate will be tested using a 
one-sided exact binomial test with a null hypothesis of CR rate less than or equal to 30% and α=0.05. 


Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
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Seattle Genetics, Inc. - Confidential 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 9 
1 
INTRODUCTION ......................................................................................................................................... 11 
1.1 
Hodgkin Lymphoma ........................................................................................................................... 11 
1.2 
Molecular Targets in the Treatment of Hodgkin Lymphoma .............................................................. 11 
1.3 
Study Treatments ................................................................................................................................. 12 
1.3.1 
Brentuximab Vedotin ............................................................................................................. 12 
1.3.2 
Nivolumab .............................................................................................................................. 13 
1.4 
Clinical Study Rationale ...................................................................................................................... 13 
2 
OBJECTIVES ............................................................................................................................................... 14 
2.1 
Primary Objectives .............................................................................................................................. 14 
2.2 
Secondary Objectives .......................................................................................................................... 14 
2.3 
Additional Objectives .......................................................................................................................... 14 
2.4 
Endpoints ............................................................................................................................................. 14 
2.4.1 
Primary Endpoints .................................................................................................................. 14 
2.4.2 
Secondary Endpoints .............................................................................................................. 14 
2.4.3 
Additional Endpoints .............................................................................................................. 15 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 16 
3.1 
Summary of Study Design .................................................................................................................. 16 
3.1.1 
Study Design Parts 1 and 2 ..................................................................................................... 16 
3.1.2 
Study Design Part 3 ................................................................................................................ 17 
3.1.3 
Safety Monitoring Committee ................................................................................................ 18 
3.1.4 
Dose-Limiting Toxicities ........................................................................................................ 19 
3.2 
Discussion and Rationale for Study Design ........................................................................................ 19 
3.2.1 
Rationale for Study Design of Same-day Dosing ................................................................... 19 
3.2.2 
Method of Assigning Patients to Treatment Groups .............................................................. 20 
3.2.3 
Rationale for Selection of Doses ............................................................................................ 20 
3.2.4 
Blinding .................................................................................................................................. 21 
4 
STUDY POPULATION................................................................................................................................ 21 
4.1 
Inclusion Criteria ................................................................................................................................. 21 
4.2 
Exclusion Criteria ................................................................................................................................ 22 
4.3 
Removal of Patients from Therapy or Assessment.............................................................................. 23 
4.3.1 
Discontinuation of Study Drug ............................................................................................... 24 
4.3.2 
Patient Withdrawal from Study .............................................................................................. 24 
5 
TREATMENTS ............................................................................................................................................ 24 
5.1 
Treatments Administered .................................................................................................................... 24 
5.2 
Brentuximab Vedotin .......................................................................................................................... 24 
5.2.1 
Description ............................................................................................................................. 24 
5.2.2 
Dose and Administration ........................................................................................................ 25 
5.2.3 
Dose Modifications ................................................................................................................ 25 
5.2.4 
Storage and Handling ............................................................................................................. 26 
5.2.5 
Packaging and Labeling ......................................................................................................... 26 
5.2.6 
Preparation.............................................................................................................................. 27 
5.3 
Nivolumab ........................................................................................................................................... 27 
5.3.1 
Description ............................................................................................................................. 27 
5.3.2 
Method of Procurement .......................................................................................................... 27 
5.3.3 
Dose and Administration ........................................................................................................ 27 
5.3.4 
Dose Modifications ................................................................................................................ 28 
5.3.5 
Storage and Handling ............................................................................................................. 31 
5.3.6 
Packaging and Labeling ......................................................................................................... 31 
5.3.7 
Preparation.............................................................................................................................. 31 
5.4 
Required Premedication and Postmedication ...................................................................................... 31 


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5.4.1 
Patients in Parts 1 and 2 .......................................................................................................... 32 
5.4.2 
Patients in Part 3 ..................................................................................................................... 32 
5.5 
Concomitant Therapy .......................................................................................................................... 32 
5.5.1 
Required Concomitant Therapy.............................................................................................. 33 
5.5.2 
Allowed Concomitant Therapy .............................................................................................. 33 
5.5.3 
Prohibited Concomitant Therapy ............................................................................................ 34 
5.6 
Management of Adverse Reactions ..................................................................................................... 34 
5.6.1 
Management of Infusion Reactions ........................................................................................ 34 
5.6.2 
Management of Suspected Progressive Multifocal Leukoencepalopathy .............................. 35 
5.6.3 
Management of Immune-Adverse Events .............................................................................. 35 
5.7 
Treatment Compliance ........................................................................................................................ 36 
6 
STUDY ACTIVITIES ................................................................................................................................... 36 
6.1 
Schedule of Events .............................................................................................................................. 36 
6.2 
Screening Visit (Days −28 to 1) .......................................................................................................... 36 
6.2.1 
Baseline Visit (Days −7 to Day 1) .......................................................................................... 37 
6.3 
Treatment Period (Day 1 to Day 21) ................................................................................................... 37 
6.3.1 
Cycle 1 Day 1 (±1 day) .......................................................................................................... 37 
6.3.2 
Cycle 1 Day 2 (+2 days) ......................................................................................................... 37 
6.3.3 
Cycle 1 Day 8 (±1 day) .......................................................................................................... 38 
6.3.4 
Cycle 1 Day 15 (±1 day) ........................................................................................................ 38 
6.3.5 
Cycle 2 Day 1 (±1 day) .......................................................................................................... 38 
6.3.6 
Cycle 2 Day 8 (±1 day) .......................................................................................................... 38 
6.3.7 
Cycle 2 Day 15 (+6 days) ....................................................................................................... 38 
6.3.8 
Cycle 3 Day 1 (±1 day) .......................................................................................................... 38 
6.3.9 
Cycle 4 Day 1 (±1 day) .......................................................................................................... 39 
6.3.10 Cycle 4 Day 2 (+2 days) ......................................................................................................... 39 
6.3.11 Cycle 4 Day 8 (±1 day) .......................................................................................................... 39 
6.3.12 Peripheral Blood Stem Cell Collection................................................................................... 39 
6.4 
End of Treatment Visit (30 to 37 days after last dose of study drug except where noted) .................. 39 
6.5 
Autologous Stem Cell Transplant ....................................................................................................... 40 
6.6 
Safety Visit (100 days [+2 weeks] after last dose of nivolumab) ........................................................ 40 
6.7 
Long-term Follow-up (±2 weeks) ....................................................................................................... 40 
6.8 
End of Study/End of Follow-up .......................................................................................................... 41 
7 
STUDY ASSESSMENTS ............................................................................................................................. 41 
7.1 
Screening/Baseline Assessments ......................................................................................................... 41 
7.2 
Response/Efficacy Assessments .......................................................................................................... 42 
7.2.1 
Parts 1 and 2 ........................................................................................................................... 42 
7.2.2 
Part 3 ...................................................................................................................................... 42 
7.3 
Pharmacokinetic and Immunogenicity Assessments ........................................................................... 44 
7.4 
Biomarker Studies ............................................................................................................................... 47 
7.4.1 
Tumor Biopsies ...................................................................................................................... 50 
7.5 
Biospecimen Repository...................................................................................................................... 50 
7.6 
Safety Assessments ............................................................................................................................. 51 
7.6.1 
Adverse Events ....................................................................................................................... 51 
7.6.2 
Clinical Laboratory Tests ....................................................................................................... 56 
7.6.3 
Physical Examination ............................................................................................................. 56 
7.6.4 
Other Safety Assessment ........................................................................................................ 57 
7.7 
Appropriateness of Measurements ...................................................................................................... 57 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 57 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 57 
8.2 
Data Management Procedures ............................................................................................................. 58 
8.3 
Access to Source Data ......................................................................................................................... 58 
8.4 
Accuracy and Reliability of Data ........................................................................................................ 59 
8.5 
Quality Assurance Procedures ............................................................................................................. 59 


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8.6 
Data Handling and Record Keeping .................................................................................................... 59 
8.6.1 
Data Handling ......................................................................................................................... 59 
8.6.2 
Investigator Record Retention ................................................................................................ 59 
9 
DATA ANALYSIS METHODS ................................................................................................................... 60 
9.1 
Determination of Sample Size ............................................................................................................. 60 
9.2 
Study Endpoint Definitions ................................................................................................................. 60 
9.2.1 
Primary Efficacy Endpoint ..................................................................................................... 60 
9.2.2 
Secondary Efficacy Endpoints................................................................................................ 61 
9.2.3 
Additional Efficacy Endpoints ............................................................................................... 62 
9.3 
Statistical and Analytical Plans ........................................................................................................... 63 
9.3.1 
General Considerations .......................................................................................................... 63 
9.3.2 
Patient Disposition ................................................................................................................. 65 
9.3.3 
Patient Characteristics ............................................................................................................ 65 
9.3.4 
Treatment Compliance ........................................................................................................... 65 
9.3.5 
Efficacy Analyses ................................................................................................................... 65 
9.3.6 
Pharmacokinetic and ATA Analyses ...................................................................................... 66 
9.3.7 
Biomarker Analyses ............................................................................................................... 66 
9.3.8 
Safety Analyses ...................................................................................................................... 66 
9.3.9 
Interim Analyses ..................................................................................................................... 67 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 68 
10.1 Informed Consent ................................................................................................................................ 68 
10.2 Ethical Review .................................................................................................................................... 68 
10.3 Regulatory Considerations .................................................................................................................. 69 
10.3.1 Investigator Information ......................................................................................................... 69 
10.3.2 Protocol Amendments and Study Termination ....................................................................... 69 
10.4 Study Documentation, Privacy and Records Retention ....................................................................... 69 
10.5 Clinical Trial Agreement ..................................................................................................................... 70 
11 REFERENCES .............................................................................................................................................. 71 
APPENDIX A: 
SCHEDULE OF EVENTS ..................................................................................................... 74 
APPENDIX B: 
PERFORMANCE STATUS SCALES CONVERSION ........................................................ 78 
APPENDIX C: 
NEW YORK HEART ASSOCIATION CLASSIFICATION ................................................ 79 
APPENDIX D: 
OVERVIEW OF LYRIC CRITERIA (PART 3 ONLY) ........................................................ 80 
APPENDIX E: 
INVESTIGATOR SIGNATURE PAGE ................................................................................ 82 
APPENDIX F: 
DOCUMENT HISTORY ....................................................................................................... 83 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Recommended dose modifications for brentuximab-associated toxicity ....................................... 26 
Table 2: 
Pharmacokinetic and ATA sampling timepoints, Parts 1 and 2 .................................................... 45 
Table 3: 
Pharmacokinetic and ATA sampling timepoints, Part 3 ................................................................ 46 
Table 4: 
Biomarker sampling timepoints, Parts 1 and 2 .............................................................................. 48 
Table 5: 
Biomarker sampling timepoints, Part 3 ......................................................................................... 49 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study design: Staggered dosing in Cycle 1 (Parts 1 and 2) ........................................................... 16 
Figure 2: 
Study design: Same-day dosing in all treatment cycles (Part 3) .................................................... 17 
 
 


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Clinical Protocol 
Amendment 4; 23 Jan 2017 
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Seattle Genetics, Inc. - Confidential 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
β-hCG 
beta human chorionic gonadotropin 
Ceoi 
concentration at the end of infusion 
Cmax 
maximum concentration 
Ctrough 
trough concentration 
CBC 
complete blood count 
CI 
confidence interval 
CmR 
complete metabolic response 
CMV 
cytomegalovirus 
con meds 
concomitant medications 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
DILI 
drug-induced liver injury 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose  
GCP 
good clinical practice 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HL 
Hodgkin lymphoma 
HRS 
Hodgkin Reed-Sternberg 
HSC 
hematopoietic stem cells 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IHC 
immunohistochemical 
IND 
Investigational New Drug 
INN 
International Nonproprietary Name 
IR 
indeterminate response 
IRB 
institutional review board 
IV 
intravenous 
JAK2 
Janus kinase 2 
LFT 
liver function test 
LYRIC 
Lymphoma Response to Immunomodulatory Therapy Criteria 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1/PD-L2 
programmed death ligand 1/programmed death ligand 2 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PmD 
progressive metabolic disease 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SPD 
sum of the products of the largest diameter 
TCR 
T cell receptor 
TSH 
thyroid stimulating hormone 
ULN  
upper limit of normal 
USAN 
United States adopted name 
 


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1 
INTRODUCTION 
1.1 Hodgkin Lymphoma 
Hodgkin lymphoma (HL) is a neoplasm of lymphoid tissue that is histopathologically defined 
by the presence of malignant Hodgkin Reed-Sternberg (HRS) cells in a background of 
inflammatory cells.  Advances in the use of combined chemotherapy and radiotherapy in HL 
over the past half century have resulted in a durable remission rate of approximately 70% 
(Connors 2005).  However, these multi-agent regimens are associated with significant 
morbidity, including secondary malignancies, cardiac disease, pulmonary disease, and 
infertility (Loge 1999) (Swerdlow 2000).  Furthermore, approximately 30–40% of patients 
presenting with HL will become refractory to initial therapy or will relapse. 
1.2 Molecular Targets in the Treatment of Hodgkin Lymphoma 
CD30, a cell membrane protein of the tumor necrosis receptor family, is uniformly expressed 
on HRS cells.  However, normal expression of CD30 is restricted to a relatively small 
population of activated T cells and B cells, making it an excellent surface protein to target 
with antibody-directed therapy (Falini 1995). 
The programmed death-1 (PD-1) cell surface membrane receptor is a member of the CD28 
family of T cell co-stimulatory receptors (Pardoll 2003).  PD-1 signaling has been shown to 
inhibit T cell activation, and expansion of previously activated cells.  Experimental 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 (Sharpe 2007).  There 
is growing evidence that HRS cell-directed PD-1 signaling in tumor infiltrating T cells 
contributes to the tumor’s ability to avoid clearance by the immune system.  The PD-1 
ligands, PD-L1 and PD-L2, are both expressed by multiple HL cell lines and PD-1 
overexpression is found in tumor-infiltrating and peripheral blood T cells of patients with HL 
(Yamamoto 2008).  PD-L1 expression in clinical samples, as detected by 
immunohistochemical (IHC) staining, is present in more than 80% of cases of HL, with 
similar rates of expression in all HL pathological subtypes (Chen 2013).  There are multiple 
mechanisms that can account for upregulated expression of PD-L1 and PD-L2 in HRS cells.  
Many cases of HL are associated with amplification of chromosome 9p24.1 which contains 
the genes PD-L1, PD-L2, and Janus kinase 2 (JAK2).  An increase in JAK2 copy number 
indirectly contributes to PD ligand overexpression through STAT1 (signal transducer and 
activator of transcription 1)-mediated transcriptional effects on PD-L1 and PD-L2 (Green 
2010).  Furthermore, Epstein–Barr virus (EBV) infection of malignant HRS cells, which is 
implicated in approximately 40% of cases of HL, contributes to overexpression of PD-L1 
even in the absence of 9p24.1 amplification.  The EBV latent membrane protein 1 exerts 
direct and indirect effects on PD-L1 promoter and enhancer elements leading to increased 
PD-L1 protein expression (Green 2012). 


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1.3 Study Treatments 
A complete summary of the clinical and nonclinical data relevant to the investigational 
products and their study in human subjects is provided in each product’s Investigator’s 
Brochure. 
1.3.1 Brentuximab Vedotin 
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) consisting of 3 
components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30; 2) the 
microtubule-disrupting agent monomethyl auristatin E (MMAE); and 3) a protease-cleavable 
linker that covalently attaches MMAE to cAC10.  The primary mechanism of anticancer 
activity of brentuximab vedotin is binding of the ADC to CD30-expressing cells, followed by 
internalization of the ADC-CD30 complex, and the release of MMAE via proteolytic 
cleavage.  Binding of MMAE to tubulin disrupts the microtubule network within the cell, 
subsequently inducing cell cycle arrest and apoptotic death of the cell.  Possible additional 
mechanisms of anticancer activity include bystander effects on nearby cells in the tumor 
microenvironment, immunogenic cell death, and antibody-dependent cellular phagocytosis 
(Oflazoglu 2007; Li 2014; Muller 2014; Gardai 2015; Kim 2015). 
In a pivotal phase 2 study of 102 patients with relapsed or refractory HL following 
autologous stem cell transplant (ASCT), treatment with brentuximab vedotin 1.8 mg/kg 
every 3 weeks resulted in an objective response rate (ORR) of 75% (95% confidence interval 
[CI], 64.9%–82.6%).  The complete response (CR) rate was 34% (95% CI, 25.2%–44.4%) 
and the median progression-free survival (PFS) for all patients on study was 5.6 months 
(95% CI, 5.0–9.0 months) (Younes 2012). 
The activity of brentuximab vedotin in patients who had previously received it was 
demonstrated in the SGN35-006 study of patients with hematologic malignancies who 
initially responded to brentuximab vedotin and then subsequently progressed (Bartlett 2014).  
In this open-label, multicenter, phase 2 study of patients with HL or systemic anaplastic large 
cell lymphoma who had responded to brentuximab vedotin monotherapy during a previous 
clinical trial (Bartlett 2014), patients were eligible if they had achieved a partial response 
(PR) or better to initial treatment with brentuximab vedotin, discontinued treatment while in 
remission, and subsequently developed disease progression or relapse.  In the retreatment 
study, patients received brentuximab vedotin 1.8 mg/kg on Day 1 of each 21-day treatment 
cycle.  Patients whose dose was reduced to 1.2 mg/kg for any reason during their initial 
therapy were given 1.2 mg/kg on Day 1 of each 21-day treatment cycle upon retreatment.  Of 
the 21 patients with HL enrolled, the median time between the last brentuximab vedotin dose 
from initial treatment and the first dose at retreatment was 11.4 months (range 4–45 months).  
The ORR and CR rates with brentuximab vedotin retreatment were 60% and 30%, 
respectively.  The median duration of response was 9.2 months (range 0.0+ to 19.5+ months).  
For patients who achieved a CR, the median duration of response was 9.4 months (range 1.7–
14.2 months).  The median PFS was 9.9 months, and the median overall survival (OS) had 
not been reached at the time of study closure.  The most common adverse events (AEs) were 
peripheral sensory neuropathy (59%), fatigue and nausea (41% each), diarrhea (38%), and 


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arthralgia, headache, peripheral motor neuropathy, and pyrexia (28% each).  The most 
common AEs that were ≥ Grade 3 consisted of anemia (17%), fatigue (14%), and 
hyperglycemia, hypophosphatemia, and thrombocytopenia (10% each).  No serious AEs 
leading to death were attributed to brentuximab vedotin. 
1.3.2 Nivolumab 
Nivolumab is a fully-human monoclonal antibody (immunoglobulin G4 [IgG4]) that targets 
PD-1.  In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39 to 2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM).  Nivolumab 
binds specifically to PD-1 and not to related members of the CD28 family such as CD28, 
ICOS, CTLA-4, and BTLA.  Nivolumab blocks the PD-1 pathway and results in a 
reproducible enhancement of both proliferation and interferon gamma (IFN-γ) release in the 
mixed lymphocyte reaction.  Using a cytomegalovirus (CMV) re-stimulation assay with 
human peripheral blood mononuclear cells (PBMC), the effect of nivolumab on 
antigen-specific recall response indicates that nivolumab augments IFN-γ secretion from 
CMV-specific memory T cells in a dose-dependent manner versus isotype-matched control.  
In vivo blockade of PD-1 by a murine analog of nivolumab enhances the antitumor immune 
response and results in tumor rejection in several immunocompetent mouse tumor models 
(MC38, SA1/N, and PAN02) (Wolchok 2009). 
A recent report from a phase 1 study of nivolumab in patients with advanced hematological 
malignancies demonstrated a high response rate in patients with relapsed or refractory HL, 
with an ORR of 87% (20/23) and a CR rate of 17% (4/23).  The responses obtained were 
durable with a 6-month PFS of 86% and no significant difference in the ORR in the subset of 
18 patients who had previously failed brentuximab vedotin (Ansell 2015). 
1.4 Clinical Study Rationale 
High dose chemotherapy with ASCT provides the best chance to achieve a durable remission 
in patients with HL who have relapsed or refractory disease after standard frontline 
combination chemotherapy (Schmitz 2002).  Salvage chemotherapy is typically given prior 
to delivering high-dose chemotherapy/ASCT to maximally debulk disease.  Patients 
achieving a metabolic CR after salvage chemotherapy have a long-term relapse-free survival 
of ~75% post-ASCT.  In contrast, patients with evidence of residual disease prior to high 
dose chemotherapy/ASCT have a long-term relapse-free survival that is only ~25% 
(Moskowitz 2010).  Because results from salvage therapy directly influence long-term 
event-free survival post-ASCT, it is critical to develop well-tolerated regimens that increase 
CR rates pre-ASCT (Moskowitz 2012). 
Given that brentuximab vedotin and nivolumab both have documented high single-agent 
response rates in HL and also work through distinct mechanisms of action, it is expected that 
combination therapy could potentially be more effective in the salvage treatment setting than 
administration of either agent alone.  Moreover, both agents are well tolerated, have few 
overlapping toxicities, and can be infused in the outpatient setting.  This study will evaluate 


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the safety and antitumor activity of combination therapy with brentuximab vedotin combined 
with nivolumab in a population of patients who have failed standard frontline chemotherapy. 
2 
OBJECTIVES 
2.1 Primary Objectives 
● 
To assess the safety profile of brentuximab vedotin administered in combination with 
nivolumab in patients with relapsed or refractory HL 
● 
To assess the antitumor activity of brentuximab vedotin administered in combination 
with nivolumab in patients with relapsed or refractory HL 
2.2 Secondary Objectives 
● 
To assess the ORR 
● 
To assess the duration of CR and objective response (OR) 
● 
To assess PFS after ASCT 
2.3 Additional Objectives 
● 
To assess OS 
● 
To compare the CR rate in patients who relapsed after frontline therapy with the CR 
rate in patients who were refractory to frontline therapy 
● 
To assess the feasibility of stem cell mobilization and collection after treatment with 
brentuximab vedotin in combination with nivolumab 
● 
To assess PFS 
● 
To assess pharmacokinetics (PK) and incidence of antitherapeutic antibodies (ATA) 
against each study drug given in combination 
● 
To assess tumor amplification and expression of PD-L1/L2 and relationship to 
response 
● 
To assess tumor microenvironment and peripheral immune status 
● 
To compare safety and efficacy of treatment with staggered versus same-day dosing 
schemes 
● 
To compare biomarker data obtained with staggered versus same-day dosing schemes 
● 
To assess efficacy in patients who previously received brentuximab vedotin 
2.4 Endpoints 
2.4.1 Primary Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of AEs and laboratory 
abnormalities 
● 
CR rate following the completion of study treatment 
2.4.2 Secondary Endpoints 
● 
ORR 


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● 
Duration of CR and OR 
● 
PFS post-ASCT 
2.4.3 Additional Endpoints 
● 
OS 
● 
PFS 
● 
Selected PK, ATA, and biomarker endpoints 


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3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is a phase 1/2, open-label, multicenter study designed to evaluate the safety and 
antitumor activity of brentuximab vedotin treatment combined with nivolumab.  The study 
will be conducted in 3 parts. 
3.1.1 Study Design Parts 1 and 2 
Patients in Parts 1 and 2 will be treated for up to four 21-day cycles.  The first dose of 
brentuximab vedotin will be given on Cycle 1 Day 1.  The first dose of nivolumab will be 
given on Cycle 1 Day 8.  For Cycle 2 and all subsequent cycles, both brentuximab vedotin 
and nivolumab will be administered on Day 1.  Nivolumab will be administered at least 
30 minutes after infusion of brentuximab vedotin is complete (Figure 1). 
Figure 1: 
Study design: Staggered dosing in Cycle 1 (Parts 1 and 2) 
 


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Patients in Parts 1 and 2 with radiographic evidence of progressive disease (PD) at the Cycle 
2 response assessment are not eligible for further treatment on the study.  All other patients in 
Parts 1 and 2 are eligible to continue treatment on study through Cycle 4.  After completion 
of the end-of-treatment (EOT) response assessments, patients are eligible to undergo ASCT.  
It is recommended that hematopoietic stem cells (HSC) be mobilized and collected after 
Cycle 4.  However, stem cell collection may occur in prior cycles after discussion with the 
medical monitor.  If patients have an unacceptable toxicity that is attributable to only one 
agent, as determined by the investigator, they will be eligible to continue on the treatment 
protocol through Cycle 4 with the tolerated drug as a single agent. 
3.1.2 Study Design Part 3 
In Part 3, patients will be treated for up to four 21-day cycles.  Both brentuximab vedotin and 
nivolumab will be administered on Day 1 of all cycles (Figure 2); nivolumab will be 
administered at least 30 minutes after infusion of brentuximab vedotin is complete. 
Figure 2: 
Study design: Same-day dosing in all treatment cycles (Part 3) 
 


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Patients in Part 3 with confirmed, unequivocal PD at Cycle 2 are not eligible for further 
treatment and will proceed to the EOT visit.  Patients with stable disease (SD) or better at the 
Cycle 2 response assessment may continue on treatment through Cycle 4.  Patients with an 
indeterminate response (IR), as defined by the Lymphoma Response to Immunomodulatory 
Therapy Criteria (LYRIC; Appendix D) (Cheson 2016), also may continue on treatment 
through Cycle 4.  After completion of the EOT response assessment, patients are eligible to 
undergo ASCT.  It is recommended that HSC be mobilized and collected after Cycle 4.  
However, stem cell collection may occur in prior cycles after discussion with the medical 
monitor.  If patients have an unacceptable toxicity that is attributable to only one agent, as 
determined by the investigator, they will be eligible to continue on the treatment protocol 
through Cycle 4 with the tolerated drug as a single agent. 
3.1.3 Safety Monitoring Committee 
In Part 1, the safety of combination treatment will be evaluated by a Safety Monitoring 
Committee (SMC) prior to expansion of enrollment to evaluate treatment effect in Part 2, as 
detailed in Section 9.3.9.  In Part 1, after 6 patients have been followed through the end of the 
dose-limiting toxicity (DLT) period, or at the point that 2 or more patients experience a DLT, 
whichever comes first, the SMC will review all available data and make a recommendation 
for one of the following: 
1. To proceed to Part 2 of the study, expanding enrollment with additional patients treated 
with the study drugs at the doses and schedule determined to be safe in Part 1 of the study 
2. To repeat Part 1 of the study and treat up to 6 additional patients at the same drug doses 
and schedule previously tested or with any of the following modifications that may 
include, but are not limited to: 
a. Dose reduction of brentuximab vedotin to 1.2 mg/kg and/or nivolumab to 1 mg/kg; of 
note, doses may not be increased above 1.8 mg/kg brentuximab vedotin or 3 mg/kg 
nivolumab 
b. Administration of combination treatment on Day 1 of every cycle 
3. To close the study to additional enrollment. 
Part 2 of the study will further characterize safety and evaluate the antitumor activity of 
brentuximab vedotin combined with nivolumab in patients who have failed standard frontline 
chemotherapy by enrolling approximately 50 additional patients at the recommended dose 
schedule determined in Part 1. 
Part 3 of the study will further characterize safety and efficacy of the study drug combination 
administered as same-day dosing in all cycles by enrolling approximately 30 additional 
patients with relapsed or refractory HL at the recommended doses as followed in Part 2.  If 
any safety signals are observed after the first 6 patients in Part 3 have been treated for 
2 cycles, then an SMC meeting will be convened. 
Details of the SMC will be documented in an SMC charter. 


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3.1.4 Dose-Limiting Toxicities 
DLTs are only assessed during Part 1 of the study.  For the purpose of this study, DLTs are 
defined as any study drug-related toxicity (brentuximab vedotin or nivolumab) that requires 
either a dose reduction or delay of more than 7 days of either study drug in Cycle 2 or delays 
the Cycle 3 Day 1 administration of combined treatment by more than 7 days.  The DLT-
evaluation period consists of the first cycle of therapy through the Cycle 3 Day 1 
administration of combined treatment.  The Investigator’s Brochures for brentuximab vedotin 
and nivolumab individually describe AEs commonly observed relative to either agent (i.e., 
neutropenia or peripheral neuropathy with brentuximab vedotin; immune-mediated AEs with 
nivolumab), as well as less common serious findings.  The respective Investigator’s 
Brochures should be referenced when attributing causality; however, the final decision 
regarding causality is at the discretion of the investigator. 
If any patient enrolled in Part 1 discontinues the study during the DLT period, that patient 
will be replaced unless discontinuation is for DLT. 
3.2 Discussion and Rationale for Study Design 
The endpoints of this study are appropriate for evaluating the safety of brentuximab vedotin 
treatment in combination with nivolumab for patients with relapsed or refractory HL.  The 
DLT evaluation in Part 1 of the study will provide an opportunity to assess safety and 
tolerability of combination treatment, the components of which have previously been 
assessed for safety in other settings.  Expanded enrollment in Part 2 is designed to assess the 
efficacy of the combination treatment based on CR rate with staggered dosing of nivolumab 
and to provide additional safety data.  The sample size is chosen to provide satisfactory 
power to exclude the previously demonstrated CR rate of single-agent brentuximab vedotin 
in a similar patient population in the case that the true CR rate of the combination treatment 
meets a clinically compelling threshold. 
3.2.1 Rationale for Study Design of Same-day Dosing 
On interim analysis, patients in Parts 1 and 2 had an ORR of 90% (95% CI 72.6%, 97.8%; 
26/29 patients) and a CR rate of 62% (95% CI 42.3%, 79.3%; 18/29 patients).  Similar results 
were reported by the ECOG-ACRIN Cancer Research Group study (E4412 Arms D and E) 
(ORR 100%, 8/8 evaluable patients; CR rate 62.5%, 5/8 patients), which enrolled patients 
with relapsed refractory HL for treatment with both brentuximab vedotin and nivolumab on 
Day 1 beginning with Cycle 1 (Diefenbach 2016).  Based on results from both studies, a 
decision was made to amend the protocol to evaluate the safety and efficacy of same-day 
dosing of the study-drug combination beginning with Cycle 1.  This new cohort, Part 3, will 
enroll patients with relapsed or refractory HL and will permit patients previously treated with 
brentuximab vedotin to explore activity of the combined regimen in brentuximab vedotin-
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3.2.2 Method of Assigning Patients to Treatment Groups 
In this open-label study, each part of the trial will enroll sequentially.  Enrollment and 
treatment in Part 1 will be completed before enrollment begins in Part 2, which will evaluate 
a staggered dosing schedule of brentuximab vedotin and  nivolumab in Cycle 1 followed by 
same-day dosing of both drugs in Cycles 2 through 4. 
After enrollment in Part 2 is complete, approximately 30 patients will be enrolled in Part 3 to 
evaluate same-day dosing of brentuximab vedotin and nivolumab in all treatment cycles. 
3.2.3 Rationale for Selection of Doses 
The recommended dose for brentuximab vedotin per its prescribing information is 1.8 mg/kg 
via intravenous (IV) infusion administered every 3 weeks.  This dose and schedule were 
evaluated in two pivotal phase 2 studies (SG035-0003 and SG035-0004) in patients with 
CD30-positive hematologic malignancies.  This dose and schedule for retreatment with 
brentuximab vedotin monotherapy were similarly evaluated in a separate phase 2 study 
(SGN35-006) with the caveat that patients enrolled for retreatment who had a dose reduction 
for any reason to 1.2 mg/kg during their initial therapy would receive brentuximab vedotin 
retreatment at the reduced dose of 1.2 mg/kg. 
The dose for nivolumab for this study is 3 mg/kg via IV infusion administered every 
3 weeks.  The approved dose for nivolumab as monotherapy is 3 mg/kg every 2 weeks for the 
treatment of melanoma and metastatic squamous non-small cell lung cancer.  However, 
nivolumab has been studied as monotherapy and in combination treatment in several tumor 
types with dosing every 3 weeks.  It was recently reported that nivolumab dose levels of 0.3, 
2, and 10 mg/kg every 3 weeks yielded similar ORR, PFS, and OS in a phase 2 trial of 
patients with metastatic renal cell carcinoma (Motzer 2015).  Moreover, nivolumab dose 
levels of 0.1, 0.3, 1, 3, and 10 mg/kg every 2 weeks were associated with very similar 
(median 64%–70%) PD-1 receptor occupancy and comparable ORR and PFS in patients with 
advanced melanoma (Topalian 2012).  These findings indicate a flat dose-response 
relationship for nivolumab across a wide dose range for both 2- and 3-week dosing 
schedules, suggesting that dosing nivolumab at 3 mg/kg every 3 weeks is appropriate in the 
current study.  These results further suggest that reduction of the nivolumab dose level to 
1 mg/kg every 3 weeks is appropriate if the combination of 3 mg/kg nivolumab with 
brentuximab vedotin results in an unfavorable safety profile. 
The rationale for staggered dosing of brentuximab vedotin and nivolumab in Cycle 1 is 
supported by the reasoning that, by delivering brentuximab vedotin, a directly cytotoxic 
agent, 1 week prior to nivolumab in Cycle 1, it is anticipated that tumor-associated antigens 
will be released and available for presentation to resident cytotoxic T cells at the same time 
that these cells become activated through PD-1 blockade.  However, because of the long half-
life of nivolumab, there is no rationale to continue staggered dosing beyond Cycle 1. 
Same-day dosing in all treatment cycles is supported by data from the ECOG-ACRIN study 
(E4412) (Diefenbach 2016).  In that study, patients in Arms D and E with relapsed or 
refractory HL were treated with brentuximab vedotin and nivolumab administered on Day 1 


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of 21-day cycles.  The regimen was well-tolerated in the 10 patients who were evaluable for 
safety, with only 1 infusion-related reaction observed.  The ORR was 100% in 8 efficacy-
evaluable patients, with a CR rate of 62.5%.  Based on the low rate of infusion-related 
reactions and promising activity observed in the E4412 study, the protocol was amended to 
explore same-day dosing in Part 3 of the SGN35-025 study. 
3.2.4 Blinding 
This is an open-label study.  Blinding will not be implemented. 
4 
STUDY POPULATION 
Patients must meet all of the enrollment criteria to be eligible for this study.  Eligibility 
criteria may not be waived by the investigator and are subject to review in the event of good 
clinical practice (GCP) audit and/or health regulatory authority inspection. 
4.1 Inclusion Criteria 
1. Documented histopathological diagnosis of classical HL, excluding nodular lymphocyte-
predominant Hodgkin lymphoma (NLPHL) 
2. Patients must have biopsy-proven (see Section 6.2) relapsed or refractory disease after 
failure of standard frontline chemotherapy for the treatment of classical HL 
● 
Relapsed disease is defined as achieving a CR to frontline therapy but then 
progressing 3 months or more after completing frontline therapy 
● 
Refractory disease is defined as never achieving a CR to frontline therapy or having a 
CR but then progressing within 3 months of completing frontline therapy 
3. Patients must have fluorodeoxyglucose positron emission tomography- (FDG-PET) avid 
and bidimensional measureable disease of at least 1.5 cm in longest axis as documented 
by radiographic technique (spiral computed tomography [CT] preferred) 
4. Patients must have confirmation of diffusing capacity of the lung for carbon monoxide 
(DLCO) over 60% (adjusted for hemoglobin) by a pulmonary function test 
5. Age 18 years and older 
6. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0–1 
7. Patients must be considered eligible to undergo autologous stem cell transplant 
8. Patients must have the following required baseline laboratory data: 
● 
Absolute neutrophil count (ANC) ≥1000/µL 
● 
Platelet count ≥50,000/µL (no platelet transfusions for prior 14 days) 
● 
Hemoglobin ≥8.5 g/dL (no red blood cell [RBC] transfusions for prior 7 days) 
● 
Serum bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with Gilbert 
Syndrome, who can have total bilirubin <3.0 x ULN) 
● 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN 


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● 
Calculated creatinine clearance of ≥30 mL/min 
9. Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose 
of brentuximab vedotin.  Females with false positive results and documented verification 
that the patient is not pregnant are eligible for participation.  Females of non-childbearing 
potential are those who are postmenopausal greater than 1 year or who have had a 
bilateral tubal ligation or hysterectomy 
10. Females of childbearing potential and males who have partners of childbearing potential 
must agree to use 2 effective contraceptive methods during the study and for 6 months 
following the last dose of brentuximab vedotin or 8 months following the last dose of 
nivolumab, whichever is later 
11. Patients or their legally authorized representative must provide written informed consent 
4.2 Exclusion Criteria 
1. Patient has received prior salvage therapy, including salvage radiotherapy, for relapsed or 
refractory classical HL 
2. Chemotherapy or biologics therapy that is not completed 4 weeks prior to the first dose of 
study drug(s), unless documented progression of underlying disease on treatment 
3. Prior radiation therapy within 3 weeks, or chest radiation ≤12 weeks prior to first dose of 
the study drug(s) 
4. For patients in Parts 1 and 2, previous treatment with brentuximab vedotin; for Part 3, 
patients with HL that is refractory to a brentuximab vedotin-containing regimen in first 
line, or patients who discontinue brentuximab vedotin due to unacceptable toxicity are 
ineligible.  Refractory disease is defined as never achieving a CR to frontline therapy or 
having a CR but then progressing within 3 months of completing frontline therapy 
5. Has received any prior immuno-oncology therapy (e.g., therapies affecting the PD-1, 
CTLA4, or CD137 pathways) 
6. Previously received an allogeneic and/or autologous stem cell transplant for HL 
7. Current therapy with other systemic antineoplastic or investigational agents 
8. Systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or 
other immunosuppressive medications within 14 days of enrollment 
● 
Inhaled or topical steroids and adrenal replacement steroid doses >10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease 
9. History of another primary invasive malignancy that has not been in remission for at least 
3 years 
10. History of progressive multifocal leukoencephalopathy (PML) 


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11. Known cerebral/meningeal disease related to the underlying malignancy 
12. Pre-existing neuropathy of Grade 2 or greater 
13. Any active Grade 3 or higher (per the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events [NCI CTCAE], Version 4.03) viral, bacterial, or fungal 
infection within 2 weeks prior to the first dose of brentuximab vedotin; routine 
antimicrobial prophylaxis is permitted 
14. Females who are pregnant or breastfeeding 
15. Known hypersensitivity to any excipient contained in the drug formulation of 
brentuximab vedotin or nivolumab 
16. Positive for hepatitis B by surface antigen expression, or any other positive test for 
hepatitis B virus indicating acute or chronic infection 
17. Active hepatitis C infection (positive by serology and confirmed by polymerase chain 
reaction [PCR] or on antiviral therapy for hepatitis C within the last 6 months) 
18. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS) 
19. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms consistent with New York 
Heart Association Class III-IV (Appendix C) within 6 months prior to their first dose of 
study drug(s) 
20. Previous history of known or suspected autoimmune disease 
● 
Patients with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted 
21. Active interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected drug-related pulmonary toxicity 
22. Known history of pancreatitis 
23. Other serious underlying medical condition that, in the opinion of the investigator, would 
impair the ability to receive or tolerate the planned treatment and follow-up 
4.3 Removal of Patients from Therapy or Assessment 
Seattle Genetics or their designee must be notified if a patient is withdrawn from study 
treatment or from the study.  The reason(s) for withdrawal must be documented in the 
patient’s medical records and case report form (CRF). 


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4.3.1 Discontinuation of Study Drug 
A patient’s treatment with study drug may be discontinued for any of the following reasons: 
● 
Completed treatment 
● 
Progressive disease 
● 
AE 
● 
Investigator decision 
● 
Patient decision, non-AE 
● 
Study termination by sponsor 
● 
Other, Non-AE 
Patients who discontinue from study treatment will remain on study for follow-up unless they 
withdraw consent.  Dose delays of both brentuximab vedotin and nivolumab resulting in 
treatment interruption of all therapy for >6 weeks require patient discontinuation from study 
treatment. 
4.3.2 Patient Withdrawal from Study 
Any patient may be discontinued from the study for any of the following reasons: 
● 
Completed study per protocol 
● 
Patient withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 
5 
TREATMENTS 
5.1 Treatments Administered 
There are two investigational agents under study in this protocol.  Brentuximab vedotin is an 
ADC consisting of the antibody cAC10, specific for human CD30; the microtubule-
disrupting agent MMAE; and a protease-cleavable linker that covalently attaches MMAE to 
cAC10.  Nivolumab is a fully human IgG4 monoclonal antibody that acts as an 
immunomodulator by blocking ligand activation of the PD-1 receptor on activated T cells. 
5.2 Brentuximab Vedotin 
Detailed information describing the preparation, administration, and storage of brentuximab 
vedotin is located in the Pharmacy Binder. 
5.2.1 Description 
Brentuximab vedotin is a sterile, preservative free, white to off-white lyophilized cake or 
powder supplied by Seattle Genetics in single-use vials for reconstitution for IV 
administration.  Each vial of the product contains brentuximab vedotin, trehalose, sodium 
citrate, and polysorbate 80.  See the Pharmacy Binder for further information. 


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5.2.2 Dose and Administration 
Brentuximab vedotin 1.8 mg/kg (or 1.2 mg/kg, if recommended by the SMC during Part 1) 
will be administered every 21 days by IV infusion given over approximately 30 minutes.  For 
patients in Part 3 who were previously treated with brentuximab vedotin and had a dose 
reduction, dose assignment must be discussed with the medical monitor. 
In the absence of infusion-related reactions, the infusion rate for all patients should be 
calculated in order to achieve a 30-minute infusion period. Brentuximab vedotin must not be 
administered as an IV push or bolus.  Brentuximab vedotin should not be mixed with other 
medications.  When both drugs are administered on Day 1 of the cycle, brentuximab vedotin 
administration should be completed at least 30 minutes prior to starting administration of 
nivolumab. 
Dosing is based on patient actual body weight.  Doses must be adjusted for patients who 
experience a ≥10% change in weight from baseline.  Other dose adjustments for changes in 
body weight are permitted per institutional standard.  An exception to weight-based dosing is 
made for patients weighing greater than 100 kg; doses will be based on 100 kg for these 
individuals.  Rounding is permissible within 5% of the nominal dose. 
5.2.3 Dose Modifications 
Table 1 describes the recommended dose modifications for brentuximab vedotin 
treatment-associated toxicity. 
Doses reduced for brentuximab vedotin-related toxicity should not be re-escalated without 
discussion with the sponsor.  Patients who discontinue nivolumab due to an AE may continue 
treatment with brentuximab vedotin monotherapy to complete the allowable 4 cycles of 
treatment.  If brentuximab vedotin is withheld at the time a cycle of nivolumab is given, once 
the AE causing the delay of brentuximab vedotin has resolved, administration of 
brentuximab vedotin should resume on the same schedule with the next cycle of combination 
therapy.  Dose delays of both brentuximab vedotin and nivolumab resulting in treatment 
interruption of all therapy for >6 weeks require patient discontinuation from study treatment. 


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Table 1: 
Recommended dose modifications for brentuximab-associated toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
neuropathy 
Continue at 
same dose level 
Reduce dose to 
1.2 mg/kg and 
resume treatmenta 
Withhold until toxicity 
resolves to ≤ Grade 2 
or baseline, then 
resume treatment at 
1.2 mg/kga 
Discontinue treatment 
Non-hematologic 
(except peripheral 
neuropathy) 
Continue at 
same dose level 
Continue at same 
dose level 
Withhold dose until 
toxicity is ≤ Grade 2 
or has returned to 
baseline, then resume 
treatment at the same 
dose levelb 
Withhold dose until 
toxicity is ≤ Grade 2 or 
has returned to 
baseline, then reduce 
dose to 1.2 mg/kg and 
resume treatment, or 
discontinue at the 
discretion of the 
investigatora,b,c 
Hematologicd 
Continue at 
same dose level 
Continue at same 
dose level 
Withhold until toxicity resolves to ≤ Grade 2 or 
baseline, then resume treatment at the same dose 
levele.  Growth factor support (G-CSF or GM-
CSF) should be considered for subsequent 
cycles.  If Grade 4 neutropenia recurs despite 
growth factor support, consider discontinuation 
or dose reduction to 1.2 mg/kg.a  
G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte macrophage colony-stimulating factor. 
a 
Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with dose delays. 
b 
Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without interruption. 
c 
Treatment should be discontinued for patients who experience Grade 4 infusion-related reactions. 
d 
Support with blood product transfusions allowed per institutional standard of care. 
e 
Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
5.2.4 Storage and Handling 
Refrigeration should be set at 2–8°C for storage of vials and solutions containing 
brentuximab vedotin.  The controlled location must be accessible only to the pharmacist, the 
investigator, or a duly designated person.  Brentuximab vedotin does not contain 
preservatives; therefore, opened and reconstituted vials of brentuximab vedotin should be 
used as soon as possible.  If not used immediately, the in-use storage should not be longer 
than 24 hours.  It is recommended that brentuximab vedotin vials and solutions be protected 
from direct sunlight until the time of use.  Reconstituted vials and solutions must not be 
shaken. 
Drug accountability instructions are provided in the Pharmacy Binder. 
5.2.5 Packaging and Labeling 
Drug product vials may be labeled as brentuximab vedotin, the United States adopted name 
(USAN) and the International Nonproprietary Name (INN), or as SGN-35, the compound 
code; the 2 names can be used interchangeably. 


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5.2.6 Preparation 
Brentuximab vedotin vials are provided via single-use containers.  Any partially used vials or 
diluted dosing solutions should be discarded using appropriate institutional drug disposal 
procedures. 
Brentuximab vedotin should be reconstituted with the appropriate amount of Sterile Water 
for Injection, United States Pharmacopeia (USP) or equivalent (see Pharmacy Binder for 
details).  The vial should be gently swirled until the contents are completely dissolved.  The 
vial must not be shaken.  The reconstituted drug product should be inspected visually for any 
particulate matter and discoloration. 
The required volume of reconstituted drug product should be diluted into an infusion bag.  
The bag should be gently inverted to mix the solution.  The bag must not be shaken.  Prior to 
administration, the reconstituted and diluted drug product should be inspected visually for 
any particulate matter and discoloration. 
Detailed drug preparation instructions are provided in the Pharmacy Binder. 
5.3 Nivolumab 
Detailed information describing the preparation, administration, and storage of nivolumab is 
located in the Pharmacy Binder. 
5.3.1 Description 
Nivolumab is a sterile, preservative free, clear to opalescent, colorless to pale-yellow solution 
supplied by Seattle Genetics in single-use vials for dilution for IV administration.  Each 
single-use vial of the product contains 100 mg/10 mL solution.  See the Pharmacy Binder for 
further information. 
5.3.2 Method of Procurement 
Nivolumab will be provided by Bristol-Myers Squibb and supplied to the study sites by 
Seattle Genetics. 
5.3.3 Dose and Administration 
For patients in Parts 1 and 2, nivolumab will be administered on Day 8 of Cycle 1 and Day 1 
of Cycles 2 through 4 of each 21-day treatment cycle.  For patients in Part 3, nivolumab will 
be administered on Day 1 of all 21-day treatment cycles.  Patients will receive nivolumab at a 
dose of 3 mg/kg (or 1 mg/kg, if recommended by the SMC during Part 1) as a 60-minute 
infusion.  When both drugs are administered on Day 1 of the cycle, nivolumab should be 
administered at least 30 minutes after completing treatment with brentuximab vedotin.  
Nivolumab infusions should be administered through an IV line containing a sterile, non-
pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).  
Other drugs should not be co-administered through the same IV line (e.g., brentuximab 
vedotin). 


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Dosing calculations should be based on the body weight assessed at baseline.  It is not 
necessary to recalculate subsequent doses if the patient weight is within 10% of the weight 
used to calculate the previous dose.  All doses should be rounded to the nearest milligram. 
The Pharmacy Binder contains specific instructions for nivolumab dose calculation, dilution, 
preparation of the infusion fluid, and administration. 
5.3.4 Dose Modifications 
Based on available information, autoimmune complications are the most likely AEs 
attributable to nivolumab.  Dose modifications for AEs are described in this section as well 
as in Appendix 2 of the nivolumab Investigator’s Brochure. 
There will be no dose escalations or reductions of nivolumab allowed, unless determined by 
the SMC to enroll patients to be treated at 1 mg/kg throughout the trial (see Section 3.1.3).  
Patients who discontinue brentuximab vedotin due to an AE may continue treatment with 
nivolumab monotherapy to complete the allowable 4 cycles of treatment.  If nivolumab is 
held at the time a cycle of brentuximab vedotin is given, once the AE causing the delay of 
nivolumab has resolved, administration of nivolumab should resume on the same schedule 
with the next cycle of combination therapy.  Dose delays of both brentuximab vedotin and 
nivolumab resulting in treatment interruption of all therapy for >6 weeks require patient 
discontinuation from study treatment.  See Section 7.6.1.1 for determining causality. 
5.3.4.1 Dose Delays 
Dose delays for nivolumab-related liver function test (LFT) abnormalities are described in 
Section 5.3.4.3.  Otherwise, nivolumab administration should be delayed for the following: 
● 
Any ≥ Grade 2 non-skin, nivolumab-related AE, with the following exception: 
○ 
Grade 2 nivolumab-related fatigue or laboratory abnormalities, other than LFT 
abnormalities (see Section 5.3.4.3), do not require a treatment delay 
● 
Any Grade 3 skin, nivolumab-related AE 
● 
Any Grade 3 nivolumab-related laboratory abnormality, other than LFT abnormalities 
(see Section 5.3.4.3), with the following exceptions for lymphopenia or asymptomatic 
amylase or lipase: 
○ 
Grade 3 lymphopenia does not require dose delay 
○ 
Any ≥ Grade 3 nivolumab-related amylase or lipase abnormality that has been 
evaluated clinically and radiographically and is without evidence of pancreatitis 
does not require dose delay.  The medical monitor should be consulted for such 
≥ Grade 3 amylase or lipase abnormalities 
● 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of nivolumab 


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Patients who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated.  Nivolumab may be resumed at the next scheduled treatment cycle if the 
AE recovers to ≤ Grade 1 or baseline, with the following exceptions: 
● 
Patients may resume nivolumab treatment in the presence of Grade 2 fatigue 
● 
Patients who have not experienced a Grade 3 nivolumab-related skin AE may resume 
nivolumab treatment in the presence of Grade 2 skin toxicity 
● 
Nivolumab-related pulmonary toxicity, diarrhea, or colitis must have resolved to 
baseline before nivolumab treatment is resumed.  Patients with persistent Grade 1 
pneumonitis after completion of a steroid taper over at least 1 month may be eligible 
for continued nivolumab treatment if discussed with and approved by the medical 
monitor 
● 
Nivolumab-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume nivolumab treatment after consultation with the 
medical monitor 
5.3.4.2 Dose Discontinuation 
Dose discontinuations for LFT abnormalities are described in Section 5.3.4.3.  Otherwise, 
nivolumab treatment should be permanently discontinued for the following: 
● 
Any Grade 2 nivolumab-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 6 weeks 
or requires systemic treatment 
● 
Any Grade 3 non-skin, nivolumab-related AE lasting more than 7 days, with the 
following exceptions for laboratory abnormalities other than LFT abnormalities (see 
Section 5.3.4.3), nivolumab-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies: 
○ 
Grade 3 nivolumab-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
○ 
Grade 3 nivolumab-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
○ 
Grade 3 nivolumab-related thrombocytopenia lasting more than 7 days or 
associated with bleeding; other Grade 3 nivolumab-related laboratory 
abnormalities other than LFT abnormalities (see Section 5.3.4.3), do not require 
treatment discontinuation 
● 
Any Grade 4 nivolumab-related AE or laboratory abnormality other than LFT 
abnormalities (see Section 5.3.4.3), except for the following events: 
○ 
Grade 4 neutropenia ≤7 days 
○ 
Grade 4 lymphopenia or leukopenia 


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○ 
Isolated Grade 4 amylase or lipase abnormalities not associated with symptoms or 
clinical manifestations of pancreatitis; consult the medical monitor for Grade 4 
amylase or lipase abnormalities 
○ 
Isolated Grade 4 electrolyte imbalances/abnormalities not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset 
○ 
Grade 4 nivolumab-related endocrinopathy AEs, such as adrenal insufficiency, 
adrenocorticotropic hormone deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with the medical 
monitor 
● 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued 
nivolumab dosing 
Any event that leads to delay in nivolumab dosing lasting >6 weeks from the previous 
nivolumab dose requires discontinuation of nivolumab treatment, with the following 
exceptions: 
● 
Dosing delays to allow for prolonged steroid tapers to manage nivolumab-related AEs 
are allowed. Prior to re-initiating nivolumab treatment in a patient with a nivolumab 
dosing delay lasting >6 weeks from the previous nivolumab dose, the medical 
monitor must be consulted. Tumor assessments should continue as per protocol even 
if nivolumab dosing is delayed. Periodic study visits to assess safety and laboratory 
studies should also continue every 6 weeks or more frequently if clinically indicated 
during such dosing delays. 
● 
Dosing delays lasting >6 weeks from the previous nivolumab dose that occur for non-
nivolumab-related reasons may be allowed if approved by the medical monitor.  Prior 
to re-initiating nivolumab treatment in a patient with a nivolumab dosing delay lasting 
>6 weeks, the medical monitor must be consulted.  Tumor assessments should 
continue as per protocol even if nivolumab dosing is delayed.  Periodic study visits to 
assess safety and laboratory studies should also continue every 6 weeks or more 
frequently if clinically indicated during such dosing delays. 
5.3.4.3 Dose Modifications for Liver Function Test Abnormalities 
Doses of nivolumab should be delayed for the following LFT abnormalities: 
● 
If a patient has a baseline AST/ALT that is within the normal limits, delay dosing for 
nivolumab-related Grade 2 (>3 to 5 x ULN) elevations 
○ 
Nivolumab may be resumed if the value improves to Grade 1 (≤3 x ULN) or 
better 


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● 
If a patient has a baseline AST/ALT in the Grade 1 range (ULN to ≤3 x ULN), delay 
dosing for nivolumab-related Grade 3 (>5 to 8 x ULN) elevations 
○ 
Nivolumab may be resumed if the value improves to Grade 2 (>3 to 5 x ULN) or 
better 
● 
If a patient has a baseline total bilirubin that is within normal limits, delay dosing for 
nivolumab-related Grade 2 elevations (>1.5 to 3 x ULN) 
○ 
Nivolumab may be resumed if the bilirubin improves to Grade 1 or better 
(≤1.5 x ULN) 
● 
If a patient has a baseline Grade 1 elevation of total bilirubin (ULN to ≤1.5 x ULN), 
delay dosing for nivolumab-related Grade 3 elevations in the range of >3 to 5 x ULN 
○ 
Nivolumab may be resumed if the total bilirubin improves to Grade 2 or better 
(≤3 x ULN) 
Doses of nivolumab should be discontinued permanently for the following LFT 
abnormalities: 
● 
AST or ALT >8 x ULN or drug-induced liver injury (DILI) 
● 
Total bilirubin >5 x ULN or DILI 
● 
Concurrent AST or ALT >3 x ULN and total bilirubin >2 x ULN 
5.3.5 Storage and Handling 
Nivolumab should be stored at 2–8°C and protected from light, freezing, and shaking.  Care 
should be taken when handling and preparing nivolumab.  Partially used vials should be 
disposed at the site per the procedures for the disposal of anticancer drugs. 
Drug accountability instructions are provided in the Pharmacy Binder. 
5.3.6 Packaging and Labeling 
Drug product vials may be labeled as nivolumab, the USAN and the INN, or as 
BMS-936558, the compound code; the 2 names can be used interchangeably. 
5.3.7 Preparation 
The drug product solution should be visually inspected for particulate matter and 
discoloration prior to administration.  The vial should be discarded if the solution is cloudy, 
is discolored, or contains extraneous particulate matter other than a few translucent-to-white, 
proteinaceous particles.  The vial should not be shaken. 
Detailed drug preparation instructions are provided in the Pharmacy Binder. 
5.4 Required Premedication and Postmedication 
Routine premedication should not be administered for the prevention of infusion-related 
reactions prior to the first dose of study drug(s). 


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5.4.1 Patients in Parts 1 and 2 
Prophylactic premedication for prevention of infusion-related reactions is to be administered 
prior to combination treatment on Day 1 of each 21-day cycle beginning with Cycle 2.  
Hydrocortisone 100 mg IV or equivalent, and an antihistamine (e.g., diphenhydramine 25–
50 mg IV or equivalent) should be given at least 30 minutes prior to infusion of brentuximab 
vedotin.  Patients who experience an infusion-related reaction with this premedication 
regimen should receive premedication with methylprednisolone 40 mg IV (or equivalent) 
with an antihistamine for all subsequent cycles.  Additional premedications for symptom 
management (e.g., acetaminophen and/or ondansetron) may also be given at the discretion of 
the investigator. 
If treatment with nivolumab or brentuximab vedotin is discontinued, premedications may be 
reduced or stopped at the discretion of the investigator during single-agent treatment for 
subsequent cycles. 
Patients should be individually evaluated to assess the need for tumor lysis prophylaxis prior 
to the first dose of brentuximab vedotin.  Patients should receive prophylaxis as appropriate 
per the institutional standards. 
5.4.2 Patients in Part 3 
Prophylactic premedication with antihistamines for prevention of infusion-related reactions is 
to be administered prior to combination treatment on Day 1 of each 21-day cycle beginning 
with Cycle 1.  Antihistamines (e.g., diphenhydramine 50 mg IV or equivalent and famotidine 
40 mg IV or equivalent) should be given at least 30 minutes prior to infusion of brentuximab 
vedotin.  Patients who experience an infusion-related reaction with this premedication 
regimen should receive additional premedication with dexamethasone 0.2 mg/kg (maximum 
10 mg IV or equivalent) for all subsequent cycles. 
Additional premedications for symptom management (e.g., acetaminophen and/or 
ondansetron) may also be given at the discretion of the investigator. 
If treatment with nivolumab or brentuximab vedotin is discontinued, premedications may be 
reduced or stopped at the discretion of the investigator during single-agent treatment for 
subsequent cycles. 
Patients should be individually evaluated to assess the need for tumor lysis prophylaxis prior 
to the first dose of brentuximab vedotin.  Patients should receive prophylaxis as appropriate 
per the institutional standards. 
5.5 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period for brentuximab vedotin or 
100 days after the patient’s last dose of nivolumab, whichever occurs later.  Any concomitant 
medication given for a study protocol-related AE should be recorded from the time of 
informed consent. 


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5.5.1 Required Concomitant Therapy 
Patients should be up-to-date on any recommended vaccinations prior to study entry.  
Additional vaccination(s) during each cycle of study treatment must be approved by the 
medical monitor. 
Required premedications to prevent infusion-related reactions are described in Section 5.4.1 
and Section 5.4.2. 
5.5.2 Allowed Concomitant Therapy 
The use of platelet and/or RBC supportive growth factors or transfusions when applicable is 
allowed.  The use of colony stimulating factors for the treatment of neutropenia per 
institutional practice is permitted during therapy. 
Patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab 
vedotin should be closely monitored for adverse reactions. 
Routine prophylaxis with vaccines is permitted prior to study entry; it is recommended that 
vaccines used do not contain live micro-organisms. 
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption).  Stable adrenal replacement steroid doses 
>10 mg daily prednisone, or prednisone equivalent, are permitted.  A brief (less than 
3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment 
of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a 
contact allergen) is permitted.  Treatment with 0.5 to 2 mg/kg/day methylprednisolone IV (or 
oral equivalent), followed by a taper, is recommended for certain immune-mediated AEs; see 
Section 5.3.4.3 for dose modifications and relevant management algorithms in Appendix 3 of 
the nivolumab Investigator’s Brochure.  Treatment with 0.5 to 1 mg/kg corticosteroids, 
followed by taper, is recommended for Grade 2 or 3 creatinine elevation or nephritis. 
Peripheral blood stem cells may be mobilized following Cycle 4 at the discretion of the 
investigator.  However, stem cell collection may occur in prior cycles after discussion with 
the medical monitor.  Collection of peripheral blood stem cells for ASCT, if applicable, 
should occur per institutional standard of care.  If stem cell collection after Cycle 4 is 
inadequate, additional collection of peripheral blood stem cells for ASCT may be performed 
per institutional standards, if applicable. 
At the discretion of the treating physician, consolidative radiotherapy or consolidative 
treatment with single-agent brentuximab vedotin may be given post-ASCT. 
Allowed medications to manage infusion-related reactions are described in Section 5.6.1.1 
and Section 5.6.1.2. 


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5.5.3 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy during the study.  Exceptions are noted in 
Section 5.5.2. 
5.6 Management of Adverse Reactions 
5.6.1 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of study treatment(s).  The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis should 
it occur.  All supportive measures consistent with optimal patient care should be given 
throughout the study according to institutional standards.  Supportive measures may include 
extending the infusion time and/or administering medications for infusion-related reactions. 
Infusion or hypersensitivity reactions may occur to either brentuximab vedotin or nivolumab.  
If such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like 
reactions.  Infusion reactions should be graded according to NCI CTCAE (Version 4.03) 
guidelines. 
5.6.1.1 Patients in Parts 1 and 2 
Premedication for the prevention of infusion reactions should be administered beginning with 
Cycle 2, at least 30 minutes prior to dosing study drug(s), and should include an 
antihistamine and low-dose corticosteroid, as described in Section 5.4.1.  If the onset of a 
reaction occurs during an infusion, the infusion may be interrupted for treatment of the 
infusion-related reaction, including treatment with antihistamines, corticosteroids, 
bronchodilator therapy, and/or antipyretics, as appropriate.  Patients who experience a 
Grade 3 infusion-related reaction to brentuximab vedotin or nivolumab may potentially 
receive additional treatment with the study drug(s) at the discretion of the investigator after 
discussion with the sponsor. 
If anaphylaxis or a Grade 4 infusion-related reaction occurs, administration of the implicated 
agent(s) (brentuximab vedotin and/or nivolumab) should be immediately and permanently 
discontinued. 
In case of late-occurring hypersensitivity symptoms to nivolumab (e.g., appearance of a 
localized or generalized pruritus within 1 week after nivolumab treatment), symptomatic 
treatment may be given (e.g., oral antihistamine or corticosteroids). 
5.6.1.2 Patients in Part 3 
For patients in Part 3, prophylactic premedication with antihistamines for prevention of 
infusion-related reactions is to be administered prior to combination treatment on Day 1 of 
each 21-day cycle as described in Section 5.4.2.  Patients who experience an infusion-related 
reaction with this premedication regimen should receive additional premedication with 
dexamethasone 0.2 mg/kg (maximum 10 mg IV or equivalent) as well as the antihistamines 


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as described in Section 5.4.2 for all subsequent cycles.  Additional premedication for 
symptom management (e.g., acetaminophen and/or ondansetron) may also be given at the 
discretion of the investigator.  If the onset of a reaction occurs during an infusion, the 
infusion may be interrupted for treatment of the infusion-related reaction, including treatment 
with antihistamines, corticosteroids, and/or bronchodilator therapy, as appropriate.  Patients 
who experience a Grade 3 infusion-related reaction to brentuximab vedotin or nivolumab 
may potentially receive additional treatment with the study drug(s) at the discretion of the 
investigator after discussion with the sponsor. 
If anaphylaxis or a Grade 4 infusion-related reaction occurs, administration of the implicated 
agent(s) (brentuximab vedotin and/or nivolumab) should be immediately and permanently 
discontinued. 
In case of late-occurring hypersensitivity symptoms to nivolumab (e.g., appearance of a 
localized or generalized pruritus within 1 week after nivolumab treatment), symptomatic 
treatment may be given (e.g., oral antihistamine or corticosteroids). 
5.6.2 Management of Suspected Progressive Multifocal Leukoencepalopathy 
Signs and symptoms of PML may include altered mental status, motor deficits such as 
hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction such as dysphasia or 
agnosia.  See the Investigator’s Brochure(s) for further details. 
If PML is suspected, hold further dosing of brentuximab vedotin and nivolumab and 
undertake a diagnostic work-up including (but not limited to): 
● 
Neurologic examinations, as warranted 
● 
Brain radiologic features by magnetic resonance imaging (MRI) 
● 
PCR analysis: John Cunningham virus (JCV) DNA detectable in cerebrospinal fluid 
 
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin and 
nivolumab. 
5.6.3 Management of Immune-Adverse Events 
Immuno-oncology agents are associated with AEs that can differ in severity and duration 
from AEs caused by other therapeutic classes.  Nivolumab is considered an immuno-
oncology agent in this protocol.  Early recognition and management of AEs associated with 
immune-oncology agents may mitigate severe toxicity.  The following groups of AEs should 
be managed per the algorithms found in Appendix 3 of the nivolumab Investigator’s 
Brochure: 
● 
Gastrointestinal 
● 
Renal 
● 
Pulmonary 
● 
Hepatic, with the following exceptions: 


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○ 
Patients with a baseline LFT level in the Grade 1 range (AST or ALT >ULN to 
3.0 x ULN and/or total bilirubin >ULN to 1.5 x ULN) should be managed by AE 
Grade-specified algorithms as applied to the absolute increase in AE Grade level 
above base line.  For example, management of a Grade 3 AST elevation for a 
patient who had a baseline AST level in the Grade 1 range would be per the 
Grade 2 algorithm. 
● 
Endocrinopathy 
● 
Skin 
● 
Neurological 
 
See Section 5.5.2 for allowed high-dose corticosteroid treatment. 
5.7 Treatment Compliance 
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 
6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
A schedule of events is provided in Appendix A.  Study activities are listed by visit in this 
section and descriptions of all study assessments are presented in Section 7. 
AEs and concomitant medications will be recorded from Day 1 (predose) through 30 days 
after the last dose of brentuximab vedotin (see Section 7.6.1.3) or 100 days after the last dose 
of nivolumab, whichever occurs later. Any study protocol-related AE should be recorded 
from the time of informed consent as well as any concomitant medications given for 
treatment of the AE. 
All procedures on dosing days must be performed predose unless otherwise specified.  
Clinical laboratory assessments (serum chemistry panel, complete blood count [CBC] with 
differential [see Section 7.6.2]), physical examination, and weight may be performed within 
1 day prior to study drug administration.  With the exception of gamma-glutamyl 
transpeptidase levels and thyroid function tests, the results from all other clinical laboratory 
assessments must be reviewed prior to study drug dosing. 
6.2 Screening Visit (Days −28 to 1) 
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history; medical history at screening includes an inflammatory condition 
review (see Section 7.1) 
● 
Electrocardiogram (ECG) 
● 
Serology for hepatitis B and EBV 


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● 
Hepatitis C serology with reflex to hepatitis C virus (HCV) RNA by PCR (see 
Section 7.6.2) 
● 
Dedicated CT of chest, neck, abdomen, and pelvis 
● 
Positron emission tomography (PET) 
● 
Tumor biopsy specimen taken after relapse or progression from frontline therapy is 
required (Note: excisional biopsy if feasible); archival sample taken at diagnosis to be 
available 
● 
Pulmonary function test 
6.2.1 Baseline Visit (Days −7 to Day 1) 
● 
Height and weight 
● 
Pregnancy test for females of childbearing potential 
● 
Physical examination 
● 
Vital signs 
● 
Performance status 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Estimated creatinine clearance 
● 
Antinuclear antibodies (ANA) 
6.3 Treatment Period (Day 1 to Day 21) 
6.3.1 Cycle 1 Day 1 (±1 day) 
● 
B symptom assessment 
● 
Serum chemistry panel (includes thyroid stimulating hormone [TSH], free T3, and 
free T4; see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Blood samples for PK and ATA assessments 
● 
Blood samples for biomarker assessments and flow cytometry 
● 
Physical examination 
● 
Weight 
● 
Brentuximab vedotin administration 
● 
Patients in Part 3 only: measurement of oxygen saturation by pulse oximetry 
● 
Patients in Part 3 only: nivolumab administration (approximately 30 minutes after 
completion of brentuximab vedotin administration) 
6.3.2 Cycle 1 Day 2 (+2 days) 
● 
Blood samples for PK assessments (patients in Part 1 only) 
● 
Blood samples for biomarker assessments (patients in Part 1 only) 


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6.3.3 Cycle 1 Day 8 (±1 day) 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Measurement of oxygen saturation by pulse oximetry prior to nivolumab 
administration (patients in Parts 1 and 2 only) 
● 
Nivolumab administration (patients in Parts 1 and 2 only) 
● 
Blood samples for PK assessments 
● 
Blood samples for biomarker assessments and flow cytometry 
6.3.4 Cycle 1 Day 15 (±1 day) 
● 
Blood samples for PK assessments (patients in Parts 1 and 3) 
● 
Blood samples for biomarker assessments and flow cytometry 
6.3.5 Cycle 2 Day 1 (±1 day) 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Blood samples for PK and ATA assessments 
● 
Blood samples for biomarker assessments and flow cytometry 
● 
Measurement of oxygen saturation by pulse oximetry 
● 
Weight 
● 
Brentuximab vedotin administration 
● 
Nivolumab administration (approximately 30 minutes after completion of 
brentuximab vedotin administration) 
6.3.6 Cycle 2 Day 8 (±1 day) 
● 
Blood samples for biomarker assessments (serum biomarkers and cytokines; plasma 
cytokines only) and flow cytometry (patients in Parts 2 and 3) 
6.3.7 Cycle 2 Day 15 (+6 days) 
● 
Perform dedicated CT of diagnostic quality including all involved sites of disease 
determined at baseline.  Patients with SD or better may continue on treatment.  
Patients in Part 3 with an IR according to LYRIC (Appendix D) also may continue on 
treatment.  Patients with confirmed/unequivocal PD must discontinue treatment and 
proceed to the EOT visit. 
6.3.8 Cycle 3 Day 1 (±1 day) 
● 
Serum chemistry panel (includes TSH, free T3, and free T4; see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Blood samples for PK and ATA assessments 
● 
Blood samples for biomarker assessments and flow cytometry 
● 
Measurement of oxygen saturation by pulse oximetry 


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● 
Physical examination 
● 
Weight 
● 
Brentuximab vedotin administration 
● 
Nivolumab administration (approximately 30 minutes after completion of 
brentuximab vedotin administration) 
6.3.9 Cycle 4 Day 1 (±1 day) 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Blood samples for PK and ATA assessments 
● 
Blood samples for biomarker assessments and flow cytometry (patients in Part 1 
only) 
● 
Measurement of oxygen saturation by pulse oximetry 
● 
Weight 
● 
Brentuximab vedotin administration 
● 
Nivolumab administration (approximately 30 minutes after completion of 
brentuximab vedotin administration) 
6.3.10 Cycle 4 Day 2 (+2 days) 
● 
Blood samples for PK assessments (patients in Part 1 only) 
● 
Blood samples for biomarker assessments (patients in Part 1 only) 
6.3.11 Cycle 4 Day 8 (±1 day) 
● 
Blood samples for PK assessments (patients in Part 1 only) 
● 
Blood samples for biomarker assessments and flow cytometry (patients in Part 1 
only) 
6.3.12 Peripheral Blood Stem Cell Collection 
Collection of peripheral blood stem cells for ASCT, if applicable, should occur per 
institutional standard of care. 
6.4 End of Treatment Visit (30 to 37 days after last dose of study drug except 
where noted) 
EOT visits should occur 30 to 37 days after the last dose of study drug(s) unless delayed due 
to an AE.  However, EOT evaluations must be performed before initiation of a new therapy, 
other than mobilization of stem cells for ASCT.  If EOT evaluations are completed before 30 
days after the last study treatment, the patient will be contacted 30 to 37 days following the 
last treatment to assess for adverse events. The following activities will be conducted at 
EOT: 
● 
B symptom assessment 
● 
Performance status 


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● 
Physical examination 
● 
Inflammatory condition review (only for those patients with certain inflammatory 
conditions of interest at Screening/Baseline) 
● 
Serum chemistry panel (includes TSH, free T3, and free T4; see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
ANA 
● 
Blood samples for PK and ATA assessments 
● 
Blood samples for biomarker assessments and flow cytometry 
● 
Tumor biopsy; optional at progression of disease or if evidence of residual disease is 
suspected (Note: Strongly recommended to confirm that radiological evidence of 
progression is correlated with active HL; when possible, excisional biopsies should be 
performed) 
● 
For patients in Parts 1 and 2: PET and dedicated CT of chest, neck, abdomen, and 
pelvis; PET and CT scans to be performed 23 to 37 days after last dose of study drug 
(as described in Section 7.2.1) 
● 
For patients in Part 3:  PET and dedicated CT of chest, neck, abdomen, and pelvis; 
PET and CT scans to be performed 15 to 30 days after last dose of study drug (as 
described in Section 7.2.2) 
● 
Bone marrow biopsy (for patients planning to proceed to ASCT) 
6.5 Autologous Stem Cell Transplant 
Patients who will have an ASCT must have the following performed prior to transplant: 
● 
Dedicated CT of chest, neck, abdomen, and pelvis; not needed if performed within 
the prior 6 weeks 
● 
PET; not needed if performed within the prior 6 weeks 
● 
Bone marrow biopsy; not needed if performed at the EOT visit 
6.6 Safety Visit (100 days [+2 weeks] after last dose of nivolumab) 
The final safety visit should occur 100 days after the last dose of nivolumab or 30–37 days 
post last dose of brentuximab vedotin (EOT visit), whichever is later.  The following 
assessments will be performed: 
● 
Physical examination, including assessment for potential immune-mediated adverse 
events 
● 
Serum chemistry panel (see Section 7.6.2) 
● 
CBC with differential (see Section 7.6.2) 
● 
Blood samples for ATA assessments 
6.7 Long-term Follow-up (±2 weeks) 
Patients who discontinue from both study drugs (brentuximab vedotin and nivolumab) will 
remain on the study for follow-up until withdrawal of consent, death, or study closure, 


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whichever occurs first.  Long-term follow-up assessments will be performed at the following 
time points post-ASCT (or post-EOT for patients who do not undergo ASCT): 100 days and 
then 6, 9, 12, 18, 24, 30, and 36 months and then per institutional standard thereafter.  
Patients who have discontinued treatment due to PD or who have initiated subsequent 
systemic chemotherapy will not have response assessed but will be followed for survival.  
Patients will be followed at this schedule until withdrawal of consent, death, or study closure, 
whichever occurs first.  The following assessments will be performed until disease 
progression; patients will be followed for survival thereafter. 
● 
Dedicated CT of chest, neck, abdomen, and pelvis; performed at 100 days and then 6, 
12, 24, and 36 months post-ASCT or post-EOT long-term follow-up visits or if 
progression is suspected based on clinical signs and symptoms 
● 
PET; performed with CT scans until the patient achieves a complete metabolic 
response (CmR) by PET 
● 
Interval medical history to assess changes in health status since prior visit 
● 
Physical examination 
● 
Disease progression status and post-study treatment received 
6.8 End of Study/End of Follow-up 
The date the patient met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 
7 
STUDY ASSESSMENTS 
7.1 Screening/Baseline Assessments 
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Tissue samples will be sent to the central pathology lab for disease confirmation and further 
evaluation of CD30 and PD-L1 expression. 
Patient medical history includes a thorough review of significant past medical history, 
current conditions, any treatment for prior malignancies and response to prior treatment, and 
any concomitant medications.  Included with medical history is a review of any inflammatory 
conditions; patients with certain inflammatory conditions of interest at Screening/Baseline 
will have an additional review at the EOT visit. 
Pulmonary function tests are required for all patients at screening.  DLCO over 60% 
(adjusted for hemoglobin) must be confirmed by a pulmonary function test prior to study 
enrollment. 


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7.2 Response/Efficacy Assessments 
7.2.1 Parts 1 and 2 
For patients in Parts 1 and 2, the determination of antitumor activity will be based on 
response assessments made according to the Lugano Classification Revised Staging System 
for malignant lymphoma (Cheson 2014) and treatment decisions by the investigator will be 
based on these assessments. 
Staging will be performed by PET and CT of diagnostic quality, with disease involvement 
determined by focal fluorodeoxyglucose (FDG) uptake in nodal and extranodal sites 
(including spleen, liver, bone marrow, and thyroid) that is consistent with lymphoma, 
according to the pattern of uptake and/or CT characteristics.  Up to six of the largest nodes, 
nodal masses, or other involved lesions that are measurable in two diameters should be 
identified as target lesions; 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. 
At Cycle 2 (Day 15 + 6 days), a CT scan of diagnostic quality will be performed to assess for 
PD; a limited scan that includes sites of disease identified at baseline is acceptable.  For 
subsequent response assessments, both PET and CT scans will be required until the patient 
achieves a CmR by PET assessment.  After the patient achieves a CmR by PET, response 
will be followed by CT scans of diagnostic quality only.  For PET-based assessments, a 
clinical response of progressive metabolic disease (PmD), no metabolic response (NmR), 
partial metabolic response (PmR), or CmR will be determined.  If only CT-based assessment 
is performed, response will be categorized as PD, SD, PR, or CR.  PmD/PD includes 
radiological evidence of progression per Lugano Classification Revised Staging System for 
malignant lymphoma (Cheson 2014).  If clinical progression is determined by the 
investigator, radiographic staging should also be performed to determine response 
assessment per Lugano Classification Revised Staging System for malignant lymphoma.  The 
PET scan metabolic uptake will be graded using the Deauville 5-point scale (Biggi 2013) 
(Barrington 2010) with a score of ≤3 considered to represent a CmR. 
Patients’ clinical data must be available for CRF source verification.  Copies of tumor images 
must be made available for review by the sponsor (or its designee), upon request. 
7.2.2 Part 3 
For patients in Part 3, the determination of antitumor activity will be assessed using the 
Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with 
the incorporation of LYRIC (Appendix D) (Cheson 2016).  Treatment decisions by the 
investigator will be based on these assessments.  Staging will be performed by PET/CT of 
diagnostic quality, with disease involvement determined by focal FDG uptake in nodal and 
extranodal sites (including spleen, liver, bone marrow, and thyroid) that is consistent with 
lymphoma according to the pattern of uptake and/or CT characteristics.  Up to six of the 
largest nodes, nodal masses, or other involved lesions that are measurable in two diameters 


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should be identified as target lesions at baseline.  If possible, target lesions should be from 
different regions of the body, and they should include mediastinal and retroperitoneal areas 
of disease whenever these sites are involved. 
At Cycle 2 (Day 15 + 6 days), a CT scan of diagnostic quality will be performed to assess for 
PD; a limited scan that includes sites of disease identified at baseline is acceptable.  For all 
other response assessments, a clinical response of PD, SD, PR, or CR will be determined 
unless tumor flare or pseudo-progression is suspected.  If tumor flare or pseudoprogression is 
not suspected, PD is defined by radiological evidence of progression according to the Lugano 
criteria (Cheson 2014).  If clinical progression is determined by the investigator, radiographic 
staging should also be performed to determine response assessment per Lugano classification 
criteria.  The PET scan metabolic uptake will be graded using the Deauville 5-point scale 
(Barrington 2010; Biggi 2013), with a score of ≤3 considered to represent a complete 
metabolic response.  Except for the Cycle 2 response assessment, both PET and CT scanning 
will be required until disease is PET negative; responses will then be followed by CT scan of 
diagnostic quality only. 
If tumor flare or pseudo-progression is suspected by the investigator during treatment, then a 
clinical response of indeterminate response (IR) will be determined until subsequent 
evaluation of radiographic imaging or biopsy confirms or refutes PD.  IR is defined 
according to the following: 
1. An increase in overall tumor burden (as assessed by the sum of the products of the largest 
diameter [SPD]) of ≥50% of up to 6 measurable lesions in the first 12 weeks of therapy, 
without clinical deterioration; 
2. Appearance of new lesions, or growth of one or more existing lesion(s) ≥50% at any time 
during treatment, occurring in the context of lack of overall progression (<50% increase) 
of overall tumor burden, as measured by SPD of up to 6 lesions at any time during 
treatment; and 
3. An increase in FDG uptake using the 5-Point Scale per the Deauville Criteria of one or 
more lesion(s) without a concomitant increase in lesion size or number. 
See Appendix D for further details and criteria for follow-up of a determination of IR. 
For patients with an IR, investigators should use clinical judgement to determine the 
appropriate course of action for further evaluation.  Repeat imaging should be performed 
according to the Schedule of Events (or sooner if clinically indicated), and PD must be 
confirmed or refuted based on LYRIC follow-up criteria for IR (Cheson 2016).  In addition, 
biopsy of sites of disease involvement should be strongly considered. 
If a patient has a second determination of IR, then subsequent repeat imaging should be 
performed between 4 and 8 weeks (or earlier if clinically indicated).  Follow-up radiographic 
assessment for patients with IR is not required if a follow-up biopsy has been performed that 
confirms the patient's response. 


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Patients’ clinical data must be available for CRF source verification.  All imaging studies 
must be copied to CDs and provided to the sponsor.  At the end of the study, the images may 
either be sent to a central radiology facility for confirmation of disease response or destroyed. 
7.3 Pharmacokinetic and Immunogenicity Assessments 
Serum concentrations of brentuximab vedotin and nivolumab, and plasma concentrations of 
MMAE (unconjugated) will be measured.  ATA against brentuximab vedotin and ATA 
against nivolumab will also be assessed. 
PK and ATA sample collection timepoints are presented for patients in Parts 1 and 2 in 
Table 2 and for patients in Part 3 in Table 3.  Refer to the Research Specimen Manual for 
information on collection, processing, storage, and shipment of samples. 
 


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Table 2: 
Pharmacokinetic and ATA sampling timepoints, Parts 1 and 2 
Cycle 
Study 
Day 
Time 
Window 
Relative Time 
Brentuximab 
Vedotin PK 
Nivolumab PK 
Brentuximab Vedotin 
+ Nivolumab ATA 
Baseline 
 
 
 
 
 
 
 
1 
Day 1 
Predose 
Within 24 hr prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
 
X 
End of infusion 
Within 15 min post end of 
brentuximab vedotin infusion 
End of brentuximab 
vedotin infusion 
X 
 
 
Day 2a 
24 hr postdose 
±4 hr 
Start of brentuximab 
vedotin infusion 
X 
 
 
Day 8 
Predose 
Within 24 hr prior to start of 
nivolumab infusion 
Start of nivolumab 
infusion 
Xa 
X 
 
End of infusion 
Within 15 min post end of 
nivolumab infusion 
End of nivolumab 
infusion 
 
X 
 
Day 15a 
336 hr postdose 
±24 hr 
Start of brentuximab 
vedotin infusion 
X 
X 
 
2 and 3 
Day 1 
Predose 
Within 24 hr prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of 
nivolumab infusion 
End of  nivolumab 
infusion 
X 
X 
 
4 
Day 1 
Predose 
Within 24 hr prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of 
nivolumab infusion 
End of nivolumab 
infusion 
X 
X 
 
Day 2a 
24 hr postdose 
±4 hr 
Start of brentuximab 
vedotin infusion 
X 
X 
 
Day 8a 
168 hr postdose 
±24 hr 
Start of brentuximab 
vedotin infusion 
X 
X 
 
EOT 
30 + 7 days post last dose of study drug(s) 
X 
X 
X 
Safety follow-up 
100 days post last dose of nivolumab 
 
 
X 
a 
Patients in Part 1 only 
 


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Table 3: 
Pharmacokinetic and ATA sampling timepoints, Part 3 
Cycle 
Study 
Day 
Time 
Window 
Relative Time 
Brentuximab 
Vedotin PK 
Nivolumab PK 
Brentuximab Vedotin 
+ Nivolumab ATA 
Baseline 
 
 
 
 
 
 
 
1 
Day 1 
Predose 
Within 24 hr prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of 
nivolumab infusion 
End of nivolumab 
infusion 
X 
X 
 
Day 8 
168 hr postdose 
±24 hr 
Start of brentuximab 
vedotin infusion 
X 
X 
 
Day 15 
336 hr postdose 
±24 hr 
Start of brentuximab 
vedotin infusion 
X 
X 
 
2  
Day 1 
Predose 
Within 24 hr prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of 
nivolumab infusion 
End of  nivolumab 
infusion 
X 
X 
 
3 
Day 1 
Predose 
Within 24 hr prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of 
nivolumab infusion 
End of  nivolumab 
infusion 
X 
X 
 
4 
Day 1 
Predose 
Within 24 hr prior to start of 
brentuximab vedotin infusion 
Start of brentuximab 
vedotin infusion 
X 
X 
X 
End of infusion 
Within 15 min post end of 
nivolumab infusion 
End of nivolumab 
infusion 
X 
X 
 
EOT 
30 + 7 days post last dose of study drug(s) 
X 
X 
X 
Safety follow-up 
100 days post last dose of nivolumab 
 
 
X 
 
 


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7.4 Biomarker Studies 
Blood and tumor samples will be collected for measurement of potential pharmacodynamic 
and patient stratification biomarkers.  Assessments may include, but are not limited to: 
● 
Flow cytometry of peripheral blood leukocytes to assess the expression of CD30, 
CD153, PD-1, PD-L1, and PD-L2 in specific T cell (Th1, Th2, Th17, native, 
activated, effector and central memory), B cell (naive, activated, memory, 
plasmablast and plasma cell), and myeloid cell (monocyte, dendritic cell) populations 
via panels which may include, but not be limited to: 
○ 
CD3, CD4, CD8, CD30, Ki67, HLA-DR+, PD-1, PD-L1, PD-L2, CD153 
○ 
CD3, CD4, CD8, CD30, CD127, CXCR3, CCR4, CCR6, CD25, CD153 
○ 
CD3, CD4, CD8, CD30, CD45RA, CD153, CD197 
○ 
CD19, CD10, CD38, CD27, IgD, CD30, CD153, CD20 
○ 
CD14, CD16, CD11c, CD3/CD19, CD56, CD30, CD153, CD123, HLA-DR, CD7 
● 
Soluble biomarkers, including but not limited to, CD30 (sCD30), CD153 (sCD153), 
PD-1 (sPD-1), and PD-L1 (sPD-L1) 
● 
Inflammatory cytokines/chemokines including, but not limited to, IFN-γ, IL-6, IL-18, 
CXCL11 (I-TAC), CXCL9, CXCL10, MIP1 beta, and TNF-α 
● 
Peripheral blood T cell receptor (TCR) repertoire and anti-CMV/EBV/FLU T cell 
responses from PBMC to assess the impact of brentuximab vedotin alone and in 
combination with nivolumab on immune status 
● 
RNA expression profiling 
Sampling timepoints are listed in Table 4 and Table 5. 
 


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Table 4: 
Biomarker sampling timepoints, Parts 1 and 2 
Cycle 
Study Day 
Time 
Window 
Relative Time 
Flow 
Cytometry 
Plasma and Serum 
Cytokines 
Serum 
Biomarkers 
RNA 
PBMC 
TCR 
1 
Day 1 
Predose 
Within 24 hr prior to 
start of brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 2a 
24 hr postdose 
±4 hr 
Start of 
brentuximab 
vedotin infusion 
 
X 
X 
X 
 
 
Day 8 
Predose 
Within 24 hr prior to 
start of nivolumab 
infusion 
Start of nivolumab 
infusion 
X 
X 
X 
X 
X 
X 
Day 15 
336 hr postdose 
±24 hr 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
2 
Day 1 
Predose 
Within 24 hr prior to 
start of brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 8b 
168 hr postdose 
±24 hr 
Start of 
brentuximab 
infusion 
X 
X 
X 
 
 
 
3 
Day 1 
Predose 
Within 24 hr prior to 
start of brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion  
X 
X 
X 
X 
X 
X 
4 
Day 1a 
Predose 
Within 24 hr prior to 
start of brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 2a 
24 hr postdose 
 ±4 hr  
Start of 
brentuximab 
vedotin infusion 
 
X 
X 
X 
 
 
Day 8a 
168 hr postdose 
±24 hr  
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
EOT 
30 + 7 days post last dose of study drug(s) 
X 
X 
X 
X 
X 
X 
a 
For patients in Part 1 only 
b 
For patients in Part 2 only 


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Table 5: 
Biomarker sampling timepoints, Part 3  
Cycle 
Study Day 
Time 
Window 
Relative Time 
Flow 
Cytometry 
Plasma and 
Serum Cytokines 
Serum 
Biomarkers 
RNA 
PBMC 
TCR 
1 
Day 1 
Predose 
Within 24 hr prior to 
start of brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 8 
168 hr postdose 
±24 hr 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 15 
336 hr postdose 
±24 hr 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
2 
Day 1 
Predose 
Within 24 hr prior to 
start of brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion 
X 
X 
X 
X 
X 
X 
Day 8 
168 hr postdose 
±24 hr 
Start of 
brentuximab 
infusion 
X 
X 
X 
 
 
X 
3 
Day 1 
Predose 
Within 24 hr prior to 
start of brentuximab 
vedotin infusion 
Start of 
brentuximab 
vedotin infusion  
X 
X 
X 
X 
X 
X 
EOT 
30 + 7 days post last dose of study drug(s) 
X 
X 
X 
X 
X 
X 
 
 


 
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7.4.1 Tumor Biopsies 
Formalin fixed paraffin-embedded tumor tissue blocks taken after relapse of prior therapy 
will be collected at screening to assess biomarkers implicated in sensitivity or resistance to 
brentuximab vedotin and/or nivolumab (e.g., CD30 expression, PD-L1/L2 amplification, and 
expression).  If tumor tissue block is not available, a minimum of approximately 20 unstained 
charged slides of the tumor tissue will be required.  If multiple blocks are available, the one 
with the highest tumor content is preferred.  If archival tumor tissues (i.e., tumor tissue 
obtained at the time of the patient’s original diagnosis and/or at the time of subsequent 
procedures conducted as part of the patient’s standard care) are available, they will be 
collected under the same criteria to understand the impact of prior treatment on CD30 and 
PD-L1/L2 expression.  If any tissue remains, the tumor pathology block may be returned to 
the original site by the Sponsor or designee at the end of the study upon request.  See the 
Laboratory Manual for details. 
Efforts should be made to take additional biopsies in patients who demonstrate disease 
progression, indeterminate response on study, or residual disease at the EOT visit.  These 
optional samples are to be tested for the expression of CD30 and PD-L1/L2 expression and 
other potential markers to understand potential delayed response and/or resistance 
mechanism. 
Assessments may include histopathology and immunohistochemistry of tumor biopsies for: 
● 
Expression of PD-L1/L2, CD30, immune cell markers and expression of other 
immune checkpoint molecules in malignant Reed-Sternberg cells and tumor 
infiltrating lymphocytes by IHC, as well as amplification of 9p24.1 
● 
Tumor infiltrating lymphocytes (CD3, CD4, CD8, Foxp3+ and ratios thereof) 
● 
Expression of CD30 and PD-1 among T, B, macrophage and myeloid cell populations 
including, but not limited to CD4, CD8, Foxp3, CD68, and CD163 
● 
Amplification and expression of PD-L1 and PD-L2 by malignant Reed-Sternberg 
cells and tumor infiltrating lymphocytes 
● 
Expression (by RNA or protein) of other immune checkpoint molecules, including, 
but not limited to Galectin-1, if an assay becomes available 
● 
Epstein-Barr Virus infection status if not previously known 
● 
Expression analysis of 23-gene predictor for outcome post-ASCT in classical HL 
7.5 Biospecimen Repository 
In the US only, for patients who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by Seattle Genetics and used for future research, 
including but not limited to the evaluation of targets for novel therapeutic agents, the biology 
of ADC sensitivity and resistance mechanisms, and to identify pharmacodynamic biomarkers 
of ADCs.  Blood and tissue samples donated for future research will be retained for a period 
of up to 25 years.  If additional consent is not provided, any remaining biological samples 
will be destroyed following study completion. 


 
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7.6 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of adverse events (AEs) including serious adverse events (SAEs), recording of 
concomitant medication and measurements of protocol-specified physical examination 
findings, pulse oximetry tests, and laboratory tests. 
Safety will be monitored over the course of the study by an SMC as described in 
Section 9.3.9. 
7.6.1 Adverse Events 
7.6.1.1 Definitions 
Adverse Event 
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, Investigational New Drug 
(IND) Safety Reporting, an AE is any untoward medical occurrence in a patient or clinical 
investigational subject administered a medicinal product and which does not necessarily have 
a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions CRF: 
● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded.  A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
● 
All medical conditions present or ongoing predose on study Day 1 should be 
recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (predose) through the end of the safety reporting period (see Section 7.6.1.3).  
Complications that occur in association with any procedure (e.g., biopsy) should be 
recorded as AEs whether or not the procedure was protocol mandated. 
● 
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
● 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in a SAE, 
or results in study termination or interruption/discontinuation of study treatment.  
When recording an AE resulting from a laboratory abnormality, the resulting medical 
condition rather than the abnormality itself should be recorded (e.g., record “anemia” 
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Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
 
Life threatening: 
The AEs placed the patient at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe. 
 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. Hospitalizations 
for elective medical or surgical procedures or treatments planned before the signing 
of informed consent in the study or routine check-ups are not SAEs by this criterion. 
Admission to a palliative unit or hospice care facility is not considered to be a 
hospitalization.  Hospitalizations or prolonged hospitalizations for scheduled 
therapy of the underlying cancer or study target disease need not be captured as 
SAEs. 
 
Disabling/incapacitating: 
Resulted in a persistent or significant incapacity or substantial disruption of the 
patient’s ability to conduct normal life functions. 
 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a patient exposed to the molecule or study 
treatment regimen before conception or during pregnancy. 
 
Medically significant: 
The AE did not meet any of the above criteria, but could have jeopardized the 
patient and might have required medical or surgical intervention to prevent one of 
the outcomes listed above or involves suspected transmission via a medicinal 
product of an infectious agent. 
Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, version 4.03.  These criteria are 
provided in the study manual. 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the 
intensity of an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the sponsor 
for defining regulatory reporting obligations (see definition for Serious Adverse Events). 


 
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Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (brentuximab vedotin, nivolumab) 
should be evaluated by the investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such 
as: 
● an event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
● an event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the population exposed to the drug (e.g., tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (e.g., due to underlying disease or occurs 
commonly in the study population), or a temporal sequence cannot be established 
with the onset of the AE and administration of the study treatment, or a causal 
relationship is considered biologically implausible 
 
The Investigator’s Brochures for brentuximab vedotin and nivolumab individually describe 
adverse events commonly observed relative to either agent (i.e., neutropenia or peripheral 
neuropathy with brentuximab vedotin; immune-mediated adverse events with nivolumab), as 
well as less common serious findings.  The respective Investigator’s Brochure should be 
referenced when attributing causality; however, the final decision regarding causality is at the 
discretion of the investigator. 
7.6.1.2 Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during patient 
questioning, discovered during physical examination, laboratory testing and/or other means 
by recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to 
elicit the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met serious criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
Diagnosis versus Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms.  Grouping of symptoms into a diagnosis should only be done if each component 
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standard medical textbooks.  If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
Adverse reactions associated with the infusion of study drugs must be recorded as both the 
NCI CTCAE term for infusion-related reaction (e.g., cytokine release syndrome, acute 
infusion reaction, or allergic or hypersensitivity reaction) and with each sign or symptom 
recorded as an individual adverse event.  Level of severity for both the overall infusion-
related reaction term and the individual signs and symptoms should also be recorded. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and the SAE form. 
The following should be considered when recording SAEs: 
● 
Death is an outcome of an event.  The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
● 
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself.  The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Cancer 
Do not use the term ‘disease progression’ alone when reporting AEs, including SAEs, 
because it is too nonspecific.  Symptoms of disease progression that meet the criteria for an 
SAE must be reported.  When possible, report the specific disease (clinical) manifestation of 
the progression (e.g., “malignant pleural effusion”, “spinal bone metastases”, 
“lymphadenopathy”, “brain metastases”).  Otherwise, it is acceptable to report the specific 
disease (e.g., non-Hodgkin lymphoma) as an SAE. 
Pregnancy 
Notification to Drug Safety: complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 6 months after the last dose of brentuximab 
vedotin or 8 months after the last dose of nivolumab, whichever is later, including any 
pregnancies that occur in the partner of a male study patient.  Only report pregnancies that 
occur in a male patient’s partner if the estimated date of conception is after the male patient’s 
first study drug(s) dose.  Email or fax to the sponsor’s Drug Safety Department within 
48 hours of becoming aware of a pregnancy.  All pregnancies will be monitored for the full 
duration; all perinatal and neonatal outcomes should be reported.  Infants should be followed 
for a minimum of 8 weeks. 
Collection of data on the CRF: all pregnancies (as described above) that occur within 
6 months after the last dose of brentuximab vedotin or 8 months of the last dose of 
nivolumab, whichever is later, will also be recorded on the Adverse Events and Pre-Existing 
Conditions CRF. 


 
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Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE.  
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions Section 7.6.1.1) should be reported as SAEs. 
7.6.1.3 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
EOT visit or 30 days after the last brentuximab vedotin dose or 100 days after the last 
nivolumab dose, whichever is later.  However, all study protocol-related AEs are to be 
recorded from the time of informed consent.  All SAEs that occur after the safety reporting 
period and are considered study treatment-related in the opinion of the investigator should 
also be reported to the sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or 
the patient dies or withdraws consent.  All non-serious AEs will be followed through the 
safety reporting period.  Certain non-serious AEs of interest may be followed until 
resolution, return to baseline, or study closure. 
7.6.1.4 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a 
minimum, the following should be included: 
● 
Patient number 
● 
Date of event onset 
● 
Description of the event 
● 
Study treatment, if known 
 
The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the 
sponsor’s Drug Safety Department within 24 hours (see email address or fax number 
specified on the SAE report form) unless otherwise instructed on the Sponsor’s SAE form.  
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 
7.6.1.5 Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.6.1.4). 
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements.  In the United States, endpoints that assess disease-related mortality 
or major morbidity as well as other SAEs that are not study endpoints, but are known 
consequences of the underlying disease or condition that are anticipated to occur in the study 
population should not be reported to the Food and Drug Administration (FDA) as individual 


 
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IND safety reports per the final rule amending the IND safety reporting requirements under 
21 CFR 312.32 and the FDA’s guidance Safety Reporting Requirements for INDs and 
Bioavailability (BA) and Bioequivalence (BE) Studies (December 2012). 
In this study, the SAEs that do not require individual IND safety reports to the FDA are 
progression of the underlying cancer and SAEs related to the mobilization of stem cells for 
ASCT.  These anticipated SAEs will be reviewed periodically by an SMC and Seattle 
Genetics Drug Safety Department.  If, upon review, an SAE is occurring at a higher rate than 
that which would be expected for HL patients being treated with either study treatment 
(brentuximab vedotin or nivolumab), then an IND safety report for the SAE will be 
submitted to the FDA. 
7.6.2 Clinical Laboratory Tests 
Samples will be drawn for local and central labs.  Local laboratory testing will be used for 
evaluating safety and making clinical decisions.  The following laboratory assessments will 
be performed by both the local and central lab to evaluate safety at scheduled timepoints (see 
Appendix A) during the course of the study: 
● 
The chemistry panel is to include the following tests: albumin, alkaline phosphatase, 
ALT, AST, blood urea nitrogen, calcium, creatinine, chloride, lactate dehydrogenase, 
phosphorus, potassium, sodium, total bilirubin, amylase, lipase, and gamma-glutamyl 
transpeptidase, serum glucose, and uric acid.  Additionally, TSH, free T3, and free T4 
must also be tested at Cycle 1, Cycle 3, and EOT. 
● 
The CBC with differential is to include the following tests: white blood cell count 
with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), platelet count, RBC count, bands and blasts, hemoglobin, and hematocrit. 
The following additional laboratory assessment(s) will be performed by local laboratories at 
the designated timepoints (see Appendix A): 
● 
Hepatitis B and C serologies; if hepatitis C serology is positive, HCV RNA test by 
PCR is required to confirm 
● 
Epstein-Barr virus serology 
● 
A serum or urine β-hCG pregnancy test for females of childbearing potential 
7.6.3 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological.  Measurements of height 
obtained within the prior 12 months may be utilized. 


 
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7.6.4 Other Safety Assessment 
7.6.4.1 Pulmonary-related signs or symptoms 
Oxygen saturation by pulse oximetry should be obtained prior to each dose of nivolumab and 
at any time a patient 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 patient 
throughout the study.  However, if the patient’s status changes, the investigator can alter the 
extent of exertion based upon their medical judgment.  If a patient shows changes on pulse 
oximetry or other pulmonary-related signs (e.g., hypoxia, fever) or symptoms (e.g., dyspnea, 
cough) consistent with possible pulmonary adverse events, the patient should be immediately 
evaluated to rule out pulmonary toxicity.  An algorithm for the management of suspected 
pulmonary toxicity can be found in Appendix 3 of the nivolumab Investigator’s Brochure.  
See Section 5.3.4 for nivolumab dose modifications and Section 5.5.2 for allowed 
concomitant therapy for pulmonary-related signs or symptoms. 
7.7 Appropriateness of Measurements 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
ATA is commonly assessed for biologics; therefore, standard tests will be performed to 
detect the possible presence of specific antibodies to brentuximab vedotin and nivolumab.  
Pharmacokinetic assessments for drug activity are also common in clinical studies. 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 Site Training and Monitoring Procedures 
A study manual with instructions for study compliance and CRF completion will be 
provided.  Prior to the enrollment of patients at the site, Seattle Genetics or its designated 
clinical and medical personnel will review the following items with the investigator and 
clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, 
registration, and withdrawal processes 
● 
Current Investigator’s Brochure/ package insert 
● 
Recording and reporting AE and SAE 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
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● 
Informed consent process 
● 
GCP guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
Patient coding and randomization (if applicable) 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study record keeping, document retention, and administrative requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site.  During monitoring visits, the Seattle Genetics representative will 
review regulatory documentation, CRFs, source documentation, and investigational product 
storage, preparation, and accountability.  The CRFs will be reviewed for completeness, 
adherence to the provided guidelines, and accuracy compared to the source documents.  The 
investigators must ensure that the monitor is allowed to inspect all source documents 
pertinent to study patients, and must cooperate with the monitor to ensure that any problems 
noted in the course of the trial are resolved.  The investigator must maintain a comprehensive 
and centralized filing system of all study-related documentation that is suitable for inspection 
by Seattle Genetics or its designated monitors and by quality assurance auditors, or 
representatives of regulatory authorities. 
8.2 Data Management Procedures 
Seattle Genetics will provide CRF Completion Guidelines for electronic CRF (eCRF) data 
entry.  Study specific data management procedures will be maintained in the data 
management plan.  Queries resulting from edit checks and/or data verification procedures 
will be posted electronically in the eCRF. 
8.3 Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory.  Appropriate measures to protect patient confidentiality are to be employed 
during monitoring.  The CRFs and related source documents will be reviewed in detail by the 
monitor at each site visit.  Original source documents or certified copies are needed for 
review.  This review includes inspection of data acquired as a requirement for participation in 
this study and other medical records as required to confirm that the information contained in 
the CRFs, such as disease assessments, AEs, and concomitant medications, is complete and 
correct.  Other study records, such as correspondence with the sponsor and the IRB/IEC and 
screening and drug accountability logs will also be inspected.  All source data and study 


 
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records must also be available for inspection by representatives of regulatory authorities and 
IRB/IEC. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) 
during monitoring visits to the study centers.  Any discrepancies will be resolved with 
the investigator or designees as appropriate. 
8.5 Quality Assurance Procedures 
The Research and Development Quality Assurance group or its designee may conduct audits 
at the clinical site or other study-related facilities and organizations.  Audit reports will be 
retained by the Research and Development Quality Assurance group of Seattle Genetics as 
part of the written record. 
8.6 Data Handling and Record Keeping 
8.6.1 Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports.  Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system.  Data changes may only be made by those individuals so authorized.  
The investigator should retain records of the changes and corrections, written and/or 
electronic. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, inpatient or office patient records) for the 
maximum period required by the country and Institution in which the study will be 
conducted, or for the period specified by Seattle Genetics, whichever is longer.  The 
investigator must contact Seattle Genetics prior to destroying any records associated with the 
study.  If the investigator withdraws from the study (due to relocation, retirement, etc), the 
records shall be transferred to a mutually agreed upon designee, such as another investigator 
or IRB/IEC.  Notice of such transfer will be provided in writing to Seattle Genetics. 


 
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9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
It is anticipated that a total of approximately 55 patients will be enrolled in Parts 1 and 2 of 
the study.  This number was chosen in order to enable an adequately powered analysis of the 
primary endpoint of CR rate and to characterize the safety profile of the combination 
treatment.  This number will be greater if multiple dose regimens are investigated in Part 1 of 
the study as only those patients from Part 1 who are treated with the dose regimen chosen for 
Part 2 will be included in the analysis of the primary endpoint. 
The sample size needed to provide adequate power to test the primary endpoint is at least 53.  
With this sample size a one-sided exact binomial test at level α=0.05 will reject the null 
hypothesis of a CR rate less than or equal to 30% approximately 90% of the time when the 
true CR rate is 50%.  For the given parameters the null will be rejected when 22 or more CRs 
are observed (i.e., CR rate ≥41.5% is observed). 
For the safety assessment of the combination treatment, a sample size of 55 patients will 
provide a 94% chance of observing at least one occurrence of an adverse event with a true 
event rate of 5%. 
For Part 3, no formal hypothesis test is specified.  The sample size of 30 patients was chosen 
to allow adequate precision of estimates for response rates and safety data.  For example, if 
63% (19/30) of patients have a CR, then the 95% exact CI is (44%, 80%).  The sample size 
of 30 patients is sufficient to perform exploratory biomarker analyses. 
East 5.4 was used to perform sample size calculations. 
9.2 Study Endpoint Definitions 
9.2.1 Primary Efficacy Endpoint 
9.2.1.1 Complete Response (CR) Rate 
CR rate is defined as the proportion of patients with best response of CR prior to ASCT or 
initiation of subsequent antitumor treatment not specified in the protocol.  In Parts 1 and 2, 
response will be determined by investigator assessment according to the Lugano 
Classification Revised Staging System for malignant lymphoma (Cheson 2014); see Section 
7.2 for details of the modified criteria.  For Part 3, response will be determined by 
investigator assessment according to the Lugano Classified Revised Staging System (Cheson 
2014) with the incorporation of LYRIC (Appendix D) (Cheson 2016).  Patients whose 
response to treatment cannot be adequately assessed according to the specified criteria will 
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9.2.2 Secondary Efficacy Endpoints 
9.2.2.1 Objective Response Rate (ORR) 
ORR is defined as the proportion of patients with best response of CR or PR prior to ASCT 
or initiation of subsequent antitumor treatment not specified in the protocol.  Response is by 
investigator assessment according to the Lugano Classification Revised Staging System for 
malignant lymphoma (Cheson 2014); see Section 7.2 for details of the modified criteria.  
Patients whose response to treatment cannot be adequately assessed according to the 
specified criteria will be classified as non-responders for the purpose of calculating ORR. 
9.2.2.2 Progression-Free Survival (PFS) after ASCT 
PFS after ASCT is defined as the time from ASCT to the first documentation of PD or to 
death due to any cause, whichever comes first.  Patients who do not undergo ASCT will not 
be included in the analysis of this endpoint.  Documentation of PD must be consistent with 
the criteria described in Section 7.2.  Specifically, PFS will be calculated as: 
 
PFS = Date of first documented PD or death – Date of ASCT + 1. 
PFS data will be censored as described below: 
● 
Patients who do not have PD and are still on study at the time of an analysis will be 
censored at the date of the most recent disease assessment prior to the analysis which 
was adequate to document PD 
● 
Patients who have started an antitumor treatment (excluding high-dose conditioning 
regimens pre-ASCT, consolidative radiotherapy pre- or post-ASCT, or consolidative 
treatment with single-agent brentuximab vedotin post-ASCT) other than the study 
treatment prior to documented PD will be censored at the date of the most recent 
disease assessment which was adequate to document PD prior to start of new therapy 
● 
Patients who are removed from study prior to documentation of PD will be censored 
at the date of the most recent disease assessment prior to study discontinuation which 
was adequate to document PD. 
If a patient does not have any adequate disease assessments after ASCT their PFS will be 
censored at one day. 
9.2.2.3 Duration of Response 
Duration of response is defined as the time from start of the first documentation of OR (CR 
or PR) to the first documentation of PD or to death due to any cause, whichever comes first.  
Duration of response will only be calculated for the group of patients achieving an objective 
response while on study.  Documentation of PD must be consistent with the criteria described 
in Section 7.2.  Duration of response data will be censored as described below: 


 
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● 
Patients who do not have PD and are still on study at the time of an analysis will be 
censored at the date of the most recent disease assessment prior to the analysis which 
was adequate to document PD 
● 
Patients who have started an antitumor treatment (excluding stem cell transplant or 
post-ASCT consolidative therapy) other than the study treatment prior to documented 
PD will be censored at the date of the most recent disease assessment prior to start of 
new therapy which was adequate to document PD 
● 
Patients who are removed from study prior to documentation of PD will be censored 
at the date of the most recent disease assessment prior to study discontinuation which 
was adequate to document PD. 
If a patient does not have any disease assessments adequate to detect PD after the first 
documentation of objective response, their duration of response will be censored at one day. 
An additional exploratory analysis of PFS may be conducted in which clinical assessment 
will be considered adequate to detect disease progression. Other exploratory analyses of PFS 
may also be performed.  These analyses may involve different definitions of events and/or 
different censoring rules; details will be provided in the statistical analysis plan (SAP). 
9.2.3 Additional Efficacy Endpoints 
9.2.3.1 Overall Survival (OS) 
Overall survival is defined as the time from date of enrollment to date of death due to any 
cause.  In the absence of confirmation of death, overall survival time will be censored at the 
last date the patient is known to be alive.  Patients lacking data beyond the date of enrollment 
will have their overall survival time censored to 1 day. 
9.2.3.2 PFS 
PFS is defined as the time from enrollment to the first documentation of PD or to death due 
to any cause, whichever comes first.  Documentation of PD must be consistent with the 
criteria described in Section 7.2.  Specifically, PFS will be calculated as: 
 
PFS = Date of first documented PD or death – Date of enrollment + 1. 
PFS data will be censored as described below: 
● 
Patients who do not have PD and are still on study at the time of an analysis will be 
censored at the date of the most recent disease assessment prior to the analysis that 
was adequate to document PD 
● 
Patients who have started an antitumor treatment (excluding high-dose conditioning 
regimens pre-ASCT, consolidative radiotherapy pre- or post-ASCT, or consolidative 
treatment with single-agent brentuximab vedotin post-ASCT) other than the study 
treatment prior to documented PD will be censored at the date of the most recent 
disease assessment that was adequate to document PD prior to start of new therapy 


 
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● 
Patients who are removed from study prior to documentation of PD will be censored 
at the date of the most recent disease assessment prior to study discontinuation that 
was adequate to document PD. 
If a patient does not have any adequate disease assessments after enrollment their PFS will be 
censored at one day. 
An additional exploratory analysis of PFS may be conducted in which clinical assessment 
will be considered adequate to detect disease progression.  Other exploratory analyses of PFS 
may also be performed.  These analyses may involve different definitions of events and/or 
different censoring rules; details will be provided in the SAP. 
9.3 Statistical and Analytical Plans 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the SAP.  A change to the data analysis methods described in the protocol will 
require a protocol amendment only if it alters site conduct (e.g., adding baseline assessments 
to define a subgroup).  The SAP will be finalized prior to database lock.  Any changes to the 
methods described in the final SAP will be described and justified in the clinical study report. 
9.3.1 General Considerations 
This is a phase 1/2 open-label study with a formal statistical hypothesis for the primary 
efficacy endpoint of CR rate.  There are no formal pre-specified hypotheses associated with 
the primary safety objective. 
In general, descriptive statistics (mean, median, standard deviation, minimum, maximum) 
will be used to summarize continuous variables collected. Frequencies and percentages will 
be used when presenting categorical variables.  Summaries will be presented overall and by 
dose regimen unless otherwise specified. 
9.3.1.1 Randomization and Blinding 
No randomization will be carried out and no blinding will be enforced as this is an open-label 
trial. 
9.3.1.2 Adjustments for Covariates 
Adjustment for covariates will not take place for analysis of the primary efficacy endpoint of 
CR rate.  Subgroup analyses and stratified analyses may be carried out for particular 
covariates of interest.  Exploratory analysis of biomarker and pharmacodynamic endpoints 
may also incorporate covariate adjustment. 
9.3.1.3 Handling of Dropouts and Missing Data 
Missing data will not be imputed, with the exception of AE dates while calculating duration 
of events. Patients with missing values of a variable other than response endpoints (CR and 
ORR) and time-to-event endpoints (PFS and OS) will be excluded from the analysis of that 
endpoint.  Patients whose disease response cannot be assessed will be scored as non-
responders for calculating the CR rate and ORR.  Censoring rules will be applied to the 


 
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estimation of the distribution of the time-to-event endpoints; details will be provided in the 
SAP. 
9.3.1.4 Multicenter Studies 
Due to the size of the trial and the number of study sites, it is not anticipated that any one site 
will accrue enough patients to warrant an analysis by site. 
9.3.1.5 Multiple Comparisons and Multiplicity 
No adjustment for multiplicity is planned as there is only a single planned hypothesis test of 
the primary efficacy endpoint. 
9.3.1.6 Data Transformations and Derivations 
Age in years will be calculated with the SAS INTCK function using informed consent date 
and birth date. 
Study Day will be calculated as Date – First Dose Date + 1 for dates on or after the first dose 
date.  For dates prior to the first dose date, Study Day will be calculated as Date – First Dose 
Date.  For all calculations of Study Day, the First Dose Date will be the earliest date of 
treatment administration for brentuximab vedotin. 
Other time variables based on two dates, e.g., Start Date and End Date, will be calculated as 
(End Date – Start Date + 1) (in days) unless otherwise specified in the planned analysis 
section. 
The following unit conversion will be implemented unless otherwise specified: 
 
Months = Days / 30.4375 
 
Years = Days / 365.25 
Baseline values used in all analyses will be the most recent non-missing measurement prior 
to the first dose of study drug. 
The EOT date will be the date the EOT visit is performed, or 30 days after the last dose of 
study drug if an EOT visit is not performed. 
For efficacy assessments, the date of response will be the latest of all radiologic scan dates 
for the given disease assessment.  The date of progression will be the earliest of all radiologic 
scan dates for the given restage assessment. 
9.3.1.7 Analysis Sets 
All Enrolled Patients Analysis Set 
The All Enrolled Patients analysis set includes all patients enrolled in the study.  The All 
Enrolled Patients set will be used for the primary efficacy analysis.  Secondary and additional 
efficacy endpoints will also be analyzed using this analysis set. 


 
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All Treated Patients Analysis Set 
The All Treated Patients analysis set includes all patients who receive any amount of 
brentuximab vedotin or nivolumab.  The All Treated Patients set will be used for presentation 
of safety data and may be used for exploratory analyses of efficacy endpoints. 
Efficacy Evaluable Analysis Set 
The Efficacy Evaluable analysis set includes all patients who had an adequate baseline 
disease assessment, received any amount of either drug, and subsequently had an adequate 
response assessment.  The Efficacy Evaluable set will be used for exploratory analysis of 
efficacy endpoints. 
9.3.1.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints.  
Detailed methodology will be provided in the SAP. 
9.3.1.9 Timing of Analyses 
Analysis of the primary endpoint will be carried out after all patients have had their EOT 
assessments.  Interim summaries of various endpoints may be presented at scientific 
congresses prior to the final analysis of the primary endpoint.  Interim summaries will also be 
presented to the SMC.  Database cutoff will be determined after all patients have completed 
treatment. 
9.3.2 Patient Disposition 
An accounting of study patients by disposition will be tabulated and the number of patients in 
each analysis set will be summarized.  Patients who discontinue study treatment and patients 
who withdraw from the study will be summarized with reason for discontinuation or 
withdrawal. 
9.3.3 Patient Characteristics 
Demographics and other baseline characteristics will be summarized.  Details will be 
provided in the SAP. 
9.3.4 Treatment Compliance 
The dose administered at each cycle for each treatment agent will be assessed and dose 
intensity will be summarized.  Details will be provided in the SAP. 
9.3.5 Efficacy Analyses 
9.3.5.1 Primary Efficacy Analyses 
CR rate at the EOT visit will be calculated using the All Enrolled Patients analysis set and 
will include all patients in this analysis set who were enrolled on the dose regimen chosen for 
Part 2.  A two-sided 90% exact binomial CI will be calculated (Clopper 1934) and the test 
will be carried out for the following null and alternative hypotheses: 


 
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● 
H0: CR rate ≤30% 
● 
H1: CR rate >30% 
The test will be carried out using a one-sided exact binomial test at level α=0.05, thus the null 
will be rejected in favor of the alternative if P <0.05 is observed. 
9.3.5.2 Secondary Efficacy Analyses 
ORR at EOT will be calculated using the All Enrolled Patients set and its two-sided 95% 
exact binomial CI will be presented (Clopper 1934).  Additional summaries of ORR may be 
presented based on patient demographics of interest.  Summaries may also be presented using 
the All Treated Patients and the Efficacy Evaluable analysis sets. PFS and duration of 
response estimates will be based on Kaplan-Meier methodology and Kaplan-Meier plots will 
be presented.  The median PFS and duration of response times will be determined and their 
two-sided 95% CI calculated using the log-log transformation method (Collett 1994). 
9.3.5.3 Additional Efficacy Analyses 
OS and PFS estimates will be based on Kaplan-Meier methodology and Kaplan-Meier plots 
will be presented.  The median OS time will be determined and its two-sided 95% CI 
calculated using the log-log transformation method (Collett 1994). 
9.3.6 Pharmacokinetic and ATA Analyses 
Pharmacokinetic parameters to be estimated for brentuximab vedotin and MMAE include the 
area under the concentration-time curve (AUC), maximum concentration (Cmax) or 
concentration at the end of infusion (Ceoi), the time Cmax occurred (Tmax), and trough 
concentration (Ctrough) for brentuximab vedotin.  For nivolumab, Ceoi and Ctrough will be 
summarized.  The incidence of ATA to brentuximab vedotin and to nivolumab will also be 
assessed. 
9.3.7 Biomarker Analyses 
Relationships of biomarkers (e.g., baseline values, absolute and relative changes from 
baseline) to efficacy, safety and PK parameters will be explored.  Relationships and 
associated data that are determined to be of interest will be summarized.  Details will be 
described separately. 
9.3.8 Safety Analyses 
9.3.8.1 Extent of Exposure 
Exposure for each treatment agent, including duration of treatment, number of cycles, total 
dose, dose modifications, and dose intensity will be summarized using the All Treated 
Patients analysis set. 
Details will be provided in the SAP. 


 
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9.3.8.2 Adverse Events 
Adverse events will be defined as treatment emergent if they are newly occurring or worsen 
following treatment with either brentuximab vedotin or nivolumab.  The incidence of all 
AEs, treatment-emergent AEs, and treatment-related AEs will be tabulated.  AEs will be 
classified by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
AEs will be listed and summarized by MedDRA preferred term, severity, and relationship to 
study drug.  In the event of multiple occurrences of the same AE with the same preferred 
term in one patient, the AE will be counted once as the occurrence.  The incidence of AEs 
will be tabulated by preferred term and treatment group.  AEs leading to premature 
discontinuation of study drug will be summarized and listed in the same manner. 
9.3.8.3 Deaths and Serious Adverse Events 
Serious adverse events will be listed and summarized in the same manner as all AEs.  Events 
with a fatal outcome will be listed. 
9.3.8.4 Clinical Laboratory Results 
Summary statistics for actual values and for change from baseline may be tabulated as 
appropriate for laboratory results and scheduled visit.  Laboratory values will be listed with 
grade per NCI CTCAE and out of normal reference range flags. 
9.3.9 Interim Analyses 
In Part 1 of the study, an SMC will monitor the trial for safety and provide guidance 
regarding possible enrollment of additional patients in Part 1 and possible expansion of 
enrollment in Part 2.  Initially 6 patients will be enrolled in Part 1.  If a patient discontinues 
treatment for reasons other than a DLT prior to 6 patients completing the DLT evaluation 
period then they will be replaced (as long as the arm remains open).  These patients will be 
monitored for DLT throughout the DLT evaluation period (see Section 3.1.4 for details 
regarding the definition of DLT and DLT-evaluable).  The SMC will review safety data and 
provide recommendations when either of the following occurs: 
1. 2 or more of the patients in the current arm are determined to have had a DLT based on 
the protocol definition. 
2. 6 patients complete the DLT evaluation period (by either remaining on treatment or 
having a DLT). 
On review of all available data, the SMC may determine that the classification of DLT was 
not appropriate for one or more of the patients, in which case enrollment may resume if the 
target of 6 patients has not yet been reached.  However, if 2 or more patients were 
determined to have experienced DLT, then expansion will not occur as the next step.  Based 
on SMC recommendations, additional patients may be enrolled at modified treatment and/or 
dosing levels (details in Section 3.1).  These additional patients will then be assessed for 
DLT in the same manner described above to determine if it is appropriate to expand 


 
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enrollment.  If it is determined by the SMC that due to safety concerns no additional dose 
levels or schedules should be enrolled, then the study will be closed to enrollment. 
Additionally, interim data from the study may be presented at scientific meetings such as the 
annual meetings of the American Society of Clinical Oncology and the American Society of 
Hematology. 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonized Tripartite Guideline E6 (R1); FDA CFR [21 CFR § 50, 56, 312]), Declaration of 
Helsinki (Brazil 2013), and all applicable regulatory requirements. 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring patients are re-consented when the informed consent document is updated during 
the study, if required.  The investigator will ensure that written informed consent is obtained 
from each patient, or legally authorized representative, if applicable to this study, by 
obtaining the signature and date on the informed consent document prior to the performance 
of protocol evaluations or procedures. 
If informed consent is obtained from a legally authorized representative for a patient who is 
unable to provide informed consent at study entry (if applicable), but the patient is later able 
to provide informed consent, the investigator must obtain written informed consent from the 
patient. 
10.2 Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s).  The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol. 


 
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● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 
10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on GCP, and all applicable local and/or regional laws, rules, and 
regulations. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination 
Any investigator-initiated changes to the protocol (with the exception of changes to eliminate 
an immediate hazard to a study patient) must be approved by the sponsor prior to seeking 
approval from the IRB/IEC, and prior to implementing.  The investigator is responsible for 
enrolling patients who have met protocol eligibility criteria.  Protocol deviations must be 
reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC policies. 
The sponsor may terminate the study at any time.  The IRB/IEC must be advised in writing 
of study completion or early termination. 
10.4 Study Documentation, Privacy and Records Retention 
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and patient 
medical records in the patient files as original source documents for the study.  If requested, 
the investigator will provide the sponsor, its licensees and collaborators, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents 
or certified copies. 
Records containing patient medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the patient 
authorization contained in the informed consent document for the study (the Authorization).  
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization.  Furthermore, CRFs and other documents to 
be transferred to the sponsor should be completed in strict accordance with the instructions 
provided by the sponsor, including the instructions regarding the coding of patient identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov. 


 
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10.5 Clinical Trial Agreement 
Payments by the sponsor to investigators and institutions conducting the trial, requirements 
for investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement. 


 
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APPENDIX A: 
SCHEDULE OF EVENTS 
 
Patients in Part 1 
Screening 
Baseline 
Enrollment 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4I 
EOTJ 
Prior to 
ASCT 
Safety  
Follow-up 
Long-term 
Follow-upL 
Visit Window 
D –28 to 1 
D –7 to 1 
D –7 to 1 
D1 (±1 day) 
Day 2 (+2 days) 
D8 (±1 day) 
D15 (±1 day) 
D1 (±1 day) 
D15  
(+ 6 days 
D1 (±1 day) 
D1 (±1 day) 
Day 2 (+2 days) 
D8 (±1 day) 
30–37 Days  
Post Last Dose 
After  
EOT visit  
performed 
100 Days  
Post Last Dose  
of Nivolumab 
±2 weeks 
Screening/ 
baseline  
assessments 
Informed Consent 
X 
 
Eligibility documentation submitted to Sponsor  
prior to study start 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory condition review 
X 
 
 
 
 
 
 
 
 
 
 
 
XM 
 
 
 
Serology (hepatitis B, C, EBV)Q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WeightR 
 
X 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Brentuximab vedotin 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
Nivolumab 
 
 
 
 
X 
 
XE 
 
XE 
XE 
 
 
 
 
 
 
PK samples 
ADC/MMAE 
 
 
XF 
X 
X 
X 
XF 
 
XF 
XF 
X 
X 
X 
 
 
 
Nivolumab 
 
 
 
 
XG 
X 
XG 
 
XG 
XG 
X 
X 
X 
 
 
 
ATA  
ATA sample 
 
 
XB 
 
 
 
X 
 
X 
X 
 
 
X 
 
X 
 
Biomarker  
samplesA 
Flow cytometry (whole blood) 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Serum and plasma cytokines 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Serum biomarkers 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
RNA expression profiling 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
PBMC 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
TCRB sequencing 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Tumor biopsy 
XC,D 
 
 
 
 
 
 
 
 
 
 
 
XK 
 
 
 
Response  
assessments 
Dedicated CT of chest, neck,  
abdomen, pelvis 
X 
 
 
 
 
 
 
XH 
 
 
 
 
XV 
XN 
 
XS 
PET 
X 
 
 
 
 
 
 
 
 
 
 
 
XV 
XN 
 
XT 
B symptom assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Bone marrow biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
XO 
XO 
 
 
Survival and disease status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Interval medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety  
assessments 
Physical examinationR 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Vital signs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetry 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
Performance status 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum chemistryR 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
 
Thyroid panel 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
XP 
 
 
 
CBC with differentialR 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
 
Estimated creatinine clearance 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antinuclear antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Con meds and AEs 
Collect any related to study procedures 
Collect from Day 1 (predose) through safety reporting period of study drug(s) 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 75 of 91 
 
Patients in Part 2 
Screening 
Baseline 
Enrollment 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4I 
EOTJ 
Prior to 
ASCT 
Safety  
Follow-up 
Long-term  
Follow-upL 
Visit Window 
D –28 to 1 
D –7 to 1 
D –7 to 1 
D1 (±1 day) 
D8 (±1 day) 
D15 (±1 day) 
D1 (±1 day) 
D8 (±1 day)  
D15 (+ 6 days 
D1 (±1 day) 
D1 (±1 day) 
30–37 Days  
Post Last Dose  
or as noted for 
scans V 
After EOT  
visit  
performed 
100 Days  
Post Last Dose  
of Nivolumab 
±2 weeks 
Screening/ 
baseline 
assessments 
Informed Consent 
X 
 
Eligibility documentation submitted to Sponsor  
prior to study start 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory condition review 
X 
 
 
 
 
 
 
 
 
 
XM 
 
 
 
Serology (hepatitis B, C, EBV)Q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
WeightR 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Brentuximab vedotin 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Nivolumab 
 
 
 
X 
 
XE 
 
 
XE 
XE 
 
 
 
 
PK samples 
ADC/MMAE 
 
 
XF 
 
 
XF 
 
 
XF 
XF 
X 
 
 
 
Nivolumab 
 
 
 
XG 
 
XG 
 
 
XG 
XG 
X 
 
 
 
ATA  
ATA sample 
 
 
XB 
 
 
X 
 
 
X 
X 
X 
 
X 
 
Biomarker  
samplesA 
Flow cytometry (whole blood) 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Serum and plasma cytokines 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Serum biomarkers 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
RNA expression profiling 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
 
PBMC 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
 
TCRB sequencing 
 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
 
Tumor biopsy 
XC,D 
 
 
 
 
 
 
 
 
 
XK 
 
 
 
Response  
assessments 
Dedicated CT of chest, neck,  
abdomen, pelvis 
X 
 
 
 
 
 
 
XH 
 
 
XV 
XN 
 
XS 
PET 
X 
 
 
 
 
 
 
 
 
 
XV 
XN 
 
XT 
B symptom assessment 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Bone marrow biopsy 
 
 
 
 
 
 
 
 
 
 
XO 
XO 
 
 
Survival and disease status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Interval medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety  
assessments 
Physical examinationR 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
Vital signs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetry 
 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
Performance status 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum chemistryR 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
Thyroid panel 
 
 
XP 
 
 
 
 
 
XP 
 
XP 
 
 
 
CBC with differentialR 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
Estimated creatinine clearance 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Antinuclear antibodies 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Con meds and AEs 
Collect any related to study procedures 
Collect from Day 1 (predose) through safety reporting period of study drug(s) 
 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 76 of 91 
 
Patients in Part 3 
Screening 
Baseline 
Enrollment 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4I 
EOTJ 
Prior to 
ASCT 
Safety  
Follow-up 
Long-term  
Follow-upL 
Visit Window 
D –28 to 1 
D –7 to 1 
D –7 to 1 
D1 (±1 day) 
D8 (±1 day) 
D15 (±1 day) 
D1 (±1 day) 
D8 (±1 day)  
D15 (+ 6 days 
D1 (±1 day) 
D1 (±1 day) 
30–37 days post 
last dose or as 
noted for scansU 
After EOT  
visit  
performed 
100 Days  
post last dose  
of nivolumab 
±2 weeks 
Screening/ 
baseline 
assessments 
Informed Consent 
X 
 
Eligibility documentation submitted to Sponsor  
prior to study start 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory condition review 
X 
 
 
 
 
 
 
 
 
 
XM 
 
 
 
Serology (hepatitis B, C, EBV)Q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
WeightR 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Brentuximab vedotin 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Nivolumab 
 
 
XE 
 
 
XE 
 
 
XE 
XE 
 
 
 
 
PK samples 
ADC/MMAE 
 
See Table 3 for PK and ATA sampling timepoints 
 
Nivolumab 
 
ATA  
ATA sample 
 
Biomarker  
samplesA 
Flow cytometry (whole blood) 
 
See Table 5 for biomarker sampling timepoints 
 
 
 
Serum and plasma cytokines 
 
 
 
Serum biomarkers 
 
 
 
RNA expression profiling 
 
 
 
PBMC 
 
 
 
TCRB sequencing 
 
 
 
Tumor biopsy 
XC,D 
 
 
 
 
 
 
 
 
 
XK 
 
 
 
Response  
Assessments 
Dedicated CT of chest, neck,  
abdomen, pelvis 
X 
 
 
 
 
 
 
XH 
 
 
XU 
 
 
XS 
PET 
X 
 
 
 
 
 
 
 
 
 
XU 
 
 
XT 
B symptom assessment 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Bone marrow biopsy 
 
 
 
 
 
 
 
 
 
 
XO 
XO 
 
 
Survival and disease status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Interval medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety  
assessments 
Physical examinationR 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
Vital signs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetry 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
Performance status 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum chemistryR 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
Thyroid panel 
 
 
XP 
 
 
 
 
 
XP 
 
XP 
 
 
 
CBC with differentialR 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
Estimated creatinine clearance 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Antinuclear antibodies 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Con meds and AEs 
Collect any related to study procedures 
Collect from Day 1 (predose) through safety reporting period of study drug(s) 
 
 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 77 of 91 
A. 
All biomarker samples are predose on the day of blood draw, if applicable. 
B. 
ATA includes the pre-dose brentuximab vedotin and nivolumab samples at Cycle 1 Day 1. 
C. 
Sample taken after relapse of prior therapy required; archival sample at diagnosis to be available. 
D. 
Prior to first dose brentuximab vedotin. 
E. 
Nivolumab administration should be at least 30 minutes after completion of brentuximab vedotin 
administration. 
F. 
See Table 2 for timing of samples for brentuximab vedotin PK and ATA. 
G. 
See Table 2 for timing of samples for nivolumab PK and ATA. 
H. 
Cycle 2 CT scan only to check for progression of disease; a limited scan that includes sites of disease identified 
at baseline is acceptable.  Patients with stable disease or better may continue on treatment, while patients with 
progression of disease are to discontinue treatment and have an EOT visit. Patients in Part 3 with an 
indeterminate response as defined by LYRIC may also continue on treatment. 
I. 
For patients who receive consolidative high-dose therapy and ASCT, peripheral blood stem cells may be 
mobilized following Cycle 4, as applicable.  If mobilized prior to Cycle 4 after discussion with the medical 
monitor, subsequent cycles should not begin until adequate recovery of peripheral blood counts and stem cell 
collection has occurred per institutional standards.  A delay of >7 days is discouraged. 
J. 
EOT evaluations should be obtained before initiation of non-protocol therapy.  If EOT evaluations are 
completed before 30 days after the last treatment, the site will conduct a phone screen 30–37 days following 
the patient’s last treatment to ensure that no changes in the AE profile have occurred. 
 
K. 
Optional at progression of disease or if evidence of residual disease is suspected. 
L. 
Follow-up to be performed at the following timepoints post-ASCT (or post-EOT for patients not receiving an 
ASCT): 100 days and then 6, 9, 12, 18, 24, 30, and 36 months, and then per institutional standard thereafter  CT 
scans will only be done if progression is suspected based on clinical signs and symptoms. 
M. 
Only for patients with findings at Screening/Baseline. 
N. 
Not required if performed within the prior 6 weeks. 
O. 
For patients planning to proceed to ASCT, a bone marrow biopsy is required; may be performed at the EOT 
visit. 
P. 
Thyroid panel includes TSH, free T3, and free T4. 
Q. 
If hepatitis C serology is positive, HCV RNA test by PCR is required to confirm. 
R. 
May be performed within 1 day prior to dosing; results from clinical laboratory tests must be reviewed prior to 
dosing. 
S. 
Not to be performed at 9, 18, and 30 months unless progression is suspected based on interval medical history 
and/or physical examination. 
T. 
Not required if patient achieves CmR. 
U. 
For patients in Part 3 only, CT and PET scans to be performed 15-30 days post last dose of study drug. 
V. 
For patients in Parts 1 and 2 only, CT and PET scans to be performed 23-37 days post last dose of study drug. 
 
 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 78 of 91 
APPENDIX B: 
PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky 
 
Lansky 
 
ECOG 
Percent 
Description 
 
Percent 
Description 
 
Score 
Description 
100 
Normal, no complaints, 
no evidence of disease. 
 
100 
Fully active, normal. 
 
0 
Normal activity.  Fully 
active, able to carry on 
all pre-disease 
performance without 
restriction. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
 
90 
Minor restrictions in 
physically strenuous 
activity. 
 
 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
 
80 
Active, but tires more 
quickly. 
 
1 
Symptoms, but 
ambulatory.  Restricted 
in physically strenuous 
activity, but ambulatory 
and able to carry out 
work of a light or 
sedentary nature (e.g., 
light housework, office 
work). 
70 
Cares for self, unable to 
carry on normal activity 
or to do active work. 
 
70 
Both greater restriction 
of, and less time spent 
in, play activity. 
 
 
60 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
 
60 
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities. 
 
2 
In bed <50% of the time.  
Ambulatory and capable 
of all self-care, but 
unable to carry out any 
work activities.  Up and 
about more than 50% of 
waking hours. 
50 
Requires considerable 
assistance and frequent 
medical care. 
 
50 
Gets dressed, but lies 
around much of the day; 
no active play; able to 
participate in all quiet 
active play and 
activities. 
 
 
40 
Disabled, requires 
special care and 
assistance. 
 
40 
Mostly in bed, 
participates in quiet 
activities. 
 
3 
In bed >50% of the time.  
Capable of only limited 
self-care, confined to bed 
or chair more than 50% 
of waking hours. 
30 
Severely disabled, 
hospitalization 
indicated.  Death not 
imminent. 
 
30 
In bed, needs assistance 
even for quiet play. 
 
 
20 
Very sick, 
hospitalization 
indicated.  Death not 
imminent. 
 
20 
Often sleeping, play 
entirely limited to very 
passive activities. 
 
4 
100% bedridden.  
Completely disabled.  
Cannot carry on any self-
care.  Totally confined to 
bed or chair. 
10 
Moribund, fatal 
processes progressing 
rapidly. 
 
10 
No play, does not get 
out of bed. 
 
 
0 
Dead. 
 
0 
Dead. 
 
5 
Dead. 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 79 of 91 
APPENDIX C: 
NEW YORK HEART ASSOCIATION CLASSIFICATION 
A Functional and Therapeutic Classification for Prescription of Physical Activity for 
Cardiac Patients 
Class I:  
patients with no limitation of activities; they suffer no symptoms from ordinary activities. 
Class II:  
patients with slight, mild limitation of activity; they are comfortable with rest or with mild 
exertion. 
Class III:  
patients with marked limitation of activity; they are comfortable only at rest. 
Class IV:  
patients who should be at complete rest, confined to bed or chair; any physical activity brings on 
discomfort and symptoms occur at rest. 
Online source: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 80 of 91 
APPENDIX D: 
OVERVIEW OF LYRIC CRITERIA (PART 3 ONLY) 
If tumor flare or pseudo-progression is suspected, then a clinical response of indeterminate 
response (IR) should be reported based on the Lymphoma Response to Immunomodulatory 
Therapy Criteria (LYRIC) (Cheson 2016). 
Definition of Indeterminate Response 
● 
IR1: An increase in overall tumor burden (as assessed by the sum of the products of 
the largest diameter [SPD]) of ≥50% of up to 6 measurable lesions in the first 
12 weeks of therapy, without clinical deterioration 
In general, patients should be experiencing clinical stability or improvement and 
must be able to tolerate continued treatment and not at risk of serious 
complications should tumor growth occur.  Symptoms related to tumor growth, 
such as pain at the tumor site or compression of adjacent structures, may not be 
considered as clinical deterioration in this context. 
● 
IR2: Appearance of new lesions, or growth of one or more existing lesion(s) ≥50% at 
any time during treatment, occurring in the context of lack of overall progression 
(<50% increase) of overall tumor burden, as measured by SPD of up to 6 lesions at 
any time during treatment; and 
This may occur early or late in the treatment course. A biopsy is strongly 
encouraged when a patient experiences this phenomenon. If the biopsy does not 
confirm the presence of viable tumor in the new or enlarging lesion(s), then the 
lesion(s) are not considered active disease and should not be used in subsequent 
SPD assessments. 
● 
IR3: An increase in fluorodeoxyglucose (FDG) uptake (using the 5-Point Scale per 
the Deauville Criteria of one or more lesion[s]) without a concomitant increase in 
lesion size or number. 
Increased immune activity at the site of tumor may manifest as an increase in 
FDG uptake. Therefore, by itself changes in uptake should not trigger an 
assignment of progressive disease (PD). The magnitude of increase in uptake in 
an immune-mediated flare compared to that in true tumor progression is not yet 
known. It is important to investigate this finding, especially in conjunction with a 
biopsy (if possible) of the lesion in question, an increase in FDG avidity of one or 
more lesions suggestive of lymphoma, without a concomitant increase in size of 
those lesions meeting PD criteria does not constitute PD. 
It is possible that, at a single time point a patient could fulfill criteria for both IR 1 or 2 AND 
IR3.  For example, there could be a new FDG-avid lesion in the absence of overall 
progression (IR2), and at the same time, increase in FDG uptake of a separate lesion (IR3).  
In such cases, the designation of IR1 or 2 should take priority (e.g., IR2 in the above 
example). 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 81 of 91 
Follow-Up of Indeterminate Response 
At 12 weeks (or earlier if clinically indicated) after a response of IR is determined by the 
Investigator, repeat imaging is mandatory and PD must be confirmed or refuted based on 
LYRIC follow-up criteria for IR.  PD should be reported if the SPD of the target lesion has 
increased further, with the considerations below: 
● 
In the case of IR1, the comparison should be between the first IR1 and the current 
SPD, with an increase of ≥10% constituting PD. In addition, there should be an 
increase of ≥5 mm (in either dimension) of at least one lesion for lesions ≤2 cm, and 
10 mm for lesions >2 cm, to be consistent with the Lugano classification (Cheson 
2016).  If the target SPD increase is <10%, the response would still be categorized as 
IR1, and the patient could continue treatment until a subsequent scan shows either PD 
(≥10% increase from first IR1 time point and an increase of >5 mm in either 
dimension of at least one lesion) or response (≥50% decrease from baseline). In this 
situation, it is reasonable to repeat imaging in 4–8 weeks to ensure absence of 
significant further increase. 
● 
In the case of IR2, the new or growing lesion(s) (unless biopsy proven to be benign) 
should be added to the target lesion(s), up to a total of no more than 6 total lesions. If 
the SPD of the newly defined set of target lesions has increased ≥50% from their 
nadir value (which may precede the IR time point), the patient should be considered 
to have PD. 
● 
In the case of IR3, since inflammatory responses may result in an increase in the 
standardized uptake value of a lesion, the patient will not be considered to have PD 
unless there is evidence of PD by an increase in lesion size or the development of new 
lesions, as noted above. 
 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 82 of 91 
APPENDIX E: 
INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
I have read the attached protocol entitled “A phase 1/2 study evaluating brentuximab vedotin in combination 
with nivolumab in patients with relapsed or refractory Hodgkin lymphoma after failure of frontline therapy.” 
I understand and agree to the provisions of the protocol, and I accept the responsibilities listed above in my role 
as principal investigator for the study. 
 
 
Investigator Signature 
 
Date 
 
 
Investigator Name, Printed 
 
 
 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 83 of 91 
APPENDIX F: 
DOCUMENT HISTORY 
Version 
Date 
Original 
27-May-2015 
Amendment 1 
21-Oct-2015 
Amendment 2 
17-Mar-2016 
Amendment 3 
29-Jul-2016 
Amendment 4 
23-Jan-2017 
 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 84 of 91 
Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Synopsis, Figure 1, 
6.7, 7.2 
Added long-term follow up assessments to the scanning schedule:  CT scans 
(chest, neck, abdomen, and pelvis) and PET scans will be performed at 
baseline, at the End of Treatment (EOT), pre-ASCT, and during long-term 
follow-up; PET is performed with CT scans until the patient is in compete 
metabolic response (CmR) by PET. 
Clarify that PET scans are needed until the patient has 
CmR. 
3.1, 3.2.1 
Removed dose levels of brentuximab vedotin and nivolumab 
Revisions provide a more high-level summary of dosing; 
exact dose levels to be determined by the SMC are noted 
in dosing and administration sections. 
5.2.2 
Added dose levels to the administration section and clarified the timing for 
completing the brentuximab vedotin administration when combined with 
nivolumab at Cycles 2–4. 
To align with the synopsis; clarify potential for dose de-
escalation based on SMC recommendation after the first 6 
patients complete treatment; clarify that brentuximab 
vedotin treatment should be completed 30 minutes prior to 
nivolumab infusion at cycles 2–4 (not cycle 1). 
5.3.2 
Correction. 
To clarify that BMS will provide nivolumab. 
5.3.3 
Added 1 mg/kg dose level to the administration. 
To clarify potential for dose de-escalation based on SMC 
recommendation after the first 6 patients complete 
treatment. 
5.3.4 
Added the following sentences:  Based on available information, 
autoimmune complications are the most likely AEs attributable to 
nivolumab.  Dose modifications for AEs are described in this section as well 
as in Appendix 2 of the nivolumab IB. 
Removed the following sentence:  There are no recommended dose 
modifications for hypothyroidism or hyperthyroidism. 
Revisions to clarify what the most likely nivolumab-
related AEs are based on current data and the location of 
dose modifications for nivolumab-related toxicities. 
Removed sentence because it is not consistent with 
recommended dose modifications for hypothyroidism and 
hyperthyroidism in following sections. 
5.3.4.3 
Revised dose modifications for total bilirubin elevations as follows: 
● If a patient has a baseline total bilirubin that is within normal limits, 
delay dosing for nivolumab-related Grade 2 elevations (>1.5 to 3 x 
ULN) 
◦ 
Nivolumab may be resumed if the bilirubin improves to Grade 1 
(≤3 x ULN) or better (≤1.5 x ULN) 
● If a patient has a baseline Grade 1 elevation of total bilirubin that is in 
the Grade 1 range (ULN to ≤1.5 x ULN), delay dosing for nivolumab-
related Grade 3 elevations in the range of (>3 to 5 x ULN) 
◦ 
Nivolumab may be resumed if the total bilirubin improves to Grade 
Revisions to clarify that the ranges in this protocol for 
LFT abnormalities are not an exact match of the CTCAE 
definitions of grade. 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
Seattle Genetics, Inc. - Confidential 
Page 85 of 91 
Section(s) 
Change 
Rationale 
2 (1 to 3 x ULN) or better (≤3 x ULN) 
Removed grade levels from discontinuation paragraph. 
5.5.2 
Added the following sentence: 
At the discretion of the treating physician, consolidative radiotherapy or 
consolidative treatment with single-agent brentuximab vedotin may be give 
post-ASCT. 
To align with censoring rules for PFS. 
5.5.2, 6.3.12 
Revised stem cell collection as follows:  Collection of peripheral blood stem 
cells for ASCT, if applicable, should occur per institutional standard of care, 
generally between 10-21 days after last dose of study drug(s).   
Protocol calls for scans at EOT (30–37 days post last 
dose), which are performed before collection of stem 
cells.  Change was made to reconcile the timing of the 
scans and the stem cell collection period and clarify that 
the scans should occur prior to the collection of stem cells 
for ASCT. 
6.1 
Added the following:  With the exception of gamma-glutamyl transpeptidase 
levels and thyroid function tests, the results from all other clinical laboratory 
assessments must be reviewed prior to study drug dosing. 
Clarify which labs must be reviewed prior to dosing. 
6.2.1, Appendix A 
Moved assessment of weight from screening visit to baseline visit; removed 
requirement for fasting glucose at baseline. 
Moved weight to be consistent with study drug dosing 
calculations; clarified that fasting glucose is not required. 
6.4 
Added the following note to the CT and PET assessments:  (may be 
performed 23 to 37 days after last dose of study drug to allow for collection 
of peripheral blood stem cells for ASCT, if applicable) 
Clarify the timing of scans should occur prior to collection 
of PBSC for ASCT. 
7.2 
Added definitions and summary of assessments for complete metabolic 
response, partial metabolic response, no metabolic response, and progressive 
metabolic disease. 
To align with Lugano Classification Revised Staging 
System for malignant lymphoma language. 
7.4 
Added biomarker tests for serum and/or plasma sPD-1 and sPD-L2, as well 
as anti-CMV/EBV/FLU T cell responses from PBMC. 
List new tests to be assessed. 
Table 2, Table 3 
Revised tables to split brentuximab vedotin PK, ATA, and biomarker 
sampling versus nivolumab PK, ATA, and biomarker sampling. 
Clarify when each sample should be taken with regard to 
study drug(s) dosing. 


 
Study SGN35-025 
Clinical Protocol 
Amendment 4; 23 Jan 2017 
Brentuximab vedotin; nivolumab 
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Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
Title 
Change medical monitor per admin letter 02 
New medical monitor 
5.3.2 
Nivolumab will be provided by supplied to study sites by Bristol-Myers 
Squibb and supplied to the study sites by Seattle Genetics. 
Clarify procurement of nivolumab 
6.4 
PET (both PET and CT) may  be performed within 23-37 days after EOT 
Clarify that a combined CT and PET may be performed at 
this time 
7.1 
Tissue samples will be sent to the central pathology lab for disease 
confirmation and further evaluation of CD30 and PD-L1 expression.  A 
subset of slides will be archived to support the sponsor’s efforts toward the 
development of a companion diagnostic test for CD30 and PD-L1 
expression. 
We are not developing this companion diagnostic test 
7.3, Table 2, 
Table 4 
Provided window and relative time clarifications for PK and biomarker 
sampling  
Clarify timing for PK and biomarker sample collection 
 
Table 4, 6.3.4, 
6.3.6, 6.3.9, 
Appendix A 
Biomarker sampling for patients in Part 2 changed as follows: 
Added Cycle 1 Study Day 15 and Cycle 2 Study Day 8 biomarker sampling; 
removed Cycle 4 Day 1 sampling  
Optimize biomarker sampling timepoints 
7.4 
Biomarker sampling clarifications 
Provide sampling flexibility for biomarker studies 
Appendix A 
Added PET assessment for patients not in CmR during long-term follow-up  
Correction to schedule of events from prior amendment 
adding PET to long-term follow-up visits 
Footnotes changed as follows: 
B ATA includes the pre-dose brentuximab vedotin sample at Cycle 1 Day 1 
and pre-dose nivolumab samples at Cycle 1 Day 8 
F See Table 2 for timing of samples for brentuximab vedotin PK and ATA 
G See Table 2 for timing of samples for nivolumab PK and ATA 
Clarify PK sampling timepoints 


 
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Summary of Changes in Amendment 3 
Section(s) 
Change 
Rationale 
5.4, 5.6.1 
Premedication required at Day 1 of each 21-day cycle beginning at Cycle 2 
To provide prophylactic premedications for potential 
infusion-related reactions with the combination of 
brentuximab vedotin and nivolumab, and to allow 
investigators to provide patients with appropriate 
premedications to minimize patient discomfort following 
treatment with brentuximab vedotin and nivolumab. 
6.6 
Updated timing of 100-day (+2 weeks) safety visit 
To clarify timing of the final safety visit for patients who 
discontinue prematurely from nivolumab 
7.6.1.2 
Edited safety reporting of adverse reactions associated with infusion of study 
drugs 
To align with the safety reporting for the combination of 
brentuximab vedotin and nivolumab 
 


 
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Summary of Changes in Amendment 4 
Section(s) 
Change 
Rationale 
Title 
Change medical monitor per admin letter 03 
New medical monitor 
List of Abbreviations 
Added abbreviations that were missing from the 
list; deleted abbreviations that were used only once 
in the document 
Correction 
Synopsis, 2.3, 3.1, 3.1.1, 3.2, 3.2.1, 5.3.3 
Added a new part to the study enrolling 30 
additional patients to be treated with brentuximab 
vedotin and nivolumab on Day 1 of all treatment 
cycles.  Details added in text to specify Parts 1 and 
2 versus Part 3 and differences in dosing schedules 
in Cycle 1.  Added Figure 2, which represents study 
design for Part 3.  
To compare the efficacy and safety of staggered 
versus same-day dosing  
Figure 1 
Added text to footnote b to indicate the window for 
EOT scans is 23–37 days post last dose of study 
drug 
Clarification  
Synopsis, 3.1, 9.2.1.1, Appendix D 
Added LYRIC response criteria (in addition to 
Lugano) for patients in Part 3 
To include formal definitions for indeterminate 
response and enable continuation of treatment in 
patients with indeterminate response at Cycle 2 
1.3.1 
Added: Possible additional mechanisms of 
anticancer activity include bystander effects on 
nearby cells in the tumor microenvironment, 
immunogenic cell death, and antibody-dependent 
cellular phagocytosis (Oflazoglu 2007; Li 2014; 
Muller 2014; Gardai 2015; Kim 2015). 
To update the description of the mechanism of 
action of brentuximab vedotin 
1.3.1 
Added description of patients with HL who were 
retreated with brentuximab vedotin.(Bartlett 2014) 
To provide rationale for enrolling patients 
previously treated with brentuximab vedotin 
Synopsis, 2.3  
Added 2 objectives: 
To compare biomarker data obtained with 
staggered versus same-day dosing 
To assess efficacy in patients who previously 
Objectives are specific for patients enrolled in 
Part 3 


 
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Section(s) 
Change 
Rationale 
received brentuximab vedotin 
3.2.2 
Added statement regarding prior study SGN35-006, 
which evaluated the benefits of retreatment with 
brentuximab vedotin; 
Added brief description of the Diefenbach (E4412) 
study (Diefenbach 2016) 
To provide rationale for retreating with 
brentuximab vedotin and for reduced dose of 
brentuximab vedotin (if necessary) for patients 
enrolled for retreatment; 
To provide rationale for treating patients with HL 
with the combination of brentuximab vedotin and 
nivolumab  
4.1 Inclusion criterion 9 
9. Females of childbearing potential must have a 
negative serum or urine beta human chorionic 
gonadotropin (β-hCG) pregnancy test result within 
7 days prior to the first dose of brentuximab 
vedotin.  Females with false positive results and 
documented verification that the patient is not 
pregnant are eligible for participation.  Females of 
non-childbearing potential are those who are 
postmenopausal greater than 1 year or who have 
had a bilateral tubal ligation or hysterectomy 
General update  
Synopsis, 4.2 Exclusion criterion 4 
4. Previous treatment with brentuximab vedotin 
4. For patients in Parts 1 and 2, previous treatment 
with brentuximab vedotin; for Part 3, patients with 
HL that is refractory to a brentuximab vedotin-
containing regimen in first line, or patients who 
discontinue brentuximab vedotin due to 
unacceptable toxicity are ineligible.  Refractory 
disease is defined as never achieving a CR to 
frontline therapy or having a CR but then 
progressing within 3 months of completing 
frontline therapy. 
As Part 3 will enroll patients for retreatment with 
brentuximab vedotin, wording of this criterion was 
updated to indicate specific details for Parts 1 and 2 
versus details for Part 3.  
Synopsis, 5.2.2 
Added details on reduced dose for patients being 
retreated with brentuximab vedotin  
To provide guidance on dosing in patients to be 
enrolled for retreatment with brentuximab vedotin 
in Part 3 
Table 1 in 5.2.3 
Footnote a, which is not new, was added for 
Clarification 


 
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Section(s) 
Change 
Rationale 
clarification to text in dose modification table to 
Grade 2 peripheral neuropathy and Grade 3/4 
hematologic AEs 
5.4.2 
Added new instructions on required premedication 
for patients in Part 3. These instructions differ from 
those for patients in Parts 1 and 2 
To eliminate from Part 3 mandatory corticosteroids 
as prophylactic premedication for infusion-related 
reactions. Premedication in Part 3 follows protocol 
E4412 (Diefenbach 2016) 
5.5.1, 5.5.2 
Removed text describing premedications and 
treatment of infusion-related reactions and replaced 
it with links to the pertinent sections describing 
these  
To eliminate redundant information that would 
have required editing to make it align with 
instructions for different parts of the study 
5.6.1.2 
Added instructions for management of infusion-
related reactions for patients in Part 3  
To provide information specific to Part 3 
6.3.1 
Added nivolumab dosing Cycle 1 Day 1 for Part 3 
only 
To add same-day dosing for Cycle 1 Day 1 for 
Part 3 
6.3.3, 6.3.4, 6.3.6, 6.4 
Added text to identify portions that are specific for 
Part 1, 2, or 3 
To add safety, biomarker, and PK sampling 
schedule for Part 3 and identify what applies to Part 
1 and/or 2 
6.3.7 
Added language regarding patients with 
indeterminate response 
Clarification relevant to Part 3 
7.2.2 
Added text describing response/efficacy 
assessments for patients in Part 3 
To include details related to LYRIC 
7.3 
Added Table 3 with PK and ATA sampling 
timepoints specific for Part 3 only 
To provide schedule of PK and ATA sampling for 
patients in Part 3 only 
7.6.1 
Changed the definition of ICH from International 
Conference on Harmonisation to International 
Council for Harmonisation 
Update of name change 
7.4 
Added Table 5 with biomarker sampling timepoints 
specific for Part 3 only 
To provide schedule of biomarker sampling for 
patients in Part 3 only 
8.3 
Added “and IRB/IEC” to the sentence “All source 
data and study records must also be available for 
To supplement the details on who is authorized to 
inspect the source data.  


 
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Section(s) 
Change 
Rationale 
inspection by representatives of regulatory 
authorities.  
9.1 
Add text related to sample size selection for Part 3  
Specify details related to Part 3 
9.3.1 
Added: Summaries will be presented overall and by 
dose regimen unless otherwise specified. 
To clarify with additional information 
Throughout  
Minor edits and corrections, including many related 
to harmonizing style throughout the document 
Corrections 
 
 

SAP_000.pdf: 
 
 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of Seattle 
Genetics, Inc. and must not be disclosed or used except as authorized in writing by Seattle Genetics, Inc. 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
SGN35-025 
Version: 
Version 1; 09Aug2017 
Protocol Title: 
A phase 1/2 study evaluating brentuximab vedotin in 
combination with nivolumab in patients with relapsed or 
refractory Hodgkin lymphoma after failure of frontline 
therapy 
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 


Protocol SGN35-025 
Statistical Analysis Plan 
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APPROVAL SIGNATURES 
Product:  
SGN-35 
Protocol Number/Amendment:  
SGN35-025/A04 
SAP Version:  
1 
Version Date:  
09Aug2017 
 
The individuals signing below have reviewed and approve this statistical analysis plan.  
 
 
 
 
 
Biostatistician 
 
Date 
 
 
 
 
 
 
 
Adcetris Lead, Biostatistics 
 
Date 
 
 
 
 
 
 
 
Medical Monitor 
 
Date 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
APPROVAL SIGNATURES ................................................................................................................................. 2 
LIST OF ABBREVIATIONS ................................................................................................................................ 4 
1 
INTRODUCTION ........................................................................................................................................... 5 
2 
STUDY OBJECTIVES ................................................................................................................................... 5 
2.1 
Primary Objectives ................................................................................................................................ 5 
2.2 
Secondary Objectives ............................................................................................................................ 5 
2.3 
Additional Objectives ............................................................................................................................ 5 
3 
STUDY ENDPOINTS .................................................................................................................................... 6 
3.1 
Primary Endpoints ................................................................................................................................. 6 
3.2 
Secondary Endpoints ............................................................................................................................. 6 
3.3 
Additional Endpoints ............................................................................................................................. 6 
4 
STUDY DESIGN ............................................................................................................................................ 6 
5 
ANALYSIS SETS ........................................................................................................................................... 7 
5.1 
All Enrolled Patients Analysis Set ........................................................................................................ 7 
5.2 
All Treated Patients Analysis Set .......................................................................................................... 8 
5.3 
Efficacy Evaluable (EE) Analysis Set ................................................................................................... 8 
6 
STATISTICAL CONSIDERATIONS ............................................................................................................ 8 
6.1 
General Principles ................................................................................................................................. 8 
6.2 
Determination of Sample Size ............................................................................................................... 8 
6.3 
Randomization and Blinding ................................................................................................................. 9 
6.4 
Data Transformations and Derivations .................................................................................................. 9 
6.5 
Handling of Dropouts and Missing Data ............................................................................................. 10 
6.6 
Multicenter Studies ............................................................................................................................. 10 
6.7 
Multiple Comparison/Multiplicity....................................................................................................... 10 
6.8 
Examination of Subgroups .................................................................................................................. 10 
6.9 
Covariates ............................................................................................................................................ 11 
6.10 Timing of Analyses ............................................................................................................................. 11 
7 
PLANNED ANALYSES .............................................................................................................................. 11 
7.1 
Disposition .......................................................................................................................................... 11 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 11 
7.3 
Protocol Deviations ............................................................................................................................. 12 
7.4 
Treatment Administration ................................................................................................................... 12 
7.5 
Efficacy Analyses ................................................................................................................................ 14 
7.5.1 
Primary Efficacy Endpoints.................................................................................................... 14 
7.5.2 
Secondary Efficacy Endpoints................................................................................................ 14 
7.5.3 
Additional Efficacy Endpoints ............................................................................................... 17 
7.5.4 
Pharmacokinetic and ATA Analyses ...................................................................................... 18 
7.5.5 
Biomarker Analysis ................................................................................................................ 18 
7.6 
Safety Analyses ................................................................................................................................... 19 
7.6.1 
Adverse Events ....................................................................................................................... 19 
7.6.2 
Concomitant Medications ....................................................................................................... 22 
7.6.3 
Deaths ..................................................................................................................................... 22 
8 
INTERIM ANALYSIS.................................................................................................................................. 22 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 23 
9.1 
Changes from the Original Protocol .................................................................................................... 23 
10 REFERENCES .............................................................................................................................................. 24 
APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES ......................... 25 
APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ...................................................................................................................................... 28 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ATA 
antitherapeutic antibodies 
ASCT 
autologous stem cell transplant 
AUC 
area under the concentration-time curve 
Ceoi 
concentration at the end of infusion 
Cmax 
maximum concentration 
Ctrough 
trough concentration 
CI 
confidence interval 
CR 
complete remission 
CSR 
clinical study report 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
eastern cooperative oncology group 
EOT 
end of treatment 
eCRF 
electronic case report form 
HL 
Hodgkin lymphoma 
IHC 
immunohistochemistry 
IRR 
infusion related reaction 
IPI 
international prognostic index  
MedDRA 
medical dictionary for regulatory activities 
MMAE 
monomethyl auristatin E 
NCI CTCAE 
national cancer institute common terminology criteria for adverse events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PN 
peripheral neuropathy 
PR 
partial remission 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMC 
safety monitoring committee 
SPD 
sum of the products of the largest diameter 
Tmax 
time at which the maximum concentration occurs 
WHO 
world health organization 


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1 
INTRODUCTION 
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGN35-025, entitled ‘A phase 1/2 study evaluating brentuximab vedotin in 
combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma after 
failure of frontline therapy’. Results of the proposed analyses will become the basis of the 
clinical study report for this protocol. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed. All planned analyses specified in this document will be performed. Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final clinical study report. Any changes will either be reflected in amendments to this plan 
before the database lock or specifically documented in the clinical study report. 
2 
STUDY OBJECTIVES  
2.1 Primary Objectives 
● 
To assess the safety profile of brentuximab vedotin administered in combination with 
nivolumab in patients with relapsed or refractory HL 
● 
To assess the antitumor activity of brentuximab vedotin administered in combination 
with nivolumab in patients with relapsed or refractory HL 
2.2 Secondary Objectives 
● 
To assess the objective response rate (ORR) 
● 
To assess the duration of complete remission (CR) and objective response (OR) 
● 
To assess progression-free survival (PFS) after autologous stem cell transplant 
(ASCT) 
2.3 Additional Objectives 
● 
To assess overall survival (OS) 
● 
To compare the CR rate in patients who relapsed after frontline therapy with the CR 
rate in patients who were refractory to frontline therapy 
● 
To assess the feasibility of stem cell mobilization and collection after treatment with 
brentuximab vedotin in combination with nivolumab 
● 
To assess PFS 
● 
To assess pharmacokinetics and antitherapeutic antibody (ATA) incidence of each 
study drug given in combination 
● 
To assess tumor amplification and expression of PD-L1/L2 and relationship to 
response 
● 
To assess tumor microenvironment and peripheral immune status 


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3 
STUDY ENDPOINTS 
3.1 Primary Endpoints 
● 
Type, incidence, severity, seriousness, and relatedness of adverse events and 
laboratory abnormalities 
● 
Complete remission rate following the completion of study treatment 
3.2 Secondary Endpoints 
● 
Objective response rate 
● 
Duration of CR and OR 
● 
Progression-free survival post-ASCT 
3.3 Additional Endpoints 
● 
Overall survival 
● 
PFS 
● 
Selected PK, ATA, and biomarker endpoints 
4 
STUDY DESIGN 
This is a phase 1/2, open-label, multicenter study designed to evaluate the safety and 
antitumor activity of brentuximab vedotin treatment combined with nivolumab in patients 
with relapsed or refractory Hodgkin lymphoma after failure of frontline therapy.  
Part 1 of the study will evaluate safety of possible dosing regimens for the combination 
treatment prior to expansion of enrollment. Following completion of Part 1, Part 2 and 3 of 
the study will further evaluate safety and efficacy of the combination treatment. 
The safety of combination treatment in Part 1 will be evaluated by a Safety Monitoring 
Committee (SMC) prior to expansion of enrollment in Part 2 to evaluate treatment effect. In 
Part 1, after 6 patients have been followed through the end of the dose-limiting toxicity 
(DLT) period, or at the point that 2 or more patients experience a DLT, whichever comes 
first, the SMC will review all available data and make a recommendation for one of the 
following: 
1. To proceed to Part 2 of the study, expanding enrollment with approximately 50 additional 
patients treated with the study drugs at the doses and schedule determined to be safe in 
Part 1 of the study 
2. To repeat Part 1 of the study and treat up to 6 additional patients, possibly with a 
modified dosing regimen 
3. To close the study to further enrollment 


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Following completion of enrollment of Part 1 and Part 2, the study was amended to add 
Part 3. Approximately 30 additional patients will be enrolled for Part 3. 
Patients will be treated for up to four 21-day cycles. Unless subsequently modified based on 
planned SMC review, treatment will be administered as described in this paragraph. In Parts 
1 and 2, the first dose of brentuximab vedotin 1.8 mg/kg will be given on Cycle 1 Day 1. The 
first dose of nivolumab 3 mg/kg will be given on Cycle 1 Day 8. For Cycle 2 and all 
subsequent cycles, brentuximab vedotin 1.8 mg/kg followed by nivolumab 3 mg/kg will be 
given on Day 1. In Part 3, both brentuximab vedotin 1.8 mg/kg and nivolumab 3 mg/kg will 
be administered on Day 1 of all Cycles. For patients in Part 3 who were previously treated 
with brentuximab vedotin and had a dose reduction, dose assignment must be discussed with 
the medical monitor. 
Lymphoma response and progression will be assessed by investigators using the Lugano 
Classification Revised Staging System for malignant lymphoma (Cheson 2014). CT scans 
(chest, neck, abdomen, and pelvis) and PET scans will be performed at baseline, at the End 
of Treatment (EOT), pre-ASCT, and during long-term follow-up; PET is performed with CT 
scans until the patient is in complete metabolic response (CmR) by PET. Pre-ASCT scans 
may be waived for patients who had an EOT scan performed within 6 weeks prior. CT scans 
of diagnostic quality will be performed at Cycle 2 to assess for progression of disease. Long-
term follow-up assessments will be performed at the following time points post-ASCT (or for 
patients who do not undergo ASCT, post-EOT): 100 days and then 6, 9, 12, 18, 24, 30, and 
36 months, and then per institutional standard thereafter. A final safety visit will be 
performed 100 days after the last dose of nivolumab or at EOT (whichever is later) to assess 
for potential immune-mediated adverse events. Patients will be followed at this schedule 
until withdrawal of consent, death, or study closure, whichever occurs first. 
For Part 3 response assessments were modified to inclue the Lymphoma Response to 
Immunomodulatory Therapy Criteria (LYRIC), which allows for an assessment of 
indeterminate response in cases where apparent progression may be due to the 
immunomodulatory effects of the treatment and not due to true disease progression.  
5 
ANALYSIS SETS 
This section defines each of the analysis sets that will be utilized. The use of each analysis set 
will be discussed in Section 7. 
5.1 All Enrolled Patients Analysis Set 
The All Enrolled Patients analysis set includes all patients enrolled in the study. The All 
Enrolled Patients set will be used for the primary efficacy analysis. Secondary and additional 
efficacy endpoints will also be analyzed using this analysis set. Patients will be analyzed 
according to the dose regimen to which they were enrolled. 


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5.2 All Treated Patients Analysis Set 
The All Treated Patients analysis set includes all patients who receive any amount of 
brentuximab vedotin or nivolumab. The All Treated Patients set will be used for presentation 
of safety data and may be used for exploratory analyses of efficacy endpoints.  
5.3 Efficacy Evaluable (EE) Analysis Set 
The Efficacy Evaluable analysis set includes all patients who had an adequate baseline 
disease assessment, received any amount of either drug, and subsequently had an adequate 
response assessment. The Efficacy Evaluable set will be used for exploratory analysis of 
efficacy endpoints. Patients will be analyzed according to actual dose regimen received. 
6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
This is a phase 1/2 open label study with a formal statistical hypothesis for the primary 
efficacy endpoint of CR rate. The test of the primary endpoint will be at level α = 0.05, using 
a 1-sided test. There are no formal pre-specified hypotheses associated with the primary 
safety objective, and no additional hypothesis tests of secondary endpoints. 
Descriptive statistics (mean, median, standard deviation, minimum, maximum) will be used 
to describe continuous variables. Frequencies and percentages will be used to describe 
categorical variables. The median survival time will be estimated using the Kaplan-Meier 
method; the associated confidence interval (CI) will be calculated based on the 
complementary log-log transformation (Collett 1994). Unless otherwise specified, confidence 
intervals will be calculated at a two-sided 95% level. 
Patients will be summarized overall and by dose regimen, unless otherwise specified in 
section 7. Additional summaries may be performed by selected patient characteristics and for 
subgroups of interest. 
Any analysis not described in this plan will be considered exploratory, and will be 
documented in the clinical study report (CSR) as a post hoc analysis or a change to the 
planned analysis. 
To comply with regulatory electronic submission guidelines, listings of all clinical data will 
be submitted as electronic data sets. To facilitate data review for the study report, only 
pertinent data listings will be created and attached to the appendix of the CSR. All statistical 
output will be produced using SAS®, version 9.4 or more recent. Other statistical software, if 
used, will be described in the CSR. 
6.2 Determination of Sample Size 
It is anticipated that a total of approximately 55 patients will be enrolled in this study in parts 
1 and 2. For Part 3 approximately 30 patients will be enrolled. This number for Part 1 and 2 
was chosen in order to enable an adequately powered analysis of the primary endpoint of CR 
rate and to characterize the safety profile of the combination treatment. This number will be 


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greater if multiple dose regimens are investigated in Part 1 of the study as only those patients 
from Part 1 who are treated with the dose regimen chosen for Part 2 will be included in the 
analysis of the primary endpoint.  
The sample size needed to provide adequate power to test the primary endpoint is at least 53. 
With this sample size, if the true CR rate is 50%, a one-sided exact binomial test at level 
α=0.05 will reject the null hypothesis of a CR rate less than or equal to 30% approximately 
90% of the time. For the given parameters the null hypothesis will be rejected when 22 or 
more CRs are observed (i.e., CR rate ≥41.5% is observed).  
For Part 3, no formal hypothesis test is specified.  The sample size of 30 patients was chosen 
to allow adequate precision of estimates for response rates and safety data.  For example, if 
63% (19/30) of patients have a CR, then the 95% exact CI is (44%, 80%).  The sample size 
of 30 patients is sufficient to perform exploratory biomarker analyses. 
For the safety assessment of the combination treatment, a sample size of 55 patients will 
provide a 94% chance of observing at least one occurrence of an adverse event with a true 
event rate of 5%.  
East 5.4 was used to perform sample size calculations. 
6.3 Randomization and Blinding 
No randomization will be carried out and no blinding will be enforced as this is an open label 
trial.  
6.4 Data Transformations and Derivations 
No data transformations are planned for the primary endpoints. 
Reported age in years will be used; if not available, age in years will be calculated with the 
SAS INTCK function (with method specified as “continuous”) using informed consent date 
and birth date. 
Study Day will be calculated as (Date - First Dose Date + 1) for dates on or after the first 
dose date. For dates prior to the first dose date, Study Day will be calculated as (Date - First 
Dose Date). For all calculations of Study Day, the First Dose Date will be the earliest date of 
treatment administration for any study drug. 
Other time variables based on two dates, e.g., Start Date and End Date, will be calculated as 
(End Date - Start Date + 1) (in days) unless otherwise specified in the planned analysis 
section. 
The following unit conversion will be implemented unless otherwise specified: 
Months = Days / 30.4375 
Years =Days / 365.25  


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Baseline values used in all analyses will be the most recent non-missing measurement prior 
to the first dose of study drug. 
The end-of-treatment (EOT) date will be the date the EOT visit is performed; if an EOT visit 
is not performed then the EOT date will be either the EOS date or 30 days after the last dose 
of any study drug, whichever is earlier. 
For efficacy assessments, the date of response will be the latest of all radiologic scan dates 
for the given restage assessment. The date of progression will be the earliest of all radiologic 
scan dates for the given restage assessment, or the date of investigator claim of clinical 
progression. An adequate tumor assessment to determine response must include a 
radiologic(CT) scan and a PET scan. Determination of progression by radiologic assessment 
may be based on CT or PET alone if there is clear evidence of PD by one of these modalities. 
While a radiologic assessment to confirm progression is strongly preferred, an investigator 
claim of clinical progression is adequate for an assessment of PD. 
6.5 Handling of Dropouts and Missing Data 
With the exception of AE dates, missing data will not be imputed.  
AE dates will be imputed for the purpose of calculating duration of events and treatment-
emergent status (see Appendix A for imputation details and Appendix B for treatment-
emergent definition). Censoring for time-to-event endpoints will be described in Section 7.5. 
with each planned analysis, as applicable. 
Patients whose disease response cannot be assessed will be scored as non-responders for 
calculating the CR rate and ORR. Patients with missing values of a variable other than 
response endpoints (CR and ORR) and time-to-event endpoints (PFS and OS) will be 
excluded from the analysis of that endpoint unless otherwise specified.  
6.6 Multicenter Studies 
There are multiple sites in this study; however it is not anticipated that any one site will 
accrue enough patients to warrant an analysis by site.  
6.7 Multiple Comparison/Multiplicity 
No multiple comparisons are planned and no alpha adjustment is needed as there is only a 
single planned hypothesis test of the primary efficacy endpoint. 
6.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected summaries. 
Subgroups may include but are not limited to the following: 
• 
Age (18-64 years, ≥65 years old) 
• 
Gender (Male, Female) 
• 
Categorized weight at baseline(<70, 70-99 and >=100 kg) 


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• 
Baseline ECOG performance status (0, 1, 2) 
6.9 Covariates 
Adjustment for covariates will not take place for analysis of the primary efficacy endpoint of 
CR rate. Subgroup analyses and covariate adjusted analyses may be carried out for particular 
covariates of interest. Exploratory analysis of biomarker and pharmacodynamic endpoints 
may also incorporate covariate adjustment.  
6.10 Timing of Analyses 
The trial is not designed to allow for early stopping for futility or favorable efficacy results. 
Analysis including hypothesis test of the CR rate for the primary endpoint for parts 1 and 2 
will be carried out after all patients have had their final response assessment prior to 
proceeding to ASCT, starting a new anti-cancer therapy, or discontinuing from the study.  
Interim summaries of various endpoints may be presented at scientific congresses prior to the 
final analysis of the primary endpoint. Interim summaries will also be presented to the SMC.  
7 
PLANNED ANALYSES 
7.1 Disposition 
An accounting of study patients by disposition will be tabulated overall and by dose regimen 
● 
The number of patients in each analysis set will be summarized.  
● 
The number and percentage of patients who discontinued treatment will be 
summarized by the primary reason for treatment discontinuation.  
● 
The number and percentage of patients who discontinued the study will be 
summarized by the primary reason for study discontinuation.  
● 
The number and percentage of screened patients who subsequently enrolled will be 
summarized. 
● 
Follow up time and subsequent treatment information will be summarized. 
● 
The number of screen failures will be summarized overall and by primary reason for 
screen failure. 
Listings of disposition data will be presented by patient for all enrolled patients, including the 
primary reasons for end of treatment and end of study for each subject. 
7.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be presented as listings and in tabular form 
overall and by dose regimen using the all enrolled patients analysis set. Demographics and 
baseline characteristics include age, gender, ethnicity, race, height, and weight. 
The following disease specific characteristics will be summarized with respect to initial 
diagnosis and baseline status (as appropriate): 


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● 
initial disease diagnosis 
● 
time from initial diagnosis to first dose of study drug 
● 
time from relapse to first dose of study drug 
● 
number and type of prior therapies 
● 
response to prior lines of therapy 
● 
disease stage 
● 
bulky disease status 
● 
extranodal disease status 
● 
bone marrow disease involvement 
● 
B symptoms 
● 
current disease status relative to fronline treatment.  
7.3 Protocol Deviations 
Important protocol deviations (defined as protocol violations by Seattle Genetics) are those 
that represent a divergence from the protocol that could have a significant effect on the 
integrity of the study data, or on the subject’s rights, safety, or welfare. Important protocol 
deviations also include exemptions to the study inclusion/exclusion criteria and will be 
summarized by category for the All Enrolled Patients analysis set. A list of patients with 
important protocol deviations will be presented. 
7.4 Treatment Administration 
Treatment administration will be summarized overall and for each dosing schedule using the 
All Treated Patients analysis set. Summary statistics for duration of therapy (weeks) and the 
number of cycles per patient will be presented, as well as the number and percentage of 
patients who were treated at each cycle and completed each cycle. Cumulative dose (mg), 
absolute dose intensity (ADI) and relative dose intensity (RDI) will be described. The 
number and percentage of patients whose dose was ever modified will be summarized by 
modification type, cycle and overall (i.e. overall drug administrations for a patient); listings 
may be presented as well. Dose modifications by dose may also be presented. 
Duration of treatment (except when calculating exposure) is defined as the time from first 
dose date of any infusional component of study treatment to the earliest of either: 
1. last dose date of any infusional component of study treatment + 21, or; 
2. date of death 
For the purpose of calculating exposure summaries, duration of treatment is defined as time 
from the first dose to 21 days after the last dose [(last dose date+21)–first dose date]. 
Intended Dose Intensity (IDI) is defined as the intended dose of drug (e.g. 1.8 mg/kg) per 
unit of time. Intended dose is based on the dose which was intended to be administered at the 


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start of the planned treatment regimen (thus a dose reduction or elimination is not considered 
planned, even though it may be indicated per protocol due to, e.g., occurrence of AEs). If a 
patient discontinues treatment for a reason unrelated to AEs, such as progressive disease, 
then the subsequent doses are not considered as intended for the purpose of calculating dose 
intensity. The IDI for brentuximab vedotin and nivolumab at possible dose regimens is 
presented in the following table: 
Regimen Component 
Intended Dose Regimen 
Unit of time per cycle 
(weeks) 
IDI 
brentuximab vedotin 
1.8 mg/kg 
3 
0.60 
brentuximab vedotin 
1.2 mg/kg 
3 
0.40 
nivolumab 
3 mg/kg 
3 
1.00 
nivolumab 
1 mg/kg 
3 
0.33 
 
Absolute Dose Intensity (ADI) is defined as the actual dose (e.g. 1.8 mg/kg) per unit of time 
that the patient received over the entire treatment period.  
Relative dose intensity (RDI) is defined as the absolute dose intensity over the intended dose 
intensity. 
RDI = ADI/IDI * 100. 
Example dose intensity calculation 
For brentuximab vedotin, consider a patient treated with an intended dose regimen of 1.8 
mg/kg for four cycles. The second dose was delayed for one week, and for the third cycle of 
the infusion was not completed and the patient received less than the full dose. At the fourth 
cycle the dose is not given at all due to an AE. 
Visit 
Intended Dose 
Regimen (mg/kg) 
Intended Dose 
(mg) 
Actual Dose 
(mg) 
Cycle Length 
C1D1 
1.8 
38 
38 
3 weeks + 1 week delay 
C2D1 
1.8 
38 
38 
3 weeks 
C3D1 
1.8 
38 
19 
3 weeks 
C4D1 
1.8 
38 
0 
3 weeks 
 
ADI (per week): 
 
= (1.8 + 1.8 + (1.8*[19/38]) + 0) / (3 wks + 1 wk delay + 3 wks + 3 wks + 3 wks) 
mg/kg per week 
 
=0.35 mg/kg per week 
RDI: 
 
=0.35/0.6 * 100 
 
=58% 


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7.5 Efficacy Analyses 
The test of the primary efficacy endpoint of CR rate will be carried out using the All Enrolled 
Patients analysis set. Other efficacy analyses will be carried out using the All Enrolled 
Patients analysis set, and may also be presented using the Efficacy Evaluable analysis set or 
the All Treated Patients analysis set. 
Unless otherwise specified, efficacy analyses will be presented by dose regimen and overall. 
Additional exploratory subgroup analyses may be carried out as well. 
7.5.1 Primary Efficacy Endpoints 
7.5.1.1 Complete Remission (CR) Rate 
CR rate is defined as the proportion of patients with best response of CR prior to ASCT or 
initiation of subsequent antitumor treatment not specified in the protocol. Response is by 
investigator assessment according to the Lugano Classification Revised Staging System for 
malignant lymphoma (Cheson 2014). For Part 3, the response assessment will also 
incorporate the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) 
(Cheson 2016). Patients whose response to treatment cannot be adequately assessed 
according to the specified criteria will be classified as non-responders for the purpose of 
calculating CR rate.  
The primary efficacy hypotheses can be expressed as follows: 
H0: CR Rate for brentuximab vedotin + nivolumab is ≤30% 
HA: CR Rate for brentuximab vedotin + nivolumab is >30% 
The CR rate at EOT will be calculated using the All Enrolled Patients analysis set and will 
include all patients in this analysis set who were enrolled at the dose regimen chosen for Part 
2. The test of the primary hypothesis will be carried out using a one-sided exact binomial test 
at level α = 0.05, thus the null will be rejected in favor of the alternative if p <0.05 is 
observed. CR rate and its two-sided 90% (to correspond with the level of the test) exact 
binomial confidence interval will be calculated (Clopper 1934). Additionally, the two-sided 
95% exact binomial confidence interval will be presented as a descriptive summary.  
CR rate will also be summarized separately for patients enrolled under dose regimens other 
than that chosen for part 2 of the study. Overall summaries of CR rate may be presented as 
well. These summaries will be considered exploratory in nature. 
7.5.2 Secondary Efficacy Endpoints 
7.5.2.1 Objective Response Rate (ORR) 
ORR is defined as the proportion of patients with best response of CR or PR prior to ASCT 
or initiation of subsequent antitumor treatment not specified in the protocol. Response is by 
investigator assessment according to the Lugano Classification Revised Staging System for 
malignant lymphoma (Cheson 2014). Patients whose response to treatment cannot be 


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adequately assessed according to the specified criteria will be classified as non-responders 
for the purpose of calculating ORR. 
The ORR at EOT will be calculated using the All Enrolled Patients set and its two-sided 95% 
exact binomial confidence interval will be presented (Clopper 1934). ORR will be presented 
by dose regimen and overall. Additional summaries of ORR may be presented based on 
patient demographics of interest. Summaries may also be presented using the All Treated 
Patients and the Efficacy Evaluable analysis sets. 
7.5.2.2 Progression-Free Survival (PFS) after ASCT 
PFS after ASCT is defined as the time from ASCT to the first documentation of PD or to 
death due to any cause, whichever comes first. Patients who do not undergo ASCT or receive 
additional anti-cancer therapy (such as an alternate salvage regimen) prior to ASCT will not 
be included in the analysis of this endpoint. Date of ASCT is defined as the reported date of 
stem cell infusion for ASCT. Documentation of PD should be consistent with the criteria 
described in section 6.4. Specifically, PFS after ASCT will be calculated as:  
PFS after ASCT = Date of first documented PD or death – Date of ASCT + 1. 
PFS data will be censored as follows: 
• Patients who do not have tumor progression and are still on study at the time of an 
analysis will be censored at the date of the most recent disease assessment prior to the 
analysis which was adequate to document progressive disease 
• Patients who have started an antitumor treatment (excluding high-dose conditioning 
regimens pre-ASCT, consolidative radiotherapy pre- or post-ASCT, or consolidative 
treatment with single-agent brentuximab vedotin post-ASCT) other than the study 
treatment prior to documented PD will be censored at the date of the most recent 
disease assessment which was adequate to document PD prior to start of new therapy  
• Patients who are removed from study prior to documentation of tumor progression 
will be censored at the date of the most recent disease assessment prior to study 
discontinuation which was adequate to document disease progression   
If a patient does not have any adequate disease assessments after ASCT their PFS will be 
censored at one day. 
Kaplan-Meier Curves depicting PFS will be generated. Additionally, median PFS and 
probability of PFS from 3 months to the end of the follow-up period will be reported at 
3 month intervals. The two-sided 95% confidence intervals (CI) for the median and 3-month 
intervals will be calculated using the complementary log-log transformation method (Collett 
1994). 
Exploratory subgroup analyses may be carried out; these analyses may involve different 
definitions of events and/or different censoring rules. 


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7.5.2.3 Duration of Complete Remission 
Duration of complete remission is defined as the time from start of the first documentation of 
complete response (CR) to the first documentation of tumor progression (PD) including 
radiographic evidence of progression and clinical progression per investigator or to death due 
to any cause, whichever comes first. 
Duration of complete remission will be censored as described below: 
• Patients who do not have documented tumor progression and are still on study at the 
time of analysis will be censored at the date of the most recent disease assessment 
prior to the analysis which was adequate to document progressive disease 
• Patients who have started an antitumor therapy (excludes stem cell transplant or post-
ASCT consolidative therapy) other than the study treatment prior to documentation of 
tumor progression will be censored at the date of the most recent disease assessment 
prior to start of new therapy which was adequate to document progressive disease 
• Patients who are removed from study prior to documentation of tumor progression 
will be censored at the date of the most recent disease assessment prior to study 
discontinuation which was adequate to document progressive disease.  
If a patient does not have any disease assessments adequate to detect PD after the first 
documentation of complete response their duration of complete remission will be censored at 
one day. 
Duration of complete remission will only be calculated for the subgroup of patients achieving 
CR. Duration of complete remission will be analyzed using Kaplan-Meier methodology and 
Kaplan-Meier plots will be provided. The median duration of complete remission and its 
two-sided 95% CI using the complementary log-log transformation method (Collett, 1994) 
will be calculated. 
7.5.2.4 Duration of Objective Response 
Duration of objective response is defined as the time from start of the first documentation of 
objective tumor response (CR or PR) to the first documentation of tumor progression 
(progressive disease, PD) including radiographic evidence of progression and clinical 
progression per investigator or to death due to any cause, whichever comes first. 
Duration of objective response will be censored as described below: 
• Patients who do not have documented tumor progression and are still on study at the 
time of analysis will be censored at the date of the most recent disease assessment 
prior to the analysis which was adequate to document progressive disease 
• Patients who have started an antitumor therapy (excludes stem cell transplant or post-
ASCT consolidative therapy) other than the study treatment prior to documentation of 
tumor progression will be censored at the date of the most recent disease assessment 
prior to start of new therapy which was adequate to document progressive disease 


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• Patients who are removed from study prior to documentation of tumor progression 
will be censored at the date of the most recent disease assessment prior to study 
discontinuation which was adequate to document progressive disease.  
If a patient does not have any disease assessments adequate to detect PD after the first 
documentation of objective response their duration of objective response will be censored at 
one day. 
Duration of objective response will only be calculated for the subgroup of patients achieving 
CR or PR. Duration of objective response will be analyzed using Kaplan-Meier methodology 
and Kaplan-Meier plots will be provided. The median duration of objective response and its 
two-sided 95% CI using the complementary log-log transformation method (Collett 1994) 
will be calculated. 
7.5.3 Additional Efficacy Endpoints 
7.5.3.1 Overall Survival (OS) 
Overall survival is defined as the time from date of enrollment to date of death due to any 
cause. In the absence of confirmation of death, overall survival time will be censored at the 
last date the patient is known to be alive. Patients lacking data beyond the date of enrollment 
will have their overall survival time censored to 1 day. 
OS=Date of death – Date of enrollment + 1. 
Kaplan-Meier Curves depicting OS will be generated. Additionally, median OS and 
probability of OS from 3 months to the end of the follow-up period will be reported at 
3 month intervals. The two-sided 95% confidence intervals (CI) for the median and 3-month 
intervals will be calculated using the complementary log-log transformation method (Collett 
1994). 
7.5.3.2 Progression-Free Survival (PFS) 
PFS is defined as the time from enrollment to the first documentation of PD or to death due 
to any cause, whichever comes first. Specifically, PFS will be calculated as:  
PFS = Date of first documented PD or death – Date of enrollment + 1. 
Progressive disease should be based on radiologic evidence of progression per investigator, 
but investigator claim of clinical progression will be considered adequate to document PD. In 
the case where both PD by radiologic assessment and clinical assessment are made, the 
earlier of the two possible dates is used as as the date of PD. 
Censoring rules are as follows: 
• Patients who do not have tumor progression and are still on study at the time of an 
analysis will be censored at the date of the most recent disease assessment prior to the 
analysis which was adequate to document progressive disease 


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• Patients who have started an antitumor treatment (excluding high-dose conditioning 
regimens pre-ASCT, consolidative radiotherapy pre- or post-ASCT, or consolidative 
treatment with single-agent brentuximab vedotin post-ASCT) other than the study 
treatment prior to documented PD will be censored at the date of the most recent 
disease assessment which was adequate to document PD prior to start of new therapy  
• Patients who are removed from study prior to documentation of tumor progression 
will be censored at the date of the most recent disease assessment prior to study 
discontinuation which was adequate to document disease progression  
If a patient does not have any adequate disease assessments after enrollment their PFS will be 
censored at one day.  
Kaplan-Meier Curves depicting PFS will be generated. Additionally, median PFS and 
probability of PFS from 3 months to the end of the follow-up period will be reported at 
3 month intervals. The two-sided 95% confidence intervals (CI) for the median and 3-month 
intervals will be calculated using the complementary log-log transformation method (Collett 
1994). 
An additional exploratory analysis of PFS may be conducted in which clinical assessment 
will be considered adequate to detect disease progression. Other exploratory analyses of PFS 
may also be performed. These analyses may involve different definitions of events and/or 
different censoring rules. 
7.5.4 Pharmacokinetic and ATA Analyses 
Pharmacokinetic parameters to be estimated for brentuximab vedotin and MMAE include 
maximum concentration (Cmax) or concentration at the end of infusion (Ceoi), the time 
Cmax occurred (Tmax), and trough concentration for brentuximab vedotin (Ctrough).  For 
nivolumab, Ceoi and Ctrough will be summarized.  The incidence of ATA to brentuximab 
vedotin and to nivolumab will also be assessed. 
If additional pharmacokinetic parameters can be estimated for some subjects, they may also 
be reported. 
7.5.5 Biomarker Analysis 
Relationships of biomarkers (e.g., baseline values, absolute and relative changes from 
baseline) to efficacy, safety and PK parameters will be explored. Relationships and 
associated data that are determined to be of interest will be summarized.  
Summaries will be presented for baseline biomarker levels assessed on peripheral blood and 
tissue blocks or unstained slides obtained at screening to evaluate potential sensitivity or 
resistance to brentuximab vedotin and/or nivolumab (e.g., CD30 expression, PD-L1 /L2 
amplification and expression). For biomarker analyses on optional tumor biopsies obtained 
after disease progression or on residual disease at EOT, samples are to be tested for the 
expression of CD30 and PD-L1/L2 expression and other potential markers to understand 
potential resistance mechanisms. 


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The analyses for pharmacodynamic biomarkers and for biomarkers related to drug 
mechanism(s) of action will be defined in a separate Biomarker Analysis Plan and may be 
included in a separate report.  
7.6 Safety Analyses 
The All Treated Patients analysis set will be used to summarize all safety endpoints. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 18.0 or higher). 
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 or higher).  
Concomitant medications will be coded using WHO Drug (version: June 2012 or more 
recent). 
7.6.1 Adverse Events 
Adverse events (AEs) will be listed and summarized by MedDRA preferred term, severity, 
and relationship to study drug in descending frequency unless otherwise specified. The 
incidence of all AEs, treatment-emergent AEs, and treatment-related AEs will be tabulated. 
For incidence reporting, if a patient reports more than one AE that was coded to the same 
system organ class or preferred term, the patient will be counted only once for that specific 
system organ class or preferred term. 
A treatment-emergent AE is defined as a newly occurring or worsening AE after the first 
dose of brentuximab vedotin or nivolumab. The incidence of AEs will be tabulated by 
preferred term and presented by dose regimen and overall. Summaries will also be presented 
for AEs occurring prior to start of ASCT and on or after start of ASCT, where start of ASCT 
is defined as the start date of conditioning regimen for ASCT. Summaries of AEs will also be 
provided dose regimen and overall for the following: 
• Pre-existing Adverse Events 
• All treatment-emergent AEs 
• AEs related to brentuximab vedotin 
• AEs related to nivolumab 
• Serious Adverse Events (SAEs) 
• SAEs related to brentuximab vedotin 
• SAEs related to nivolumab 
• AEs leading to dose delay of brentuximab vedotin or/and nivolumab 
• AEs leading to dose reduction of brentuximab vedotin or/and nivolumab 
• AEs leading to dose interruption (full dose received) of brentuximab vedotin or/and 
nivolumab 


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• AEs leading to dose elimination of brentuximab vedotin or/and nivolumab 
• AEs leading to treatment discontinuation 
• AEs that started during infusion, 
• AEs that started within 24 hours post infusion, 
• Treatment-emergent AEs by system organ class, preferred term and maximum 
severity; at each system organ class or preferred term, multiple occurrences of events 
within a patient are counted only once at the highest severity 
• Grade 3 – 5 treatment-emergent AEs 
• Treatment-emergent AEs by system organ class and preferred term 
• AEs of peripheral neuropathy identified by the broad search MedDRA SMQ 
“peripheral neuropathy” 
• Infusion related reactions due to brentuximab vedotin, or/and nivolumab 
• Onset of infusion reactions related to brentuximab vedotin, or/and nivolumab by 
preferred term by cycle 
Listings will be presented for all adverse events, serious adverse events, adverse events 
leading to treatment discontinuation, and adverse events leading to death. 
7.6.1.1 Adverse Events of Special Importance 
Adverse events of peripheral neuropathy, infusion related reactions, immune-related AEs, 
and other rare serious AEs may be considered AEs of special importance. 
Resolution of selected adverse events will be defined as event status of recovered/resolved or 
recovered/resolved with sequelae; or return to baseline or lower severity as of the latest 
assessment for pre-existing events. The date of resolution is defined as follows: for events 
with an onset after the first dose date, if event outcome is “recovered/resolved” or 
“recovered/resolved with sequelae”, then the date of resolution is the event end date; for 
events ongoing at baseline, if event severity returns to baseline severity or lower as of the last 
recorded severity, then the date of resolution is the date of severity change to baseline or 
lower severity. 
For events that are not resolved, improvement is defined as decrease by at least one grade 
from worst grade as of the latest assessment. The date of improvement is defined as follows: 
for events that did not resolve and decrease by one grade or more from the worst post-
baseline severity as of the last recorded severity (i.e., severity did not subsequently worsen), 
then the date of improvement is the start date when the post-baseline grade becomes lower 
than the worst grade for the first time without any subsequent grade(s) equal to the worst 
grade. 
Time to resolution is computed from start date of first treatment emergent episode of the 
event or start date of newly onset event after first dose of treatment drug to date of resolution. 


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Time to improvement is computed from start date of the worst grade of the event. Time to 
resolution /improvement will be summarized at the event level. 
For summaries of events or summaries of patients with events ongoing at EOT, EOT is 
defined as the EOT visit or 30 days after the last dose of either study drug. 
Time to onset of treatment-emergent adverse events is defined as time from the date of first 
dose to start date of first treatment emergent episode of the event or start date of newly onset 
event after first dose of treatment drug. In the analyses of time to onset by grade, the events 
should be excluded where the specified grade only occurs after a higher grade. 
Peripheral Neuropathy 
Peripheral Neuropathy (PN) is defined by the peripheral neuropathy MedDRA SMQ broad 
search. The incidence of PN at baseline will be summarized. The incidence of treatment-
emergent and treatment-related PN will each be summarized by preferred term and severity. 
The incidence of PN leading to treatment discontinuation or requiring dose modification will 
be summarized. Time to onset, resolution, and improvement of PN events will be 
summarized. 
Subjects with any event of treatment-emergent PN will be categorized into groups according 
to the following criteria: 
• 
Resolution of all events 
• 
At least 1 event resolved, but all other peripheral neuropathy events did not improve 
• 
Improvement of at least one event 
o All events either improved or resolved 
o Some events improved, some events resolved and some events neither 
improved nor resolved 
o Some events improved but no events resolved 
• 
No improvement or resolution of any events 
The number of subjects will be summarized for the categories defined as above.The 
incidence of treatment-emergent motor neuropathy will be summarized by preferred term and 
severity. Time to resolution and improvement of motor neuropathy events will be 
summarized. 
Infusion related reactions 
Infusion related reactions (IRR) are defined as any event indicated as IRR by the 
investigator. The incidence of IRR will be summarized by preferred term and severity. The 
incidence of IRR leading to treatment discontinuation or requiring dose modification will be 
summarized for each infusional study drug component. The number of cycles of treatment to 
first onset of IRR will be summarized. 


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7.6.1.2 Clinical Laboratory Parameters 
Clinical laboratory data (hematology, serum chemistry and coagulation panel) will be 
summarized by treatment group. All laboratory results through the end of treatment visit will 
be presented in standardized units. Both observed data and changes from baseline for 
chemistry and hematology will be summarized with descriptive statistics. In addition, 
laboratory data will be summarized by the worst post-baseline NCI CTCAE grade for each 
parameter. 
Laboratory results and NCI CTCAE grades for hematology and serum chemistry will be 
presented in data listings. Normal ranges will be documented and out-of-range values will be 
flagged. 
7.6.2 Concomitant Medications 
Concomitant medications will be summarized by the WHO Drug substance name and listed 
by patient. Transfusions, colony-stimulating factors, corticosteroids, and erythropoietin 
stimulating agents will also be summarized by the WHO Drug substance name. Summaries 
will also be presented for the subset of patients who had any IRR reported, as well as for the 
subset of patients who had any immune-related AE reported. 
7.6.3 Deaths 
Summaries of deaths will be presented by dose regimen and overall. Deaths that occur within 
the safety reporting period (i.e., within 30 days of last study treatment with brentuximab 
vedotin or 100 days of nivolumab, whichever is later) will be presented, as well as deaths that 
occur beyond this time point. In addition, primary cause of death will be summarized by 
descending MedDRA preferred term (unless otherwise specified) and summarized by dose 
regimen and overall. Death information will be listed by patient. 
8 
INTERIM ANALYSIS  
An SMC consisting of all Principal Investigators and the sponsor’s Medical Monitor will 
monitor the trial for safety and efficacy and will convene periodically during the study.  
In Part 1 of the study, an SMC will monitor the trial for safety and provide guidance 
regarding possible enrollment of additional patients in Part 1 and possible expansion of 
enrollment in Part 2. Initially 6 patients will be enrolled in Part 1. If a patient discontinues 
treatment for reasons other than a DLT prior to 6 patients completing the DLT evaluation 
period then they will be replaced (as long as the arm remains open). These patients will be 
monitored for DLT throughout the DLT evaluation period. The SMC will review safety data 
and provide recommendations when either of the following occurs: 
1. 2 or more of the patients in the current arm are determined to have had a DLT based on 
the protocol definition.  
2. 6 patients complete the DLT evaluation period (by either remaining on treatment or 
having a DLT).  


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On review of all available data, the SMC may determine that the classification of DLT was 
not appropriate for one or more of the patients, in which case enrollment may resume if the 
target of 6 patients has not yet been reached. However, if 2 or more patients were determined 
to have experienced DLT, then expansion will not occur as the next step. Based on SMC 
recommendations, additional patients may be enrolled at modified treatment and/or dosing 
levels. These additional patients will then be assessed for DLT in the same manner described 
above to determine if it is appropriate to expand enrollment. If it is determined by the SMC 
that due to safety concerns no additional dose levels or schedules should be enrolled, then the 
study will be closed to enrollment.  
An ongoing real-time review of serious AEs (SAEs) in all parts of this study will be 
conducted by the Seattle Genetics Program Safety Monitoring Team. 
Additionally, interim data from the study may be presented at scientific meetings such as the 
annual meetings of the American Society of Clinical Oncology and the American Society of 
Hematology.  
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Original Protocol 
There are no changes from the original protocol. 


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10 REFERENCES 
Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, Hoos A, Barrington SF and Armand P 
(2016). Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory 
therapy. Blood 128: 2489-2496. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance AL, Lymphoma 
G, Eastern Cooperative Oncology G, European Mantle Cell Lymphoma C, Italian Lymphoma F, European 
Organisation for R, Treatment of Cancer/Dutch Hemato-Oncology G, Grupo Espanol de Medula O, German 
High-Grade Lymphoma Study G, German Hodgkin's Study G, Japanese Lymphorra Study G, Lymphoma Study 
A, Group NCT, Nordic Lymphoma Study G, Southwest Oncology G and United Kingdom National Cancer 
Research I (2014). Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32: 3059-68. 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 26: 404-413. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. London, 
Chapman & Hall: 237-251. 
 


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APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT 
DATES 
The algorithm below should be used to impute pre-existing condition and adverse event (AE) 
start dates for which only partial information is known. For ease of reading, both pre-existing 
conditions and AEs will be referred to as AE for the remainder of this document. The 
algorithm should be applied to every AE record on a record by record basis. AE start dates 
should be imputed before imputation of AE condition end date in all cases. The AE condition 
end date should only be used in the imputation of the AE start date if it is a complete, known 
date. 
AE day and month are missing 
● 
If the year is the same as the year of first dose of investigational agent and the onset 
period and/or onset time indicate that the start of the AE was pre-dose: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of investigational agent) 
● 
If the year is the same as the year of first dose of investigational agent and the onset 
period and/or onset time indicate that the start of the AE was post-dose: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of investigational agent) 
● 
If the year is before the year of first dose of investigational agent: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, 
December 31st see example 2 below) 
● 
If the year is after the year of first dose of investigational agent: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, 
January 31st see example 2 below) 
AE month only is missing 
● 
Treat day as missing and replace both month and day according to the above 
procedure 
AE day only is missing 
● 
If the month/year is the same as the month/year of first dose of investigational agent 
and the onset period and/or onset time indicate that the start of the AE was pre-dose: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, day 
prior to first dose of investigational agent) 
● 
If the month/year is the same as the month/year of first dose of investigational agent 
and the onset period and/or onset time indicate that the start of the AE was post-dose: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, first 
dose date of investigational agent) 


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● 
If the month/year is before the month/year of first dose of investigational agent: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, last 
day of the month) 
● 
If the month/year is after the month/year of first dose of investigational agent: 
○ 
AE start date will be imputed as the minimum of (AE condition end date*, last day 
of the month) 
* Only use condition end date if known and complete end date is available. 
 
The following algorithm should be used to impute AE condition end dates. The AE records 
for a condition/event should be sorted by the imputed start dates then record position (order 
of entry into the eCRF). After sorting, if any condition end date month/year is greater than 
any subsequent record end date month/year, then change the imputed start day only to end of 
month. Repeat as necessary.  
After sorting the AE records, apply the following rules to partial or missing AE condition end 
dates: 
For all records excluding the last chronological record for a condition/event 
● 
AE condition end date will be imputed as the start date of the subsequent record 
For the last chronological record for a condition/event 
● 
If outcome is “recovered/resolved”, ”recovered/resolved with sequelae”, or “fatal” 
apply the following:  
○ 
If only year is provided for the end date and year is equal to the year of the last 
dose date: 
• AE condition end date will be imputed as the minimum of (last dose date+30, 
death date, data extraction date, December 31st of the end date year) 
○ 
If only year is provided for the end date and year is not equal to the year of the 
last dose date: 
• AE condition end date will be imputed as the minimum of (death date, data 
extraction date, December 31st of the end date year) 
○ 
If month and year are provided for the end date: 
• AE condition end date will be imputed as the minimum of (death date, data 
extraction date, last day of the end date month/year) 
● 
If outcome is “recovering/resolving”, “not recovered/resolved”,“unknown”, or blank: 
○ 
AE condition end date will not be imputed. 


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Example 1 
AESPID 1: Condition/Event HEADACHE 
First dose date 01JAN2012 
Prior to imputation 
Start date 
Condition end date 
Severity 
Outcome 
Onset 
UNUNK2011 
15APR2012 
1 
not recovered/resolved 
pre-ICF 
15APR2012 
UNMAY2012 
2 
recovering/resolving 
post 1st dose 
UNMAY2012 
UNJUN2012 
1 
not recovered/resolved 
post 1st dose 
UNJUN2012 
UNJUN2012 
3 
recovering/resolving 
post 1st dose 
UNJUN2012 
10JUL2012 
2 
recovering/resolving 
post 1st dose 
10JUL2012 
-- 
1 
not recovered/resolved 
post 1st dose 
Post imputation 
Start date 
Condition end date 
Severity 
Outcome 
31DEC2011 
15APR2012 
1 
not recovered/resolved 
15APR2012 
31MAY2012 
2 
recovering/resolving 
31MAY2012 
30JUN2012 
1 
not recovered/resolved 
30JUN2012 
30JUN2012 
3 
recovering/resolving 
30JUN2012 
10JUL2012 
2 
recovering/resolving 
10JUL2012 
-- 
1 
not recovered/resolved 
Example 2 (highlights choice of last day of the month as opposed to the 1st or the 15th) 
AESPID 4: Condition/Event NAUSEA 
First dose date 01APR2012 
Prior to imputation 
Start date 
Condition end date 
Severity 
Outcome 
Onset 
UNUNK2011 
25APR2012 
1 
not recovered/resolved 
pre-ICF 
25APR2012 
UNAPR2012 
2 
recovering/resolving 
post 1st dose 
UNAPR2012 
04MAY2012 
1 
recovered/resolved 
post 1st dose 
Post imputation 
Start date 
Condition end date 
Severity 
Outcome 
31DEC2011 
25APR2012 
1 
not recovered/resolved 
25APR2012 
31APR2012 
2 
recovering/resolving 
31APR2012 
04MAY2012 
1 
recovered/resolved 
 


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APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH 
RESPECT TO AE CLASSIFICATION 
The algorithm below should be used to determine whether an adverse event (AE) is classified 
as a treatment-emergent adverse event (TEAE). A TEAE is defined as any AE which is 
newly occurring or worsening in severity, where newly occurring means that the AE was not 
present at baseline. For ease of reading, both pre-existing conditions and AEs will be referred 
to as AEs for the remainder of this document. AE dates should be imputed in accordance 
with the algorithm detailed in Appendix A. prior to determination of TEAE classification. 
Details of the TEAE classification are as follows: 
1) Determine the first/earliest dose date of any study treatment (for combination studies this 
includes any component of the regimen) 
2) Baseline AEs: classify an AE as a baseline AE if it satisfies both of criteria 1 and 2 
below: 
1. The onset period field is: “started before the signing of informed consent”; or “started 
after consent but before the first dose of any study treatment”; or, the onset period 
field is missing and the AE start date is prior to the first dose date of any study drug 
(step 1, above). 
2. The stop date satisfies either of i or ii below: 
i. The stop date is the same as or a later date than the first dose date of any study 
treatment 
ii. The stop date is missing with outcome equal to  
● 
recovering/resolving (this outcome may or may not be associated with a date), 
or 
● 
not recovered/not resolved, or  
● 
unknown. 
● 
Note: if the AE has no outcome or stop date provided, the CRF data should be 
queried 
Note: If the event ended on Day 1 (the date of first dose of any study drug) it will be 
considered a baseline event. 
3) Post-baseline AEs: classify an AE as post-baseline if it meets either of criteria 1 or 2 
below: 
1. The onset period of the AE is “started after the first dose of any study treatment” 
2. The onset period of the AE is missing and the AE start date is the same as or a later 
date than the first dose date of any study treatment 
4) Compare post-baseline AEs to baseline AEs using the lower level term (LLT) and 
determine classification. Note that classification may not be possible and the TEAE 
variable will be missing: 
1. Classify all baseline AEs as not treatment emergent (not TEAEs). 
2. If a baseline and post-baseline AE have the same LLT but the post-baseline AE has a 
greater CTC grade then classify the post-baseline AE as a TEAE. If the post-baseline 


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grade is less than or equal to the baseline grade then the post-baseline AE is not a 
TEAE. 
3. If there are no baseline AEs with a matching LLT for the post-baseline AE then 
classify the post-baseline AE as a TEAE. 
4. If the post-baseline AE is uncoded then classify the post-baseline AE as a TEAE. 
 
NOTE: 
For summaries which include only treatment emergent AEs include all AEs which are 
classified as TEAEs as well as those AEs for which TEAE status could not be determined 
(e.g., the value of the TEAE variable may be missing if the event cannot be identified as 
baseline or post-baseline - missing information on the AE CRF should be queried). Only 
exclude those AEs which were determined to not be treatment emergent. 
Events that have an end date prior to the first dose date (e.g. protocol procedure related 
events) should be classified as not treatment emergent (not TEAEs).