Clinical trial NCT03646123
Conditions: Hodgkin Lymphoma
Keywords: Brentuximab vedotin Doxorubicin Vinblastine Dacarbazine Nivolumab Seattle Genetics
Sponsor: Seagen Inc.
Start date: 2019-01-28; Completion date: 2024-08-23
Enrollment: 255 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will study two treatment combinations for classical Hodgkin lymphoma (cHL). This trial will find out if these two treatment combinations work to treat cHL. It will also find out what side effects occur. A side effect is anything the drug does besides treating cancer. This study will have three parts (Parts A, B, and C).

The drugs used in Part A are a combination of targeted anticancer drug (brentuximab vedotin) and three chemotherapy drugs (doxorubicin, vinblastine, and dacarbazine). These four drugs are called "A+AVD." Participants will be treated with granulocyte colony stimulating factor (G-CSF) following every dose of A+AVD for 6 cycles of treatment (12 doses).

Part A will look at whether the A+AVD drug combination reduces the number of participants who experience the side effect of febrile neutropenia. Febrile neutropenia is a very low white blood cell count and a fever, which can be life threatening.

Parts B and C will use drug combination of brentuximab vedotin, plus nivolumab, doxorubicin, and dacarbazine. These four drugs are called "AN+AD." Parts B and C will study how well the drugs work to treat cHL and what side effects they cause.

Detailed description:
This study will have three parts.

Part A of the study is designed to evaluate the incidence of febrile neutropenia, efficacy, and dose intensity in participants with advanced stage classical Hodgkin lymphoma (cHL) receiving granulocyte colony stimulating factor primary prophylaxis (G-PP) administration during treatment with frontline A+AVD. In Part A, participants will be treated with granulocyte colony stimulating factor (G-CSF) following every dose of A+AVD for 6 cycles of treatment. Participants will be treated using institutional standard of care practices for the majority of treatment decisions.

Part B is designed to evaluate the combination of brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) as frontline treatment in participants with advanced cHL. In Part B, participants will be given AN+AD combination for 6 cycles of treatment. This part of the trial will look at whether this combination of drugs is effective and tolerable in participants with Stage II with bulky mediastinal disease and Stage III or IV cHL.

Part C is designed to evaluate AN+AD as frontline treatment in participants with early stage cHL. In Part C, participants will be given AN+AD combination for 4 cycles of treatment. This part of the trial will look at whether this combination of drugs is effective and tolerable in participants with Stage I or II cHL with non-bulky mediastinal disease.

Arms: arm 1: Brentuximab vedotin (A) plus doxorubicin (+A), vinblastine (V), and dacarbazine (D) administered by intravenous (IV) infusion in participants with advanced stage classical Hodgkin lymphoma (cHL) during each treatment cycle. arm 2: Brentuximab vedotin (A) plus nivolumab (N), doxorubicin (+A), and dacarbazine (D) administered separately by IV infusion in participants with Stage II bulky mediastinal disease and Stage III or IV cHL during each treatment cycle. arm 3: Brentuximab vedotin (A) plus nivolumab (N), doxorubicin (+A), and dacarbazine (D) administered separately by IV infusion in participants with Stage I or II cHL with non-bulky mediastinal disease during each treatment cycle.
Interventions: intervention 1: brentuximab vedotin intervention 2: doxorubicin intervention 3: vinblastine intervention 4: dacarbazine intervention 5: G-CSF intervention 6: nivolumab
Intervention descriptions: intervention 1: 1.2 mg/kg by IV infusion intervention 2: 25 mg/m\^2 by IV infusion intervention 3: 6 mg/m\^2 by IV infusion intervention 4: 375 mg/m\^2 by IV infusion intervention 5: Granulocyte colony stimulating factor (G-CSF) primary prophylaxis administered 24-36 hours after each dose of A+AVD intervention 6: 240 mg by IV infusion

Protocol documents:
Prot_000.pdf: 
 
 
Protocol Number: 
SGN35-027 
Version: 
Amendment 7, 31 July 2023 
Protocol Title: 
Multiple Part Clinical Trial of Brentuximab Vedotin in 
Classical Hodgkin Lymphoma Subjects 
Investigational 
Product: 
Brentuximab vedotin 
Brief Title: 
Clinical Trial of Brentuximab Vedotin in Classical Hodgkin 
Lymphoma  
Phase: 
2 
IND Number: 
071634 
EudraCT Number: 
2020-004027-17 
Sponsor: 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Medical Monitor: 
 
Seagen Inc. 
Office Tel: 
 
Mobile Tel: 
 
E-mail: 
 
SAE Email or Fax: 
See email or fax number specified on the SAE report form. 
 
 
 


Study SGN35-027  
Clinical Protocol 
Amendment 7; 31-July-2023 
Brentuximab vedotin  
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PROTOCOL SYNOPSIS  
Protocol Number  
SGN35-027 
Version  
Amendment 7 
Phase  
2 
Product Name  
Brentuximab vedotin 
Sponsor  
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title  
Multiple Part Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma Subjects 
Study Objectives – Part A  
Primary  
● To assess the treatment-emergent febrile neutropenia (FN) rate in subjects with previously untreated, 
advanced stage, classical Hodgkin lymphoma (cHL) treated with brentuximab vedotin, doxorubicin, 
vinblastine, and dacarbazine (A+AVD) and granulocyte colony stimulating factor (G-CSF) primary 
prophylaxis (G-PP) 
Secondary  
● To assess the incidence and severity of adverse events of clinical interest (AECI) 
● To assess dose intensity, dose reductions, and dose delays related to any component of A+AVD 
● To assess primary refractory disease rates 
● To assess subsequent anticancer therapy utilization  
● To assess end of treatment (EOT) complete response (CR) rates 
● To assess physician-reported progression-free survival (PFS) rate at 2 years 
Study Objectives – Parts B and C  
Primary  
● To assess the CR rate at EOT with brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) 
in subjects with previously untreated cHL. 
Secondary  
● To assess the safety and tolerability of AN+AD  
● To assess the overall response rate (ORR)  
● To assess the duration of response (DOR) 
● To assess the duration of complete response (DOCR) 
● To assess event-free survival (EFS)  
● To assess PFS 
● To assess overall survival (OS) 
Study Population  
Key eligibility criteria include treatment-naïve subjects (aged ≥12 years in the US and aged ≥18 years outside 
the US) with classical Hodgkin lymphoma (cHL). Part A will enroll subjects with Ann Arbor Stage III or IV 
cHL. Part B will enroll subjects with Ann Arbor Stage I or II cHL with bulky mediastinal disease (defined as a 
single node or nodal mass with a diameter ≥10 cm on computed tomography [CT] imaging) or Stage III or IV 
cHL. Part C will enroll subjects with Ann Arbor Stage I or II cHL without bulky disease. Subjects must have 
bidimensional measurable disease, as documented by positron emission tomography (PET)/CT or CT imaging, 
and qualifying baseline laboratory data. Subjects are excluded if they have nodular lymphocyte predominant 


Study SGN35-027  
Clinical Protocol 
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HL. Subjects with active cerebral/meningeal disease related to the underlying malignancy, including signs or 
symptoms of progressive multifocal leukoencephalopathy (PML) or history of PML, are also excluded. 
Number of Planned Subjects  
Approximately 240 subjects will be enrolled in this study: approximately 40 in Part A, approximately 50 in Part 
B, and approximately 150 in Part C. 
Study Design  
This is an open-label, multiple part, multicenter, phase 2 clinical trial. Part A will assess the incidence of febrile 
neutropenia, efficacy, and dose intensity in subjects receiving G-PP during treatment with A+AVD. Subjects 
will be treated using institutional standard of care practices for the majority of treatment decisions. A+AVD will 
be administered as described below on days 1 and 15 of a 28-day cycle, with the addition of G-PP 24–36 hours 
postdose. Part B will evaluate the efficacy and tolerability of AN+AD in subjects with Stage I or II cHL with 
bulky mediastinal disease or Stage III or IV cHL. Part C will evaluate the efficacy and tolerability of AN+AD in 
subjects with Stage I or II cHL without bulky mediastinal disease. AN+AD will be administered as described 
below. Subjects will receive up to 6 cycles of treatment in Parts A and B. Subjects in Part C will receive 
4 cycles of treatment. For Part C, one interim analysis will be performed after approximately 50 subjects have 
completed response assessment at EOT.  
Safety will be monitored by collecting and evaluating information regarding adverse events (AEs) and 
laboratory test results. The Safety Monitoring Committee consisting of the study medical monitor, drug safety 
representative, study site investigators, and study biostatistician will evaluate the safety of AN+AD over the 
course of the study. Disease assessments will be conducted at Cycle 2 (Parts B and C only) and at EOT. Follow 
up assessments for Part A will occur per institutional standard of care and must include an EOT PET scan. For 
Parts B and C, disease assessments will be performed during follow-up every 3 months after the EOT visit for 
the first year, then every 6 months for 2 additional years. Subjects will then continue in follow-up for 
2 additional years (5 years total), with physical exams required every 6 months and disease assessments 
required every 12 months. PET will continue after EOT if CT scan is positive, following the same schedule as 
CT scans. An additional safety visit will be required for Part B and C subjects 100 days after the last dose of 
nivolumab or 30 days after the last dose of brentuximab vedotin (concurrent with EOT), whichever is later. As 
of Amendment 6, Parts A and B were completed. 
Treatment Product, Dose, and Mode of Administration – Part A  
A+AVD treatment consists of brentuximab vedotin 1.2 mg/kg (A) plus doxorubicin 25 mg/m2 (+A), vinblastine 
6 mg/m2 (V) and dacarbazine 375 mg/m2 (D). A+AVD will be administered by intravenous (IV) infusion on 
Days 1 and 15 of each 28-day cycle as follows: 
A: Brentuximab vedotin will be administered at 1.2 mg/kg 
+A: Doxorubicin will be administered at 25 mg/m2 
V: Vinblastine will be administered at 6 mg/m2 
D: Dacarbazine will be administered at 375 mg/m2 
Brentuximab vedotin will be administered at 1.2 mg/kg IV over approximately 30 minutes. 
G-PP will be administered following all doses of A+AVD, beginning with Cycle 1 and continuing throughout 
all treatment cycles. G-PP will be administered as follows: 
● Pegfilgrastim: 6 mg subcutaneous (SC) 24 to 36 hours after A+AVD per dose 
● Filgrastim: 5 mcg/kg (300 to 480 mcg, rounded to the nearest vial) SC daily, beginning 24 to 36 hours after 
A+AVD per dose, for a minimum of 5 days. Additional doses beyond 5 days are at the discretion of the 
investigator. 


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Clinical Protocol 
Amendment 7; 31-July-2023 
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Treatment Product, Dose, and Mode of Administration – Parts B and C  
AN+AD consists of brentuximab vedotin 1.2 mg/kg (A), nivolumab 240 mg (N), doxorubicin 25 mg/m2 (A), 
and dacarbazine 375 mg/m2 (D). All study drugs will each be administered separately by IV infusions on 
Days 1 and 15 of each 28-day cycle for up to 6 cycles in Part B and for 4 cycles in Part C. 
The study drugs for AN+AD must be administered in the following order: doxorubicin and dacarbazine, 
followed by brentuximab vedotin, followed by nivolumab. Nivolumab will be administered at least 30 minutes 
after the end of the brentuximab vedotin infusion. 
Duration of Treatment  
Subjects will receive up to 6 cycles (approximately 6 months) of treatment with either A+AVD and G-PP 
(Part A) or AN+AD (Part B); subjects in Part C will receive 4 cycles (approximately 4 months) of treatment 
with AN+AD. 
Efficacy Assessments  
For Part A, disease response and progression will be assessed by investigators using the Lugano Classification 
Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014). CT scans of chest, 
neck, abdomen, and pelvis will be conducted at baseline and at EOT. PET scans will be conducted at baseline 
and EOT. 
For Parts B and C, CT scans of the chest, neck, abdomen, and pelvis will be conducted at Baseline, Cycle 2, and 
EOT. During follow-up, CT scans will be required every 3 months after EOT for a year, followed by every 
6 months for 2 years. The final 2 years of follow up will require CT scans once every 12 months. To decrease 
radiation exposure, CT scans of neck will be mandated at Baseline only; restaging imaging will only be 
repeated if neck disease is present at Baseline. In Parts B and C, PET scans will be conducted at Baseline, 
Cycle 2, and EOT. PET will only continue after EOT if CT is positive, following the same schedule as the CT 
scans. 
Disease response and progression will be assessed by investigators using the Lugano Classification Revised 
Staging System for malignant lymphoma (Cheson 2014) with the incorporation of Lymphoma Response to 
Immunomodulatory Therapy Criteria (LYRIC) for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 
2016).  
Safety Assessments  
Safety assessments will include the surveillance and recording of AEs, physical examination findings, and 
laboratory tests. 
Statistical Methods  
Safety and efficacy endpoints will be summarized with descriptive statistics. For Part A, the rate of FN and its 
95% confidence interval (CI) will be presented. For Parts B and C, the CR rate at EOT and its 95% CI will be 
presented. 
Descriptive statistics will be presented that include the number of observations, mean, median, standard 
deviation, minimum and maximum for continuous variables, and the number and percentages for categorical 
variables. Time to event endpoints will be analyzed using Kaplan-Meier methodology. 
Unless otherwise specified, exact CIs will be presented, calculated at 2-sided 95% level. 
The sample size for each part was chosen to provide adequate precision for estimation of the primary endpoint. 
For Part A, if 4 of 40 subjects have FN, the FN rate and associated 95% exact CI would be 10% (95% CI: 2.8%, 
23.7%). For Part B, if 45 of 50 subjects have a CR at EOT, the CR rate at EOT and associated 95% exact CI 
would be 90% (95% CI: 78.2%, 96.7%). For Part C, if 142 of 150 subjects have a CR at EOT, the CR rate at 
EOT and associated 95% exact CI would be 95% (95% CI: 89.8%, 97.7%). 


Study SGN35-027  
Clinical Protocol 
Amendment 7; 31-July-2023 
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TABLE OF CONTENTS  
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 9 
1 
INTRODUCTION ......................................................................................................................................... 12 
1.1 
Hodgkin Lymphoma ........................................................................................................................... 13 
1.2 
Clinical Experience with Brentuximab Vedotin and A+AVD ............................................................ 13 
1.3 
Clinical Experience with Nivolumab .................................................................................................. 14 
1.4 
Study Rationale .................................................................................................................................. 15 
1.4.1 
Part A ................................................................................................................................... 15 
1.4.2 
Parts B and C ........................................................................................................................ 16 
1.4.3 
Risk:Benefit .......................................................................................................................... 17 
2 
OBJECTIVES ............................................................................................................................................... 18 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 19 
3.1 
Summary of Study Design .................................................................................................................. 19 
3.1.1 
End of Study ......................................................................................................................... 20 
3.1.2 
Safety Monitoring Committee .............................................................................................. 20 
3.2 
Discussion and Rationale for Study Design........................................................................................ 20 
3.2.1 
Part A ................................................................................................................................... 20 
3.2.2 
Parts B and C ........................................................................................................................ 21 
3.2.3 
Method of Assigning Subjects to Treatment Groups ........................................................... 21 
3.2.4 
Rationale for Selection of Doses .......................................................................................... 21 
3.2.5 
Blinding and Unblinding ...................................................................................................... 22 
4 
STUDY POPULATION................................................................................................................................ 22 
4.1 
Inclusion Criteria ................................................................................................................................ 22 
4.2 
Exclusion Criteria ............................................................................................................................... 24 
4.3 
Removal of Subjects From Therapy or Assessment ........................................................................... 26 
4.3.1 
Discontinuation of Study Treatment .................................................................................... 26 
4.3.2 
Subject Withdrawal From Study .......................................................................................... 26 
5 
TREATMENTS ............................................................................................................................................ 28 
5.1 
Treatments Administered.................................................................................................................... 28 
5.2 
Brentuximab Vedotin ......................................................................................................................... 29 
5.2.1 
Description ........................................................................................................................... 29 
5.2.2 
Dose and Administration ...................................................................................................... 29 
5.2.3 
Method of Procurement ........................................................................................................ 29 
5.2.4 
Dose Modifications .............................................................................................................. 29 
5.2.5 
Storage and Handling ........................................................................................................... 31 
5.2.6 
Packaging and Labeling ....................................................................................................... 31 
5.2.7 
Preparation ........................................................................................................................... 31 
5.3 
Doxorubicin, Vinblastine, and Dacarbazine ....................................................................................... 31 
5.3.1 
Description ........................................................................................................................... 31 
5.3.2 
Method of Procurement ........................................................................................................ 32 
5.3.3 
Dose and Administration ...................................................................................................... 32 
5.3.4 
Dose Modifications .............................................................................................................. 32 
5.3.5 
Storage and Handling ........................................................................................................... 32 
5.3.6 
Packaging and Labeling ....................................................................................................... 32 
5.3.7 
Preparation ........................................................................................................................... 33 
5.4 
Granulocyte Colony Stimulating Factor ............................................................................................. 33 
5.4.1 
Description ........................................................................................................................... 33 
5.4.2 
Method of Procurement ........................................................................................................ 33 
5.4.3 
Dose and Administration ...................................................................................................... 33 
5.4.4 
Dose Modifications .............................................................................................................. 33 
5.4.5 
Storage and Handling ........................................................................................................... 33 
5.4.6 
Packaging and Labeling ....................................................................................................... 33 


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5.4.7 
Preparation ........................................................................................................................... 33 
5.5 
Nivolumab .......................................................................................................................................... 33 
5.5.1 
Description ........................................................................................................................... 33 
5.5.2 
Method of Procurement ........................................................................................................ 34 
5.5.3 
Dose and Administration ...................................................................................................... 34 
5.5.4 
Dose Modifications .............................................................................................................. 34 
5.5.5 
Storage and Handling ........................................................................................................... 36 
5.5.6 
Packaging and Labeling ....................................................................................................... 36 
5.5.7 
Preparation ........................................................................................................................... 36 
5.6 
Concomitant Therapy ......................................................................................................................... 36 
5.6.1 
Required Concomitant Therapy ........................................................................................... 37 
5.6.2 
Allowed Concomitant Therapy ............................................................................................ 37 
5.6.3 
Prohibited Concomitant Therapy ......................................................................................... 37 
5.7 
Management of Adverse Reactions .................................................................................................... 38 
5.7.1 
Management of Infusion Reactions ...................................................................................... 38 
5.7.2 
Management of Tumor Lysis Syndrome .............................................................................. 40 
5.7.3 
Management of Suspected PML .......................................................................................... 40 
5.7.4 
Management of Immune-Adverse Events (Parts B and C only)........................................... 40 
5.7.5 
Management of Overdose .................................................................................................... 41 
5.8 
Treatment Compliance ....................................................................................................................... 42 
6 
STUDY ACTIVITIES ................................................................................................................................... 43 
6.1 
Schedule of Events ............................................................................................................................. 43 
6.2 
Screening Visit (Day –28 to Day 1).................................................................................................... 43 
6.2.1 
Baseline Visit (Day –7 to Day 1) ......................................................................................... 44 
6.3 
Treatment Period (Day 1 to Day 28) .................................................................................................. 44 
6.3.1 
Part A ................................................................................................................................... 44 
6.3.2 
Parts B and C ........................................................................................................................ 45 
6.4 
End of Treatment Visit (30 to 37 days after last dose of study drug) ................................................. 47 
6.5 
Parts B and C: Safety Visit (100 to 114 days after last dose of nivolumab, or 30 to 37 days after last 
dose of study medication other than nivolumab, whichever is later) .................................................. 47 
6.6 
Long-term Follow-up ......................................................................................................................... 48 
6.6.1 
Part A ................................................................................................................................... 48 
6.6.2 
Parts B and C ........................................................................................................................ 48 
6.7 
End of Follow-up ................................................................................................................................ 49 
7 
STUDY ASSESSMENTS ............................................................................................................................. 49 
7.1 
Screening/Baseline Assessments ........................................................................................................ 49 
7.2 
Response/Efficacy Assessments ......................................................................................................... 49 
7.3 
Biomarker Studies .............................................................................................................................. 51 
7.3.1 
Tumor Biopsy (Parts B and C) ............................................................................................. 51 
7.3.2 
Biomarkers in Tumor Tissue (Parts B and C) ...................................................................... 51 
7.3.3 
Biomarkers in Peripheral Blood (Part C Only) .................................................................... 51 
7.4 
Safety Assessments............................................................................................................................. 51 
7.4.1 
Adverse Events ..................................................................................................................... 52 
7.4.2 
Clinical Laboratory Tests ..................................................................................................... 59 
7.4.3 
Physical Examination ........................................................................................................... 59 
7.4.4 
Sponsor Safety Reporting to Regulatory Authorities ........................................................... 59 
7.5 
Appropriateness of Measurements...................................................................................................... 60 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 61 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 61 
8.2 
Data Management Procedures ............................................................................................................ 61 
8.3 
Access to Source Data ........................................................................................................................ 62 
8.4 
Accuracy and Reliability of Data........................................................................................................ 62 
8.5 
Quality Assurance Procedures ............................................................................................................ 62 
8.6 
Data Handling and Record Keeping ................................................................................................... 62 


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8.6.1 
Data Handling ...................................................................................................................... 62 
8.6.2 
Investigator Record Retention .............................................................................................. 63 
9 
DATA ANALYSIS METHODS ................................................................................................................... 63 
9.1 
Determination of Sample Size ............................................................................................................ 66 
9.2 
Study Endpoint Definitions ................................................................................................................ 66 
9.2.1 
Part A ................................................................................................................................... 66 
9.2.2 
Parts B and C ........................................................................................................................ 67 
9.3 
Statistical and Analytical Plan ............................................................................................................ 68 
9.3.1 
General Considerations ........................................................................................................ 68 
9.3.2 
Subject Disposition .............................................................................................................. 70 
9.3.3 
Subject Characteristics ......................................................................................................... 70 
9.3.4 
Treatment Compliance ......................................................................................................... 70 
9.3.5 
Efficacy Analyses ................................................................................................................. 70 
9.3.6 
Pharmacokinetic and Immunogenicity Analyses.................................................................. 71 
9.3.7 
Safety Analyses .................................................................................................................... 71 
9.3.8 
Interim Analyses .................................................................................................................. 72 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 74 
10.1 Informed Consent ............................................................................................................................... 74 
10.2 Ethical Review .................................................................................................................................... 74 
10.3 Regulatory Considerations.................................................................................................................. 75 
10.3.1 
Investigator Information ....................................................................................................... 75 
10.3.2 
Protocol Amendments and Study Termination .................................................................... 75 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 75 
10.5 Clinical Trial Agreement .................................................................................................................... 75 
11 REFERENCES .............................................................................................................................................. 76 
APPENDIX A: 
SCHEDULE OF EVENTS – PART A ................................................................................. 79 
APPENDIX B: 
SCHEDULE OF EVENTS – PARTS B AND C ................................................................. 80 
APPENDIX C: 
PERFORMANCE STATUS SCALES CONVERSION ...................................................... 82 
APPENDIX D: 
INTERNATIONAL PROGNOSTIC FACTORS SCORING FOR ADVANCED 
HODGKIN LYMPHOMA ............................................................................................................................ 83 
APPENDIX E: 
NEW YORK HEART ASSOCIATION CLASSIFICATION .............................................. 84 
APPENDIX F: 
OVERVIEW OF LYRIC CRITERIA (PARTS B AND C ONLY) ..................................... 85 
APPENDIX G: 
GUIDANCE ON CONTRACEPTION ................................................................................ 88 
APPENDIX H: 
KATZ INDEX OF INDEPENDENCE IN ACTIVITIES OF DAILY LIVING .................. 90 
APPENDIX I: 
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE VERSION 4.0 ....... 91 
APPENDIX J: 
INVESTIGATOR SIGNATURE PAGE .............................................................................. 99 
APPENDIX K: 
DOCUMENT HISTORY ................................................................................................... 100 
 


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Clinical Protocol 
Amendment 7; 31-July-2023 
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LIST OF IN-TEXT TABLES  
Table 1: 
Objectives and corresponding endpoints ....................................................................................... 18 
Table 2: 
Study treatment – Part A ............................................................................................................... 28 
Table 3: 
Study treatment – Parts B and C .................................................................................................... 28 
Table 4: 
Dose modifications for brentuximab vedotin-associated toxicity .................................................. 30 
Table 5: 
Dose modifications for brentuximab vedotin treatment of subjects with renal or hepatic 
impairment ..................................................................................................................................... 31 
Table 6: 
Nivolumab Dose Modifications ..................................................................................................... 34 
Table 7: 
Overview of Study Outcome Measurements – Part A ................................................................... 64 
Table 8: 
Overview of Study Outcome Measurements – Parts B and C ....................................................... 65 
 
LIST OF IN-TEXT FIGURES  
Figure 1: 
Incidence of febrile neutropenia with G-PP administration in Cycle 1 ......................................... 15 
Figure 2: 
Study design – Part A .................................................................................................................... 19 
Figure 3: 
Study design – Parts B and C ........................................................................................................ 20 
 


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Clinical Protocol 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
ABVD 
doxorubicin, bleomycin, vinblastine, and dacarbazine 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AECI 
adverse event of clinical interest 
ALT 
alanine aminotransferase 
AN+AD 
brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine 
AST 
aspartate aminotransferase 
ATG 
anti-thymocyte globulin 
A+AVD 
brentuximab vedotin, doxorubicin, vinblastine, dacarbazine 
AVD 
doxorubicin, vinblastine, dacarbazine 
β-hCG 
beta human chorionic gonadotropin 
BNP 
B-type natriuretic peptide 
BV 
brentuximab vedotin  
CBC 
complete blood count 
cHL 
classical Hodgkin lymphoma 
CI 
confidence interval 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CT 
computed tomography 
CYP 
cytochrome P450 
CZ 
Czechia 
DILI 
drug-induced liver injury 
DOCR 
duration of complete response 
DOR 
duration of response 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose  
FEV1 
forced expiratory volume in 1 second 
FFPE 
formalin fixed paraffin-embedded 
FFS 
failure-free survival 
FN 
febrile neutropenia 
G-CSF 
granulocyte colony stimulating factor 
G-PP 
G-CSF primary prophylaxis 


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GFR 
glomerular filtration rate 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HL 
Hodgkin lymphoma 
HRS 
Hodgkin Reed-Sternberg 
HuMAb 
humanized monoclonal antibody 
IB 
investigator’s brochure 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IFN-γ 
interferon gamma 
IMAE 
Immune-mediated adverse event 
IND 
investigational new drug 
I-O 
immuno-oncology 
IR 
indeterminate response 
IRB 
institutional review board 
IV 
intravenous 
JCV 
John Cunningham virus 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LYRIC 
Lymphoma Response to Immunomodulatory Therapy Criteria 
MDRD 
Modification of Diet in Renal Disease [study] 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
mPFS 
modified progression-free survival 
MRI 
magnetic resonance imaging 
MUGA 
multi-gated acquisition  
NCI CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PET 
positron emission tomography 
PmD 
progressive metabolic disease 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PN 
peripheral neuropathy 
PPS 
per-protocol analysis set 
PR 
partial response 
q2wk 
every 2 weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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SC 
subcutaneous 
Scr 
serum creatinine 
SD 
standard deviation 
SD 
stable disease 
SMC 
safety monitoring committee 
SPD 
sum of the product of the largest diameters 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
ULN  
upper limit of normal 
USP 
United States Pharmacopeia 


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1 
INTRODUCTION  
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. Targeted delivery of MMAE to 
CD30-expressing tumor cells is the primary mechanism of action of brentuximab vedotin. 
Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently 
inducing cell cycle arrest and apoptotic death of the cell. Other nonclinical studies suggest 
additional contributory mechanisms of action, including antibody-dependent cellular 
phagocytosis; bystander effects on nearby cells in the tumor microenvironment due to 
released MMAE; and immunogenic cell death due to endoplasmic reticulum stress, which 
drives exposure of immune activating molecules that can promote a T-cell response.  
Nivolumab is a fully-humanized monoclonal antibody (HuMAb; immunoglobulin G4 
[IgG4]) that targets programmed cell death protein 1 (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 (MLR). 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 anti-tumor immune response and results in tumor 
rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).  
This is an open-label, multiple part, multicenter, phase 2 clinical trial. Part A is designed to 
evaluate the impact of granulocyte colony stimulating factor (G-CSF) primary prophylaxis 
(G-PP) administration in the frontline treatment of advanced classical Hodgkin lymphoma 
subjects (cHL) treated with brentuximab vedotin plus doxorubicin, vinblastine, and 
dacarbazine (A+AVD). Brentuximab vedotin is approved for treatment of previously 
untreated Stage III or IV cHL subjects in combination with chemotherapy. Subjects will be 
treated with up to 6 cycles of A+AVD. All subjects will receive G-PP support beginning with 
Cycle 1, and for every subsequent dose throughout all administered treatment cycles. The 
components of A+AVD will be administered as described in Section 5.  
Part B is designed to evaluate the combination of brentuximab vedotin, nivolumab, 
doxorubicin, and dacarbazine (AN+AD) as frontline treatment in subjects with advanced 
cHL (Stage I/II with bulky mediastinal disease [defined as a single node or nodal mass with a 
diameter ≥10 cm on computed tomography (CT) imaging], or Stage III or IV). Part C is 
designed to evaluate AN+AD as frontline treatment in subjects with early stage cHL 
(Stage I/II without bulky mediastinal disease). Subjects will be treated with 6 cycles of 
A+AVD in Part A, up to 6 cycles of AN+AD in Part B, and 4 cycles of AN+AD in Part C. 


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The components of AN+AD will be administered as described in Section 5. For both Part B 
and Part C, after approximately 10 subjects have completed Cycle 2, the Safety Monitoring 
Committee (SMC) will assess the safety of AN+AD. Safety will be assessed separately for 
Part B and Part C. An additional SMC meeting will occur after approximately 50 subjects in 
Part C have completed their end of treatment (EOT) assessment.  
For summaries of clinical and non-clinical data, please refer to the brentuximab vedotin 
Investigator’s Brochure, and prescribing information for all other agents. 
1.1 Hodgkin Lymphoma  
Hodgkin lymphoma (HL) is a neoplasm of lymphoid tissue, histopathologically defined by 
the presence of malignant Hodgkin Reed-Sternberg (HRS) cells in a background of 
inflammatory cells. The characteristic surface antigen expressed on HRS cells is CD30. 
In 2018, approximately 8500 new cases of HL were estimated to be diagnosed in the US 
(Siegel 2018). Approximately 40% of subjects will be diagnosed with advanced HL, defined 
here as Ann Arbor Stage III or IV disease (Shenoy 2011; Noone 2017). Advanced HL is 
characterized by supra- and sub-diaphragmatic or more widespread disease. It is associated 
with diminished survival; the 5 year failure-free survival (FFS) rate for subjects with Stage 
III/IV HL is 67%, in contrast with an 82% 5 year FFS rate for subjects with Stage I/II HL 
(Gordon 2013). 
The presence of bulky mediastinal disease on chest x-ray has historically been considered a 
poor prognostic factor in early stage HL (Mauch 1978). Bulky mediastinal disease is often 
defined by the maximal transverse diameter of the largest lymph node mass ≥ 10 cm, or more 
than a third of the transthoracic diameter at any level of thoracic vertebrae as determined by 
CT, retaining the criteria previously measured with chest x-ray (Cheson 2014). Kumar et al 
demonstrated that subjects without bulky mediastinal disease showed improved 4-year 
relapse-free survival on multidimensional CT imaging (using a novel definition of ≥7 cm) vs 
subjects with bulky disease (94% vs 81%, respectively). This retrospective analysis reviewed 
185 subjects with early stage HL treated with chemotherapy alone vs combined modality 
therapy (Kumar 2016).  
1.2 Clinical Experience with Brentuximab Vedotin and A+AVD  
Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine received 
approval in patients with previously untreated, advanced cHL in the US (Stage III and IV) 
and Europe (Stage IV) based on the ECHELON-1 trial, an open-label, international, 
multicenter, randomized Phase 3 clinical trial in subjects with previously untreated 
Stage III or IV cHL. Subjects were assigned to receive up to six 28-day cycles of treatment 
with either doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or A+AVD. The 
primary endpoint of the trial was modified progression-free survival (mPFS), defined as the 
time to progression, death, or noncomplete response and use of subsequent anticancer 
therapy, as adjudicated by an independent review committee.  


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ECHELON-1 demonstrated that treatment with A+AVD, in comparison with standard 
treatment with ABVD, resulted in a statistically significant improvement in mPFS (Connors 
2018). The 2 year mPFS rate in the A+AVD group was 82.1% (95% confidence interval 
(CI): 78.8, 85.0) vs 77.2% (95% CI: 73.7, 80.4) for the ABVD group; the hazard ratio for 
progression, death, or modified progression was 0.77 (95% CI: 0.60, 0.98). Additionally, 
treatment with A+AVD resulted in lower incidence of pulmonary toxicity (1% vs 3% treated 
with ABVD). However, the incidence of neutropenia, including ≥ Grade 3 neutropenia and 
febrile neutropenia (FN), and rates of ≥ Grade 3 infections, were higher in the A+AVD 
treatment group than in the ABVD treatment group. The prevalence of neutropenia and FN 
was mitigated in a sub-set of subjects who received G-PP (29% vs 70% without G-PP, and 
11% vs 21% without G-PP, respectively) (Straus 2018a). This resulted in the independent 
data monitoring committee’s recommendation of primary prophylaxis with G-CSF and the 
recommendation for the use of G-PP beginning in Cycle 1 in the product labeling. Peripheral 
neuropathy (PN) was reported for 67% of subjects treated with A+AVD and 43% of subjects 
treated with ABVD. Grade 3 neuropathy was reported for 10% of A+AVD-treated subjects 
and 2% of ABVD-treated subjects.  
Recent data from Abramson et al of 34 subjects with previously untreated Stage I/II cHL 
with non-bulky mediastinal disease showed a 100% complete response (CR) rate at EOT 
with brentuximab vedotin, doxorubicin, and dacarbazine. Additionally, the study reported 
progression-free survival (PFS) and overall survival (OS) rates of 100% at the time of last 
follow up (median duration 15 months). These data suggest that vinblastine may not be 
required for efficacy (Abramson 2018). Furthermore, toxicity was notable for a low 
incidence of peripheral neuropathy (56%, consisting of Grade 1 or 2 only). Eight of 
34 subjects (24%) had neutropenia, but only 2 subjects (6%) had Grade 3 neutropenia; there 
were no cases of Grade 4 neutropenia or febrile neutropenia. No subject received growth 
factor support. 
1.3 Clinical Experience with Nivolumab  
The combination of brentuximab vedotin and nivolumab appears to be active and well 
tolerated in cHL. In one trial in 62 subjects in the first salvage setting, the combination 
produced a 61% CR rate (Herrera 2018) and subjects were able to undergo subsequent stem 
cell transplant. Adverse events (AEs) were mostly Grades 1 and 2. Infusion-related reactions 
occurred in 44% of subjects overall; however, <10% of subjects required treatment with 
systemic corticosteroids. In another trial of 19 subjects with relapsed/refractory cHL who had 
received a median of 3 prior therapies, the combination produced a 50% CR rate (Diefenbach 
2017). The regimen was also considered to be well tolerated in this setting, although 
2 subjects experienced pneumonitis (1 Grade 3 event that was considered to be a 
dose-limiting toxicity and 1 Grade 5 event in an elderly subject). Grade 3 AEs were rash, 
pruritus, and neutropenia, and occurred in 1 subject each. In another trial in 11 previously 
untreated subjects with cHL over 60 years-old and ineligible for or declining conventional 
combination chemotherapy, the combination of brentuximab vedotin and nivolumab 


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produced a 55% CR rate (Friedberg 2018). No new safety signals were identified and the 
combination was considered to be well tolerated. 
The combination of nivolumab has also been shown to be well tolerated when combined with 
doxorubicin, vinblastine, and dacarbazine (N+AVD). Ramchandren and colleagues observed 
a 67% CR rate with the multi-agent combination in 51 subjects with newly-diagnosed 
advanced stage cHL (Ramchandren 2019). Neutropenia was reported for 55% of subjects and 
treatment-related febrile neutropenia was reported for 10% of subjects. 
1.4 Study Rationale  
1.4.1 Part A  
Based on the results of the ECHELON-1 clinical trial, the FDA has approved the use of 
brentuximab vedotin in combination with chemotherapy in previously untreated subjects with 
Stage III/IV HL, and recommended the use of G-PP beginning in Cycle 1. In the sub-set of 
subjects who received G-PP in ECHELON-1, there were lower rates of Grade 3 or higher 
neutropenia (29% vs 70% without G-PP) and FN (11% vs 21% without G-PP) (Straus 
2018a). The highest incidence of FN occurred in the ECHELON-1 study during Cycle 1 
(Connors 2018). When G-PP was administered during Cycle 1 to a sub-set of subjects, the 
rate of Cycle 1 FN decreased from 11% to 1% (Figure 1), (Straus 2018a). In addition, these 
subjects experienced fewer infections and Grade 3 or higher AEs (Straus 2018a). 
Furthermore, subjects who received G-PP in ECHELON-1 had an improved efficacy as 
demonstrated by 84.6% mPFS at 2 years vs 81.7% without G-PP (Straus 2018a). The 2-year 
mPFS for subjects treated with ABVD in ECHELON-1 was 77.2%. Support with G-PP 
resulted in fewer dose delays during A+AVD treatment (35% vs 49% without G-PP), dose 
reductions (20% vs 26% without G-PP), and hospitalizations (29% vs 38% without G-PP).  
Figure 1: 
Incidence of febrile neutropenia with G-PP administration in Cycle 1 
 
 
Part A will further assess the impact of G-PP administration during A+AVD treatment on the 
incidence of FN, efficacy, and dose intensity, and may provide additional information on the 
dosing of G-CSF in subjects receiving A+AVD. 


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1.4.2 Parts B and C  
The combination of brentuximab vedotin and nivolumab as well as each agent combined 
separately with doxorubicin, vinblastine, and dacarbazine have been shown to be active and 
well tolerated in the treatment of cHL.  
Part B will evaluate the combination of AN+AD in advanced stage HL. Yasenchak et al 
examined the combination of brentuximab and nivolumab as frontline treatment for subjects 
≥60 years with advanced stage HL who were ineligible for or declined conventional 
chemotherapy. Preliminary results showed an overall response rate (ORR) of 100%, a CR 
rate of 72%, and a partial response (PR) rate of 28% (Yasenchak 2019). The regimen was 
well tolerated; the most common treatment-related AEs of any grade were fatigue (48%), 
peripheral sensory neuropathy (38%), diarrhea, infusion-related reactions, and pyrexia (24% 
each). Three subjects had immune-related AEs with a maximum severity of Grade 3. 
Part C will evaluate the combination of AN+AD in early stage HL. Preliminary results from 
Abramson et al regarding the combination of brentuximab vedotin, doxorubicin, and 
dacarbazine for frontline treatment in early stage HL showed high interim and EOT CR rates 
of 94% and 100%, respectively, suggesting that vinblastine may not be required for efficacy 
and may contribute to toxicity in the frontline setting (Abramson 2018). The most common 
treatment-related AEs of any grade included nausea (79%), peripheral sensory neuropathy 
(56%), fatigue (50%), constipation (38%) and alopecia (35%). Grade 3 or higher AEs were 
limited to nausea (3%), neutropenia (6%), and vomiting (3%). 
It is therefore reasonable to expect that the replacement of vinblastine with nivolumab, in 
combination with doxorubicin, brentuximab vedotin, and dacarbazine will result in high 
response rates and be well tolerated, with potentially less toxicity than vinblastine-containing 
regimens (A+AVD, N+AVD, ABVD).  
Subjects in Part B will be treated with up to 6 cycles of brentuximab, nivolumab, 
doxorubicin, and dacarbazine (AN+AD), while subjects in Part C will be treated with 
4 cycles of AN+AD. The components of AN+AD will be administered as described in 
Section 5. After approximately 10 subjects have completed Cycle 2, the SMC will assess the 
safety of AN+AD. Safety will be assessed separately for Part B and Part C. An additional 
SMC meeting will occur after approximately 50 subjects in Part C have completed their EOT 
assessment. For Part C, one interim analysis will be performed after approximately 
50 subjects have completed response assessment at EOT.  


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1.4.3 Risk:Benefit  
Historical standard of care treatment options for patients with advanced HL have been 
associated with poor survival (Gordon 2013). In the ECHELON-1 trial, an open-label, 
international, multicenter, randomized Phase 3 clinical trial in subjects with previously 
untreated Stage III or IV cHL, the complementary mechanisms of action of brentuximab 
vedotin with A+AVD, enhanced antitumor activity with significant improvement in mPFS 
(see Section 1.2). 
The combination of brentuximab vedotin and nivolumab was active and well tolerated in 
cHL with improved CR rate of 61% in relapsed or refractory cHL (Herrera 2018). The 
combination of N+AVD as found to have a 67% CR rate in subjects with newly diagnosed 
advanced stage cHL (Ramchandren 2019; Section 1.3). In another trial of 11 previously 
untreated subjects with cHL over 60 years-old and ineligible for or declining conventional 
combination chemotherapy, the combination of brentuximab vedotin and nivolumab 
produced a 55% CR rate (Friedberg 2018). Section 1.4.2 provides additional information on 
the better outcome of this combination therapy. Given the demonstrated activity of 
brentuximab vedotin as well as nivolumab as treatment of cHL, the evaluation of this 
regimen is anticipated to provide benefit to these patients with acceptable known toxicity. 
The toxicity profile of the combination in cHL is expected to be consistent with that of 
previous studies. Neutropenia and associated complications, including febrile neutropenia 
and infections, infusion related reactions, and peripheral neuropathy were considered the 
most clinically important AEs for the combination regimen. Investigators may decide to 
discontinue study treatment at any time for any of the reasons listed in Section 4.3.1. 
The same rationale regarding the use of brentuximab vedotin and nivolumab applies when 
considered as treatment of early stage cHL. Current accepted therapies for early stage cHL 
include chemotherapy regimens, radiation, and combined modality therapy of chemotherapy 
and radiation. These regimens are associated with high cure rates of 85-90% (Meyer 2012) 
but are also associated with high rates of serious morbidity and mortality in long-term 
survivors, particularly second primary malignancies and cardiovascular disease (Straus 
2018b). 
Recent data in 34 subjects with previously untreated Stage I/II cHL with non-bulky disease, 
treatment with brentuximab vedotin, doxorubicin, and dacarbazine showed CR, PFS and OS 
rates of 100% at EOT (Abramson 2018). The promising responses observed with the 
combination of brentuximab vedotin and nivolumab as treatment of advanced cHL as well as 
the evidence of activity in earlier stage disease provide a compelling rationale to evaluate the 
combination of brentuximab vedotin and nivolumab. 
 
 


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2 
OBJECTIVES  
This study will evaluate the efficacy and safety of A+AVD in advanced cHL subjects treated 
with G-PP in Part A, and the treatment of cHL with AN+AD in Parts B and C. Specific 
objectives and corresponding endpoints for the study are summarized below ( 
Table 1). 
Table 1: 
Objectives and corresponding endpoints 
Primary Objectives 
Corresponding Primary Endpoints 
● Part A: To assess the treatment-emergent febrile 
neutropenia rate in subjects with previously 
untreated, advanced stage, cHL treated with A+AVD 
and G-CSF primary prophylaxis (G-PP) 
● Part A: The febrile neutropenia rate in subjects 
treated with A+AVD and G-PP 
● Parts B and C: To assess the complete response (CR) 
rate at EOT with AN+AD in subjects with previously 
untreated cHL 
● CR rate at EOT 
Secondary Objectives 
Corresponding Secondary Endpoints 
Part A: 
● To assess the incidence and severity of adverse 
events of clinical interest 
Part A: 
● The rates and severity of each AECI 
● To assess dose intensity, dose reductions, and dose 
delays related to any component of A+AVD 
● Mean dose intensity; the rates of dose reduction 
and dose delays related to any component of 
A+AVD 
● To assess primary refractory disease rates 
● The primary refractory disease rate 
● To assess subsequent anticancer therapy utilization 
● The rates of each subsequent anticancer therapy 
taken by subjects 
● To assess end of treatment (EOT) complete 
response rate 
● The complete response rate at EOT 
● To assess physician-reported progression-free 
survival rate at 2 years 
● Physician-reported PFS  
Parts B and C: 
● To assess the safety and tolerability of AN+AD 
Parts B and C: 
● Incidence, severity, seriousness, and relatedness 
of AEs; incidence and severity of lab 
abnormalities 
● To assess the overall response rate (ORR) 
● Estimate the ORR 
● To assess the duration of response (DOR) 
● DOR 
● To assess the duration of complete response 
(DOCR) 
● DOCR 
● To assess the event-free survival (EFS) 
● EFS 
● To assess the progression-free survival (PFS) 
● PFS 
● To assess the overall survival (OS) 
● OS 
 


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3 
INVESTIGATIONAL PLAN  
3.1 Summary of Study Design  
This is an open-label, multiple part, multicenter, phase 2 clinical trial. Part A is designed to 
evaluate the rate of FN for treatment-naïve subjects with advanced classical HL (cHL) who 
have been treated with A+AVD and G-PP. In Part A, subjects will receive 6 cycles of 
A+AVD as described in Sections 5.2.2 and 5.3.3. Parts B and C are designed to evaluate the 
CR rate in subjects treated with AN+AD. Up to approximately 240 subjects will be treated in 
this clinical trial. 
A study schema for Part A is provided in Figure 2 and for Parts B and C in Figure 3. See 
Appendix A for the schedule of events for Part A; Appendix B provides the schedule of 
events for Parts B and C. As of Amendment 6, Parts A and B were completed. 
Figure 2: 
Study design – Part A 
 
A. Note: G-PP should be started 24 to 36 hours from A+AVD and follow instructions in Section 5.4.3 
 


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Figure 3: 
Study design – Parts B and C 
 
a 
Response assessments will include PET and diagnostic-quality CT scan on Day 25-28 of Cycle 2, and at EOT. 
b 
Follow-up period for Parts B and C includes 2 additional years (5 years total). 
 
3.1.1 End of Study  
The study will be closed approximately 5 years after the last subject receives the last dose, or 
when no subjects remain in follow-up, whichever occurs first (Section 6.6). In addition, the 
Sponsor may terminate the study at any time (see Section 10.3.2). 
3.1.2 Safety Monitoring Committee  
For Parts B and C, the SMC will monitor the safety of AN+AD throughout the study. The 
SMC is composed of the study medical monitor, study biostatistician, drug safety 
representative, and study site investigators.  
The SMC will meet to evaluate safety after approximately 10 subjects have completed 
Cycle 2. An additional SMC meeting will be held after approximately 50 subjects in Part C 
have completed their EOT assessment. The committee will also monitor the safety of 
participants through regular and/or ad hoc meetings that include review of AEs and lab 
abnormalities. 
Further details are provided in the SMC charter. 
3.2 Discussion and Rationale for Study Design  
3.2.1 Part A  
The use of G-PP was not mandated in the ECHELON-1 clinical trial. However, the use of 
G-PP is recommended per approved product labeling. Thus, an open-label trial design with 


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consistent use of G-PP will allow for additional clinical assessment of the safety and efficacy 
of A+AVD when used with G-PP as described in the approved product labeling. Further, 
Part A will include subjects with inclusion and exclusion criteria that are somewhat broader 
than the original ECHELON-1 clinical trial, allowing for assessment of a more representative 
subject population. Additional analyses may compare the results with those observed in the 
ECHELON-1 trial. 
3.2.2 Parts B and C  
The combination of brentuximab vedotin and nivolumab has shown promising preliminary 
antitumor activity and is well tolerated as discussed in Section 1.3 (Diefenbach 2017; Herrera 
2018; Hong 2018). Thus, evaluation of the safety and efficacy of AN+AD combination is 
warranted. 
The endpoints of the study are appropriate for evaluating the efficacy and safety of the 
combination of AN+AD. The primary efficacy endpoint of this study, CR rate at EOT, is a 
direct measure of antitumor activity. To further assess the efficacy in this study, ORR, 
duration of response (DOR), duration of complete response (DOCR), event-free survival 
(EFS), PFS, and OS will be evaluated as secondary endpoints.  
3.2.3 Method of Assigning Subjects to Treatment Groups  
Upon approval of subject registration, eligible subjects with advanced cHL will be assigned 
to Part A or Part B based on subject and investigator preference. Subjects with Stage I or II 
cHL with bulky mediastinal disease will be assigned to Part B. Subjects with Stage I or II 
cHL without bulky disease will be assigned to Part C. As of Amendment 6, Parts A and B 
were completed. 
3.2.4 Rationale for Selection of Doses  
3.2.4.1 Part A  
The recommended dose for brentuximab vedotin in combination with chemotherapy for 
treatment-naïve subjects with Stage III or IV cHL is 1.2 mg/kg intravenous (IV) every 
2 weeks (q2wk) for a maximum of 6 cycles (12 doses). 
Treatment with 1.2 mg/kg brentuximab vedotin in combination with doxorubicin at 
25 mg/m2, vinblastine at 6 mg/m2, and dacarbazine at 375 mg/m2 was studied in the 
ECHELON-1 trial. This dosing regimen has been established as effective and safe for 
treatment of subjects with Stage III or IV HL. As the additional analyses in this study depend 
in part on data from ECHELON-1 subjects, this dosing regimen will be used in this clinical 
trial. 
3.2.4.2 Parts B and C  
All subjects will be treated with brentuximab vedotin 1.2 mg/kg, nivolumab 240 mg, 
doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2. Each study drug will be administered 


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separately by IV infusion on Days 1 and 15 of each 28-day cycle. Subjects in Part B will 
receive up to 6 cycles of treatment. Subjects in Part C will receive 4 cycles of treatment. 
The recommended dose for brentuximab vedotin in combination with chemotherapy for 
previously untreated Stage III or IV cHL is 1.2 mg/kg up to a maximum of 120 mg based on 
100 kg body weight, every 2 weeks for a maximum of 6 cycles (12 doses). Doses up to 
2.4 mg/kg have been evaluated in studies in subjects with CD30-positive hematologic 
malignancies. 
Doxorubicin at 25 mg/m2 and dacarbazine at 375 mg/m2 in combination with the above dose 
of brentuximab vedotin has been studied in the ECHELON-1 trial. This dosing regimen has 
been established as effective and safe for treatment of subjects with advanced stage HL.  
The approved dose for nivolumab as monotherapy for cHL is 240 mg every 2 weeks or 
480 mg every 4 weeks (nivolumab approved product labeling). In the CheckMate 205 study, 
subjects with newly diagnosed cHL were given nivolumab (240 mg every 2 weeks), followed 
by the combination of NAVD, which resulted in an ORR of 84% (Ramchandren 2019).  
After approximately 10 subjects have completed 2 cycles of treatment, the SMC will assess 
the safety of AN+AD (Section 3.1.2). An additional SMC meeting will occur after 
approximately 50 subjects in Part C have completed their EOT assessment. Safety will be 
evaluated separately for Part B and Part C. 
3.2.5 Blinding and Unblinding  
This is an open-label study. 
4 
STUDY POPULATION  
The subject population to be studied is treatment-naïve subjects with classical HL. 
Subjects 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 a 
good clinical practice audit and/or health regulatory authority inspection. As of 
Amendment 6, Parts A and B were completed. 
4.1 Inclusion Criteria  
1. Treatment-naïve, cHL subjects: 
a. Subjects enrolling in Part A of the study must have Ann Arbor Stage III or IV 
disease. 
b. Subjects enrolling in Part B of the study must have Ann Arbor Stage I or II cHL with 
bulky mediastinal disease (defined as a single node or nodal mass measuring 10 cm or 
greater in diameter as determined by CT imaging), or Stage III or IV disease. 
c. Subjects enrolling in Part C of the study must have Ann Arbor Stage I or II cHL 
without bulky disease. 


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2. Histologically confirmed cHL according to the current World Health Organization 
Classification (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte 
depleted, classical HL, or not otherwise specified). 
a. Subjects enrolling in Parts B and C must submit a tumor block for analysis (see 
Section 7.3.1). Availability of tissue must be confirmed prior to enrollment. If a 
tumor block is not available, unstained slides (a minimum of 10 unstained slides for 
Part B and 12 unstained slides for Part C) may be submitted instead of a tumor block. 
3. Bidimensional measurable disease as documented by PET/CT or CT imaging. Must have 
at least one lesion >15 mm (1.5 cm) in the longest diameter on cross-sectional imaging, 
measurable in 2 perpendicular dimensions on CT (or MRI), and FDG avid by PET. 
4. Age 12 years or older in the United States. For regions outside of the United States, 
subjects must be age 18 years or older.  
5. An Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
6. Subjects 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. Subjects with false positive results and documented verification 
that the subject is not pregnant are eligible for participation. Subjects of non-childbearing 
potential are those who are postmenopausal >1 year or who have had a bilateral 
oophorectomy or hysterectomy. 
7. Subjects of childbearing potential must agree not to breastfeed or donate ova, starting at 
the time of informed consent and continuing through 7 months after the final dose of 
study drug. 
8. If sexually active in a way that could result in pregnancy, subjects of childbearing 
potential must agree to use 2 contraception methods (including 1 highly effective) during 
the study and for 7 months following the last dose of study drug (see Appendix G). 
Subjects who can father children and have partners of childbearing potential must agree 
to use 2 contraception methods during the study and for 7 months following the last dose 
of study drug (see Appendix G). Subjects who can father children must be willing to 
refrain from sperm donation starting at the time of consent and continuing through the 
study period and for at least 7 months after the final dose of study drug. Subjects born 
male who are sexually active with a pregnant or breastfeeding person must use 
contraceptives outlined in Appendix G to prevent secondary exposure to seminal fluid.  
9. The subject or the subject’s legally acceptable representative must provide written 
informed consent. For subjects less than 18 years old, a parent or legally acceptable 
representative must provide written informed consent; if applicable, the subject should 
also provide assent per institutional standards. 
10. The following baseline laboratory data:  


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● 
absolute neutrophil count ≥1500/µL unless there is known bone marrow involvement 
● 
platelet count ≥75,000/μL  
● 
serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with 
Gilbert’s disease or documented hepatic involvement with lymphoma 
● 
estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease (MDRD) study equation as applicable for 
subjects ≥18 years old, or bedside Schwartz formula for subjects <18 years old (see 
Section 7.4.2) 
● 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN or 
≤5 x ULN if there is documented hepatic involvement of HL 
● 
hemoglobin ≥8 g/dL 
4.2 Exclusion Criteria  
1. Nodular lymphocyte predominant HL. 
2. History of another malignancy within 3 years before the first dose of study drug or any 
evidence of residual disease from a previously diagnosed malignancy. Exceptions are 
malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as 
adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Subjects 
with nonmelanoma skin cancer, localized prostate cancer, or carcinoma in situ of any 
type are not excluded if they have undergone complete resection.  
3. Prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy 
(e.g., immunoglobulin replacement, other monoclonal antibody therapies) within 4 weeks 
of first study drug dose. 
4. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways. 
5. Active cerebral/meningeal disease related to the underlying malignancy, including signs 
or symptoms of progressive multifocal leukoencephalopathy (PML) or history of PML. 
Subjects with a history of cerebral/meningeal disease related to the underlying 
malignancy are allowed if prior CNS disease has been treated. 
6. 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 study drug. Routine antimicrobial 
prophylaxis is permitted. 
7. Current therapy with other systemic anti-neoplastic or investigational agents. 
8. Planned consolidative radiotherapy during the study treatment period (Parts B and C 
only). 


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9. Active interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected drug-related pulmonary toxicity (Parts B and C only). 
10. Grade 3 or higher pulmonary disease unrelated to underlying malignancy. 
11. Documented history of idiopathic interstitial pneumonia or diffusing capacity of the lung 
for carbon monoxide (adjusted for hemoglobin) <50% predicted. 
12. 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 (see Appendix E) within 6 months prior to their first dose 
of brentuximab vedotin. 
13. Subjects with Child-Pugh B or C hepatic impairment. 
14. Other serious underlying medical condition that, in the opinion of the investigator, would 
impair the subject’s ability to receive or tolerate the planned treatment and follow-up. 
15. Neurologic disease compromising at least 1 Activity of Daily Living (total dependence) 
per Katz Index of Independence in Activities of Daily Living (Appendix H), or poorly 
controlled by medication per the investigator’s assessment. 
16. Grade 2 or higher peripheral sensory or motor neuropathy at baseline. 
17. Left ventricular ejection fraction <45% or symptomatic cardiac disease (including 
symptomatic ventricular dysfunction, symptomatic coronary artery disease, and 
symptomatic arrhythmias), or previous treatment with complete cumulative doses of 
doxorubicin or other anthracyclines. 
18. Subjects with acute or chronic graft-versus-host-disease (GvHD) or receiving 
immunosuppressive therapy as treatment for or prophylaxis agent against GvHD. 
19. Previous treatment with brentuximab vedotin. 
20. Known to be positive for hepatitis B by surface antigen expression. Known to be positive 
for hepatitis C infection (positive by polymerase chain reaction (PCR) or on antiviral 
therapy for hepatitis C within the last 6 months). Subjects who have been treated for 
hepatitis C infection are permitted if they have documented sustained virologic response 
of 12 weeks.  
21. Known to be positive for human immunodeficiency virus (HIV).  
22. Subjects who are pregnant or breastfeeding. 
23. Known hypersensitivity to any excipient contained in the drug formulation of 
brentuximab vedotin, any component of AVD, nivolumab, doxorubicin, dacarbazine, 
filgrastim, or pegfilgrastim.  


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24. Treatment with botanical preparations (e.g., herbal supplements, traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to treatment (Parts B and 
C only). 
25. Subjects who have received a live or attenuated vaccine within 30 days prior to treatment 
and 100 days after the last dose (Parts B and C only). 
26. Subjects with an active autoimmune disease or any other condition requiring systemic 
treatment with either corticosteroids within 14 days (>10 mg daily prednisone equivalent) 
or other immunosuppressive medications within 30 days of starting treatment (Parts B 
and C only). Inhaled, ocular, intra-articular, or topical steroids, and adrenal replacement 
steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 
a. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 
4.3 Removal of Subjects From Therapy or Assessment  
Seagen Inc. or their designee must be notified if a subject is withdrawn from study treatment 
or from the study. The reason(s) for withdrawal must be documented in the subject’s medical 
records and case report form (CRF). 
4.3.1 Discontinuation of Study Treatment  
A subject’s study treatment may be discontinued for any of the following reasons: 
● 
Completed treatment per protocol  
● 
Progressive disease (PD) 
● 
Adverse event (AE) 
● 
Pregnancy 
● 
Investigator decision 
● 
Subject decision, non-AE 
● 
Study termination by sponsor 
● 
Other, non-AE 
Subjects who discontinue from study treatment will remain on study for follow-up unless 
they withdraw consent. CZ only: Subjects who discontinue study treatment due to a lack of 
clinical benefit following Cycle 2 PET will only remain on study for survival follow-up and 
subsequent therapy must be recorded. 
4.3.2 Subject Withdrawal From Study  
Any subject may be discontinued from the study for any of the following reasons: 
● 
Completed study per protocol 


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● 
Subject withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 
● 
Death 
● 
Other 


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5 
TREATMENTS  
5.1 Treatments Administered  
For Part A, the treatment regimen A+AVD consists of brentuximab vedotin, doxorubicin, 
vinblastine, and dacarbazine. For Parts B and C, the treatment regimen AN+AD consists of 
brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine. 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 HuMAb that targets PD-1. Doxorubicin is a 
cytotoxic anthracycline antibiotic. Vinblastine is a stathmokinetic oncolytic agent. 
Dacarbazine is an anticancer agent. 
Commercially available forms of G-CSF include filgrastim and pegfilgrastim. Both are 
glycoproteins that regulate production of neutrophils and affect neutrophil proliferation, 
differentiation, and function.  
The study treatments to be administered in Part A are described in summary in Table 2 and in 
detail in Sections 5.2, 5.3, and 5.4. The study treatments to be administered in Parts B and C 
are described in summary Table 3 and in detail in Sections 5.2, 5.3, and 5.5. As of 
Amendment 6, Parts A and B were completed. 
Table 2: 
Study treatment – Part A 
Drug Administered 
Day 1 
24–36 hours 
post A+AVD 
Day 15 
24–36 hours  
post A+AVD 
Doxorubicin (25 mg/m2) 
X 
 
X 
 
Vinblastine (6 mg/m2) 
X 
 
X 
 
Dacarbazine (375 mg/m2) 
X 
 
X 
 
Brentuximab vedotin (1.2 mg/kg)  
X 
 
X 
 
G-PPa 
 
Xa 
 
Xa 
a 
G-PP to be administered beginning 24–36 hours post each dose of A+AVD. Dose and length of administration vary 
depending on type of drug used; see Section 5.4.3 
 
Table 3: 
Study treatment – Parts B and C 
Drug Administereda 
Day 1 
Day 15 
Doxorubicin (25 mg/m2) 
X 
X 
Dacarbazine (375 mg/m2) 
X 
X 
Brentuximab vedotin (1.2 mg/kg)  
X 
X 
Nivolumab (240 mg) 
X 
X 
a 
On dosing days, the order of administration will be doxorubicin and dacarbazine, followed by brentuximab vedotin, 
then nivolumab. Nivolumab will be administered at least 30 minutes after the end of infusion with brentuximab 
vedotin. 


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5.2 Brentuximab Vedotin  
Detailed information describing the preparation, administration, and storage of brentuximab 
vedotin can be located in the Pharmacy Binder. 
5.2.1 Description  
Brentuximab vedotin is a sterile, preservative free, white to off-white lyophilized cake or 
powder in single-use vials for reconstitution for IV administration. Each vial of the product 
contains brentuximab vedotin, trehalose dihydrate, sodium citrate dihydrate, citric acid 
monohydrate, and polysorbate 80. See the Pharmacy Binder for further information. 
5.2.2 Dose and Administration  
Brentuximab vedotin 1.2 mg/kg will be administered on days 1 and 15 by IV infusion given 
over approximately 30 minutes, for up to six 28-day cycles. In the absence of infusion-related 
reactions, the infusion rate for all subjects 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. Brentuximab 
vedotin administration should be limited to a maximum of 120 mg q2wk. In Parts B and C, 
brentuximab vedotin should be administered after the end of the infusion of doxorubicin or 
dacarbazine, and 30 minutes prior to infusion of nivolumab when administered on the same 
day. 
Weight-based dosing is based on subject actual body weight. Doses must be adjusted for 
subjects who experience a ≥10% change in weight from baseline. Subject weight must be 
measured during all relevant assessment windows as described in the schedule of events. 
Other dose adjustments for changes in body weight are permitted per institutional standard. 
Rounding is permissible within 5% of the nominal dose. An exception to weight-based 
dosing is made for subjects weighing greater than 100 kg; doses will be based on 100 kg 
for these individuals. The maximum dose calculated per administration in this study is 
120 mg (1.2 mg/kg).  
5.2.3 Method of Procurement  
Brentuximab vedotin will be supplied to study sites by Seagen Inc. 
5.2.4 Dose Modifications  
Table 4 describes the dose modifications for study treatment-associated toxicity. Table 5 
describes dose modifications for subjects with impaired renal or hepatic function. Dose 
reductions of brentuximab vedotin below 0.9 mg/kg are not allowed, and further toxicities 
are managed with dose delays or permanent discontinuation. If any component of the 
regimen is discontinued due to AE, subjects may remain on study and continue to receive the 
remaining treatment components. Subjects who discontinue brentuximab vedotin due to AE 
after receiving only 1 cycle are ineligible to continue on the study. Refer to Section 6 of the 
Investigator’s Brochure (IB) for additional information on the safety of brentuximab vedotin, 
and guidance regarding appropriate safety monitoring for subjects. 


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Table 4: 
Dose modifications for brentuximab vedotin-associated toxicity  
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sensory 
Neuropathy 
Continue at 
same dose level 
Reduce BV dose 
to 0.9 mg/kg and 
resume treatment 
Withhold BV until PN 
is ≤ Grade 2, then 
reduce dose to 
0.9 mg/kg and resume 
treatment; if already at 
0.9 mg/kg, continue 
dosing at that dose. 
Discontinue 
treatment with BV 
Motor 
Neuropathy 
Continue at 
same dose level 
Reduce BV dose 
to 0.9 mg/kg and 
resume treatment 
Discontinue treatment 
with BV 
Discontinue 
treatment with BV 
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 levela. 
Withhold dose until 
toxicity is ≤ Grade 2 
or has returned to 
baseline, then reduce 
dose to 0.9 mg/kg 
and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator a,b. 
Hematologicc 
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 leveld. For Grade 3 or 4 neutropenia, 
growth factor support (G-CSF or GM-CSF) or 
prophylaxis should be considered for 
subsequent cycles if not already administered. 
If Grade 4 neutropenia recurs despite growth 
factor support, consider discontinuation or dose 
reduction to 0.9 mg/kg. 
a 
Subjects who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without 
interruption. 
b 
Treatment should be discontinued for subjects who experience Grade 4 infusion-related reactions. 
c 
Support with blood product transfusions allowed per institutional standard of care. 
d 
Subjects who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption.  
 


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Table 5: 
Dose modifications for brentuximab vedotin treatment of subjects with renal or 
hepatic impairment 
Degree of Impairment 
Recommended Dose Adjustment 
Renal Impairment 
 
Mild (CrCL ≥50–80 mL/min) 
Moderate (CrCL ≥30–50 mL/min) 
None 
None 
Severe (CrCL <30 mL/min) 
Avoid use 
Hepatic Impairment 
 
Mild (Child-Pugh A) 
Reduce dose to 0.9 mg/kg, up to a maximum of 
90 mg every 2 weeks 
Moderate (Child-Pugh B) 
Severe (Child-Pugh C) 
Avoid use 
Avoid use 
 
5.2.5 Storage and Handling  
Refer to the brentuximab vedotin Pharmacy Binder for more information regarding storage 
and handling. 
5.2.6 Packaging and Labeling  
Refer to the brentuximab vedotin Pharmacy Binder for more information regarding 
packaging and handling. 
5.2.7 Preparation  
Refer to the brentuximab vedotin Pharmacy Binder for more information regarding 
preparation. 
5.3 Doxorubicin, Vinblastine, and Dacarbazine  
5.3.1 Description  
All subjects in Part A of this study will be administered AVD: doxorubicin, vinblastine, and 
dacarbazine. All subjects in Parts B and C of this study will be administered doxorubicin and 
dacarbazine. Doxorubicin is a cytotoxic anthracycline antibiotic. Vinblastine is a 
stathmokinetic oncolytic agent. Dacarbazine is an anticancer agent. 


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5.3.2 Method of Procurement  
In the United States, doxorubicin, vinblastine, and dacarbazine will be supplied by the study 
site from commercial sources, and billed to subjects and/or their third-party payer (insurance, 
a healthcare provider, or applicable government program). 
In regions outside of the United States, doxorubicin and dacarbazine will be provided by 
Seagen Inc. via a central pharmacy, or will be supplied by the study site from a local source 
to be reimbursed by Seagen Inc. 
5.3.3 Dose and Administration  
Part A: AVD will be administered by IV infusion on Days 1 and 15 of each 28-day cycle as 
follows: 
+A: Doxorubicin will be administered at 25 mg/m2 
V: Vinblastine will be administered at 6 mg/m2 
D: Dacarbazine will be administered at 375 mg/m2 
AVD is to be administered per institutional standards. Brentuximab vedotin is to be 
administered as described in Section 5.2.2. 
Parts B and C: Doxorubicin and dacarbazine will be administered by IV infusion on 
Days 1 and 15 of each 28-day cycle as follows: 
A: Doxorubicin will be administered at 25 mg/m2 
D: Dacarbazine will be administered at 375 mg/m2 
Each agent is to be administered per institutional standards and the current approved product 
label. Brentuximab vedotin is to be administered as described in Section 5.2.2, and 
nivolumab is to be administered as described in Section 5.5.3. 
5.3.4 Dose Modifications  
Dose modifications of doxorubicin, vinblastine, and dacarbazine due to toxicity are allowed 
per institutional standards and according to the product’s prescribing information at the 
discretion of the investigator. Permitted dose modifications include discontinuation of a 
treatment component. Refer to the product’s prescribing information for dose modification 
recommendations. 
5.3.5 Storage and Handling  
Refer to the product label(s) for more information regarding storage and handling. 
5.3.6 Packaging and Labeling  
Refer to the product label(s) for more information regarding packaging and labeling. 


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5.3.7 Preparation  
Refer to the product label(s) for more information regarding preparation. 
5.4 Granulocyte Colony Stimulating Factor  
5.4.1 Description  
Filgrastim (including biosimilar) and pegfilgrastim can be used as G-CSF in the study. Both 
are glycoproteins that regulate production of neutrophils and affect neutrophil proliferation, 
differentiation, and function.  
5.4.2 Method of Procurement  
Filgrastim and pegfilgrastim will be supplied by the study site from commercial sources, and 
billed to subjects and/or their third-party payer (insurance, a healthcare provider, or 
applicable government program). 
5.4.3 Dose and Administration  
In Part A, G-CSF will be administered after each dose of A+AVD, following dosing on 
Days 1 and 15 of every treatment cycle, as follows:  
● 
Pegfilgrastim: 6 mg subcutaneous (SC) 24 to 36 hours after A+AVD per dose 
● 
Filgrastim: 5 mcg/kg (300 to 480 mcg, rounded to the nearest vial) SC daily, 
beginning 24 to 36 hours after A+AVD per dose, for a minimum of 5 days. 
Additional doses beyond 5 days are permitted at the discretion of the investigator. 
5.4.4 Dose Modifications  
Refer to the product label(s) for more information regarding dose modifications. 
5.4.5 Storage and Handling  
Refer to the product label(s) for more information regarding storage and handling. 
5.4.6 Packaging and Labeling  
Refer to the product label(s) for more information regarding packaging and labeling. 
5.4.7 Preparation  
Refer to the product label(s) for more information regarding preparation. 
5.5 Nivolumab  
5.5.1 Description  
All subjects in Parts B and C of this study will be administered the PD-1 checkpoint inhibitor 
nivolumab. The addition of nivolumab in combination with brentuximab vedotin, 
doxorubicin, and dacarbazine in newly diagnosed subjects with cHL is considered 
investigational. 


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Nivolumab is a sterile, preservative-free, clear to opalescent, colorless to pale-yellow 
solution supplied by Seagen Inc. in single-use vials for dilution for IV administration. Each 
single-use vial of the product contains 100 mg/10 mL solution. Detailed information 
describing the preparation, administration, and storage of nivolumab is located in the 
Pharmacy Binder. 
5.5.2 Method of Procurement  
Nivolumab will be provided by Bristol-Myers Squibb and supplied to study sites by Seagen 
Inc.  
5.5.3 Dose and Administration  
Nivolumab will be administered by IV infusion on Day 1 and Day 15 of each 28-day 
treatment cycle. Subjects will receive nivolumab at a dose of 240 mg as a 30-minute 
infusion. Nivolumab should be administered at a set dose of 240 mg and neither reduced nor 
increased. 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). 
The Pharmacy Binder contains specific instructions for nivolumab dose calculation, dilution, 
preparation of the infusion fluid, and administration. 
5.5.4 Dose Modifications  
Nivolumab administration should be withheld or discontinued as described in Table 6. The 
recommended management of gastrointestinal (GI), renal, pulmonary, hepatic, 
endocrinopathy, skin, neurological, and myocarditis AEs are provided in Appendix I. 
Table 6: 
Nivolumab Dose Modifications 
Adverse Reaction 
Severity* 
Dose Modification 
Colitis  
Grade 2 diarrhea or colitis 
Withhold dosea 
Grade 3 diarrhea or colitis 
Withhold dosea when 
administered as a single agent  
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold dosea 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/ 
non-HCCb 
Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 3 and up to 5 times 
the upper limit of normal (ULN) or total bilirubin more 
than 1.5 and up to 3 times the ULN 
Withhold dosea 
AST or ALT more than 5 times the ULN or total 
bilirubin more than 3 times the ULN  
Permanently discontinue 
Hepatitis/ HCCb 
If AST/ALT is within normal limits at baseline and 
increases to more than 3 and up to 5 times the ULN 
Withhold dosec 


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Adverse Reaction 
Severity* 
Dose Modification 
If AST/ALT is more than 1 and up to 3 times ULN at 
baseline and increases to more than 5 and up to 10 times 
the ULN 
If AST/ALT is more than 3 and up to 5 times ULN at 
baseline and increases to more than 8 and up to 10 times 
the ULN  
If AST or ALT increases to more than 10 times the ULN 
or total bilirubin increases to more than 3 times the ULN  
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis  
Withhold dosea 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal 
Insufficiency 
Grade 2 adrenal insufficiency 
Withhold dosea 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 Diabetes 
Mellitus 
Grade 3 hyperglycemia 
Withhold dosea 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and 
Renal 
Dysfunction 
Serum creatinine more than 1.5 and up to 6 times the 
ULN 
Withhold dosea 
Serum creatinine more than 6 times the ULN 
Permanently discontinue 
Skin 
Grade 3 rash or suspected Stevens-Johnson syndrome 
(SJS) or toxic epidermal necrolysis (TEN)  
Withhold dosea 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New-onset moderate or severe neurologic signs or 
symptoms 
Withhold dosea 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
First occurrence 
Recurrence of same Grade 3 adverse reactions 
 
Withhold dosea 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater prednisone or 
equivalent for more than 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions lasting 
12 weeks or longer 
Permanently discontinue 
Note: Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 
(NCI CTCAE v4). 
a 
Resume treatment when adverse reaction improves to Grade 0 or 1. 
b 
HCC: hepatocellular carcinoma. 
c 
Resume treatment when AST/ALT returns to baseline. 
 
5.5.4.1 Resuming Treatment Following Dose Delays  
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently 
if clinically indicated and resume nivolumab dosing when re-treatment criteria are met. 
See Table 6 in Section 5.5.4 for dose delays and discontinuations. 
Subjects may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 


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● 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
● 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity. 
● 
For subjects with Grade 2 AST, ALT and/or total bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with 
corticosteroids, if needed, is complete. 
● 
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline 
before treatment is resumed. Grade ≥3 adrenal insufficiency requires discontinuation 
regardless of control with hormone replacement. 
Prior to re-initiating treatment in a subject with a dosing delay lasting >6 weeks, the medical 
monitor must be consulted. Tumor assessments should continue as per protocol even if 
dosing is delayed. Periodic study visits to assess safety and laboratory studies should also 
continue per protocol or more frequently if clinically indicated during such dosing delays. 
Permitted dose modifications include permanent discontinuation of nivolumab. Subjects may 
remain on study and continue to receive the remaining treatment components. There are no 
recommended dose modifications of nivolumab for hyperthyroidism or hypothyroidism.  
If nivolumab is held due to AE, once the AE has resolved administration of nivolumab 
should resume on the same schedule at the next cycle of therapy. 
5.5.5 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. 
5.5.6 Packaging and Labeling  
Refer to the investigational product label for information regarding packaging and labeling. 
5.5.7 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. 
5.6 Concomitant Therapy  
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period (see Section 7.4.1.3). Any 


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concomitant medication given for a study protocol-related AE should be recorded from the 
time of informed consent. 
5.6.1 Required Concomitant Therapy  
There are no required concomitant therapies. 
5.6.2 Allowed Concomitant Therapy  
Subjects are allowed premedication regimens for anti-emesis purposes and prevention of 
infusion-related reactions, including corticosteroids, dosing <10 mg daily prednisone 
equivalent or per local standard of care. Subjects are permitted the use of topical, ocular, 
intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic 
absorption). Doses of >10 mg daily prednisone or prednisone equivalent are allowed for 
stable adrenal replacement. A brief (<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. Further details are 
described in Section 5.7.1. 
Subjects who are receiving strong Cytochrome P450 (CYP) 3A4 inhibitors concomitantly 
with brentuximab vedotin should be closely monitored for adverse reactions. 
Growth factor support or prophylaxis (G-CSF or GM-CSF) should be considered for subjects 
who are at risk for, currently have, or have recently recovered from, neutropenia. CZ only: 
Primary prophylaxis with G-CSF or GM-CSF from the first dose is recommended for all 
subjects with previously untreated Hodgkin’s lymphoma receiving combination therapy with 
brentuximab vedotin. 
5.6.3 Prohibited Concomitant Therapy  
Subjects may not receive other investigational drugs, immunosuppressive medications 
(exception: corticosteroid doses of >10 mg daily prednisone, or prednisone equivalent for 
anti-emesis and prevention of infusion-related reactions are allowed), radiotherapy, or 
systemic anti-neoplastic therapy from Day 1 through EOT. In addition, other prohibited 
concomitant therapies should be excluded in accordance with the approved prescribing 
information for each agent. Exceptions are noted in Section 5.6.2. 
5.6.3.1 Prohibited Concomitant Therapy – Parts B and C  
The following are prohibited for Parts B and C only: 
● 
Any subject for whom the investigator intends to administer consolidative 
radiotherapy to any lesions (i.e., large mediastinal masses).  
● 
Immunosuppressive doses of systemic corticosteroids (e.g., prednisone >10 mg/day) 
(premedication regimens for anti-emesis and prevention of infusion-related reactions 
are allowed). 


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● 
Any complementary medications (e.g., herbal supplements or traditional Chinese 
medicines) intended to treat the disease under study. Such medications are allowed if 
they are used as supportive care. 
● 
Any live or attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral 
polio, and measles, mumps, rubella (MMR)) during treatment and until 100 days post 
last dose of nivolumab 
5.7 Management of Adverse Reactions  
Management of AEs should occur per institutional standards. Additional information 
regarding treatment-emergent AEs (TEAEs) for brentuximab vedotin is available in the 
brentuximab vedotin IB. Management of immune-mediated AEs (IMAEs) for nivolumab is 
available in Appendix I. 
5.7.1 Management of Infusion Reactions  
Infusion-related reactions may occur during the infusion of study treatment. The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis should 
it occur. All supportive measures consistent with optimal subject 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. 
Subjects will be monitored for a period of 2 hours post-infusion of brentuximab vedotin at 
each visit. Infusion or hypersensitivity reactions may occur within 24 hours or more than 
24 hours post-dose, respectively, 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. 
5.7.1.1 Part A  
Subjects who have experienced a Grade 1 or Grade 2 infusion-related reaction should be 
premedicated for subsequent infusions. Premedication may include acetaminophen, an 
antihistamine, and a corticosteroid administered 30–60 minutes prior to each brentuximab 
vedotin infusion or according to institutional standards. 
Subjects who experience a Grade 3 or Grade 4 infusion-related reaction may potentially 
receive additional treatment per institutional standards. 
If anaphylaxis occurs, drug administration should be immediately and permanently 
discontinued and appropriate medical therapy provided per institutional standards. 
5.7.1.2 Parts B and C  
If an infusion or hypersensitivity reaction occurs from nivolumab, it might manifest with 
fever, chills, rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, 
bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the study medical monitor and reported as a serious adverse event 


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(SAE) if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(V4.03) guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate: 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
● 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 
30 minutes before additional nivolumab administrations. 
For Grade 2 symptoms: (Therapy or infusion interruption indicated but responds promptly 
to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hrs): 
● 
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor 
participant until resolution of symptoms. Corticosteroid and/or bronchodilator therapy 
may also be administered as appropriate. If the infusion is interrupted, then restart the 
infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur, then no further 
study medication will be administered at that visit. 
● 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg should be administered at least 30 minutes before nivolumab 
infusions. If necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) 
may be used. 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [e.g., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; urgent intervention indicated): 
● 
Immediately discontinue infusion of study drug. Begin an IV infusion of normal 
saline and treat the subject as follows: Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of 
a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 
50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject 
should be monitored until the investigator is comfortable that the symptoms will not 
recur. Study drug will be permanently discontinued. Investigators should follow their 


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institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery of the symptoms. 
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine or corticosteroids). 
5.7.2 Management of Tumor Lysis Syndrome  
Subjects with rapidly proliferating tumor and high tumor burden may be at risk of tumor lysis 
syndrome and should be individually evaluated to assess the need for tumor lysis prophylaxis 
prior to the first dose of brentuximab vedotin. Subjects should receive prophylaxis as 
appropriate per the institutional standards. 
5.7.3 Management of Suspected PML  
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 brentuximab vedotin prescribing information for further details. 
If PML is suspected, hold further brentuximab vedotin dosing 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. 
5.7.4 Management of Immune-Adverse Events (Parts B and C only)  
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration from AEs caused by other therapeutic classes. Nivolumab is considered an I-O agent 
in this protocol. Early recognition and management of AEs associated with I-O agents may 
mitigate severe toxicity. Immune-mediated adverse reactions, which may be severe or fatal, 
can occur in any organ system or tissue including the following: 
● 
Immune-mediated pneumonitis 
● 
Immune-mediated colitis 
● 
Immune-mediated hepatitis and hepatoxicity 
● 
Immune-mediated endocrinopathies 
● 
Immune-mediated dermatologic adverse reactions 
● 
Immune-mediated nephritis and renal dysfunction 
The following groups of AEs should be managed per the algorithms found in Appendix I: 
● 
Gastrointestinal 
● 
Renal 


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● 
Pulmonary 
● 
Hepatic, with the following exceptions: 
○ 
Subjects 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 
subject who had a baseline AST level in the Grade 1 range would be per the 
Grade 2 algorithm 
● 
Endocrinopathy 
● 
Skin 
● 
Neurological 
● 
Myocarditis (EU-specific) 
See Section 5.6.2 for allowed high-dose corticosteroid treatment 
5.7.5 Management of Overdose  
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
Brentuximab vedotin  
Weight-based dosing for brentuximab vedotin is based on subject actual body weight (see 
Section 5.2.2), with the exception of subjects weighing greater than 100 kg; doses will be 
based on 100 kg for these individuals. The maximum dose of brentuximab vedotin 
calculated per administration in this study is 120 mg. 
In the event of an overdose of brentuximab vedotin ≥10%, study personnel should: 
● 
Care for and medically stabilize the subject until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of brentuximab vedotin. 
● 
Notify the Medical Monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (e.g., exact amount of brentuximab vedotin administered, 
subject weight) and AEs, if any. 
Nivolumab  
In the event of an overdose of nivolumab, study personnel should: 
● 
Notify the Medical Monitor as soon as they become aware of the overdose 
● 
Closely monitor the subject for AEs, SAEs, and laboratory abnormalities 
● 
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF 


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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
Doxorubicin, Vinblastine, Dacarbazine  
In the event of an overdose of any other study drug (doxorubicin, vinblastine, dacarbazine), 
the event should be managed according to the product label and/or the institutional standard 
of care, and promptly reported to the Sponsor.  
5.8 Treatment Compliance  
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 


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6 
STUDY ACTIVITIES  
6.1 Schedule of Events  
AEs and concomitant medications will be recorded from Day 1 (predose) through the safety 
reporting period (see Section 7.4.1.3). Any study protocol-related AE, as well as any 
concomitant medications given for treatment of the AE, should be recorded from the time of 
informed consent. 
Clinical laboratory assessments (serum chemistry panel, complete blood count [CBC] with 
differential [manual differential if clinically indicated, see Section 7.4.2], and weight) may be 
performed within 1 day prior to administration of study drug. The results from all relevant 
clinical laboratory assessments must be reviewed prior to dosing per institutional standards. 
It is recommended that subjects be monitored for renal and hepatic function per the 
brentuximab vedotin product labeling. 
The schedule of events for Part A and Parts B and C are provided in Appendix A and 
Appendix B, respectively. Study activities are listed by visit in this section and descriptions 
of all study assessments are presented in Section 7. As of Amendment 6, Parts A and B 
were completed. 
6.2 Screening Visit (Day –28 to Day 1)  
● 
Informed consent 
● 
Study eligibility per inclusion/exclusion criteria 
● 
Medical history 
● 
International prognostic score for Part B only (Appendix D) 
● 
Echocardiogram/multi-gated acquisition (MUGA) scan (can be within the past month 
for Parts B and C only) 
● 
Electrocardiogram (ECG) 
● 
CT scan (a CT of diagnostic quality of the chest, neck, abdomen, and pelvis is 
required) 
○ 
CT scans up to 3 days prior to Day -28 (i.e., Day -31) will be accepted 
○ 
To decrease radiation exposure, CT scans of neck will be mandated at Baseline 
only; restaging imaging will only be repeated if neck disease is present at 
Baseline 
● 
PET scan (Note: a CT of diagnostic quality may be combined with PET to satisfy the 
requirements for CT and PET scanning) 
○ 
PET scans up to 3 days prior to Day -28 (i.e., Day -31) will be accepted 
● 
Initiate collection of archived tumor tissue specimen or fresh tumor biopsy 
(Section 7.3.1) (For Parts B and C only) 
● 
CZ only: HBV and HIV serological testing (positive results will result in subject 
being considered ineligible for enrollment) 


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● 
CZ only: HCV PCR testing (positive results will result in subject being considered 
ineligible for enrollment) 
6.2.1 Baseline Visit (Day –7 to Day 1)  
● 
Height and weight (For subjects <18 years, height must be measured at this visit; for 
subjects ≥18 years, height measured within 12 months is acceptable) 
● 
Pregnancy test for subjects of childbearing potential 
● 
Physical exam  
● 
ECOG performance status (Appendix C) 
● 
Hemoglobin A1c 
● 
B symptom assessment 
● 
CBC with differential 
● 
Serum chemistry panel (includes thyroid stimulating hormone [TSH], free T3, and 
free T4; see Section 7.4.27.3.2) 
● 
Estimated glomerular filtration rate (eGFR) calculation per MDRD 
6.3 Treatment Period (Day 1 to Day 28)  
6.3.1 Part A  
6.3.1.1 Part A: Cycles 1–6 Day 1  
● 
Weight 
● 
If Baseline Visit activities occur within 1 day prior to Cycle 1, Day 1, the assessments 
do not need to be repeated at the Cycle 1 Day 1 visit. 
● 
Results from clinical laboratory assessments must be reviewed prior to study drug 
administration, including evaluation of hepatic and renal function. 
○ 
CBC with differential 
○ 
Serum chemistry panel 
● 
A+AVD administration 
● 
Pregnancy test for subjects of childbearing potential 
6.3.1.2 Part A: Cycles 1–6 Days 2–6  
● 
G-PP administration 24 to 36 hours from the last dose of the A+AVD regimen. See 
Section 5.4.3.  
○ 
Pegfilgrastim: 6 mg SC  
○ 
Filgrastim: 5 mcg/kg SC daily for a minimum of 5 days. 
6.3.1.3 Part A: Cycles 1–6 Day 15  
● 
Weight 
● 
Results from clinical laboratory assessments must be reviewed prior to study drug 
administration, including evaluation of hepatic and renal function. 


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○ 
CBC with differential 
○ 
Serum chemistry panel 
● 
A+AVD administration 
6.3.1.4 Part A: Cycles 1–6 Days 16–20  
● 
G-PP administration 24 to 36 hours from the last dose of the A+AVD regimen. See 
Section 5.4.3.  
○ 
Pegfilgrastim: 6 mg SC  
○ 
Filgrastim: 5 mcg/kg SC daily for a minimum of 5 days 
6.3.2 Parts B and C  
6.3.2.1 Parts B and C: Cycle 1 Day 1  
● 
Prior to dosing, confirm subject eligibility per inclusion/exclusion criteria 
● 
If Baseline visit activities occur within 1 day prior to Cycle 1, Day 1, the assessments 
do not need to be repeated at the Cycle 1 Day 1 visit 
● 
CBC with differential  
● 
Serum chemistry panel (should include amylase and lipase along with TSH, free T3, 
and free T4; see Section 7.4.2) 
● 
eGFR (Section 7.4.2) 
● 
Peripheral blood collection for biomarker analyses (Part C only; see Section 7.3.3) 
● 
Results from clinical laboratory assessments must be reviewed prior to study drug 
administration 
● 
Pregnancy test for subjects of childbearing potential 
● 
Physical exam, including weight for dosing  
● 
Doxorubicin and dacarbazine administration (Section 5.3) 
● 
Brentuximab vedotin administration (Section 5.2) 
● 
Nivolumab administration (Section 5.5; approximately 30 minutes after completion of 
BV administration) 
● 
B symptom assessment (not required if completed at Baseline); Note: Subjects will be 
monitored for a period of 2 hours post-infusion of brentuximab vedotin at each visit 
6.3.2.2 Parts B and C: Cycle 1 Day 15  
● 
ECOG Performance status (Appendix C) 
● 
Results from clinical laboratory assessments must be reviewed prior to study drug 
administration: 
○ 
Serum chemistry panel (Section 7.4.2) 
○ 
eGFR (Section 7.4.2) 
○ 
CBC with differential (Section 7.4.2) 
● 
Doxorubicin and dacarbazine administration (Section 5.3) 


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● 
Brentuximab vedotin administration (Section 5.2) 
● 
Nivolumab administration (Section 5.5; approximately 30 minutes after completion of 
BV administration) 
6.3.2.3  Part B: Cycles 2–6 Day 1; Part C: Cycles 2–4 Day 1  
● 
Results from clinical laboratory assessments must be reviewed and must confirm 
eligibility prior to study drug administration 
● 
Serum chemistry panel (for Cycle 3 only, must include TSH, free T3, and free T4; see 
Section 7.4.2)  
● 
eGFR (Section 7.4.2) 
● 
Peripheral blood collection for biomarker analyses (Part C only; Cycles 2 and 4; see 
Section 7.3.3) 
● 
CBC with differential (Section 7.4.2) 
● 
Physical exam, including weight 
● 
Pregnancy test for subjects of childbearing potential 
● 
B-symptom assessment 
● 
ECOG Performance status (Appendix C) 
● 
Doxorubicin and dacarbazine administration (Section 5.3) 
● 
Brentuximab vedotin administration (Section 5.2) 
● 
Nivolumab administration (Section 5.5; approximately 30 minutes after completion of 
BV administration) 
6.3.2.4 Part B: Cycles 2–6 Day 15; Part C: Cycles 2–4 Day 15  
● 
ECOG Performance status (Appendix C) 
● 
CBC with differential 
● 
Serum chemistry panel 
● 
eGFR (Section 7.4.2) 
● 
Doxorubicin and dacarbazine administration (Section 5.3) 
● 
Brentuximab vedotin administration (Section 5.2) 
● 
Nivolumab administration (Section 5.5; approximately 30 minutes after completion of 
BV administration) 
6.3.2.5 Parts B and C: Cycle 2 Disease Status (Days 25-28)  
● 
CT scan (CT of diagnostic quality of the chest, neck, abdomen, and pelvis is 
required). 
○ 
To decrease radiation exposure, CT scans of neck will be mandated at Baseline 
only; restaging imaging will only be repeated if neck disease is present at 
Baseline. 
● 
PET scan.  
Note: a CT of diagnostic quality may be combined with PET to satisfy the 


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requirements for CT and PET scanning. Refer to Section 7.2 for further guidance on 
Deauville scale grading for PET scans.  
6.4 End of Treatment Visit (30 to 37 days after last dose of study drug)  
EOT visits should occur 30 to 37 days after the last dose of study drug unless delayed due to 
an AE. However, EOT evaluations must be performed before initiation of a new therapy. If 
EOT evaluations are completed before 30 days after the last study treatment, the subject will 
be contacted 30 to 37 days following the last treatment to assess for AEs.  
● 
Pregnancy test for subjects of childbearing potential (Parts B and C only) 
● 
ECOG performance status (Appendix C) 
● 
Physical exam 
● 
CBC with differential (see Section 7.4.2) 
● 
Serum chemistry panel (for Parts B and C, must include TSH, free T3, and free T4; 
see Section 7.4.2) 
● 
eGFR (Section 7.4.2) 
● 
Peripheral blood collection for biomarker analyses (Part C only, see Section 7.3.3) 
● 
Hemoglobin A1c 
● 
CT of diagnostic quality of neck, chest, abdomen, and pelvis 
○ 
To decrease radiation exposure, CT scans of neck will be mandated at Baseline 
only; restaging imaging will only be repeated if neck disease is present at 
Baseline. 
● 
PET scan (Note: a CT of quality may be combined with PET to satisfy the 
requirements for CT and PET scanning) 
○ 
No CT or PET scan is required if the subject had CT/PET scans within a week 
prior to EOT or if the subject discontinued due to radiographically confirmed PD. 
● 
B symptom assessment 
6.5 Parts B and C: Safety Visit (100 to 114 days after last dose of nivolumab, 
or 30 to 37 days after last dose of study medication other than nivolumab, 
whichever is later)  
The final safety visit should occur 100 to 114 days after the last dose of nivolumab or 
30 to 37 days post last dose of brentuximab vedotin, doxorubicin, or dacarbazine (concurrent 
with the EOT visit), whichever is later. The following assessments will be performed: 
● 
Physical exam, including assessment for potential immune-mediated AEs 
● 
Serum chemistry panel (Section 7.4.2) 
● 
eGFR (Section 7.4.2) 
● 
CBC with differential (Section 7.4.2) 
● 
Record disease status, survival status, and any subsequent anticancer therapies 
received. 


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6.6 Long-term Follow-up  
6.6.1 Part A  
Subjects will remain in follow-up until death, withdrawal of consent, or completion of 
2 years of long-term follow-up (from EOT visit), whichever occurs first.  
Subjects will be followed for disease status assessment per investigator until disease 
progression; subjects will be followed for survival and subsequent anticancer therapy 
thereafter. 
Follow-up visits will occur every 12 (±1) weeks from the EOT visit. 
Subjects who withdraw from study treatment due to PD will not have disease status assessed 
but will continue to be followed for survival and subsequent anticancer therapy.  
6.6.2 Parts B and C  
Subjects who do not have confirmed disease progression will have the following assessments 
every 3 months after the EOT visit for the first year (3 months, 6 months, 9 months, and 
1 year), and every 6 months for an additional 2 years: 
● 
Dedicated CT of chest, neck, abdomen, and pelvis; performed at the timepoints above 
and if progression is suspected based on clinical signs and symptoms 
○ 
To decrease radiation exposure, CT scans of neck will be mandated at Baseline 
only; restaging imaging will only be repeated if neck disease is present at 
Baseline 
● 
PET; performed in addition to CT scans if CT is positive at the prior timepoint in 
PET-negative disease (Refer to Section 7.2 for further guidance on Deauville scale 
grading for PET scans)  
● 
Physical examination 
● 
Disease status  
● 
SAEs related to treatment 
Subjects will then continue in follow-up for 2 additional years (5 years total). For the final 2 
years, a physical exam should be performed every 6 months and a dedicated CT of chest, 
neck, abdomen, and pelvis should be performed every 12 months. CT scans of neck will only 
be repeated if neck disease is present at Baseline. 
All subjects, including those who have progressed and/or have started a subsequent therapy 
to treat progressive or relapsed cHL, will have the following assessments: 
● 
Survival status and subsequent anticancer therapies received  
Note: 3-month follow-up may be performed with 100-day safety visit 
● 
Resolution of PN, if applicable 
● 
SAEs related to treatment 


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For Part C only, peripheral blood may be collected at the time of disease progression if the 
subject has provided additional consent (see Section 7.3.3). 
6.7 End of Follow-up  
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 
7 
STUDY ASSESSMENTS  
7.1 Screening/Baseline Assessments  
Only subjects who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Subject 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.  
7.2 Response/Efficacy Assessments  
In Part A, the determination of antitumor activity will be based on response assessments 
made according to the Lugano Classification Revised Staging System for nodal non-Hodgkin 
and Hodgkin lymphomas (Cheson 2014). In Parts B and C, the determination of antitumor 
activity will be based on objective response assessments made according to Lugano 
Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the 
incorporation of Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) 
(Appendix F) (Cheson 2016). Treatment decisions by the investigator will be based on these 
assessments.  
Staging will be performed by CT of diagnostic quality and PET scan, with disease 
involvement determined by focal fluorodeoxyglucose (FDG) uptake in nodal and extranodal 
(including spleen, liver, bone marrow, and thyroid) sites that is consistent with lymphoma, 
according to the pattern of uptake and/or CT characteristics. A CT of diagnostic quality may 
be combined with the PET scan when both are required per protocol. Up to 6 of the largest 
nodes, nodal masses, or other involved lesions that are measurable in 2 diameters should be 
identified as target lesions at baseline; 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. 
Progressive metabolic disease (PmD), no metabolic response (NmR), partial metabolic 
response (PmR), or complete metabolic response (CmR) will be determined using PET-based 
response at each assessment. If only CT-based assessment is performed, response will be 
categorized as progressive disease (PD), stable disease (SD), partial response (PR), or 
complete response (CR). In Parts B and C, if tumor flare or pseudo-progression is suspected, 
a determination should not be made at that time. PmD/PD includes radiological evidence of 
progression per Lugano classification criteria (Part A); for Parts B and C, incorporate 
LYRIC. If clinical progression is determined by the investigator, radiographic staging should 


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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. 
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. 
Treatment with checkpoint inhibitors, such as nivolumab in Parts B and C, can result in false 
positive PET imaging. LYRIC criteria recommends repeat PET imaging and/or biopsy to 
further evaluate PET-positive (D4 or D5) lesions identified at the EOT response assessment. 
Repeat PET imaging and/or biopsy is required to further evaluate PET-positive PD. 
If tumor flare or pseudo-progression is suspected by the investigator during subject treatment 
in Parts B or C, then a clinical response of indeterminate response (IR) will be determined 
until subsequent evaluation of radiographic imaging or biopsy confirms or refutes PD. There 
are 3 categories of IR, as follows: 
1. IR1: An increase in overall tumor burden (as assessed by the sum of the product of the 
diameters [SPD]) of ≥50% of up to 6 measurable lesions in the first 12 weeks of therapy, 
without clinical deterioration; 
2. IR2: Appearance of new lesions, or growth of 1 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. IR3: An increase in FDG uptake of 1 or more lesion(s) without a concomitant increase in 
lesion size or number. 
See Appendix F for further details and criteria for follow-up of a determination of IR. 
For subjects 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 subject 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 subjects with IR is not required if a follow-up biopsy has been performed that 
confirms the subject's response. If the subject continues in follow up after confirmation, 
subsequent follow-up visits should be per the schedule of events. 
Subjects’ 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.  


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7.3 Biomarker Studies  
Biomarker assessments will be performed in tumor tissue as outlined in Section 7.3.2. If a 
tumor sample is obtained as part of standard of care during the study, a part of that sample 
should be submitted to the sponsor for biomarker testing. 
7.3.1 Tumor Biopsy (Parts B and C)  
Subjects in Parts B and C must provide tumor tissue for biomarker analysis. Availability of 
archival tumor tissue (non-bone sites) must be confirmed prior to enrollment. A formalin 
fixed paraffin-embedded (FFPE) tumor tissue block is preferred. If a FFPE tumor tissue 
block is not available, the investigator should consult with the medical monitor. For Part C 
only, subjects who provide additional consent may provide optional biopsy tissue at the time 
of progression. 
Biomarker assessments will not be used for subject selection. Correlative studies will be 
conducted to gain a better understanding of target-response relationship, predictive 
biomarkers, mechanism of action, and possible resistance mechanisms. 
7.3.2 Biomarkers in Tumor Tissue (Parts B and C)  
To understand the relationship between the biological characteristics of tumors before 
treatment and subject outcomes, tissue from pre-treatment specimens will be examined. 
Biopsies will be assessed for specific, predictive, and prognostic biomarkers in the tumor. If 
tissue is available from a standard of care biopsy collected after enrollment, it may also be 
examined. Biomarker assessments in tumor tissue may include, but are not limited to, PD-L1, 
characterization of the tumor microenvironment, tumor subtyping, profiling of somatic 
mutations or alterations in genes or RNA commonly altered in cancer, and drug effects. 
Assays may include, but are not limited to, immunohistochemistry and next generation 
sequencing of RNA and DNA. 
7.3.3 Biomarkers in Peripheral Blood (Part C Only)  
For Part C only, peripheral blood samples will be taken prior to initiation of study therapy, 
on-treatment, post-treatment, and at progression (Appendix B). Sample collection at the time 
of disease progression is optional and will be collected from subjects who give additional 
consent. 
Analysis of peripheral blood samples will include, but are not limited to, peripheral blood 
mononuclear cells, plasma, serum, circulating tumor-free DNA, and/or RNA/DNA from 
whole blood. These analyses will assess biomarkers associated with disease or treatment 
outcomes. 
7.4 Safety Assessments  
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, recording of concomitant medication, and measurements 
of protocol-specified physical examination findings and laboratory tests. 


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In Parts B and C, the safety of AN+AD will be assessed by the SMC. The SMC will review 
accumulating safety data after approximately 10 subjects have completed Cycle 2. If the 
SMC determines that the risks outweigh the benefits of AN+AD, the sponsor may choose to 
halt enrollment in Parts B or C of the study. 
7.4.1 Adverse Events  
7.4.1.1 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 subject 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 (during and post-dose) through the end of the safety reporting period (see 
Section 7.4.1.3). 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 an 
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” rather than “low hemoglobin”). 


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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 subject 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 resulted in hospitalization or prolonged an existing insubject 
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: 
An AE that resulted in a persistent or significant incapacity or 
substantial disruption of the subject’s ability to conduct normal life 
functions. 
Congenital 
anomaly or birth 
defect: 
An adverse outcome in a child or fetus of a subject 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 subject 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. Potential drug-induced liver injury (DILI) also is considered a 
medically significant event (see Section 7.4.1.2 for the definition of 
potential DILI.) 
 
Adverse Event Severity  
AE severity should be graded using the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (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, above). 


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Relationship of the Adverse Event to Study Treatment  
The relationship of each AE to each study treatment (A+AVD or AN+AD) 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: 
• A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic 
injury, Stevens-Johnson Syndrome) 
• One or more occurrences of 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 (IB) for BV and nivolumab individually 
describe adverse events commonly observed relative to either agent (i.e., 
neutropenia or PN with brentuximab vedotin; immune-mediated adverse 
events with nivolumab), as well as less common serious findings. The 
respective IB should be referenced when attributing causality; however, the 
final decision regarding causality is at the discretion of the investigator. 
 
7.4.1.2 Procedures for Eliciting and Recording Adverse Events  
Investigator and study personnel will report all AEs and SAEs whether elicited during 
subject 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 SAE criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 


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Diagnosis vs 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 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
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. 
Important exceptions for this study are adverse reactions associated with the infusion of 
study drug. For infusion-related reactions, record as both the NCI CTCAE terms of ‘cytokine 
release syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity reaction’ and 
record each sign or symptom as an individual AE. The level of severity for the overall 
infusion-related reaction and each sign or symptom should be recorded separately. 
Recording Serious Adverse Events  
For SAEs, record the event(s) on the AE 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 the AE 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  
Since progression of underlying malignancy is being assessed as an efficacy variable, it 
should not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of 
Disease”, or “Malignant disease progression” and other similar terms should not be used to 
describe an AE or SAE. However, clinical symptoms of progression may be reported as AEs 
or SAEs if the symptom cannot be determined as exclusively due to progression of the 
underlying malignancy or does not fit the expected pattern of progression for the disease 
under study. In addition, complications from progression of the underlying malignancy 
should be reported as AEs or SAEs. 
Peripheral Neuropathy  
PN TEAEs which are ongoing, newly occurring, or worsen during the safety reporting period 
will be followed during long-term follow-up and recorded in the electronic case report form 
(eCRF). These events could include, but are not limited to peripheral sensory neuropathy, 
peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, muscular weakness, 
and demyelinating polyneuropathy. Such events, regardless of seriousness, are to be followed 
for all changes in severity until the sooner of resolution to baseline or study closure. 
Brentuximab vedotin dose modification guidelines were provided for PN events higher than 
Grade 1 as shown in Table 4.  


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Immune-mediated Adverse Events  
Every AE must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events that are potentially immune-mediated, additional information 
will be collected on the subject’s CRF. 
IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated 
component for which non-inflammatory etiologies (e.g., infection or tumor progression) have 
been ruled out. IMAEs can include events with an alternate etiology which were exacerbated 
by the induction of autoimmunity. Information supporting the assessment will be collected 
on the subject’s CRF. 
Pregnancy  
Female subjects are advised to avoid pregnancy during treatment and for at least 7 months 
after the final dose of study drugs (Appendix G). Male subjects are advised that brentuximab 
vedotin may damage spermatozoa and testicular tissue, resulting in possible genetic 
abnormalities. Male subjects with partners of childbearing potential are required to use 
effective contraception during study treatment and for at least 7 months after the final dose of 
study drugs. 
Notification to Drug Safety  
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 7 months after the last dose of study drug(s), including any pregnancies that 
occur in the partner of a male study subject. Only report pregnancies that occur in a male 
subject’s partner if the estimated date of conception is after the male subject’s first study 
drug dose. Email or fax to the sponsor’s Drug Safety Department within 24 hours of 
becoming aware of a pregnancy. As part of this study, all pregnancies will be monitored for 
the full duration; and 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 30 days of the last dose of study 
drug(s), will also be recorded on the Adverse Events and Pre-Existing Conditions CRF. 
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 7.4.1.1) should be reported as SAEs. 


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Potential Drug-Induced Liver Injury  
The observation of the critical importance of altered liver function has been referred to 
informally as Hy’s Law (Reuben 2004). Hy’s Law can be used to estimate severity and the 
likelihood that a study drug may cause an increased incidence of severe hepatotoxicity. 
The absence of hepatotoxicity in clinical trials provides a limited predictive value for 
potential hepatotoxicity in the clinical setting(s) being studied. However, finding 1 Hy’s Law 
case in clinical trials is ominous; finding 2 cases is highly predictive of a potential for severe 
DILI. 
Definition  
Briefly, potential Hy’s Law cases include the following 3 components: 
1. Aminotransferase (ALT and/or AST) elevation >3xULN 
AND 
2. Total bilirubin >2xULN, without initial findings of cholestasis (i.e., elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
Reporting Requirements  
Any potential Hy’s Law case should be handled as a serious adverse reaction associated 
with the use of the drug and reported promptly to the Sponsor on an SAE form. 
Reporting should include all available information and should initiate close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary 
data. 
Follow-up for Abnormal Laboratory Results Suggesting Potential DILI  
In general, an increase of serum ALT or AST to >3xULN should be followed by repeat 
testing within 48 to 72 hours of serum ALT, AST, alkaline phosphatase, and total bilirubin, 
to confirm the abnormalities and to determine whether they are worsening. 
Appropriate medical assessment should be initiated to investigate potential confounding 
factors and alternative causes of hepatotoxicity. During this investigation, consider 
withholding study drug. 


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7.4.1.3 Reporting Periods for Adverse Events, Serious Adverse Events, and 
Adverse Events of Clinical Interest  
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 study drug administration (Part A), 30 days after the last 
dose of brentuximab vedotin, doxorubicin, dacarbazine or 100 days after the last dose of 
nivolumab, whichever is later (Parts B and C only). 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 subject dies or withdraws consent. For Parts B and C, any SAEs or TEAEs of PN will be 
followed until resolution, return to baseline, or study closure. 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.  
7.4.1.4 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 a SAE form. At a 
minimum, the following should be included: 
● 
Subject number 
● 
Date of event onset 
● 
Description of the event 
● 
Study treatment, if known 
● 
Investigator causality assessment 
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).  
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 


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7.4.2 Clinical Laboratory Tests  
The following laboratory assessment(s) will be performed by local laboratories at scheduled 
timepoints (see Appendix A for Part A and Appendix B for Parts B and C) 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, eGFR, glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, and uric acid. 
For Parts B and C, the chemistry panel should also include amylase and lipase; 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, hemoglobin, and hematocrit.  
● 
Hemoglobin A1c. 
● 
The estimated GFR should be calculated using the MDRD equation as applicable for 
subjects ≥18 years old, with serum creatinine (Scr) reported in mg/dL.  
 
GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
African American). 
● 
The estimated GFR should be calculated using the bedside Schwartz formula for 
subjects <18 years old, with Scr reported in mg/dL. 
eGFR = 0.43 x (height/Scr). 
● 
A serum or urine β-hCG pregnancy test for subjects of childbearing potential.  
Except for pregnancy testing, results of clinical laboratory tests are to be submitted to a 
central repository. 
7.4.3 Physical Examination  
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Vital signs (blood pressure, 
heart rate, and temperature) will also be assessed. For adult subjects, measurements of height 
obtained within the prior 12 months may be utilized. Weight should be obtained for accurate 
dose calculation. 
7.4.4 Sponsor Safety Reporting to Regulatory Authorities  
Investigators are required to report all SAEs to the sponsor (see Section 7.4.1.4). The sponsor 
will report all SAEs, including suspected unexpected serious adverse reactions (SUSARs) to 
regulatory authorities as required per local legislation or regulatory reporting requirements. 
 


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7.5 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. 
Response will be assessed according to the Lugano Classification Revised Staging System 
for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014) in Part A, incorporating 
LYRIC in Parts B and C, which are standardized criteria for evaluating response in Hodgkin 
lymphoma. The intervals of evaluation in this protocol are considered appropriate for disease 
management. 


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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 subjects at the site, Seagen Inc. 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 
● 
Recording and reporting AEs and SAEs 
● 
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 
approval process 
● 
Informed consent process 
● 
Good clinical practice guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
Subject coding and randomization (if applicable) 
● 
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 Seagen Inc. representative will 
typically 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 subjects, 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 Seagen Inc. or its designated monitors and by quality assurance 
auditors, or representatives of regulatory authorities. 
8.2 Data Management Procedures  
Seagen Inc. 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. 


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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 subject confidentiality are to be employed 
during monitoring. The CRFs and related source documents will typically 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 records must also be available for inspection by representatives of 
regulatory authorities and the 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 during monitoring visits to the 
study centers and/or by centralized monitoring. Any discrepancies will be resolved 
with the investigator or designees as appropriate. 
8.5 Quality Assurance Procedures  
The Research and Development Quality 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 group of Seagen Inc. 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 
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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, insubject or office subject records) for the 
maximum period required by the country and Institution in which the study will be 
conducted, or for the period specified by Seagen Inc., whichever is longer. The investigator 
must contact Seagen Inc. 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 Seagen Inc. 
9 
DATA ANALYSIS METHODS  
An overview of study outcome measurements is provided in Table 7. 
 


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Table 7: 
Overview of Study Outcome Measurements – Part A 
Primary Objective 
Corresponding Primary Endpoint 
Corresponding Measurement 
Timeframe 
● To assess the treatment-emergent 
febrile neutropenia rate in subjects 
with previously untreated, advanced 
stage, cHL treated with A+AVD and 
G-CSF primary prophylaxis (G-PP) 
● The febrile neutropenia rate in subjects 
treated with A+AVD and G-PP 
● Proportion of subjects with 
treatment-emergent FN. 
● EOT 
Secondary Objectives 
Corresponding Secondary Endpoints 
Corresponding Measurements 
Timeframes 
● To assess the incidence and severity of 
adverse events of clinical interest 
● The rates and severity of each AECI 
● Proportion of subjects with 
treatment-emergent FN. 
● Duration of study 
● To assess dose intensity, dose 
reductions, and dose delays related to 
any component of A+AVD 
● Mean dose intensity; the rates of dose 
reduction and dose delays related to 
any component of A+AVD 
● Mean dose intensity; proportion of 
subjects with dose reduction; 
proportion of subjects with dose 
delays. 
● EOT 
● To assess primary refractory disease 
rates 
● The rate of primary refractory disease 
● Proportion of subjects with primary 
refractory disease. 
● Within 3 months of EOT 
● To assess subsequent anticancer 
therapy utilization 
● The rates of each subsequent 
anticancer therapy taken by subjects 
● Proportion of subjects with 
subsequent anticancer therapies. 
● Duration of study 
● To assess end of treatment complete 
response rates 
● The complete response rate at EOT 
● Proportion of subjects with 
complete response at EOT. 
● EOT 
● To assess physician-reported 
progression-free survival rate at 
2 years 
● The physician-reported PFS  
● PFS rate at 2 years. 
● 2 years from treatment start date 


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Table 8: 
Overview of Study Outcome Measurements – Parts B and C 
Primary Objective 
Corresponding Primary Endpoint 
Corresponding Measurement 
Timeframe 
● To assess the complete response (CR) 
rate at EOT with AN+AD in subjects 
with previously untreated cHL 
● CR rate at EOT 
● CR rate  
● EOT 
Secondary Objectives 
Corresponding Secondary Endpoints 
Corresponding Measurements 
Timeframes 
● To assess the safety and tolerability of 
AN+AD 
● The rates of each AE 
● Incidence, severity, seriousness, 
and duration of AEs. 
● Incidence and severity of lab 
abnormalities 
● Duration of study 
● To assess the overall response rate 
(ORR) 
● Estimate the ORR  
● ORR at EOT  
● EOT 
● To assess the duration of response 
(DOR) 
● Assess the DOR 
● Time point estimates for DOR 
● Duration of study 
● To assess the duration of complete 
response (DOCR) 
● Assess the DOCR 
● Time point estimates for DOCR 
● Duration of study 
● To assess the event-free survival (EFS) ● Assess EFS  
● Time point estimates for EFS 
● Duration of study 
● To assess the progression-free survival 
(PFS) 
● Assess PFS  
● Time point estimates for PFS 
● Duration of study 
● To assess the overall survival (OS)  
● Assess OS 
● Time point estimates for OS 
● Duration of study 


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9.1 Determination of Sample Size  
For Part A, approximately 40 subjects will be enrolled in order to provide an adequate level 
of precision for the estimate of the FN rate. If 4 of 40 subjects experience FN, the FN rate is 
10% with 95% CI (2.8%, 23.7%) based on the exact Clopper-Pearson method (Clopper 
1934); if 2 of 40 subjects experience FN, the FN rate is 5% (95% CI: 0.6%, 16.9%); if 6 of 
40 subjects experience FN, the FN rate is 15% (95% CI: 5.7%, 29.8%).  
For Part B, approximately 50 subjects will be enrolled in order to provide an adequate level 
of precision for the estimate of the CR rate at EOT. If 45 of 50 subjects have a CR at EOT, 
the CR rate at EOT is 90% with 95% CI (78.2%, 96.7%) based on the exact Clopper-Pearson 
method (Clopper 1934); if 42 of 50 subjects have a CR at EOT, the CR rate at EOT is 
84% (95% CI: 70.9%, 92.8%) ; if 48 of 50 subjects have a CR at EOT, the CR rate at EOT is 
96% (95% CI: 86.3%, 99.5%). The 73% CR rate at EOT observed in the A+AVD arm in the 
ECHELON-1 trial was considered the relevant benchmark when determining an appropriate 
sample size for Part B (Connors 2018). 
For Part C, approximately 150 subjects will be enrolled in order to provide an adequate 
power to reject the hypothesis that CR rate at EOT is ≤90%. Assuming a CR rate of 95%, 
150 subjects would provide approximately 80% power to reject the null hypothesis of a CR 
rate at EOT ≤90% with a 1-sided alpha = 0.05 and using an empirical variance estimate (East 
v6.4). This sample size calculation accounts for the interim futility analysis which is further 
described in Section 9.3.8.  
9.2 Study Endpoint Definitions  
9.2.1 Part A  
9.2.1.1 Febrile Neutropenia Rate  
The FN rate is defined as the proportion of subjects who experience treatment-emergent FN. 
9.2.1.2 Primary Refractory Disease Rate  
The primary refractory disease rate is defined as the proportion of subjects with less than CR 
or relapse within 3 months of EOT, according to the Lugano Classification Revised Staging 
System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014).  
9.2.1.3 Complete Response Rate at EOT  
The complete response rate is defined as the proportion of subjects with CR at EOT 
according to the Lugano Classification Revised Staging System for nodal non-Hodgkin and 
Hodgkin lymphomas (Cheson 2014). Subjects who do not have a post-baseline assessment 
will be scored as non-responders for calculating the CR.  
9.2.1.4 Physician-Reported Progression Free Survival  
The physician-reported PFS is defined as the time from start of study treatment to first 
documentation of progression per investigator or to death due to any cause, whichever comes 


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first. Subjects without progression or death will be censored; censoring details will be 
provided in the SAP. 
9.2.1.5 End of Treatment PET Negativity Rate  
End of treatment PET negativity rate is defined as the proportion of subjects who are PET 
negative at EOT. Subjects are considered PET negative at EOT if they have a Deauville 
score ≤3 at EOT. 
9.2.2 Parts B and C  
9.2.2.1 Complete Response Rate at EOT  
CR rate at EOT is defined as the proportion of subjects with CR at EOT, according to the 
Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) with 
the incorporation of LYRIC (Cheson 2016), in subjects with previously untreated cHL. 
Subjects who do not have a post-baseline assessment will be scored as non-responders for 
calculating the CR rate at EOT.  
9.2.2.2 Objective Response Rate  
ORR is defined as the proportion of subjects with CR or partial response (PR) at EOT 
according to the Lugano Classification Revised Staging System for malignant lymphoma 
(Cheson 2014) with the incorporation of LYRIC (Cheson 2016) in subjects with previously 
untreated cHL.  
9.2.2.3 Duration of Response  
Duration of response (DOR) is defined as the time from the first documentation of objective 
tumor response (CR or PR) to the first documentation of tumor progression (per the Lugano 
Classification Revised Staging System for malignant lymphoma (Cheson 2014) with the 
incorporation of LYRIC (Cheson 2016)) or death, whichever comes first. Subjects without 
progression or death will be censored; details will be provided in the statistical analysis plan 
(SAP). Duration of response will only be calculated for the subgroup of subjects achieving a 
CR or PR. 
Duration of complete response (DOCR) is defined as the time from start of the first 
documentation of complete tumor response (CR) to the first documentation of tumor 
progression (per the Lugano Classification Revised Staging System for malignant lymphoma 
(Cheson 2014) with the incorporation of LYRIC (Cheson 2016)) or death, whichever comes 
first. DOCR will only be calculated for the subgroup of subjects achieving CR. Censoring 
will be in a manner similar to DOR. 
9.2.2.4 Event-free Survival  
Event-free survival (EFS) is defined as the time from the start of study treatment to the first 
documentation of objective tumor progression, death due to any cause, or receipt of 
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Subjects without progression, death, or receipt of subsequent anticancer therapy to treat 
residual or progressive disease will be censored; details are provided in the SAP. 
9.2.2.5 Progression-free Survival  
PFS is defined as the time from start of study treatment to first documentation of objective 
tumor progression or death. Subjects without progression or death will be censored; details 
are provided in the SAP. 
9.2.2.6 Overall Survival  
Overall survival is defined as the time from start of study treatment to date of death due to 
any cause. In the absence of confirmation of death, survival time will be censored at the last 
date the subject is known to be alive.  
9.3 Statistical and Analytical Plan  
The statistical and analytical plan presented below summarizes the more complete plan to be 
detailed in the statistical analysis plan (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). 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  
In general, descriptive statistics will be presented that include the number of observations, 
mean, median, standard deviation, minimum and maximum for continuous variables, and the 
number and percentages for categorical variables. 
Unless otherwise specified, CIs will be calculated at the 2-sided 95% level. 
The 2-sided 95% exact CI using the Clopper-Pearson method (Clopper 1934) will be 
calculated for the response rates where applicable (e.g., ORR). 
For time-to-event endpoints, analyses will be performed using Kaplan-Meier methodology. 
Kaplan-Meier curves will be presented. KM rates and the associated 95% CI will be 
calculated based on the complementary log-log transformation (Collett 1994). 
9.3.1.1 Adjustments for Covariates  
No covariate adjustment is planned in the analyses. 
9.3.1.2 Handling of Dropouts and Missing Data  
With the exception of time-to-event endpoints, no imputation will be conducted for missing 
data unless otherwise specified in the SAP. 
Subjects who do not have at least 1 post-baseline response assessment as specified in 
Section 7.2 will be counted as non-responders. 


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9.3.1.3 Multicenter Studies  
There are multiple centers in this study, however it is not anticipated that any center will 
accrue enough subjects to warrant an analysis by center. Site-to-site variation will not be 
adjusted in the analyses. 
9.3.1.4 Multiple Comparisons and Multiplicity  
No multiple comparisons or multiplicity adjustment is planned for this study. No formal 
hypothesis test will be performed. 
9.3.1.5 Data Transformations and Derivations  
Time variables based on 2 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. 
Baseline values used in statistical analyses will be the most recent non-missing measurement 
prior to the first dose of BV unless otherwise specified in the SAP. 
9.3.1.6 Analysis Sets  
Full Analysis Set  
For Part A, the full analysis set (FAS) includes all subjects who receive at least 1 dose of 
A+AVD (any of the study drugs in the regimen). The FAS will be used for all safety and 
efficacy analyses. Subject demographics and baseline disease characteristics will be 
summarized based on FAS. 
For Parts B and C, the full analysis set will include all subjects who are enrolled and receive 
any amount of the combination therapy in the study. A subject is considered enrolled if 
he/she has met all criteria for participation in the study and has Seagen Inc. approval as 
documented in the eCRF. The full analysis set will be used as the primary dataset for efficacy 
and safety analysis. Subject demographics and baseline disease characteristics will be 
summarized based on the full analysis set. 
Per-protocol Analysis Set  
For Part A, the per-protocol analysis set (PPS) includes all FAS subjects who received G-PP 
and did not have any important protocol deviations. The PPS will be used for the analysis for 
primary endpoint and may be used for analyses for selected secondary endpoints. 
9.3.1.7 Examination of Subgroups  
Subgroup analyses may be carried out for some endpoints. Detailed methodology will be 
provided in the SAP. 
9.3.1.8 Timing of Analyses for Part A  
The primary analysis will be performed when all subjects in the full analysis set for Part A 
have completed the safety reporting period. 


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9.3.1.9 Timing of Analyses for Parts B and C  
The primary analysis for each part will be performed when all subjects in the full analysis set 
for that part have had their status determined for the primary endpoint of CR rate at EOT. 
9.3.2 Subject Disposition  
The number of subjects enrolled, treated with A+AVD or AN+AD, and completing the study 
will be summarized. An accounting of study subjects by disposition will be tabulated and the 
number of subjects in each analysis set will be summarized. Subjects who discontinue study 
treatment will be summarized by reason for discontinuation and will be listed with the timing 
and reason for discontinuation. Subjects who withdraw from the study will be summarized by 
reason for withdrawal and will be listed with the timing and reason for withdrawal or 
termination. 
9.3.3 Subject 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/dose for each treatment agent will be assessed and dose 
intensity will be summarized. For Parts B and C, treatment administration will be 
summarized for the full analysis set. Summary statistics for duration of therapy (weeks) and 
the number of cycles per subject will be presented, as well as the number and percentage of 
subjects who were treated at each cycle and completed each cycle. 
Details will be provided in the SAP. 
9.3.5 Efficacy Analyses  
9.3.5.1 Primary Efficacy Analyses – Part A  
For Part A, the rate of FN is the primary endpoint. FN rate and the exact 2-sided 95% CIs 
using the Clopper-Pearson method (Clopper 1934) will be calculated.  
9.3.5.2 Primary Efficacy Analyses – Parts B and C  
For Parts B and C, the CR rate at EOT is the primary endpoint. CR rate at EOT will be 
summarized according to investigator. CR rate at EOT and the exact 2-sided 95% CIs using 
the Clopper-Pearson method (Clopper 1934) will be calculated. 
For Part C a hypothesis test will be performed. The null and alternative hypotheses are: 
• Null hypothesis: CR rate at EOT ≤90% 
• Alternative hypothesis: CR rate at EOT >90% 
The null hypothesis will be tested at a 1-sided alpha of 0.05. The associated p-value will be 
calculated based on the normal approximation with an empirical estimate of the variance. If 
p <0.05 is observed, the null hypothesis will be rejected in favor of the alternative hypothesis. 


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If enrollment in Part C is stopped prior to completion, no hypothesis testing will be 
performed. 
9.3.5.3 Secondary Efficacy Analyses – Part A  
For Part A, the primary refractory disease rate, the complete response rate and the EOT PET 
response rate will be derived and its two-sided 95% exact binomial CI will be presented 
(Clopper 1934).  
The physician-reported PFS rate and OS rate will be based on Kaplan-Meier methodology 
and Kaplan-Meier plots will be presented. For PFS, the 2 year rate and the associated 95% CI 
will be presented. 
9.3.5.4 Secondary Efficacy Analyses – Parts B and C  
For Parts B and C, ORR at EOT and the exact 2-sided 95% CIs using the Clopper-Pearson 
method (Clopper 1934) will be calculated. 
Secondary endpoints of DOR, EFS, PFS, and OS are time-to-event endpoints and will be 
analyzed using Kaplan-Meier methodology. Kaplan-Meier plots will be presented and event 
rates at a range of follow-up times and their associated 95% CIs will be presented; EFS and 
PFS rates at 1 and 2 years and the associated 95% CIs will be presented. Further analysis 
details will be provided in the SAP. 
Detailed methodology will be provided in the SAP. 
9.3.6 Pharmacokinetic and Immunogenicity Analyses  
No pharmacokinetic or immunogenicity analyses will be performed. 
9.3.7 Safety Analyses  
9.3.7.1 Extent of Exposure  
For Part A, exposure of each treatment agent, including duration of each treatment per cycle, 
number of cycles, total dose, dose modifications (delays, holds, and reductions), cumulative 
dose, and dose intensity will be summarized and listed using the FAS.  
The number of subjects who received pegylated as well as non-pegylated G-CSF will be 
summarized by cycle as well as the duration of each. A breakdown of the types of G-CSF 
medications will be provided. 
For Parts B and C, duration of treatment will be summarized and listed. 
Duration of treatment, number of cycles, total dose and dose intensity will be summarized. 
Dose modifications will also be summarized. 
Details will be provided in the SAP. 


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9.3.7.2 Adverse Events  
An overview of AEs will be presented, including a tabulation of the incidence of all AEs, 
TEAEs, treatment-related AEs, grade 3 and higher AEs, SAEs, treatment-related SAEs, 
deaths, and AEs leading to study treatment discontinuation. Adverse events will be defined 
as treatment emergent if they are newly occurring or worsen following study treatment. 
Adverse events will be classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) and graded using NCI CTCAE, 
Version 4.03.  
AEs will also be listed and summarized by preferred term, severity, and relationship to study 
drug. The incidence of AEs will be tabulated by preferred term. AEs leading to premature 
discontinuation of a study drug will be summarized and listed in the same manner. 
For Part A, AEs will be assessed during the study from Day 1 dosing and through 30 days 
following last dose of study drug. For Parts B and C, AEs will be assessed during the study 
from Day 1 dosing and through 30 days following the last dose of brentuximab vedotin, 
doxorubicin, or dacarbazine, or 100 days following the last dose of nivolumab, whichever is 
later. Certain non-serious AEs of interest may be followed until resolution, return to baseline, 
or study closure. 
9.3.7.3 Deaths and Serious Adverse Events  
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be listed. 
9.3.7.4 Clinical Laboratory Results  
For laboratory results, summary statistics for actual values and for change from baseline may 
be tabulated as appropriate by scheduled visit. Laboratory values will be listed with grade per 
NCI CTCAE Version 4.03 and flagged when values are outside the normal reference range. 
9.3.7.5 Pregnancies  
Pregnancies in female subjects and in female partners of male subjects will be summarized as 
well as the outcomes of these pregnancies.  
9.3.8 Interim Analyses  
The SMC will be responsible for monitoring patient safety in Parts B and C of the study (see 
Section 7.4). 
One interim futility analysis will be performed for Part C after approximately 50 subjects 
have completed response assessment at EOT. At this interim futility analysis, if the CR rate 
at EOT is ≤80% (40/50 or fewer subjects with CR at EOT), the sponsor in consultation with 
the SMC may decide to stop further enrollment of Part C of the trial.  


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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. 


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10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS  
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 (R2); 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 subjects 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 subject, or legally acceptable 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 acceptable representative for a subject who is 
unable to provide informed consent at study entry (if applicable), but the subject is later able 
to provide informed consent, the investigator must obtain written informed consent from the 
subject. 
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 
● 
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. 
● 
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. 


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10.3 Regulatory Considerations  
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, 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  
Protocol amendments will be submitted to the IRB/IEC prior to implementing. The 
investigator is responsible for enrolling subjects 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  
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the investigator until notified 
by the sponsor in writing that retention is no longer necessary. 
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 subject 
medical records in the subject 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 subject medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the subject 
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 subject 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. 
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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CheckMate 205 study. J Clin Oncol. 2019;37(23):1997-2007. 
 
Reuben A. Hy's law. Hepatology. 2004;39(2):574-8. 
 
Shenoy P, Maggioncalda A, Malik N, Flowers CR. Incidence patterns and outcomes for 
Hodgkin lymphoma patients in the United States. Adv Hematol. 2011;2011:725219. 
 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. 
 
Straus DJ, Collins GP, Walewski JA, et al. Improving outcomes with brentuximab vedotin 
(BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin 
lymphoma. J Clin Oncol. 2018a;36(Suppl 15):Abstract 7534. 
 
Straus DJ, Jung SH, Pitcher B, et al. CALGB 50604: risk-adapted treatment of nonbulky 
early-stage Hodgkin lymphoma based on interim PET. Blood. 2018b;132(10):1013-
21. 
 


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Yasenchak CA, Bordoni R, Yazbeck V, et al. Phase 2 study of frontline brentuximab vedotin 
plus nivolumab in patients with Hodgkin lymphoma aged ≥60 years. Blood. 
2019;134(Suppl 1):Abstract 237. 
 


 
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APPENDIX A: SCHEDULE OF EVENTS – PART A  
 
 
Screening/BaselineA 
Enrollment 
Every 28-day cycle 
EOT 
F/UB 
 
Day 
D –28 to 
1 
D –7 to 
1 
Within 7D of 1st 
dose 
D1 
D2 
D15 
D16 
Within 
30–37D of 
last doseC 
Every 
12 wks 
 
Visit window 
 
 
 
 
 
 
 
 
±1 wk 
Screening/ 
Baseline 
Assessments  
Inclusion/Exclusion 
X 
 
Submit eligibility confirmation to  
Sponsor prior to treatment 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Echocardiogram/MUGA scan 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
Pregnancy test  
(subjects of childbearing potential) 
 
X 
X 
 
 
 
 
 
Safety 
Assessments 
Physical exam 
 
X 
 
 
 
 
X 
 
Height  
 
X 
 
 
 
 
 
 
WeightD 
 
X 
X 
 
X 
 
 
 
CBC with differentialD 
 
X 
X 
 
X 
 
X 
 
Serum chemistry panelD 
 
X 
X 
 
X 
 
X 
 
Hgb A1c 
 
X 
 
 
 
 
X 
 
 
ECOG performance status 
 
X 
 
 
 
 
 
X 
 
 
Concomitant medications 
Related to study proceduresE 
Collect from Day 1 predose through safety reporting period of 
study drug(s) 
 
 
Adverse event collection 
Treatment 
A+AVD administrationF 
 
 
 
X 
 
X 
 
 
 
Filgrastim administration 
 
 
 
 
XG 
 
XG 
 
 
Pegfilgrastim administration 
 
 
 
 
XG 
 
XG 
 
 
Response 
Assessment 
CT of chest, neck, abdomen, pelvis 
XK 
 
 
 
 
 
 
XJ 
 
PET scanH 
XK 
 
 
 
 
 
 
XJ 
 
B symptom assessment 
 
X 
 
 
 
 
 
X 
 
Disease status 
 
 
 
 
 
 
 
 
XI 
Survival/subsequent anticancer 
treatment 
 
 
 
 
 
 
 
 
X 
A. 
If Baseline Visit activities occur within 1 day of Cycle 1 Day 1, they do not need to be repeated. 
B. 
Subjects will remain in follow-up until death, withdrawal of consent, or completion of 2 years of 
long-term follow-up (from EOT visit), whichever occurs first. 
C. 
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT 
evaluations are completed before 30 days following the last study treatment, conduct a phone 
screen 30–37 days following the subject’s last study treatment to ensure that no changes in AE 
profile have occurred. 
D. 
Clinical laboratory assessments may be performed 1 day prior to A+AVD administration. 
E. 
From time of informed consent 
F. 
A+AVD should be administered as described in Section 5.  
G. 
Either filgrastim or pegfilgrastim should be started 24–36 hours from the last dose of the A+AVD 
regimen and administered as described in Section 5.4.3. Filgrastim should be administered for a 
minimum of 5 days. 
H. 
A CT of diagnostic quality may be combined with the PET scan when both are required per 
protocol 
I. 
Disease status will be followed until the subject experiences progressive disease 
J. 
Not required if conducted 1 week prior to EOT 
K. 
Scans collected within 3 days prior to Day -28 will be accepted 


 
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APPENDIX B: SCHEDULE OF EVENTS – PARTS B AND C  
 
 
Screening/ Baseline 
Enrollment 
Every 28-day 
cycle 
Disease 
Assessment 
EOT 
Safety 
F/UA 
 
Day 
D –28 to 1 
(-3 days) 
D –
7 to 
1 
Within 7D of 
1st dose 
D1 
D15 
Cycle 2 
Day 25 
Within  
30–37D of 
last doseB 
100 days 
post last 
doseC 
Every 
12 wks 
 
Visit window 
 
 
 
2d 
2d 
+3d 
 
+2 wk 
1 wk 
 
Screening/ Baseline 
Assessments  
Inclusion/Exclusion, medical history 
X 
X 
Submit eligibility 
confirmation to  
Sponsor prior to treatment 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
International prognostic score (Part B 
only) 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
Collection of archived tumor specimen 
or fresh tumor biopsyR 
X 
 
 
 
 
 
 
 
Pregnancy test (subjects of childbearing 
potential) 
 
X 
X 
 
 
X 
 
 
 
CZ only: HBV and HIV serological 
testing 
XW 
 
 
 
 
 
 
 
 
 
CZ only: HCV PCR testing 
XX 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical examD 
 
X 
 
X 
 
 
X 
X 
XE 
CBC with differential 
 
X 
XK 
X 
 
X 
X 
 
Chemistry panel 
 
XI 
XI, J, K 
XI 
 
XI, J 
XI 
 
eGRFS 
 
X 
X 
X 
 
X 
X 
 
Peripheral blood collectionF 
 
 
 
XF, G 
 
 
XF 
 
XF, H 
Hgb A1c 
 
X 
 
 
 
 
X 
 
 
B symptom assessment 
 
X 
 
XK 
 
 
X 
 
 
ECOG performance status 
 
X 
 
XK 
X 
 
X 
 
 
Echocardiogram/MUGA scanL 
X 
 
 
 
 
 
  
 
 
 
Concomitant medications 
Related to study proceduresM 
Collect from Day 1 predose through safety reporting period of 
study drug(s) 
 
 
Adverse event collectionM, N 
Treatment 
Study drug administration 
 
 
 
X 
X 
 
 
 
 
Response Assessment 
CT of neck, chest, abdomen, pelvis 
XQ, V 
 
 
 
 
XV 
XT, V 
 
XP, V 
PET 
XQ 
  
 
 
 
XU 
XU 
 
XO, P 
Tumor biopsy 
 
 
 
 
 
 
 
 
XH 
Survival and post-treatment therapies 
 
 
 
 
 
 
 
X 
X 
A. 
For Parts B and C, disease assessments will be performed during follow-up every 
3 months after the EOT visit for the first year, then every 6 months for 2 additional years. 
Subjects will then continue in follow-up for 2 additional years (5 years total), with 
physical exams required every 6 months and disease assessments required every 
12 months. Timing of follow up visits should be relative to EOT visit and not relative to 
last dose. 
B. 
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT 
evaluations are completed before 30 days following the last study treatment, conduct a 
phone screen 30-37 days following the subject’s last study treatment to ensure that no 
changes in AE profile have occurred. 
C. 
The safety visit will be 100-114 days after last dose of nivolumab or 30–37 days post last 
dose of BV (concurrent with the EOT visit), whichever is later. 
D. 
Physical exam includes vital signs (blood pressure, heart rate, temperature), height (at 
baseline) and weight 
G. 
Cycles 1, 2, and 4 only 
H. 
Collected only at the time of progression if the subject provides additional consent 
I. 
Must include amylase and lipase (Section 7.4.2) 
J. 
Must include TSH, free T3, T4 at cycles 1, 3, and EOT only (Section 7.4.2) 
K. 
Not required if assessed within 1 day prior to C1D1 
L. 
Performed within 1 month prior to enrollment is acceptable 
M. 
From time of informed consent  
N. 
All PN TEAEs will be followed until resolution, return to baseline, or study closure and entered in the 
eCRF. Telephone contact is acceptable 
O. 
May discontinue after EOT if negative 
P. 
Parts B and C: PET-CT scan every 3 months post-EOT for one year, then every 6 months for an 
additional 2 years. For the final 2 years, PET-CT scan every 12 months. 
Q. 
Scans collected within 3 days prior to Day -28 will be accepted. 
R. 
Refer to Section 7.3.1 for details 


 
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E. 
Parts B and C: Physical exam to follow the PET-CT scan schedule for the first 3 years of 
long-term follow-up. For the final 2 years, a physical exam should occur every 6 months. 
F. 
Part C only 
S. 
eGFR will be calculated per MDRD. 
T. 
No CT or PET scan is required if the subject had CT/PET scans within a week prior to EOT or if the 
subject discontinued due to radiographically confirmed PD. 
U. 
CT of diagnostic quality may be combined with PET to satisfy the requirements for CT and PET 
scanning. Refer to Section 7.2 for further guidance on Deauville scale grading for PET scans. 
V. 
To decrease radiation exposure, CT scans of neck will be mandated at Baseline only, restaging imaging 
will only be repeated if neck disease is present at Baseline. 
W. 
CZ only: Serological testing will be completed, positive results will result in subject being considered 
ineligible for enrollment. 
X. 
CZ only: PCR testing will be completed, positive results will result in subject being considered ineligible 
for enrollment. 


 
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APPENDIX C: 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. 
 


 
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APPENDIX D: INTERNATIONAL PROGNOSTIC FACTORS SCORING FOR 
ADVANCED HODGKIN LYMPHOMA  
One Point To Be Assigned for Each Prognostic Factor: 
Serum albumin <4 g/dL 
Hemoglobin <10.5 g/dL 
Male sex 
Stage IV disease 
Age ≥45 years 
White cell count ≥15,000 mm3 
Lymphocyte count <600 mm3 or <8% of white-cell count 
Source: (Hasenclever 1998) A Prognostic Score for Advanced Hodgkin’s Disease. 
 


 
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APPENDIX E: 
NEW YORK HEART ASSOCIATION CLASSIFICATION  
A Functional and Therapeutic Classification for Prescription of Physical Activity for 
Cardiac Subjects  
Class I:  
subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities. 
Class II:  
subjects with slight, mild limitation of activity; they are comfortable with 
rest or with mild exertion. 
Class III:  subjects with marked limitation of activity; they are comfortable only at 
rest. 
Class IV:  subjects 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 


 
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APPENDIX F: 
OVERVIEW OF LYRIC CRITERIA (PARTS B AND C ONLY)  
If tumor flare or pseudo-progression is suspected, then a clinical response of 
indeterminate response (IR) should be reported based on the Lugano Classification 
Revised Staging System for malignant lymphoma (Cheson 2014) with the incorporation 
of LYRIC (Cheson 2016). 
Definition of Indeterminate Response 
• IR1: An increase in overall tumor burden (as assessed by the SPD) of ≥50% of up to 
6 measurable lesions in the first 12 weeks of therapy, without clinical deterioration. 
This pattern may be seen as a consequence of either delayed response or early 
immune-mediated flare. At least within the context of clinical trials, a biopsy is 
encouraged in this case because this may help to distinguish the two and, if positive, will 
confirm the impression of PD. However, if negative for lymphoma, it will support the 
concept of pseudoprogression and contribute to our understanding of this phenomenon. 
When such a biopsy is neither safe nor feasible, decisions must be based on a repeat scan 
12 weeks after the initial determination of IR. 
It is recognized that “clinical deterioration” is subjective. In some cases, the simple 
growth of a nodal or tumor mass could worsen the symptoms mechanically related to that 
mass, such as pain at the tumor site or compression of adjacent structures, etc. Such an 
increase in symptoms that can be directly attributed to the size of the tumor mass may not 
be considered as clinical deterioration in this context. However, in most cases, subjects 
should be experiencing clinical stability or improvement by investigator assessment to be 
considered as having IR, and in all cases, the patient must be considered likely to tolerate 
continued treatment and not at risk of serious complications should further tumor growth 
occur.  
• 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. 
This phenomenon may occur early or late in the treatment course, and therefore, unlike 
IR1, is not defined by its temporal relationship to treatment initiation. Both within and 
outside the context of clinical trials, a biopsy is strongly encouraged in such cases. 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 FDG uptake of 1 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) with checkpoint inhibitors. The magnitude of increase in uptake 
in an immune-mediated flare compared to that in true tumor progression is not yet known. 


 
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It is important to investigate this finding, especially in conjunction with a biopsy of the 
lesion in question. 
While awaiting a better characterization of this phenomenon, we propose that, under the 
modified response criteria, 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 subject could fulfill criteria for both IR1 or IR2 
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 IR2 should take priority (e.g., IR2 in the 
above example). 
These 3 patterns of IR as defined above (IR1, IR2, and IR3) may have very different 
mechanisms and clinical implications. Therefore, it is critical that data are collected in a 
consistent manner so that these 3 possible atypical response types occurring within the 
context of checkpoint inhibitors can be distinguished. 


 
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Follow-Up of Indeterminate Response  
In subjects categorized as having any of the above types of IR, it is mandatory to obtain a 
repeat imaging after an additional 12 weeks (or earlier if clinically indicated). At that 
time, response should be re-evaluated, and the subject should be considered to have true 
PD 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 ≥1 lesion for lesions ≤2 cm, and 
10 mm for lesions >2 cm, to be consistent with the Lugano classification (Cheson 
2016). The 10% threshold is empiric but designed to account for variability in 
measurement, especially when taken along with the minimum increase (Oxnard 
2011). If the target SPD increase is <10%, the response would still be categorized 
as IR1, and the subject 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 ≥1 lesion) or response (≥50% decrease from baseline). In this 
situation, it is reasonable to repeat imaging in 4–8 weeks of the original IR1 time 
point 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 subject 
should be considered to have PD. 
● 
In the case of IR3, because inflammatory responses may result in an increase in 
the standardized uptake value of a lesion, the subject 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. 
Importantly, if a subject is assessed as having IR and then “true” PD at a subsequent 
time point (without an intervening objective response between IR and PD), the IR 
assessment should be subsequently be corrected to PD for reporting purposes to the 
date of the prior designation of IR. We recognize that these lesions may remain stable 
during the time of observation, but, even if this is the case, the initial designation of 
IR should be changed to PD. 


 
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APPENDIX G: GUIDANCE ON CONTRACEPTION  
For the purposes of this guidance, complete abstinence, if consistent with the subject’s 
preferred lifestyle, is an acceptable form of contraception. Complete abstinence is defined 
as abstinence starting from the time of informed consent and continuing throughout the 
study and until the end of systemic exposure (at least 7 months after the final dose of 
study drug; see Section 4.1). 
Acceptable methods for highly effective birth control (preventing 
conception)  
Subjects who are of childbearing potentiala or whose partners are of childbearing 
potential and who are sexually active in a way that could lead to pregnancy may 
choose to use any TWO of the following methods (please see acceptable 
combinations below): 
● Hormonal methods of contraception (excluding progestin-only pills; method must 
be associated with inhibition of ovulation), unless contraindicated  
● Intrauterine device with failure rate <1% 
● Tubal ligation 
● Vasectomy (at least 90 days from the date of surgery with a semen analysis 
documenting azoospermia) 
● Barrier method (male or female condom with or without spermicide, cervical cap 
with or without spermicide, diaphragm with or without spermicide)b  
▫ All male subjects must use a condom (with pregnant/breastfeeding and 
non-pregnant/non-breastfeeding partners) during treatment and 7 months after 
the last dose of study drug. 
a 
A person of childbearing potential is defined as anyone born female who has experienced menarche and who has 
not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has 
not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person born female 
over age 45 in the absence of other biological, physiological, or pharmacological causes. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. 
b 
A barrier method should only be used with a highly effective birth control method that is not a barrier method. 
Barrier methods alone, including a double-barrier method, are not considered highly effective contraceptive 
measures (see unacceptable methods of contraception). 
Acceptable combinations of contraceptive methods:  
• Hormonal method and vasectomy 
• Hormonal method and barrier method 
• Intrauterine device and vasectomy 
• Intrauterine device and barrier method 
• Tubal ligation and vasectomy 
• Tubal ligation and barrier method 
 
 


 
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Acceptable methods for preventing secondary exposure to seminal fluid  
Subjects born male and who are sexually active with a pregnant or breastfeeding 
person, must use the contraceptives in Option 1 or 2: 
• Option 1: Male condom (with or without spermicide) and cervical cap  
• Option 2: Male condom (with or without spermicide) and diaphragm  
Unacceptable methods of contraception  
• Periodic abstinence 
• Spermicide only 
• No method 
• Progestin-only pills 
• Withdrawal 
• Concomitant use of female and male 
condoms 
• Rhythm 
• Barrier methods alone, including 
double-barrier methods 


 
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APPENDIX H: KATZ INDEX OF INDEPENDENCE IN ACTIVITIES OF DAILY 
LIVING  
 
 


 
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APPENDIX I: 
MANAGEMENT ALGORITHMS FOR STUDIES UNDER 
CTCAE VERSION 4.0  
These general guidelines constitute guidance to the Investigator and may be 
supplemented by discussions with the Medical Monitor representing the Sponsor. The 
guidance applies to all immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according 
to standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. 
The oral equivalent of the recommended IV doses may be considered for ambulatory 
patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should 
be taken into account when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive 
diagnostic or therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
GI Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat 
accordingly and continue I-O therapy. Opiates/narcotics may mask symptoms of 
perforation. Infliximab should not be used in cases of perforation or sepsis. 
Grade of Diarrhea/Colitis 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Diarrhea: <4 stools/day 
over baseline; 
Colitis: asymptomatic 
• 
Continue I-O therapy 
per protocol 
• 
Symptomatic treatment 
• 
Close monitoring for worsening 
symptoms 
• 
Educate patients to report worsening 
immediately 
If worsens: 
• 
Treat as Grade 2 or 3/4 
Grade 2 
Diarrhea: 4-6 stools per 
day over baseline; IV 
fluids indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain, 
blood in stool 
• 
Delay I-O therapy per 
protocol 
• 
Symptomatic treatment 
If improves to Grade 1: 
• 
Resume I-O therapy per protocol 
If persists >5-7 days or recur: 
• 
0.5-1.0 mg/kg/day methylprednisolone 
or oral equivalent 
• 
When symptoms improve to Grade 1, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
I-O therapy per protocol. 
If worsens or persists >3-5 days with oral 
steroids: 
• 
Treat as Grade 3/4 
Grade 3-4 
Diarrhea (G3): ≥7 stools 
per day over baseline; 
incontinence; IV fluids 
• 
Discontinue I-O therapy 
per protocol 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV 
or IV equivalent 
If improves: 
• 
Continue steroids until Grade 1, then 
taper over at least 1 month 
If persists >3-5 days, or recurs after 
improvement: 


 
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Grade of Diarrhea/Colitis 
(NCI CTCAE v4) 
Management 
Follow-up 
≥24 hrs; interfering with 
ADL 
Colitis (G3): severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs 
G4: life-threatening, 
perforation 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
• 
Consider lower 
endoscopy 
• 
Add infliximab 5 mg/kg (if no 
contraindication). Note: Infliximab 
should not be used in cases of 
perforation or sepsis 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
Grade of 
Creatinine 
Elevation 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Creatinine >ULN 
and > than baseline 
but ≤1.5x baseline 
• 
Continue I-O therapy per 
protocol 
• 
Monitor creatinine weekly 
If returns to baseline: 
• 
Resume routine creatinine monitoring per 
protocol 
If worsens: 
• 
Treat as Grade 2 or 3/4 
Grade 2-3 
Creatinine >1.5x 
baseline to ≤6x 
ULN 
• 
Delay I-O therapy per 
protocol 
• 
Monitor creatinine every 
2-3 days 
• 
0.5 to 1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• 
Consider renal biopsy with 
nephrology consult 
If returns to Grade 1: 
• 
Taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume I-O 
therapy and routine creatinine monitoring 
per protocol 
If elevations persists >7 days or worsen: 
• 
Treat as Grade 4 
Grade 4 
Creatinine >6x 
ULN 
• 
Discontinue I-O therapy per 
protocol 
• 
Monitor creatinine daily 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• 
Consult nephrologist 
• 
Consider renal biopsy 
If returns to Grade 1: 
• 
Taper steroids over at least 1 month and 
add prophylactic antibiotics for 
opportunistic infections. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
 
 


 
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Pulmonary Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Evaluate with imaging and pulmonary consultation. 
Grade of Pneumonitis 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes 
only 
• 
Consider delay of I-O 
therapy 
• 
Monitor for symptoms 
every 2-3 days 
• 
Consider Pulmonary and 
ID consults 
• 
Re-image at least every 3 weeks 
If worsens: 
• 
Treat as Grade 2 or 3/4 
Grade 2 
Mild to moderate new 
symptoms 
• 
Delay I-O therapy per 
protocol 
• 
Pulmonary and ID 
consults 
• 
Monitor Symptoms daily, 
consider hospitalization 
• 
1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• 
Consider bronchoscopy, 
lung biopsy 
• 
Re-image every 1-3 days 
If improves: 
• 
When symptoms return to near baseline, 
taper steroids over at least 1 month and 
then resume I-O therapy per protocol 
and consider prophylactic antibiotics 
If not improving after 2 weeks or worsening: 
• 
Treat as Grade 3-4 
Grade 3-4 
Severe new symptoms; 
New/worsening 
hypoxia; 
life-threatening 
• 
Discontinue I-O therapy 
per protocol 
• 
Hospitalize 
• 
Pulmonary and ID 
consults 
• 
2.0 to 4.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
• 
Consider bronchoscopy, 
lung biopsy 
If improves to baseline: 
• 
Taper steroids over at least 6 weeks 
If not improving after 48 hrs or worsening: 
• 
Add additional immunosuppression 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
 
 


 
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Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Consider imaging for obstruction. 
Grade of Liver 
Test Elevation 
(NCI CTCAE 
v4) 
Management 
Follow-up 
Grade 1 
AST or ALT 
>ULN to 3.0x 
ULN and/or 
T.bili >ULN to 
1.5x ULN 
• 
Continue I-O therapy 
• 
Continue LFT monitoring per protocol 
If worsens: 
• 
Treat as Grade 2 or 3/4 
Grade 2 
AST or ALT 
>3.0 to ≤5x 
ULN and/or 
T.bili >1.5 to 
≤3x ULN 
• 
Delay I-O therapy per 
protocol 
• 
Increase frequency of 
monitoring to every 
3 days 
If returns to baseline: 
• 
Resume routine monitoring, resume I-O therapy 
per protocol 
If elevation persist >5-7 days or worsen: 
• 
0.5 to 1 mg/kg/day methylprednisolone or oral 
equivalent and when LFT returns to Grade 1 or 
baseline, taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy 
per protocol 
Grade 3-4 
AST or ALT 
>5x ULN or 
T.bili >3x ULN 
• 
Discontinue I-O therapy* 
• 
Increase frequency of 
monitoring to every 
1-2 days 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV 
or IV equivalent* 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
• 
Consult 
gastroenterologist 
If returns to Grade 2: 
• 
Taper steroids over at least 1 month 
If does not improve in >3-5 days, worsens or 
rebounds: 
• 
Add mycophenolate mofetil 1 g BID 
• 
If no response within an additional 3-5 days, 
consider other immunosuppressants per local 
guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
* 
The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 
For subjects with HICC, please refer to the protocol for specific details. 
 
 


 
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Endocrinopathy Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Consider visual field testing, endocrinology consultation, and 
imaging. 
Asymptomatic TSH elevation 
• 
Continue I-O therapy per protocol 
If TSH <0.5x LLN, or TSH >2x ULN, or consistently out of range in 
2 subsequent measurements: include fT4 at subsequent cycles as 
clinically indicated; consider endocrinology consult 
Symptomatic endocrinopathy 
• 
Evaluate endocrine function 
• 
Consider pituitary scan 
Symptomatic with abnormal 
lab/pituitary scan: 
• 
Delay I-O therapy per 
protocol 
• 
1-2 mg/kg/day 
methylprednisolone IV or PO 
equivalent 
• 
Initiate appropriate hormone 
therapy 
No abnormal lab/pituitary MRI 
scan but symptoms persist: 
• 
Repeat labs in 
1-3 weeks/MRI in 1 month 
If improves (with or without 
hormone replacement): 
• 
Taper steroids over at least 
1 month and consider 
prophylactic antibiotics for 
opportunistic infections 
• 
Resume I-O therapy per 
protocol 
• 
Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component. 
Suspicion of adrenal crisis 
(e.g., severe dehydration, 
hypotension, shock out of 
proportion to current illness) 
• 
Delay or discontinue I-O 
therapy per protocol 
• 
Rule out sepsis 
• 
Stress dose of IV steroids 
with mineralocorticoid 
activity 
• 
IV fluids 
• 
Consult endocrinologist 
• 
If adrenal crisis is ruled out, 
then treat as above for 
symptomatic endocrinopathy 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g, prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
 
 


 
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Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
Grade of Rash 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1-2 
Covering ≤30% 
BSA* 
• 
Symptomatic therapy 
(e.g., antihistamines, 
topical steroids) 
• 
Continue I-O therapy 
per protocol 
If persists >1-2 weeks or recurs: 
• 
Consider skin biopsy 
• 
Delay I-O therapy per protocol 
• 
Consider 0.5-1.0 mg/kg/day 
methylprednisolone IV or oral equivalent. 
Once improving, taper steroids over at least 
1 month, consider prophylactic antibiotics 
for opportunistic infections, and resume I-O 
therapy per protocol. 
If worsens: 
• 
Treat as Grade 3-4 
Grade 3-4 
Covering >30% 
BSA; Life 
threatening 
consequences*^ 
• 
Delay or discontinue I-O 
therapy per protocol 
• 
Consider skin biopsy 
• 
Dermatology consult 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV 
or IV equivalent 
If improves to Grade 1: 
• 
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic 
infections 
• 
Resume I-O therapy per protocol 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
* 
Refer to NCI CTCAE v4 for term-specific grading criteria. 
^ 
If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for 
assessment and treatment. If SJS or TEN is diagnosed, permanently discontinue I-O therapy. 
Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
Grade of Neurological 
Toxicity 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Asymptomatic or mild 
symptoms; Intervention 
not indicated 
• 
Continue I-O therapy per 
protocol 
• 
Continue to monitor patient 
If worsens: 
• 
Treat as Grade2 or 3-4 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• 
Delay I-O therapy per protocol 
• 
Treat symptoms per local 
guidelines 
• 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or PO 
equivalent 
If improves to baseline: 
• 
Resume I-O therapy per protocol 
when improved to baseline 
If worsens: 
• 
Treat as Grade 3-4 
Grade 3-4 
• 
Discontinue I-O therapy per 
protocol 
If improves to Grade 2: 


 
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Grade of Neurological 
Toxicity 
(NCI CTCAE v4) 
Management 
Follow-up 
Severe Symptoms; 
Limiting self-care ADL; 
Life-threatening 
• 
Obtain neurology consult 
• 
Treat symptoms per local 
guidelines 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• 
Add prophylactic antibiotics for 
opportunistic infections 
• 
Taper steroids over at least 
1 month 
If worsens or atypical presentation: 
• 
Consider IVIG or other 
immunosuppressive therapies 
per local guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
Myocarditis Adverse Event Management Algorithm 
Grade of Myocarditis 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 2 
Symptoms with mild to 
moderate activity or 
exertion 
• 
Delay I-O therapy; hospitalization 
with cardiac monitoring 
• 
Urgent cardiology consultation for 
evaluation and management 
o 
Troponin and BNP 
o 
ECG ± continuous 
cardiac monitoring 
o 
Echocardiogram 
o 
Cardiac MRI 
• 
Prompt initiation of 2 mg/kg/day 
methylprednisolone IV or 
equivalent 
• 
If worsens, intensify treatment 
according to grade 
• 
Upon recovery, taper steroids 
over at least 1 month with 
close monitoring of troponin 
and BNP as well as for new 
symptoms 
• 
Repeat cardiac MRI for post 
treatment assessment and 
cardiology follow-up 
• 
Retreatment may be 
considered after recovery and 
completion of steroid taper 
Grade 3 
Severe with symptoms at 
rest or with minimal 
activity or exertion; 
intervention indicated 
 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support) 
• 
Permanently discontinue I-O 
therapy 
• 
Hospitalize to intensive cardiac 
monitoring 
• 
Cardiac evaluation in include: 
o 
Troponin and BNP 
monitoring 
o 
ECG ± continuous 
cardiac monitoring 
o 
Echocardiogram 
o 
Cardiac MRI 
o 
Myocardial biopsy if 
feasible 
• 
Immediate initiation of 
2.0 mg/kg/day 
methylprednisolone IV or 1 g IV 
bolus 
• 
Consider adding a second 
immunosuppressive agent 
• 
Additionally, for Grade 4: 
o 
Hospitalize/transfer to 
institution with expertise 
• 
If no improvement, consider 
additional 
immunosuppression 
• 
Upon recovery, taper steroids 
over at least 1 month with 
close monitoring of troponin 
and BNP as well as for new 
symptoms 
• 
Repeat cardiac MRI for post 
treatment assessments and 
cardiology follow-up 


 
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Grade of Myocarditis 
(NCI CTCAE v4) 
Management 
Follow-up 
in intensive cardiac 
monitoring 
o 
Consider ATG as second 
agent given its immediate 
effect 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at 
start of tapering or earlier, once sustained clinical improvement is observed. Lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. Prophylactic antibiotics should be considered in the setting of ongoing 
immunosuppression. 
 
 


 
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APPENDIX J: 
INVESTIGATOR SIGNATURE PAGE  
 
Investigator Statement and Signature  
 
I have read the attached protocol entitled Multiple Part Clinical Trial of Brentuximab 
Vedotin in Classical Hodgkin Lymphoma Subjects 
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 
 
 
 


 
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APPENDIX K: DOCUMENT HISTORY  
Version 
Date 
Original 
12-Jul-2018 
Amendment 1 
09-Nov-2018 
Amendment 2 
27-Aug-2019 
Amendment 3 
30-Mar-2020 
Amendment 4 
11-Nov-2020 
Amendment 5 
16-Apr-2021 
Amendment 6 
29-Nov-2021 
Amendment 7 
xx-July-2023 
 
 


 
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Summary of Changes in Amendment 1  
Section(s) 
Change 
Rationale 
Title page 
Change of medical monitor to 
 
will be providing clinical oversight of 
the study 
Title page, 
7.4.1.2, and 
7.4.1.4 
Changed Serious Adverse Event reporting 
information 
To align with current Seagen Inc. practice 
6.5 
Revised long-term follow-up (LTFU) 
information to indicate that participants 
will remain in LTFU for up to 2 years 
from the End of Treatment visit 
To clarify the timeline for LTFU for proper 
site operations 
Appendix C 
Replaced the International Prognostic 
Index (IPI) score sheet with International 
Prognostic Score (IPS) information.  
Correction 
 


 
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Summary of Changes in Amendment 2  
Section(s) 
Change 
Rationale 
Throughout 
Added Part B: Treatment of cHL subjects 
with brentuximab vedotin, nivolumab, 
doxorubicin, and dacarbazine (AN+AD) 
Exploration of a novel combination 
treatment to assess safety and the potential 
for efficacy in this subject population. 
Throughout 
Various administrative changes were made 
throughout  
To provide clarity when necessary and 
conform to editorial standards 
Section 1 
Added information on nivolumab 
To provide context for the exploration of 
nivolumab as part of this novel combination 
treatment 
Section 1.2 
Revised section to indicate experience with 
brentuximab vedotin and A+AVD 
To provide context for Part A of the study 
Section 1.3 
Added information on clinical experience 
with nivolumab 
To provide context for the exploration of 
nivolumab as part of this novel combination 
treatment 
Section 1.4.2 
Added a study rationale for Part B 
To provide a rationale for the addition of 
this novel combination treatment 
Section 2 
Added objectives for Part B 
To provide objectives and the corresponding 
endpoints for Part B, as this part will be 
evaluated separately from Part A 
Section 3 
Added information on the study design for 
Part B 
To provide information regarding the design 
and execution of Part B and the study 
rationale for Part B 
Section 3.1 
Revision of the study population to a total of 
90 subjects 
To provide the approximate number of 
subjects for both parts of the study 
Section 4.1 
Revised inclusion criteria, including the 
following key points: 
 
● Part B to allow subjects with Stage IIA 
with bulky and Stage IIB cHL 
● Subjects 12+ years will be allowed to 
enroll 
● Subjects must have an ECOG of 1 or 2 
To provide an appropriate subject 
population for testing AN+AD 
Section 4.2 
Revised exclusion criteria, including the 
addition of the following: 
 
● Planned consolidative radiotherapy (Part 
B only) 
● Active interstitial lung disease that is 
symptomatic or may interfere with 
management of drug-related pulmonary 
toxicity (Part B only) 
● Idiopathic interstitial pneumonia or 
diffusing capacity of the lung for carbon 
monoxide <50% predicted 
● Subjects with acute or chronic graft-
versus-host-disease (GvHD) or receiving 
immunosuppressive therapy as treatment 
for or prophylaxis agent against GvHD. 
● Previous treatment with brentuximab 
vedotin. 
To provide an appropriate subject 
population for testing AN+AD 


 
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Section(s) 
Change 
Rationale 
Section 5.1 
Provided details for treatment administration 
for Part B 
To provide guidance on administering 
AN+AD 
Section 5.2 
Modified to indicate that a pharmacy binder 
will be provided for brentuximab vedotin  
Seagen Inc. will provide brentuximab 
vedotin (previously commercial supply for 
Part A) 
Section 5.2.3 
Added a section to indicate that brentuximab 
vedotin will be provided by Seagen Inc. 
Updated to indicate a switch to clinical 
rather than commercial supply 
Table 4 
Updated information for dose modifications 
for brentuximab vedotin-associated toxicity 
To provide management information for 
specific potential toxicities 
Section 5.3.3 
Added information on administration of 
doxorubicin and dacarbazine for Part B 
To provide information on administration of 
these agents 
Section 5.5 
Added a section to provide information on 
nivolumab treatment administration 
To provide information on administration of 
nivolumab for Part B 
Section 
5.6.2.1 
Added a section to provide information on 
allowed concomitant therapy as applies to 
Part B only 
To provide information on allowed 
concomitant therapy for Part B 
Section 5.6.3 
Added information indicating that planned 
consolidative radiotherapy of lesions is 
exclusionary for Part B 
To clarify that investigators must exclude 
subjects for whom they plan to administer 
this type of radiotherapy 
Section 5.7.1 
Added information on infusion or 
hypersensitivity reactions that may occur in 
response to either brentuximab vedotin or 
nivolumab 
To provide guidance on common symptoms 
of these reactions 
Section 5.7.4 
Added a section with information on the 
management of immune-adverse events 
To provide guidance on these events, which 
are associated with nivolumab as an 
immuno-oncology agent 
Section 6.3.2 
Added a section on procedures for Part B 
To provide guidance on study tests and 
procedures required for Part B 
Section 6.4 
Revised the EOT visit procedures 
To provide guidance on EOT tests or 
procedures required for Part B and further 
clarification on the timing of CT/PET scans 
Section 6.5 
Added a section to detail procedures 
required at the safety visit for Part B 
To provide guidance on the timing of the 
safety visit and the tests and procedures 
required at this visit 
Section 6.6.2 
Added a section to detail long-term follow-
up procedures for Part B 
To provide guidance on the tests and 
procedures required during long-term 
follow-up for Part B 
Section 7.2 
Added information on response/efficacy 
assessments for Part B 
To provide guidance on determination of 
antitumor activity in Part B 
Section 7.3 
Added information to indicate that the safety 
in Part B will be assessed by a Safety 
Monitoring Committee 
To provide guidance on the timing of this 
safety analysis and potential subsequent 
activities 
Section 7.3.1 
Revised as needed throughout to provide 
appropriate safety management for the study 
with the addition of Part B. This includes a 
longer safety reporting period for Part B, 
due to safety requirements for nivolumab. 
To provide guidance on appropriate 
identification, reporting, and management of 
potential adverse events  
Section 9 
Revised throughout to provide appropriate 
statistical analysis information for the 
revised subject population size for Part A, 
and for the newly added Part B 
To provide information on the anticipated 
statistical analysis for the study 


 
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Section(s) 
Change 
Rationale 
Appendix B 
Added a schedule of events for Part B 
To provide information on the tests and 
procedures required for Part B during study 
cycles 


 
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Summary of Changes in Amendment 3  
Section(s) 
Change 
Rationale 
Throughout 
Added Part C: Treatment of early stage 
cHL subjects with brentuximab vedotin, 
nivolumab, doxorubicin, and dacarbazine 
(AN+AD) 
Exploration of a novel combination 
treatment to assess safety and the potential 
for efficacy in an early stage cHL subject 
population. 
Throughout 
Various administrative changes were 
made throughout  
To provide clarity when necessary and 
conform to editorial standards 
Section 1.1 
Added background information on the 
impact of bulky mediastinal disease in the 
cHL population 
To provide background information on this 
specific cHL population 
Section 1.2 
Added information regarding the clinical 
experience of combination treatment with 
brentuximab vedotin, doxorubicin, and 
dacarbazine, and associated common 
adverse events 
To provide detailed information on the use 
of these drugs in combination and their 
expected potential adverse events 
Section 1.4.2 
Provided information on the use of 
brentuximab vedotin and nivolumab in 
combination and clarified that vinblastine 
may not be required for regimen efficacy 
To provide complete information on the 
rationale for Parts B and C 
Section 3.1.1 
Added a new section to describe the 
composition, meeting schedule, and 
objectives for the Safety Monitoring 
Committee (SMC) for Parts B and C of 
the study 
To clarify the process and responsibilities 
associated with the SMC 
Section 3.2.3 
Added the following sentence to “Method 
of Assigning Subjects to Treatment 
Groups”: 
 
Subjects with Stage II cHL with bulky 
mediastinal disease will be assigned to 
Part B. Subjects with Stage I or II cHL 
with non-bulky mediastinal disease will 
be assigned to Part C. 
To provide direction on enrolling subjects in 
either Part B or Part C 
Section 
3.2.4.2 
Added the following information to 
“Rationale for Selection of Doses”: 
 
Subjects in Part B will receive up to 
6 cycles of treatment. Subjects in Part C 
will receive 4 cycles of treatment. 
To provide direction on the number of 
treatment cycles for subjects in either Part B 
or Part C  
Section 
3.2.4.2 
Clarified that safety will be evaluated 
separately for Parts B and C  
To clarify the process of SMC oversight of 
Parts B and C 


 
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Section(s) 
Change 
Rationale 
Section 4.1 
Modified inclusion criterion 1: 
 
Part B will enroll Ann Arbor Stage II cHL 
with bulky mediastinal disease or Stage 
III or IV cHL 
 
Part C will enroll Ann Arbor Stage I or II 
with non-bulky mediastinal cHL 
To provide enrollment criteria for subjects 
in either Part B or C 
Section 4.1 
Modified inclusion criterion 2a to specify 
that subjects enrolling in Part C must 
submit a tumor block for analysis 
To provide direction on tumor biopsy tissue 
requested for Part C participation 
Section 4.1 
Modified inclusion criterion 9 to indicate 
that serum bilirubin can be ≤3 x ULN for 
subjects with documented hepatic 
involvement with lymphoma 
To clarify baseline laboratory data 
requirements for inclusion of these subjects 
Table 4 
Changed the recommendation for 
management of Grade 2 sensory 
neuropathy from “continue at same dose 
level” to “reduce BV dose to 0.9 mg/kg”  
To provide updated guidance on the 
management of Grade 2 sensory neuropathy 
Section 5.2.4 
Added text to clarify that dose 
modifications may include permanent 
discontinuation of brentuximab vedotin 
To provide clear guidance on appropriate 
dose modifications and the impact on the 
study treatment regimen 
Section 5.2.4 
Clarified that subjects who discontinue 
brentuximab vedotin due to AE after only 
1 cycle of treatment may not continue on 
the study 
To provide appropriate safety measures for 
subjects who have AEs early in treatment 
Section 5.5.3 
Reduced the duration of nivolumab 
administration from 60 to 30 minutes 
To align with the current recommendation 
for nivolumab administration 
Section 5.5.3 
Added the following sentence: 
 
Nivolumab should be administered at a 
set dose of 240 mg and neither reduced 
nor increased. 
To clarify that nivolumab should be neither 
reduced nor increased in dose 
Section 
5.5.4.1 
Added text to clarify that dose 
modifications may include permanent 
discontinuation of nivolumab 
To provide clear guidance on appropriate 
dose modifications and the impact on the 
study treatment regimen 
Section 
5.5.4.1 
Added the following sentence: 
 
If nivolumab is held due to AE, once the 
AE has resolved administration of 
nivolumab should resume on the same 
schedule at the next cycle of therapy. 
To clarify the appropriate timing for 
resuming nivolumab treatment after an AE-
related hold 
Section 6 
Added the following sample collection for 
Part C only to Cycle 1 Day 1; Cycles 2 
and 4, Day 1; the End of Treatment visit, 
and long-term follow-up (optional): 
 
To provide direction for blood collection 
used for biomarker analyses in Part C 


 
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Section(s) 
Change 
Rationale 
Peripheral blood collection for biomarker 
analyses 
Section 6.6.2 
Added clarification that PET must be 
performed in addition to CT scans if CT is 
positive at the prior time point in 
PET-negative disease 
To clarify the time point when PET/CT may 
be required 
Section 6.6.2 
Added the following for Part C: 
 
Subjects in Part C who do not have 
disease progression will continue in long-
term follow-up for an additional 2 years. 
During this period, a physical exam 
should be performed every 6 months and 
a dedicated CT of chest, neck, abdomen, 
and pelvis should be performed every 12 
months.  
To provide for a 5 year follow-up period for 
Part C subjects 
Section 6.6.2 
Added the following sentence: 
 
For Part C only, peripheral blood may be 
collected at the time of disease 
progression if the subject has provided 
additional consent 
To provide for optional biomarker sample 
collection during long-term follow-up at the 
time of disease progression 
Section 7.3.1 
Added the following sentence: 
 
For Part C only, subjects who provide 
additional consent may provide optional 
biopsy tissue at the time of progression. 
To provide for optional biomarker sample 
collection during long-term follow-up at the 
time of disease progression 
Section 7.3.3 
Added a section to describe collection and 
analysis of peripheral blood for Part C 
To describe the possible analyses that could 
occur with these samples 
Section 
7.4.1.3 
Extended the safety reporting window for 
Parts B and C to 100 days 
To provide an appropriate window for 
collection of information regarding AEs that 
may occur in Parts B or C 
Section 9.1 
Added information on the statistical 
determination of sample size for Part C 
To provide background information on 
sample size selection for Part C 
Appendix B 
Revised as needed to align with 
operational changes throughout Parts B 
and C 
To align with operational changes as needed 
Appendix G 
Revised to match current best practices in 
contraceptive guidance for subjects 
participating in this clinical trial 
To provide clarity on contraceptive 
expectations and options during subject 
participation in this clinical trial 
 


 
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Summary of Changes in Amendment 4  
Section(s) 
Change 
Rationale 
Protocol Synopsis; 
Section 1; 
Section 3.2.3; 
Section 4.1 
Part B: Added subjects with Ann 
Arbor Stage I cHL with bulky 
mediastinal disease 
Early stage bulky mediastinal cHL to 
include both Stage I with bulky disease 
and Stage II with bulky disease 
Protocol Synopsis; 
Section 1; 
Section 3.2.3; 
Section 4.1 
Part C: Changed “non-bulky” to 
“without bulky” for subjects with 
Ann Arbor Stage I or II cHL enrolled 
in Part C 
To provide clarification 
Throughout 
Changed “Seattle Genetics” to 
“Seagen Inc.” 
Updated to reflect change in sponsor 
name 
Throughout 
Removed USPI references 
Updated to global indications 
Throughout 
Removed FDA references 
Updated to meet global regulatory 
requirements 
Throughout 
Addition of EMA indications and 
updated clinical experience for 
brentuximab vedotin 
Updated to add EMA indications 
Title Page 
Addition of EudraCT Number  
Updated to meet EU Regulatory 
requirements 
Title Page 
Addition of mobile telephone for 
medical monitor 
To provide additional contact 
information for medical monitor 
Protocol Synopsis 
Removed the following text: 
 
Subjects are excluded if they have 
nodular lymphocyte predominant HL 
or have symptomatic neurologic 
disease that compromises normal 
activities of daily living or requires 
medication. 
To provide high-level exclusion criteria 
for synopsis; deleted text is in body of 
the protocol 
Protocol Synopsis 
Removed the following text: 
 
Prior immunosuppressive 
chemotherapy, therapeutic radiation, 
or any immunotherapy (e.g., 
immunoglobulin replacement, or 
other monoclonal antibody therapies, 
including IO agents) must be 
completed a minimum of 4 weeks 
prior to the first study dose of any 
study drug. 
To align with the treatment-naïve study 
design of the protocol 
Protocol Synopsis 
Added the following to efficacy 
assessments: 
 
To decrease radiation exposure, CT 
scans of neck will be mandated at 
Baseline only; restaging imaging will 
only be repeated if neck disease is 
present at Baseline. 
To provide clarification 
Protocol Synopsis; 
Section 1; 
Section 4.1 
Added definition of bulky disease 
(≥10 cm by CT imaging) 
To provide clarity in classifying cHL 
with or without bulky mediastinal 
disease 
Section 1; 
Section 1.4.2; 
Section 7.4 
Updated text as follows: 
 
To provide clarity on safety assessment 
by SMC 


 
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…after approximately 10 subjects 
have completed treatment Cycle 2… 
Section 1.2 
Added the following text: 
 
The prevalence of neutropenia and 
FN was mitigated in a sub-set of 
subjects who received G-PP (29% vs 
70% without G-PP, and 11% vs 21% 
without G-PP, respectively) (Straus 
2018a). 
Additional rationale for use of G-PP 
Section 1.2 
Removed the following text: 
 
and SMC 
To correct previous version; SMC was 
not part of recommendation of primary 
prophylaxis 
Section 1.4.1 
Removed the following text: 
 
Further analysis has demonstrated a 
noted difference in study results in North 
America when compared to other regions 
(Connors 2018; Ramchandren 2018). 
Subjects in the North American intent to 
treat (ITT) population demonstrated an 
mPFS by independent review facility at 2 
years of 84.3% for A+AVD vs 73.7% for 
ABVD (hazard ratio (HR)=0.60, 95% CI; 
0.40, 0.90). 2 year PFS by investigator in 
the North American population was 
88.1% for A+AVD subjects vs 76.4% for 
ABVD subjects (HR=0.50, 95% CI; 
0.32 0.79). 
To align with global regulatory updates 
Section 1.4.2 
Added the following for SMC 
assessment: 
 
If an SMC determines that the risks 
outweigh the benefits of AN+AD, 
the sponsor may choose to halt 
enrollment in Parts B or C of the 
study. 
To provide clarity with other sections 
of the protocol 
Figure 3 
Updated Footnote “B” to the 
following: 
c 
 
d 
Follow-up period for Parts B and C 
includes 2 additional years (5 years 
total). 
To clarify that 5-year total follow-up 
applies to Parts B and C 
Section 3.1.1 
Definition of End of Study added  
Updated to meet EU Regulatory 
requirements 
Section 3.2.4.2 
Added the following bolded text: 
 
The recommended dose for 
brentuximab vedotin in combination 
with chemotherapy for previously 
untreated Stage III or IV cHL is 
1.2 mg/kg up to a maximum of 
120 mg based on 100 kg body 
weight 
To provide clarity for maximum dose 
of brentuximab vedotin 
Section 4.1 
Updated required age for inclusion 
with the following bolded text: 
 
Age 12 years or older in the United 
States. For regions outside of the 
Updated to provide clarity on age for 
inclusion in regions outside of the 
United States 


 
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United States, subjects must be age 
18 years or older. 
Section 4.1 
Added the following to inclusion 
criteria: 
 
Subjects of childbearing potential 
must agree not to breastfeed or 
donate ova, starting at the time of 
informed consent and continuing 
through 7 months after the final dose 
of study drug. 
Updated to align with protocol 
template updates 
Section 4.1 
Adjusted the following inclusion 
criteria: 
 
If sexually active in a way that could 
result in pregnancy, subjects of 
childbearing potential must agree to 
use 2 effective contraception 
methods (including 1 highly 
effective) during the study and for 
6 7 months following the last dose of 
study drug (see Appendix G). 
Subjects who can father children and 
have partners of childbearing 
potential must agree to use 
2 effective contraception methods 
during the study and for 7 months 
following the last dose of study drug 
(see Appendix G). Subjects who can 
father children must also be willing 
to refrain from sperm donation 
starting at the time of consent and 
continuing through the study 
period and for at least 7 months 
after the final dose of study drug 
during this time. Subjects born male 
who are sexually active with a 
pregnant or breastfeeding person 
must use contraceptives outlined in 
Appendix G to prevent secondary 
exposure to seminal fluid. 
Updated to align with protocol 
template updates and adhere to global 
regulatory requirements 
Section 4.1 
Adjusted the following inclusion 
criteria: 
 
…estimated glomerular filtration rate 
(GFR) ≥30 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease 
(MDRD) study equation as applicable 
for subjects ≥18 years old, or bedside 
Schwartz formula for subjects 
<18 years old (see Section 7.4.2). 
 
Added bedside Schwartz formula as 
this is more appropriate for pediatrics 
Section 4.2 
Removed the following from 
Exclusion Criterion #3: 
 
unless underlying disease has 
progressed on treatment 
To provide clarity since all subjects 
will be receiving first line treatment in 
this study 


 
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Section 4.2 
Updated Exclusion Criterion #15: 
 
Neurologic disease compromising at 
least 1 Activity of Daily Living (total 
dependence) per Katz Index of 
Independence in Activities of Daily 
Living (Appendix H), or poorly 
controlled by medication per the 
investigator’s assessment. 
To include a co-morbidity assessment 
tool for evaluation of Activities of 
Daily Living 
Section 4.2 
Added the following bolded text to 
Exclusion Criterion #25: 
 
Subjects who have received a live or 
attenuated vaccine within 30 days prior 
to treatment and 100 days after the last 
dose (Parts B and C only). 
Updated to align with text in Section 
5.6.3.1 
Section 4.2 
Added the following bolded text to 
Exclusion Criterion #26: 
 
Inhaled, ocular, intra-articular, or 
topical steroids, and adrenal 
replacement steroid doses >10 mg 
daily prednisone equivalent, are 
permitted in the absence of active 
autoimmune disease. 
To provide clarity for steroids allowed 
in the absence of active autoimmune 
disease 
Section 5.2.2 
Added the following bolded text: 
 
The maximum dose calculated per 
administration in this study is 
120 mg (1.2 mg/kg). 
To provide clarity for maximum dose 
of brentuximab vedotin 
Section 5.2.4 
Moved text describing dose 
modifications 
To better describe information listed in 
the dose modification tables 
Section 5.2.4 
Added the following text: 
 
Refer to Section 6 of the 
Investigator’s Brochure for 
additional information on the safety 
of brentuximab vedotin, and 
guidance regarding appropriate 
safety monitoring for subjects. 
To provide additional guidance on 
safety of brentuximab vedotin 
Section 5.3.2 
Updated with the following bolded text: 
 
In the United States, doxorubicin, 
vinblastine, and dacarbazine will be 
supplied by the study site from 
commercial sources, and billed to 
subjects and/or their third-party payer 
(insurance, a healthcare provider, or 
applicable government program). 
 
In regions outside of the United States, 
doxorubicin and dacarbazine will be 
provided by Seagen Inc. via a central 
pharmacy, or will be supplied by the 
study site from a local source to be 
reimbursed by Seagen Inc. 
To provide clarity for drug 
procurement methods for regions 
outside of the United States 
Section 5.4.1 
Adjusted text describing G-CSF use 
in the study 
To provide clarity on G-CSF 


 
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Section 5.6.2 
Added the following bolded text: 
 
Subjects are allowed premedications 
for prevention of infusion-related 
reactions, including corticosteroids, 
dosing <10 mg prednisone equivalent 
or per local standard of care. 
… 
Growth factor support or prophylaxis 
(G-CSF or GM-CSF) should be 
considered for subjects who are at risk 
for, currently have, or who have 
recently recovered from, neutropenia. 
To provide clarity on allowed 
premedication 
Section 5.6.2 
Removed the following subheading: 
 
5.6.2.1 Allowed Concomitant 
Therapy  Parts B and C Only 
To clarify that the allowed concomitant 
therapies listed are applicable to all 
parts of the study 
Section 5.6.3.1 
Added the following bolded text: 
 
Immunosuppressive doses of 
systemic corticosteroids (e.g., 
prednisone >10 mg/day) 
(premedications for prevention of 
infusion-related reactions are 
allowed). 
To provide clarity on allowed 
premedication 
Section 5.7.1 
Added the following bolded text: 
 
Subjects will be monitored for a 
period of 2 hours post-infusion of 
brentuximab vedotin. Infusion or 
hypersensitivity reactions may occur 
within 24 hours or more than 
24 hours post-dose, respectively, to 
either brentuximab or nivolumab. 
To provide clarity for 
infusion/hypersensitivity reactions 
Section 5.7.4 
Added “Myocarditis (EU-specific)” 
to AEs 
Updated to meet EU Regulatory 
requirements 
Section 6.2 
Updated header to “Screening Visit 
(Day -28 to Day 1)” 
To correct a typo in A03 
Section 6.2; 
Appendix B 
Changed acceptable window for 
echocardiogram/multi-gated 
acquisition scan from within the past 
6 months to within the past 1 month 
Updated to adhere to global regulatory 
requirements 
Section 6.2 
Added the following for Screening 
Activities: 
 
• 
CT scans up to 3 days prior to 
Day -28 (i.e., Day -31) will be 
accepted 
• 
PET scans up to 3 days prior to 
Day -28 (i.e., Day -31) will be 
accepted 
To expand window for allowed 
Screening scans 
Section 6.3.1.1; 
Section 6.3.2.1; 
Section 6.3.2.3 
Added pregnancy testing to D1 of 
every cycle 
To comply with EU regulations 
Section 6.3.2.1 
Added “CBC with differential (not 
required if completed at Baseline 
To align with the schedule of events 


 
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visit within 1 day prior to Cycle 1, 
Day 1)” 
Section 6.3.2.1 
Added “B symptom assessment (not 
required if completed at Baseline)” 
To align with the schedule of events 
Section 6.3.2.2 
Added “ECOG Performance status 
(Appendix C)” 
 
To align with the schedule of events 
Section 6.4 
Removed the following bullet point 
from EOT visit: 
• 
International prognostic score 
(Part A only; Appendix D) 
This assessment should only occur at 
baseline and is not useful at EOT. 
Section 6.5 
Removed “±2 weeks” for nivolumab 
safety visit window and updated to 
“100 to 114 days” 
To provide clarify that the final safety 
visit cannot occur 2 weeks before the 
100-day point post-nivolumab; 2 weeks 
after the 100-day point has been added 
to the Schedule of Evaluations 
Section 6.5 
Added “doxorubicin, or dacarbazine” 
To provide clarity for “study 
medication other than nivolumab” 
Section 6.6.2 
Added the following for last 2 years 
of follow-up: 
 
Subjects will then continue in 
follow-up for 2 additional years 
(5 years total).  
To provide clarity on long-term 
follow-up and clarify this applies to 
both Parts B and C. 
Section 6.7 
Removed “End of Study” from 
heading 
End of Study definition added in new 
Section (Section 3.1.1) 
Section 7.3.1 
Updated text as follows: 
 
Subjects in Parts B and C should 
must provide tumor tissue for 
biomarker analysis. Availability of 
archival tumor tissue (non-bone 
sites) must be confirmed collected 
within 3 months of prior to 
enrollment is requested, if available. 
To provide clarity on tumor tissue 
collection 
Section 7.4.1.2 
Updated time to notify Drug Safety 
Department of pregnancy from 48 
hours to 24 hours 
Updated to adhere to global regulatory 
requirements 
Section 7.4.1.2 
Updated time after final study drug 
dose to 7 months for pregnancy 
reporting 
Updated to adhere to global regulatory 
requirements 
Section 7.4.1.2 
Updated time to avoid pregnancy to 
7 months after the final dose of study 
drugs, and added reference to 
Appendix G for Pregnancy 
To provide additional guidance on 
Pregnancy  
Section 7.4.1.3 
Updated text as follows: 
 
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 study drug 
administration (Part A), 30 days 
after the last dose of brentuximab 
vedotin, doxorubicin, dacarbazine 
or 100 days after the last study drug 
administration dose of nivolumab, 
To provide clarity and align with safety 
visit window 


 
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whichever is later (Parts B and C 
only). 
Section 7.4.2 
Added “Hemoglobin A1c” to clinical 
laboratory tests 
To align with Schedule of Events and 
provide clarity to sites 
Section 7.4.2 
Updated the following: 
 
• 
The estimated GFR should be 
calculated using the MDRD equation 
as applicable for subjects ≥18 years 
old, with serum creatinine (Scr) 
reported in mg/dL.  
 
GFR (mL/min/1.73 m2) = 175 x 
(Scr)-1 154 x (Age)-0 203 x (0.742 if 
female) x (1.212 if African 
American) 
 
• 
The estimated GFR should be 
calculated using the bedside 
Schwartz formula for subjects 
<18 years old, with Scr reported in 
mg/dL. 
 
eGFR = 0.43 x (height/Scr) 
 
Added bedside Schwartz formula as 
this is more appropriate for pediatrics 
Section 7.4.3 
Added the following text: 
 
Vital signs (blood pressure, heart 
rate, and temperature) will also be 
assessed. 
To provide clarity on assessments 
included in each physical examination 
Section 7.4.4 
Added Section 7.4.4. Sponsor Safety 
Reporting to Regulatory Authorities 
To provide clarity on safety reporting 
Section 9.1 
Changed “84.3%” to “94.3%” 
To correct typo in version A03 
Section 9.3.7.2 
Updated time points for AE 
assessments in Parts B and C 
To align with changes made in Section 
7.4.1.3 
Section 9.3.8 
Added the following: 
 
An SMC will be responsible for 
monitoring patient safety in Parts B and 
C of the study (see Section 7.4). 
This study is not designed to allow for 
early stopping for futility or favorable 
efficacy results. A formal interim 
efficacy or futility analysis is not 
considered meaningful or practical for 
this study. An ongoing real-time review 
of SAEs will be conducted by the Seagen 
Inc. Drug Safety Department. 
To provide clarity on interim analyses 
Section 10.1 
Removed the following text: 
 
For phase 1 studies, it is preferable 
for a subject to provide consent 
themselves. 
Removed for phase 2 study purposes 
Section 10.4 
Added the following text: 
 
Government agency regulations and 
directives require that all study 
documentation pertaining to the 
conduct of a clinical trial must be 
retained by the investigator until 
Updated to adhere to global regulatory 
requirements 


 
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notified by the sponsor in writing 
that retention is no longer necessary. 
Appendix A 
Removed IPS assessment from EOT 
visit in Part A Schedule of Events 
To align with change made in Section 
6.4 
Appendix A 
Added footnote “B” with the 
following: 
 
Subjects will remain in follow-up 
until death, withdrawal of consent, or 
completion of 2 years of long-term 
follow-up (from EOT visit), 
whichever occurs first. 
To align with protocol text 
Appendix A 
Updated footnote labels 
To allow for consistency after insertion 
of new footnote “B” 
Appendix A 
Added footnote “K” with the 
following: 
 
Scans collected within 3 days prior to 
Day -28 will be accepted 
To align with changes made in Section 
6.3.2.1 
Appendix A; 
Appendix B 
Added pregnancy screening on D1 of 
every cycle 
To comply with EU regulations 
Appendix B 
Added the following for Screening 
period heading: 
 
(-3 days) 
To align with changes made in Section 
6.3.2.1 
Appendix B 
Updated 100-day safety visit heading 
with “+2 weeks” 
To align with changes in Section 6.5 
Appendix B 
Removed thyroid panel from safety 
assessments 
To provide clarity because thyroid 
panel is already included in the 
chemistry panel safety assessment 
Appendix B 
Added “amylase” and “lipase” to 
footnote “I” 
To align with Section 7.4.2 which 
states that for Parts B and C, the 
chemistry panel should also include 
amylase and lipase 
Appendix B 
Moved “PET” from Baseline time 
point to Screening time point 
To align with Section 6.2 which lists 
the PET scan during screening, not 
baseline analysis 
Appendix B 
Updated footnote “C” as the 
following: 
 
The final safety visit should occur 
100-114 days after the last dose of 
nivolumab or 30–37 days post last 
dose of BV (concurrent with the 
EOT visit), whichever is later. 
To align with changes in Section 6.5 
Appendix B 
Updated footnote “A” as the 
following: 
 
For Parts B and C, disease 
assessments will be performed 
during follow-up every 3 months 
after the EOT visit for the first year, 
then every 6 months for 2 additional 
years. Subjects will then continue in 
follow-up for 2 additional years (5 
To align with protocol text 


 
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years total), with physical exams 
required every 6 months and disease 
assessments required every 12 
months. Timing of follow up visits 
should be relative to EOT visit and 
not relative to last dose. 
Appendix B 
Updated footnote “D” with the 
following bolded text: 
 
Physical exam includes vital signs 
(blood pressure, heart rate, 
temperature), height (at baseline) 
and weight 
To align with updates made in 
Section 7.4.3 
Appendix B 
Added footnote “K” to the following 
at Baseline: 
 
CBC with differential 
Physical exam 
Chemistry panel 
To clarify that if Baseline Visit 
activities occur within 1 day prior to 
Cycle 1, Day 1, the assessments do not 
need to be repeated at the Cycle 1, 
Day 1 visit 
Appendix B 
Added footnote “J” to D1 of every 
28-day cycle under chemistry panel 
safety assessments 
To provide clarity to sites that these 
assessments are only required at 
Cycles 1 and 3 during treatment cycles 
Appendix B 
Added footnote “Q” with the 
following: 
 
Scans collected within 3 days prior to 
Day -28 will be accepted 
To align with changes made in Section 
6.3.2.1 
Appendix B 
Added footnote “R” with the 
following: 
 
Refer to Section 7.3.1 for details 
To align with updates made in 
Section 7.3.1 
Appendix G 
Updated with global guidance on 
contraception 
Updated to adhere to global regulatory 
requirements 
Appendix H 
Added Katz Index of Independence 
in Activities of Daily Living 
To provide clarity to Exclusion 
Criterion #15 


 
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Summary of Changes in Amendment 5  
Section(s) 
Change 
Rationale 
Protocol 
synopsis 
For Part C, one interim analysis will 
be performed after approximately 
50 subjects have completed response 
assessment at EOT. At the interim 
futility analysis, if the CR rate at EOT 
is ≤80% (40/50 or fewer subjects with 
CR at EOT), the sponsor in 
consultation with the SMC may 
decide to stop further enrollment of 
the trial. 
In response to MSK research Council 
comments 
Section 1 
The components of AN+AD will be 
administered as described in Section 5. 
For both Part B and Part C, after 
approximately 10 subjects have 
completed Cycle 2, an SMC will assess 
the safety of AN+AD. Safety will be 
assessed separately for Part B and Part 
C. An additional SMC meeting will 
occur after approximately 50 subjects 
in Part C have completed their EOT 
assessment.  
Clarification 
Section 1.4.1 
(Straus 2018a). The highest incidence of 
FN occurred in the ECHELON 1 study 
during Cycle 1) (Straus 2018a). The 
highest incidence of FN occurred in 
the ECHELON-1 study during Cycle 
1 (Connors 2018). When G-PP was 
administered during Cycle 1 to a sub-set 
of subjects, the rate of Cycle 1 FN 
decreased from 11% to 1% (Figure 1), 
(Straus 2018a). In addition, these 
subjects experienced fewer infections 
and Grade 3 or higher AEs (Straus 
2018a). (Straus 2018a). In addition, 
these subjects experienced fewer 
infections and Grade 3 or higher AEs 
(Straus 2018a). Furthermore, subjects 
who received G-PP in ECHELON-1 
had an improved efficacy as 
demonstrated by 84.6% mPFS at 2 
years vs 81.7% without G-PP (Straus 
2018a).  
Clarification 
Section 1.4.2 
The combination of brentuximab 
vedotin and nivolumab appears to be 
active and well tolerated in cHL. Each 
agent has been as well as each agent 
combined separately with doxorubicin, 
vinblastine, and dacarbazine and also 
have been shown to be active and well 
tolerated in the treatment of cHL. 
Part B will evaluate the combination 
of AN+AD in advanced stage HL. 
Yasenchak et al examined the 
combination of brentuximab and 
nivolumab as frontline treatment for 
subjects ≥60 years with advanced stage 
Clarification 


 
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Section(s) 
Change 
Rationale 
HL who were ineligible for or declined 
conventional chemotherapy. Preliminary 
results showed an overall response rate 
(ORR) of 100%, a CR rate of 72%, and 
a partial response (PR) rate of 28% 
(Yasenchak 2019). Additionally, 
preliminary, The regimen was well-
tolerated; the most common 
treatment related adverse events of 
any grade were fatigue (48%), 
peripheral sensory neuropathy (38%), 
diarrhea, infusion-related reactions, 
and pyrexia (24% each). Three 
subjects had immune-related AEs 
with a maximum severity of Grade 3. 
Part C will further evaluate the 
combination of AN+AD in early stage 
HL. 
The most common treatment-related 
adverse events of any grade included 
nausea (79%), peripheral sensory 
neuropathy (56%), fatigue (50%), 
constipation (38%), and alopecia 
(35%). Grade 3 or higher AEs were 
limited to nausea (3%), neutropenia, 
(6%), and vomiting (3%). 
An additional SMC meeting will occur 
after approximately 50 subjects in 
Part C have completed their EOT 
assessment. For Part C, one interim 
analysis will be performed after 
approximately 50 subjects have 
completed response assessment at 
EOT. If an SMC determines that the 
risks outweigh the benefits of AN+AD, 
the sponsor may choose to halt 
enrollment in Parts B or C of the study. 
Section 1.4.3 
Historical standard of care treatment 
options for patients with advanced HL 
have been associated with poor 
survival (Gordon 2013). In the 
ECHELON-1 trial, an open-label, 
international, multicenter, 
randomized Phase 3 clinical trial in 
subjects with previously untreated 
Stage III or IV cHL, the 
complementary mechanisms of action 
of brentuximab vedotin with A+AVD, 
enhanced antitumor activity with 
significant improvement in mPFS (see 
Section 1.2). 
The combination of brentuximab 
vedotin and nivolumab was active and 
welltolerated in cHL with improved 
CR rate of 61% in relapsed or 
refractory cHL (Herrera 2018). The 
combination of N+AVD as found to 
have a 67% CR rate in subjects with 
To address Italy Health Authority feedback 


 
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Section(s) 
Change 
Rationale 
newly diagnosed advanced stage cHL 
(Ramachandren 2019; Section 1.3). In 
another trial of 11 previously 
untreated subjects with cHL over 60 
years-old and ineligible for or 
declining conventional combination 
chemotherapy, the combination of 
brentuximab vedotin and nivolumab 
produced a 55% CR rate (Friedberg 
2018). Section 1.4.2 provides 
additional information on the better 
outcome of this combination therapy. 
Given the demonstrated activity of 
brentuximab vedotin as well as 
nivolumb as treatment of cHL, the 
evaluation of this regimen is 
anticipated to provide benefit to these 
patients with acceptable known 
toxicity. The toxicity profile of the 
combination in cHL is expected to be 
consistent with that of previous 
studies. Neutropenia and associated 
complications, including febrile 
neutropenia and infections, infusion 
related reactions, and peripheral 
neuropathy were considered the most 
clinically important AEs for the 
combination regimen. Investigators 
may decide to discontinue study 
treatment at any time for any of the 
reasons listed in Section 4.3.1. 
 The same rationale regarding the use 
of brentuximab vedotin and 
nivolumab applies when considered as 
treatment of early stage cHL. Current 
accepted therapies for early stage cHL 
include chemotherapy regimens, 
radiation, and combined modality 
therapy of chemotherapy and 
radiation. These regimens are 
associated with high cure rates of 85-
90% (Meyer 2012) but are also 
associated with high rates of serious 
morbidity and mortality in long-term 
survivors, particularly second 
primary malignancies and 
cardiovascular disease (Straus 2018b). 
Recent data in 34 subjects with 
previously untreated Stage I/II cHL 
with non-bulky disease, treatment 
with brentuximab vedotin, 
doxorubicin, and dacarbazine showed 
CR, PFS and OS rates of 100% at 
EOT (Abramson 2018). The 
promising responses observed with 
the combination of brentuximab 
vedotin and nivolumab as treatment 
of advanced cHL as well as the 


 
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evidence of activity in earlier stage 
disease provide a compelling rationale 
to evaluate the combination of 
brentuximab vedotin and nivolumab. 
Section 3.1.2 
The SMC will meet to evaluate safety 
after approximately 10 subjects have 
completed Cycle 2. Additionally, the 
committee will An additional SMC 
meeting will be held after 
approximately 50 subjects in Part C 
have completed their EOT 
assessment. The committee will also 
monitor the safety of participants 
through regular and/or ad hoc meetings 
that include review of adverse events 
and lab abnormalities 
In response to MSK research Council 
comments 
Section 3.2.3 
Subjects with Stage I or II cHL without 
bulky medistinal disease will be 
assigned to Part C. 
Clarification 
Section 4.1 
Subjects enrolling in Part C of the study 
must have Ann Arbor Stage I or II cHL 
without bulky mediastinal disease. 
Clarification 
Section 4.2 
Documented history of Iidiopathic 
interstitial pneumonia or diffusing 
capacity of the lung for carbon 
monoxide (adjusted for hemoglobin) 
<50% predicted. 
Clarification 
Table 4 
or prophylaxis should be considered for 
subsequent cycles if not already 
administered 
Clarification 
Section 5.7.1 
Subjects will be monitored for a period 
of 2 hours post-infusion of brentuximab 
vedotin at each visit. 
Clarification 
Section 6.2 
• 
To decrease radiation 
exposure, CT scans of neck 
will be mandated at Baseline 
only; restaging imaging will 
only be repeated if neck 
disease is present at Baseline. 
● 
Initiate collection of archived 
tumor tissue specimen or fresh 
tumor biopsy (Section 7.3.1) 
(For Parts B and C only)  
 
Clarification 
Section 6.2.1 
Height and weight (For subjects <18 
years, height must be measured at this 
visit; for subjects ≥18 years, height 
measured within 12 months is 
acceptable) 
Clarification 


 
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Section 6.3.2.1 
CBC with differential (not required if 
completed at Baseline visit within 1 day 
prior to Cycle 1, Day 1) 
 
Serum chemistry panel, (includes 
should include amylase and lipase 
along with TSH, free T3, and free T4 
(see Section 7.4.2) 
 
B symptom assessment (not required if 
completed at Baseline); Note: Subjects 
will be monitored for a period of 
2 hours post-infusion of brentuximab 
vedotin at each visit 
Clarification 
Section 6.3.2.5 
To decrease radiation exposure, CT 
scans of neck will be mandated at 
Baseline only; restaging imaging will 
only be repeated if neck disease is 
present at Baseline 
Clarification 
Section 6.4 
To decrease radiation exposure, CT 
scans of neck will be mandated at 
Baseline only; restaging imaging will 
only be repeated if neck disease is 
present at Baseline 
Clarification 
Section 6.6.1 
Follow-up visits will occur every 
12 (±1) weeks from the EOT visit 
 
Section 6.6.2 
• 
To decrease radiation 
exposure, CT scans of neck 
will be mandated at Baseline 
only; restaging imaging will 
only be repeated if neck 
disease is present at Baseline. 
• 
Disease status 
• 
SAEs related to treatment 
Subjects will then continue in follow-up 
for 2 additional years (5 years total). 
For the final 2 years, a physical exam 
should be performed every 6 months 
and a dedicated CT of chest, neck, 
abdomen, and pelvis should be 
performed every 12 months. CT scans 
of neck will only be repeated if neck 
disease is present at Baseline. 
 
• 
Survival status and subsequent 
anticancer therapies received  
Note: 3-month follow-up may 
be performed with 100-day 
safety visit 
• 
Resolution of PN, if applicable 
• 
SAEs related to treatment 
Clarification 
Section 9.1 
For Part B, approximately 50 subjects 
will be enrolled in order to provide an 
adequate level of precision for the 
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estimate of the CR rate at EOT. If 
45 of 50 subjects have a CR at EOT, the 
CR rate at EOT is 90% with 95% CI 
(78.2%, 96.7%) based on the exact 
Clopper-Pearson method (Clopper 
1934); if 42 of 50 subjects have a CR at 
EOT, the CR rate at EOT is 
84% (95% CI: 70.9%, 92.8%) ; if 48 of 
50 subjects have a CR at EOT, the CR 
rate at EOT is 96% (95% CI: 86.3%, 
99.5%). The 73% CR rate at EOT 
observed in the A+AVD arm in the 
ECHELON-1 trial was considered the 
relevant benchmark when 
determining an appropriate sample 
size for Part B (Connors 2018). 
 
For Part C, approximately 150 subjects 
will be enrolled in order to provide an 
adequate level of precision for the 
estimate of the CR rate at EOT. power 
to reject the hypothesis that CR rate 
at EOT is ≤90%. Assuming a CR rate 
of 95%, 150 subjects would provide 
approximately 80% power to reject 
the null hypothesis of a CR rate at 
EOT ≤90% with a 1-sided 
alpha = 0.05 and using an empirical 
variance estimate (East v6.4). This 
sample size calculation accounts for 
the interim futility analysis which is 
further described in section 9.3.8If 142 
of 150 subjects have a CR at EOT, the 
CR rate at EOT is 95% with 95% CI 
(89.8%, 97.7%) based on the exact 
Clopper Pearson method (Clopper 
1934); if 135 of 150 subjects have a CR 
at EOT, the CR rate at EOT is 
90% (95% CI: 84.0%, 94.3%) ; if 146 of 
150 subjects have a CR at EOT, the CR 
rate at EOT is 97% (95% CI: 93.3%, 
99.3%). 
Section 9.3.5.2 
CR rate at EOT and the exact 2-sided 
95% CIs using the Clopper-Pearson 
method (Clopper 1934) will be 
calculated. 
 
For Part C a hypothesis test will be 
performed. The null and alternative 
hypotheses are: 
• 
Null hypothesis: CR rate at 
EOT ≤ 90% 
• 
Alternative hypothesis: CR 
rate at EOT > 90% 
The null hypothesis will be tested at a 
1-sided alpha of 0.05. The associated 
p-value will be calculated based on the 
In response to MSK research Council 
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normal approximation with an 
empirical estimate of the variance. If 
p <0.05 is observed the null hypothesis 
will be rejected in favor of the 
alternative hypothesis. 
If enrollment in Part C is stopped 
prior to completion no hypothesis 
testing will be performed. 
Section 9.3.8  
This study is not designed to allow for 
early stopping for futility or favorable 
efficacy results. A formal interim 
efficacy or futility analysis is not 
considered meaningful or practical for 
this study. An ongoing real time review 
of SAEs will be conducted by the 
Seagen Inc. Drug Safety Department. 
One interim futility analysis will be 
performed for Part C after 
approximately 50 subjects have 
completed response assessment at 
EOT. At this interim futility analysis, 
if the CR rate at EOT is ≤80% 
(40/50 or fewer subjects with CR at 
EOT), the sponsor in consultation 
with the SMC may decide to stop 
further enrollment of Part C of the 
trial. 
In response to MSK research Council 
comments 
Appendix B 
Confirm availability of archived tumor 
specimenR 
Collection of archived tumor tissue 
specimen or fresh tumor biopsyR 
Clarification 
Appendix B 
Updated Footnote I: 
Must include TSH, free T3, free T4, 
amylase, and lipase (section 7.4.2) 
Footnote J:  
Must include TSH, free T3, T4 at 
cycles 1, 3, and EOT only (see Section 
7.4.2) 
To match Section 7.4.2 
Appendix B 
Added footnotes S, T, U, and V 
Clarification 
 
 


 
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Summary of Changes in Amendment 6  
Section(s) 
Change 
Rationale 
Throughout 
Various administrative changes were 
made throughout  
To provide clarity when necessary and 
conform to editorial standards 
Protocol 
Synopsis  
Study 
Population 
Key eligibility criteria include 
treatment-naïve subjects (aged ≥12 years 
in the US and aged ≥18 years outside 
of the US) with classical Hodgkin 
lymphoma (cHL). 
Clarification, updating language to match 
eligibility criteria. 
Protocol 
Synopsis  
Study 
Population 
Part B will enroll subjects with Ann 
Arbor Stage 1 or II cHL with bulky 
mediastinal disease (defined as a single 
node or nodal mass with a diameter 
≥10 cm on CT imaging) or Stage III or 
IV cHL. 
Clarification of the definition of bulky 
mediastinal disease. 
Protocol 
Synopsis  
Study Design 
For Part C, one interim analysis will be 
performed after approximately 
50 subjects have completed response 
assessment at EOT. At this interim 
futility analysis, if the CR rate at EOT is 
≤80% (40/50 or fewer subjects with CR 
at EOT), the sponsor in consultation 
with the Safety Monitoring Committee 
(SMC) may decide to stop further 
enrollment of the trial. 
Clarification 
As of Amendment 6, Parts A and B 
were completed. 
Clarification 
Protocol 
Synopsis  
Efficacy 
Assessments 
Disease response and progression will 
be assessed by investigators using the 
Lugano Classification Revised Staging 
System for malignant lymphoma 
(Cheson 2014) with the incorporation 
of Lymphoma Response to 
Immunomodulatory Therapy Criteria 
(LYRIC) modification of Lugano 
Classification Revised Staging System 
for nodal non-Hodgkin and Hodgkin 
lymphomas (Cheson 2016). 
Clarification 
Table of 
Contents 
Updated pagination 
Inclusion of Appendix I 
Administrative 
Section 1 
Part B is designed to evaluate the 
combination of brentuximab vedotin, 
nivolumab, doxorubicin, and 
dacarbazine (AN+AD) as frontline 
treatment in subjects with advanced cHL 
(Stage I/II with bulky mediastinal 
disease [defined as a single node or 
nodal mass with a diameter ≥10 cm on 
CT imaging], or Stage III or IV). 
Clarification of the definition of bulky 
mediastinal disease. 
Section 1.2 
Eight of 34 subjects (24%) had 
neutropenia, but only 2 subjects (6%) 
had Grade 3 neutropenia; there were no 
cases of Grade 4 neutropenia or febrile 
neutropenia. 
Clarification 
Section 1.4.2 
For Part C, one interim analysis will be 
performed after approximately 50 
Clarification 


 
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subjects have completed response 
assessment at EOT. If an SMC 
determines that the risks outweigh the 
benefits of AN+AD, the sponsor may 
choose to halt enrollment in Parts B or C 
of the study. 
Sections 3.1, 
3.2.3, 4, 5.1 and 
6.1 
As of Amendment 6, Parts A and B 
were completed. 
Clarification 
Section 3.2.4.2 
After approximately 10 subjects have 
completed 2 cycles of treatment, an 
SMC will assess the safety of AN+AD 
(Section 3.1.2 Section 3.1.1). 
Administrative, correcting cross-reference 
link. 
Section 4.1 
Subjects enrolling in Part B of the study 
must have Ann Arbor Stage I or II cHL 
with bulky mediastinal disease (defined 
as a single node or nodal mass 
measuring 10 cm or greater in diameter 
as determined by CT imaging) or Stage 
III or IV disease. 
Clarification of the definition of bulky 
mediastinal disease. 
Section 4.1 
If a tumor block is not available, contact 
the medical monitor to discuss 
alternative specimen arrangments 
unstained slides (a minimum of 10 
unstained slides for Part B, and 12 
unstained slides for Part C) may be 
submitted instead of a tumor block. 
Clarification 
Section 5.2.4 
If any component of the regimen is 
discontinued due to AE, Ssubjects may 
remain on study and continue to receive 
the remaining treatment components. 
Clarification 
Section 5.5.4 
Nivolumab administration should be 
withheld or discontinued as described in 
Table 6. The recommended 
management of gastrointestinal (GI), 
renal, pulmonary, hepatic, 
endocrinopathy, skin, neurological, 
and myocarditis adverse events are 
provided in Appendix I. 
Clarification, to provide reference to guidance 
regarding the clinical management of 
common IMAEs that occur with nivolumab. 
Section 5.6.2 
Subjects are allowed premedications 
regimens for anti-emesis purposes and 
prevention of infusion-related reactions, 
including corticosteroids, dosing <10 
mg daily prednisone equivalent or per 
local standard of care.  
Clarification 
Stabel adrenal replacement steroid 
Ddoses of >10 mg daily prednisone or 
prednisone equivalent are allowed for 
stable adrenal replacement.  
Clarification 
Section 5.6.3 
Subjects may not receive other 
investigational drugs, 
immunosuppressive medications 
(exception: corticosteroid doses of >10 
mg daily prednisone, or prednisone 
equivalent for anti-emesis and 
premedications prevention of 
infusion-related reactions are 
Clarification 


 
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allowed), radiotherapy, or systemic anti-
neoplastic therapy from Day 1 through 
EOT. 
Sections 5.6.3.1 
Immunosuppressive doses of systemic 
corticosteroids (e.g., prednisone 
>10 mg/day) (premedications regimens 
for anti-emesis and prevention of 
infusion-related reactions are allowed). 
Clarification 
Section 5.7 
Additional information regarding 
treatment-emergent AEs (TEAEs) for 
brentuximab vedotin is available in the 
brentuximab vedotin IB. Management 
of immune-mediated AEs (IMAEs) 
for nivolumab is available in 
Appendix I. 
To provide reference to guidance regarding 
the clinical management of common IMAEs 
that occur with nivolumab. 
Section 5.7.4 
Immune-mediated adverse reactions, 
which may be severe or fatal, can 
occur in any organ system or tissue 
including the following groups of AEs 
should be managed per the algorithms 
found in Appendix 4 of the nivolumab 
IB: 
• 
Immune-mediated 
pneumonitis 
• 
Immune-mediated colitis 
• 
Immune-mediated hepatitis 
and hepatoxicity 
• 
Immune-mediated 
endocrinopathies 
• 
Immune-mediated 
dermatologic adverse 
reactions 
• 
Immune-mediated nephritis 
and renal dysfunction 
The following groups of AEs should 
be managed per the algorithms found 
in Appendix I: 
To provide provide awareness of common 
immune-mediated adverse reactions that can 
occur with nivolumab. To provide reference 
to guidance regarding the clinical 
management of common AEs that can occur 
with nivolumab. 
Section 6.2 
International prognostic score for Part 
B only (Appendix D) 
International prognostic score is applicable to 
only advanced stage patients 
Section 6.2.1 
• 
Estimated glomerular filtration 
rate (eGFR) calculation per MDRD 
Administrative, defined first use of 
abbreviation 
Sections 6.3.2.1, 
6.3.2.2, 6.3.2.3, 
6.3.2.4, 6.4, and 
6.5 
• 
eGFR (Section 7.4.2) 
Clarification, to update language to be 
consistent with eligibility criteria. 
Section 6.6.2 
• 
Dedicated CT of chest, neck, 
abdomen, and pelvis; performed at 
the timepoints above or and if 
progression is suspected based on 
clinical signs and symptoms 
Clarification that imaging should be 
conducted at the timepoints and to do 
additional imaging if progression is suspected 
(not as a substitute to the timepoints). 
Section 7.2 
IR1: An increase in overall tumor 
burden (as assessed by the sum of the 
products of the largest diameters [SPD]) 
of ≥50% of up to 6 measurable lesions 
Clarification, updated to match LYRIC 
criteria language. 


 
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in the first 12 weeks of therapy, without 
clinical deterioration; 
IR3: An increase in FDG uptake using 
the 5 Point Scale per the Deauville 
Criteria of 1 or more lesion(s) without a 
concomitant increase in lesion size or 
number. 
Clarification, updated to match LYRIC 
criteria language. 
Section 7.4.2 
● 
The chemistry panel is to include 
the following tests: albumin, alkaline 
phosphatase, ALT, AST, blood urea 
nitrogen, calcium, creatinine, chloride, 
eGFR, glucose, lactate dehydrogenase 
(LDH), phosphorus, potassium, sodium, 
total bilirubin, and uric acid. 
Clarification, to update language to be 
consistent with eligibility criteria. 
Section 9.2.2.1 
CR rate at EOT is defined as the 
proportion of subjects with CR at EOT, 
according to the Lugano Classification 
Revised Staging System for malignant 
lymphoma (Cheson 2014) with the 
incorporation of Lymphoma Response 
to Immunomodulatory Therapy Criteria 
(LYRIC) (Cheson 2016), in subjects 
with previously untreated cHL. 
Clarification 
Section 9.2.2.2 
ORR is defined as the proportion of 
subjects with CR or partial response 
(PR) at EOT according to the Lugano 
Classification Revised Staging System 
for malignant lymphoma (Cheson 
2014) with the incorporation of 
Lymphoma Response to 
Immunomodulatory Therapy Criteria 
(LYRIC) (Cheson 2016) in subjects with 
previously untreated cHL. 
Clarification 
Section 9.2.2.3 
Duration of response (DOR) is defined 
as the time from the first documentation 
of objective tumor response (CR or PR) 
to the first documentation of tumor 
progression (per the Lugano 
Classification Revised Staging System 
for malignant lymphoma (Cheson 
2014) with the incorporation of 
Lymphoma Response to 
Immunomodulatory Therapy Criteria 
(LYRIC) (Cheson 2016)) or death, 
whichever comes first. 
Clarification 
Duration of complete response (DOCR) 
is defined as the time from start of the 
first documentation of complete tumor 
response (CR) to the first documentation 
of tumor progression (per the Lugano 
Classification Revised Staging System 
for malignant lymphoma (Cheson 
2014) with the incorporation of 
Lymphoma Response to 
Immunomodulatory Therapy Criteria 
Clarification 


 
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(LYRIC) (Cheson 2016)) or death, 
whichever comes first. 
Appendix A 
Removed International prognostic score 
from Schedule of Events Table 
Clarification, International Prognostic Score 
is applicable to only advanced stage patients 
Appendix B 
International prognostic score (Part B 
only) 
Clarification, International Prognostic Score 
is applicable to only advanced stage patients 
Added eGFRS to Schedule of Events 
Table. 
Removed footnote “S” from Day-7 to 1 
Screening/Baseline visit for Chemistry 
panel. 
Clarification, updated to match inclusion 
criteria. 
Appendix F 
If tumor flare or pseudo-progression is 
suspected, then a clinical response of 
indeterminate response (IR) should be 
reported based on the Lugano 
Classification Revised Staging System 
for malignant lymphoma (Cheson 
2014) with the incorporation of 
Lymphoma Response to 
Immunomodulatory Therapy Criteria 
(LYRIC) (Cheson 2016). 
Clarification 
This pattern may be seen as a 
consequence of either delayed 
response or early immune-mediated 
flare. At least within the context of 
clinical trials, a biopsy is encouraged 
in this case because this may help to 
distinguish the two and, if positive, 
will confirm the impression of PD. 
However, if negative for lymphoma, it 
will support the concept of 
pseudoprogression and contribute to 
our understanding of this 
phenomenon. When such a biopsy is 
neither safe nor feasible, decisions 
must be based on a repeat scan 12 
weeks after the initial determination 
of IR. 
It is recognized that “clinical 
deterioration” is subjective. In general 
some cases, the simple growth of a 
nodal or tumor mass could worsen the 
symptoms mechanically related to 
that mass, such as pain at the tumor 
site or compression of adjacent 
structures, etc. Such an increase in 
symptoms that can be directly 
attributed to the size of the tumor 
mass may not be considered as clinical 
deterioration in this context. 
However, in most cases, subjects 
should be experiencing clinical stability 
or improvement and must be able by 
investigator assessment to be 
considered as having IR, and in all 
cases, the patient must be considered 
likely to tolerate continued treatment 
Clarification, updated to match LYRIC 
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and not at risk of serious complications 
should further 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. 
This phenomenon may occur early or 
late in the treatment course, and 
therefore, unlike IR1, is not defined 
by its temporal relationship to 
treatment initiation. Both within and 
outside the context of clinical trials, 
Aabiopsy is strongly encouraged when a 
subject experiences this phenomenon in 
such cases. 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 FDG uptake 
(using the 5 Point Scale per the 
Deauville Criteria of one 1 or more 
lesion(s)) without a concomitant 
increase in lesion size or number. 
Clarification, updated to match LYRIC 
criteria language. 
Appendix F 
Therefore, by itself changes in uptake 
should not trigger an assignment of 
progressive disease (PD) with 
checkpoint inhibitors. 
Clarification, updated to match LYRIC 
criteria language. 
It is important to investigate this finding, 
especially in conjunction with a biopsy 
(if possible) of the lesion in question. 
While awaiting a better 
characterization of this phenomenon, 
we propose that, under the modified 
response criteria, 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 
subject could fulfill criteria for both IR1 
or IR2 AND IR3:. Ffor 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 
IR2 should take priority (e.g., IR2 in the 
above example). 
These 3 patterns of IR as defined 
above (IR1, IR2, and IR3) may have 
very different mechanisms and 
clinical implications. Therefore, it is 
Clarification, updated to match LYRIC 
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critical that data are collected in a 
consistent manner so that these 3 
possible atypical response types 
occurring within the context of 
checkpoint inhibitors can be 
distinguished. 
At In subjects categorized as having 
any of the above types of IR, it is 
mandatory to obtain a repeat imaging 
after an additional 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. At 
that time, response should be re-
evaluated, and the subject should be 
considered to have true PD 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 ≥1at least one lesion 
for lesions ≤2 cm, and 10 mm for 
lesions >2 cm, to be consistent with 
the Lugano classification (Cheson 
2016). The 10% threshold is 
empiric but designed to account 
for variability in measurement, 
especially when taken along with 
the minimum increase (Oxnard 
2011). If the target SPD increase is 
<10%, the response would still be 
categorized as IR1, and the subject 
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 ≥1at least one 
lesion) or response (≥50% decrease 
from baseline). In this situation, it is 
reasonable to repeat imaging in 
4-8 weeks of the original IR1 time 
point to ensure absence of 
significant further increase. 
Clarification, updated to match LYRIC 
criteria language. 
Appendix F 
● 
In the case of IR3, since because 
inflammatory responses may result 
in an increase in the standardized 
uptake value of a lesion, the subject 
will not be considered to have PD 
unless there is evidence of PD by an 
increase in lesion size or the 
Clarification, updated to match LYRIC 
criteria language. 


 
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development of new lesions, as 
noted above. 
Importantly, if a subject is assessed as 
having IR and then “true” PD at a 
subsequent time point (without an 
intervening objective response 
between IR and PD), the IR 
assessment should be subsequently be 
corrected to PD for reporting 
purposes to the date of the prior 
designation of IR. We recognize that 
these lesions may remain stable 
during the time of observation, but, 
even if this is the case, the initial 
designation of IR should be changed 
to PD. 
Appendix I 
Inclusion of Appendix 4A from 
Nivolumab IB v21 
To provide guidance regarding the clinical 
management of common IMAEs that occur 
with nivolumab. 
Appendix J 
Renumbered as a result of inclusion of 
Appendix I above. 
Administrative change 
Appendix K 
Renumbered as a result of inclusion of 
Appendix I above. 
Administrative change 


 
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Section 4.3.1 
Added the following: 
● 
Czechia (CZ) only: Lack of clinical 
benefit following Cycle 2 PET, at which 
time consolidative radiotherapy or 
another established treatment may be 
indicated, per the discretion of the study 
investigator 
 
CZ only: Subjects who discontinue 
treatment due to a lack of clinical benefit 
following Cycle 2 PET will only remain 
on study for survival follow-up and 
subsequent therapy must be recorded. 
To incorporate CZ-specific changes into 
global protocol. 
To provide clarity of discontinuation criteria 
Section 5.6.2 
Added the following: 
CZ only: Primary prophylaxis with G-
CSF or GM-CSF from the first dose is 
recommended for all subjects with 
previously untreated Hodgkin’s 
lymphoma receiving combination therapy 
with SGN-35. 
To incorporate CZ-specific changes into 
global protocol. 
To provide clarity on concominant therapy 
allowed. 
Section 6.2 
Added the following:  
● 
CZ only: HBV and HIV serological 
testing (positive results will result in 
subject being considered ineligible for 
enrollment) 
● 
CZ only: HCV PCR testing 
(positive results will result in subject 
being considered ineligible for 
enrollment) 
To incorporate CZ-specific changes into 
global protocol. 
To provide clarity on virologic assessment 
and eligibility criteria 
Appendix B 
Added HBV and HIV serological testing 
during screening (CZ only) 
To incorporate CZ-specific changes into 
global protocol. 
To align with updates made in Section 6.2 
Appendix B 
Added HCV PCR testing during 
screening (CZ only) 
To incorporate CZ-specific changes into 
global protocol. 
To align with updates made in Section 6.2 
Appendix B 
Added footnote “W” with the following: 
Serological testing will be completed, 
positive results will result in subject 
being considered ineligible for 
enrollment. 
To incorporate CZ-specific changes into 
global protocol. 
To align with updates made in Section 6.2 
Appendix B 
Added footnote “X” with the following:  
PCR testing will be completed, positive 
results will result in subject being 
considered ineligible for enrollment. 
To incorporate CZ-specific changes into 
global protocol. 
To align with updates made in Section 6.2 
 

SAP_001.pdf: 
 
 
 
P art or all of t he i nf or mati o n i n t his statistical a nal ysis pla n ma y be u n p u blis he d material. Acc or di n gl y, t his 
d oc u me nt is t o be treate d as c o nfi de ntial a n d restricte d t o its i nte n de d use. T his material is t he pr o pe rt y of 
Seattle Ge netics, I nc. a n d m ust n ot b e discl ose d or use d e xce pt as a ut h orize d i n writi n g b y Seattle Ge netics, I nc.  
S T A TI S TI C A L A N A L Y SI S  P L A N  
 
Pr ot oc ol N u m ber:  
S G N 3 5 -0 2 7  
Versi o n:  
A me n d me nt 6 , 2 9 -N o v -2 0 2 1  
Pr ot oc ol Title:  
M ulti ple Part Cli nical Trial of Bre nt u xi ma b Ve d oti n i n Classical 
H o d g ki n L y m p h o ma S u bjects  
S p o ns or:  
Sea ge n , I nc. 
2 1 8 2 3 3 0t h Dri ve S E  
B ot hell, W A 9 8 0 2 1, U S A  
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2  of 2 7  
A P P R O V A L SI G N A T U R E S  
Pr o d uct:  
Bre nt u xi ma b ve d oti n  
Pr ot oc ol N u m ber/ A me n d me nt  
S G N 3 5 -0 2 7 A me n d me nt 6  
S A P Versi o n:  
2 . 1 
Versi o n D ate:  
2 7 F e b-2 0 2 3  
 
T he i n di vi d uals si g ni n g b el o w ha ve re vie we d a n d a p pr o ve t his statistical a nal ysis pla n.  
 
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
 
 
 
Date  
 
 
 
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 3  of 2 7  
T A B L E O F C O N T E N T S  
1  
I N T R O D U C TI O N ........................................................................................................................................... 6  
2  
S T U D Y O BJ E C TI V E S  ................................................................................................................................... 6  
2. 1  
Pri mar y O bj ecti ves  ................................................................................................................................ 6  
2. 2  
Sec o n dar y O bj ecti ves  ............................................................................................................................ 6  
3  
S T U D Y E N D P OI N T S  .................................................................................................................................... 7  
3. 1  
Pri mar y E n d p oi nts  ................................................................................................................................. 7  
3. 2  
Sec o n dar y E n d p oi nts  ............................................................................................................................. 7  
4  
S T U D Y D E SI G N  ............................................................................................................................................ 7  
5  
A N A L Y SI S S E T S  ........................................................................................................................................... 9  
5. 1  
F ull A nal ysis Set  ................................................................................................................................... 9  
5. 2  
P er -Pr ot oc ol ( P P) A nal ysis Set  .............................................................................................................. 9  
5. 3  
Efficac y -E val ua ble ( E E) A nal ysis Set  ................................................................................................. 1 0  
6  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................................................... 1 0  
6. 1  
Ge neral Pri nci ples  ............................................................................................................................... 1 0  
6. 2  
Deter mi nati o n of Sa m ple Size  ............................................................................................................. 1 0  
6. 3  
Ra n d o mizati o n a n d Bli n di n g  ............................................................................................................... 1 1  
6. 4  
Data Tra nsf or mati o ns a n d Deri vati o ns  ................................................................................................ 1 1  
6. 4. 1  
Ge neral  ................................................................................................................................... 1 1  
6. 4. 2  
Res p o nse Assess me nt  ............................................................................................................. 1 1  
6. 5  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ............................................................................................. 1 3  
6. 6  
M ultice nter St u dies  ............................................................................................................................. 1 3  
6. 7  
M ulti ple C o m paris o n/ M ulti pli cit y ....................................................................................................... 1 3  
6. 8  
E xa mi nati o n of S u b gr o u ps  .................................................................................................................. 1 3  
6. 9  
C o variates  ............................................................................................................................................ 1 3  
6. 1 0  Ti mi n g of A nal ys es  ............................................................................................................................. 1 3  
7  
P L A N N E D A N A L Y S E S  .............................................................................................................................. 1 4  
7. 1  
Dis p ositi o n  .......................................................................................................................................... 1 4  
7. 2  
De m o gra p hic a n d B aseli ne C haracteristics  ......................................................................................... 1 4  
7. 3  
Pr ot oc ol De viati o ns  ............................................................................................................................. 1 4  
7. 4  
Treat me nt A d mi nistrati o n  ................................................................................................................... 1 4  
7. 5  
Efficac y A nal yses  ................................................................................................................................ 1 5  
7. 5. 1  
Pri mar y E n d p oi nts  .................................................................................................................. 1 5  
7. 5. 2  
Sec o n dar y E n d p oi nts  .............................................................................................................. 1 6  
7. 6  
Safet y A nal yses  ................................................................................................................................... 1 8  
7. 6. 1  
A d verse E ve nts  ....................................................................................................................... 1 8  
7. 6. 2  
A d verse E ve nts of Cli nical I nt erest  ........................................................................................ 1 9  
7. 6. 3  
Cli nical La b orat or y P ara meters  .............................................................................................. 2 0  
7. 6. 4  
E C O G P erf or ma nce Stat us  ..................................................................................................... 2 1  
7. 6. 5  
Vital Si g ns  .............................................................................................................................. 2 1  
7. 6. 6  
C o nc o mita nt Me dicati o ns  ....................................................................................................... 2 1  
8  
I N T E RI M A N A L Y S E S ................................................................................................................................ 2 1  
9  
C H A N G E S F R O M P L A N N E D  A N A L Y S E S  .............................................................................................. 2 1  
9. 1  
C ha n ges fr o m t he Ori gi nal Pr ot oc ol  .................................................................................................... 2 1  
9. 2  
A d mi nistrati ve c ha n ges a n d clarificati o ns. C ha n ges fr o m t he Ori gi nal S A P  ....................................... 2 2  
1 0  R E F E R E N C E S  .............................................................................................................................................. 2 3  
1 1  A P P E N DI C E S  ............................................................................................................................................... 2 4  
A P P E N DI X A: I M P U T A TI O N O F P A R TI A L L Y U N K N O W N A D V E R S E E V E N T D A T E S  ......................... 2 4  
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 4  of 2 7  
List of A b bre viati o ns  
A B V D  
d o x or u bici n, ble o m yci n, vi n bl asti ne, a n d dacar bazi ne  
A E  
a d verse e ve nt  
A E CI  
a d verse e ve nt of cli nical i nterest  
A N + A D  
bre nt u xi ma b ve d oti n, ni v ol u ma b, d o x or u bici n, a n d dacar bazi ne  
A + A V D  
bre nt u xi ma b ve d oti n, d o x or u bici n, vi n blasti ne, dacar bazi ne  
B V  
bre nt u xi ma b ve d oti n  
c H L 
classical H o d g ki n l y m p h o ma  
CI  
c o nfi de nce i nter val  
C R  
c o m plete res p o nse  
C R F  
case re p ort f or m  
C T  
c o m p ute d t o m o gra p h y  
D O C R  
d urati o n of c o m plete res p o nse  
D O R  
d urati o n of res p o nse  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
E F S  
e ve nt -free s ur vi val 
e C R F  
electr o nic case re p ort f or m  
E O T  
e n d of treat me nt  
F A S  
f ull a nal ysis set 
F D G  
fl u or o de o x y gl uc ose  
F N  
fe brile ne utr o pe nia 
G -C S F  
gra n ul oc yte c ol o n y sti m ulati n g fact or  
G -P P  
G -C S F pri mar y pr o p h yla xis  
H L  
H o d g ki n l y m p h o ma  
I M A E 
I m m u ne-me diate d a d verse e ve nt  
I R 
i n deter mi nate res p o nse 
I V 
i ntra ve n o us 
L Y RI C  
L y m p h o ma Res p o nse t o I m m u n o m o d ulat or y T hera p y Criteria  
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
M M A E  
m o n o met h yl a uristati n E  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute’s C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
O R R  
o verall res p o nse rate  
O S  
o verall s ur vi val  
P D  
pr o gressi ve disease  
P E T  
p ositr o n e missi o n t o m o gra p h y 
P F S  
pr o gressi o n -free s ur vi val 
P m D  
pr o gressi ve meta b olic disease  
P N  
peri p heral ne ur o pat h y  
P R  
partial res p o nse  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 5  of 2 7  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
S D  
sta ble disease 
S M C  
safet y m o nit ori n g c o m mittee 
S P D  
s u m of t he pr o d ucts of t he lar gest dia meter  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 6  of 2 7  
1  
I N T R O D U C TI O N 
T his d oc u me nt o utli nes t he statistical met h o ds t o be i m ple me nte d wit hi n t he sc o pe of Pr ot oc ol 
S G N 3 5 -0 2 7 , e ntitle d “ M ulti ple Part Cli nical Trial of 
Bre nt u xi ma b Ve d oti n i n Classical 
H o d g ki n L y m p h o ma S u bjects ”.  Res ults of t he pr o p ose d a nal ys es will bec o me t he basis of t he 
cli nical st u d y re p ort f or t his pr ot oc ol.  
T he p ur p ose of t his pla n is t o pr o vi de s pecific g ui d eli nes fr o m w hic h t he a nal ysis will pr o cee d.  
All pla n ne d a nal yses s pecifie d i n t his d oc u me nt will be perf or me d.  A n y c h a n ges t o t his pla n, 
i n t he f or m of “ p ost h oc” or “ data dri ve n” a nal yses will be i de ntifie d as s uc h i n t he fi nal cli nical 
st u d y re p ort.  A n y c h a n ges will eit her be reflecte d i n a me n d me nts t o t his pla n bef ore t he 
data base l oc k or s pecificall y d oc u m e nte d i n t he cli nical st u d y re p ort.  
2  
S T U D Y O B J E C TI V E S  
2. 1  Pri m ar y O bj e cti v e s  
● 
Part A: T o assess t he treat me nt -e mer ge nt fe brile n e utr o pe nia ( F N) rate i n s u bjects wit h 
pre vi o usl y u ntreate d, a d v a nce d sta ge, classical H o d g ki n l y m p h o ma (c H L) treate d wit h 
bre nt u xi ma b ve d oti n, d o x or u bici n, vi n blasti ne, a n d d acar bazi ne ( A + A V D) a n d 
gra n ul oc yte c ol o n y sti m ulati n g fact or ( G -C S F) pri mar y pr o p h yla xis ( G -P P)  
● 
Parts B a n d C: T o assess t he c o m plete res p o nse ( C R) rate at E O T wit h bre nt u xi ma b 
ve d oti n, ni v ol u ma b, d o x or u bici n, a n d dacar bazi ne ( A N + A D) i n s u bjects 
wit h 
pre vi o usl y u ntr eate d c H L  
2. 2  S e c o n d ar y O bj e cti v e s  
P art A:  
● 
T o assess t he i nci de nce a n d se verit y of a d v erse e v e nts of cli nical i nterest ( A E CI)  
● 
T o assess d ose i nte nsit y, d ose re d ucti o ns, a n d d os e dela ys relate d t o a n y c o m p o ne nt of 
A + A V D  
● 
T o assess pri mar y refract or y dise ase rates  
● 
T o assess s u bse q ue nt a ntica ncer t hera p y utilizati o n  
● 
T o assess e n d of tr eat me nt ( E O T) c o m plete res p o nse ( C R) rates  
● 
T o assess p h ysi c ia n-re p orte d pr o gressi o n-free s ur vi val ( P F S) rate at 2 years 
P art B a n d C:  
● 
T o assess t he safet y a n d t olera bilit y of A N + A D  
● 
T o assess t he o verall res p o nse rate ( O R R)  
● 
T o assess t he d urati o n of res p o nse ( D O R)  
● 
T o assess t he d urati o n of c o m plete res p o nse ( D O C R)  
● 
T o assess t he e v e nt -free s ur vi val ( E F S) 
● 
T o assess t he pr o gressi o n -free s ur vi val ( P F S) 
● 
T o assess t he o verall s ur vi val ( O S)  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 7  of 2 7  
3  
S T U D Y E N D P OI N T S  
3. 1  Pri m ar y  E n d p oi nt s  
● 
Part A: T he fe brile ne utr o pe nia rate i n s u bjects treate d wit h A + A V D a n d G -P P  
● 
Part B a n d C: C R rate a t E O T 
3. 2  S e c o n d ar y  E n d p oi nt s  
P art A:  
● 
T he rates a n d se verit y of eac h A E CI  
● 
Mea n d ose i nte nsit y; t he rates of d ose re d u cti o n a n d d ose dela ys relate d t o a n y 
c o m p o ne nt of A + A V D  
● 
T he pri mar y refract or y disease rate  
● 
T he rates of eac h s u bse q ue nt a ntica ncer t hera p y t a ke n b y s u bjects 
● 
T he C R rate at E O T  
● 
P h ysicia n -re p orte d P F S 
P art B a n d C:  
● 
I n ci de nce, se verit y, s eri o us ness, a n d relat e d ness of A Es; i nci de nce a n d se v erit y of la b 
a b n or malities  
● 
O R R  
● 
D O R  
● 
D O C R  
● 
E F S  
● 
P F S  
● 
O S  
4  
S T U D Y D E SI G N  
T his is a n o p e n -la bel, m ulti ple part, m ultice nter, p hase 2 cli nical tri al. Part A will ass ess t he 
i nci de nce of fe brile n e utr o pe nia, efficac y, a n d d os e i nte nsit y i n s u bjects recei vi n g G P P d uri n g 
treat me nt wit h A + A V D. S u bjects will be treate d usi n g i nstit uti o nal sta n dar d of care practices 
f or t he maj orit y of treat me nt decisi o ns. A + A V D will be a d mi nistere d as descri be d b el o w o n 
da ys 1 a n d 1 5 of a 2 8 -d a y c ycle, wit h t he a d diti o n of G -P P 2 4 – 3 6 h o urs p ost d ose. Part B will 
e val uate t he efficac y a n d t olera bilit y o f A N + A D i n s u bjects wit h Sta ge I or II c H L wit h b ul k y 
me diasti nal disease or Sta ge III or I V c H L. Part C will e val uate t he efficac y a n d t olera bilit y of 
A N + A D i n s u bjects wit h Sta ge I or II c H L wit h o ut b ul k y diseas e . A N + A D will be a d mi nistere d 
as descri be d bel o w. S u bjects will recei ve u p t o 6 c ycl es of treat me nt i n Parts A a n d B. S u bjects 
i n Part C will recei ve 4 c ycl es of treat me nt. F or Part C, o ne i nteri m a nal ysis will be perf or me d 
after a p pr o xi matel y 5 0 s u bjects ha ve c o m plete d res p o nse assess me nt at E O T. At t his i nteri m 
f utilit y a nal ysis, if t he C R rate at E O T is ≤8 0 % ( 4 0/5 0 or  fe wer s u bjects wit h C R at E O T), t he 
s p o ns or i n c o ns ultati o n wit h t he Safet y M o nit ori n g C o m mittee ( S M C) ma y deci d e t o st o p 
f urt her e nr oll me nt of t he trial. 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 8  of 2 7  
Safet y will be m o nit ore d b y c ollecti n g a n d e val u ati n g i nf or mati o n re gar di n g a d v erse e ve nts 
( A Es) a n d la b orat or y test res ults. A S M C c o nsisti n g of t he st u d y me di cal m o nit or, dr u g safet y 
re pres e ntati ve, st u d y site i n vesti gat ors, a n d st u d y bi ostatisticia n will e val uate t he safet y of 
A N + A D o ver t he c o urse of t he st u d y. Diseas e assess me nts will be c o n d ucte d at C ycle 2 ( Parts 
B a n d C o nl y) a n d at E O T. F oll o w u p ass ess me nts f or Part A will occ ur per i nstit uti o nal 
sta n dar d of care a n d m ust i ncl u de a n E O T P E T sca n. F or Parts B a n d C, disease  assess me nts 
will be perf or me d d uri n g f oll o w -u p e v er y 3 m o nt hs after t he E O T visit f or t he first year, t h e n 
e ver y 6 m o nt hs f or 2 a d diti o nal years. S u bjects will t he n c o nti n ue i n f oll o w -u p f or 2 a d diti o nal 
years ( 5 years t otal), wit h p h ysical e x a ms re q uire d  e ver y 6 m o nt hs a n d disease assess me nts 
re q uire d e ver y 1 2 m o nt hs. P E T will c o nti n ue after E O T if C T sca n is p ositi ve, f oll o wi n g t he 
sa me sc h e d ule as C T s ca ns. A n a d diti o nal safet y visit will b e re q uire d f or Parts B a n d C 
s u bjects 1 0 0 da ys after t he last d ose of ni v ol u ma b or 3 0 da ys after t he last d ose of bre nt u xi ma b 
ve d oti n (c o nc urre nt wit h E O T), w hic he ver is later.  
A st u d y sc h e ma f or Part A is pr o vi de d i n Fi g ure 1  a n d f or Parts B a n d C i n Fi g ure 2 . A 
detaile d st u d y assess me nt sc he d ule ca n b e f o u n d i n t he pr ot oc ol.  
Fi g ure 1 : 
St u d y desi g n –  P art A  
 
A.  N ote: G -P P s h o ul d be starte d 2 4 t o 3 6 h o urs fr o m A + A V D a n d f oll o w i nstr ucti o ns i n Pr ot o c ol Secti o n 5. 4. 3.  
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 9  of 2 7  
Fi g ure 2 : 
St u d y desi g n –  P arts B a n d C  
 
a 
Res p o nse assess me nts will i n cl u de P E T a n d dia g n ostic -q ualit y C T sca n o n Da y 2 5 -2 8 o f C ycle 2, a n d at E O T. 
b  
F oll o w -u p peri o d f or P arts B a n d C i n cl u des 2 a d diti o nal ye ars ( 5 years t otal).  
 
5  
A N A L Y SI S S E T S  
T his secti o n defi nes eac h of t he a nal ysis sets t hat will be utilize d.  T he use of eac h a n al ysis set 
will be disc usse d i n Secti o n 7 . 
5. 1  F ull A n al y si s S et  
F or Part A, t he f ull a n al ysis set ( F A S) i ncl u d es all s u bjects w h o recei ve at least 1 d os e of 
A + A V D (a n y of t he st u d y dr u gs i n t he re gi me n). T he F A S will be use d f or all safet y a n d 
effic ac y a n al ys es. S u bject de m o gra p hi cs a n d baseli ne disease c haracteristics 
will be 
s u m marize d base d o n F A S. 
F or Parts B a n d C, t he f ull a nal ysis set will i ncl u de all s u bjects w h o are e nr olle d a n d recei v e 
a n y a m o u nt of t he c o m bi nati o n t hera p y i n t he st u d y. A s u bject is c o nsi dere d e nr olle d if he/s he 
has met all criteria f or partici pati o n i n t he st u d y a n d has Sea ge n I n c. a p pr o val as d oc u me nte d 
i n t he e C R F. T he f ull a n al ysis set will be use d as t he pri mar y datas et f or efficac y a n d s afet y 
a nal ysis. S u bje ct de m o gra p hics a n d b aseli ne dis ease c haract eristics will be s u m marize d base d 
o n t he f ull a nal ysis set.  
5. 2  P er -Pr ot o c ol ( P P) A n al y si s S et  
F or Part A, t he per -pr ot o c ol a nal ysis set ( P P S) i ncl u des all F A S s u bjects w h o  recei ve d G-P P 
a n d di d n ot ha ve a n y i m p orta nt pr ot oc ol de viati o ns. T he P P S will be use d f or t he a nal ysis f or 
pri mar y e n d p oi nt a n d ma y be us e d f or a nal yses f or selecte d s ec o n dar y e n d p oi nts.  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d o ti n 
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 0  of 2 7  
5. 3  Effi c a c y -E v al u a bl e ( E E) A n al y si s S et  
T he Efficac y -E val ua ble ( E E) se t i ncl u des all treate d s u bjects w h o ha d a b as eli ne disease 
assess me nt a n d c o m plete d E O T res p o nse assess m e nt.  
6  
S T A TI S TI C A L C O N SI D E R A TI O N S  
6. 1  G e n er al Pri n ci pl e s  
U nless ot her wise s pecifi e d, all s u m mar y a n d a n al ys es will be pr o vi de d b y part.  All a n al ys es 
will be descri pti ve; h o we ver, c o nfi de n ce i nter vals ( CIs) ma y b e prese nte d t o descri be precisi o n 
of esti mates.  
Descri pti ve statistics ( mea n, me dia n, sta n dar d d e viati o n, mi ni m u m, a n d ma xi m u m) will be 
use d t o s u m marize c o nti n u o us varia bles.  Fre q ue ncies a n d perce nta g es will be use d t o 
s u m marize cate g orical varia bles.   
U nless ot her wise s pecifi e d, all CIs will be calc ulate d at t w o -si de d 9 5 % le vel.  N o m ulti ple 
c o m paris o ns are pla n ne d,  a n d n o al p ha a dj ust me nt is nee de d i n t his p hase 2 st u d y.  
A n y a nal ysis n ot descri b e d i n t his pla n will be c o nsi dere d e x pl orat or y a n d  will be d oc u me nte d 
i n t he cli nical st u d y re p ort ( C S R) as a p ost h oc a nal ysis or a c ha n ge t o t he pl a n ne d a n al ysis. 
T o c o m pl y wit h re g ulat or y el ectr o nic s u b missi o n g ui deli nes, listi n gs of all cli nical data will be 
s u b mitte d as electr o nic data sets.  T o facilitate data re vie w f or t he st u d y re p ort, o nl y p erti ne nt 
data listi n gs will be creat e d a n d attac he d t o t he a p pe n di x of t he C S R.  All statistical o ut p ut will 
be pr o d uce d usi n g S A S ®, versi o n 9. 4 or m ore rece nt.  O t her statistical s oft ware, if use d, will 
be descri b e d i n t he cli nic al st u d y re p ort.  
6. 2  D et er mi n ati o n of S a m pl e Si z e  
F or Part A, a p pr o xi matel y 4 0 s u bjects will be e nr olle d i n or der t o pr o vi de a n a de q uate le vel of 
precisi o n f or t he esti mate of t he F N rate. If 4  of 4 0 s u bjects e x perie nce F N, t he F N rate is 1 0 % 
wit h 9 5 % CI ( 2. 8 %, 2 3. 7 %) base d o n t h e e x act Cl o p per -Pears o n met h o d ( C ollett 1 9 9 1 ); if 2 
of 4 0 s u bjects e x perie nce F N, t he F N rate is 5 % ( 9 5 % CI: 0. 6 %, 1 6. 9 %); if 6 of 4 0 s u bjects 
e x perie nce F N, t he F N rate is 1 5 % ( 9 5 % CI: 5. 7 %, 2 9. 8 %).  
F or Part B, a p pr o xi matel y 5 0 s u bjects will be e nr olle d i n or der t o pr o vi de a n a de q uate le vel of 
precisi o n f or t he esti mate of t he C R rate at E O T. If 4 5 of 5 0 s u bjects ha v e a  C R at E O T, t he 
C R rate at E O T is 9 0 % wit h 9 5 % CI ( 7 8. 2 %, 9 6. 7 %) base d o n t he e x act Cl o p per -Pears o n 
met h o d ( C ollett 1 9 9 1 ); if 4 2 of 5 0 s u bjects ha ve a C R at E O T, t he C R rate at E O T is 8 4 % ( 9 5 % 
CI: 7 0. 9 %, 9 2. 8 %); if 4 8 of 5 0 s u bjects ha ve a C R at E O T, t he C R rate at E O T is 9 6 % ( 9 5 % 
CI: 8 6. 3 %, 9 9. 5 %). T he 7 3 % C R rate at E O T o bs er ve d i n t h e A + A V D ar m i n t he E C H E L O N -
1 trial was c o nsi dere d t h e rele v a nt be nc h mar k w he n deter mi ni n g a n a p pr o priate sa m ple siz e 
f or Part B ( C o n n ors 2 0 1 8). 
F or Part C, a p pr o xi matel y 1 5 0 s u bjects will be e nr olle d i n or der t o pr o vi d e a de q uate p o wer t o 
reject t he h y p ot h esis t hat C R rate at E O T is ≤ 9 0 %. Ass u mi n g a C R rat e of 9 5 %, 1 5 0 s u bjects 
w o ul d pr o vi de a p pr o xi matel y 8 0 % p o wer t o reject t he n ull h y p ot hesis of a C R rate at E O T ≤ 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 1  of 2 7  
9 0 % wit h a 1 -si de d al p ha = 0. 0 5 a n d usi n g a n e m pirical varia nce esti mate ( East ®  v 6. 4). T his 
sa m ple siz e cal c ulati o n acc o u nts f or t he i nteri m f utilit y a nal ysis w hic h is f urt her d escri be d i n 
Secti o n 8.  
6. 3  R a n d o mi z ati o n a n d Bli n di n g  
N ot a p plica ble.  
6. 4  D at a Tr a n sf or m ati o n s a n d D eri v ati o n s  
6. 4. 1  G e n er al  
Re p orte d a ge i n years will be use d; if n ot a vaila ble, a ge i n years will be calc ulate d wit h t he 
S A S I N T C K f u ncti o n ( wit h met h o d s pecifi e d as “c o nti n u o us”) usi n g i nf or me d c o ns e nt date 
a n d birt h date.  
St u d y D a y will be calc ul ate d as Date – First D os e Date + 1 f or dates o n or after t he first d ose 
date.  F or dates pri or t o t he first d os e d ate, St u d y D a y will be calc ulate d as Date – First D os e 
Date.  F or all cal c ulati o ns of St u d y Da y, t he First D ose Date will be t he earliest date of 
treat me nt a d mi nistrati o n f or st u d y dr u g. 
Ot her ti me v aria bles bas e d o n t w o dates, e. g., Start Date a n d E n d Date, wi ll be calc ulate d as 
( E n d Date– Start D ate + 1) (i n da ys) u nless ot her wis e s pecifie d i n t he pl a n ne d a nal ysi s s ecti o n. 
T he f oll o wi n g u nit c o n v ersi o n will be i m ple me nte d u nless ot her wise s pecifie d:  
M o nt hs = Da ys /3 0. 4 3 7 5  
Years = Da ys /3 6 5. 2 5  
U nless ot her wise s pecifie d, bas eli ne val ues use d i n all a nal yses will be t he m ost rece nt n o n -
missi n g meas ure m e nt pri or t o t he first d ose of st u d y dr u g. 
T he e n d -of -treat me nt ( E O T) date will be t he d ate t he E O T visit is perf or me d; if a n E O T visit 
is n ot perf or me d t h e n t he E O T date will be eit her t he E O S date or 3 0 da ys after t he last d ose 
of a n y st u d y dr u g, w hic h e ver is earlier.  
6. 4. 2  R e s p o n s e A s s e s s m e nt  
I n Part A, t he deter mi nati o n of a ntit u m or acti vit y will be base d o n res p o nse assess me nts ma de 
acc or di n g t o t he L u ga n o Classificati o n Re vise d Sta gi n g S yste m f or n o d al n o n -H o d g ki n a n d 
H o d g ki n l y m p h o mas (C h es o n 2 0 1 4 ). I n Parts B a n d C, t he deter mi nati o n of a ntit u m or acti vit y 
will be base d o n o bjecti ve res p o nse assess me nts ma de acc or di n g t o L u ga n o Classificati o n 
Re vi se d Sta gi n g S yste m f or mali g n a nt l y m p h o m a (C hes o n 2 0 1 4 ) wit h t he i nc or p orati o n of 
L y m p h o ma Res p o nse t o I m m u n o m o d ulat or y T hera p y  Criteria ( L Y RI C) (C hes o n 2 0 1 6 ). 
Pr o gressi ve meta b olic disease ( P m D), n o meta b olic res p o nse ( N m R), partial meta b olic 
res p o nse ( P m R), or c o m plete meta b olic res p o nse ( C m R) will be deter mi ne d usi n g P E T -base d 
res p o nse at eac h assess me nt. If o nl y C T-bas e d assess me nt is perf or me d, res p o nse will be 
cate g orize d as pr o gressi ve disease ( P D), sta ble dise ase ( S D), partial res p o nse ( P R), or c o m plete 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 2  of 2 7  
res p o nse ( C R). I n Parts B a n d C, if t u m or fl are or pse u d o-pr o gressi o n is s us pecte d, a 
deter mi nati o n s h o ul d n ot be ma de at t hat ti me. P m D/ P D i ncl u des ra di ol o gical e vi de nce of 
pr o gressi o n per L u ga n o classificati o n criteria ( Part A); f or Parts B a n d C, i n c or p orat e L Y RI C. 
If cli nical pr o gressi o n is deter mi ne d b y t he i nvesti gat or, ra di o gra p hic sta gi n g s h o ul d als o be 
perf or me d t o deter mi ne res p o nse assess me nt per L u ga n o classificati o n crit eria. T he P E T sca n 
meta b olic u pta ke will be gra de d usi n g t h e Dea u ville 5 -p oi nt scale (Barri n gt o n 2 0 1 0 ; Bi g gi 
2 0 1 3 ) wit h a sc ore of ≤3 c o nsi dere d t o re pres e nt a c o m plete meta b olic res p o nse. B ot h P E T a n d 
C T sca n ni n g will be re q uire d u ntil disease is P E T ne gati ve;  res p o ns es will t he n be f oll o we d b y 
C T sca n of dia g n ostic q u alit y o nl y.  
Treat me nt wit h c hec k p oi nt i n hi bit ors, s uc h as ni v ol u ma b i n Parts B a n d C, ca n res ult i n false 
p ositi ve P E T i ma gi n g. L Y RI C criteria rec o m me n d re peat P E T i ma gi n g a n d/ or bi o ps y  wit hi n 
1 2 wee ks  t o f urt her e v al uate P E T-p ositi ve ( D 4 or D 5) lesi o ns i de ntifie d at t he E O T res p o nse 
assess me nt. Re peat P E T i ma gi n g a n d/ or bi o ps y  wit hi n 1 2 wee ks  is re q uire d t o f urt her e val uate 
P E T -p ositi ve P D.  
If t u m or flare or pse u d o-pr o gressi o n is s us pecte d b y t he i n vesti gat or d uri n g s u bject tr eat me nt 
i n Parts B or C, t he n a cli nical res p o nse of i n deter mi nate res p o nse (I R) will be deter mi ne d u ntil 
s u bse q ue nt e val u ati o n of ra di o gra p hi c i ma gi n g or bi o ps y c o nfir ms or ref ut es P D. T here are 3 
cate g ories of I R, as f oll o ws : 
1.  I R 1: A n i ncrease i n o verall t u m or b ur de n (as ass esse d b y t he s u m of t h e pr o d ucts of t h e 
lar gest dia meter [ S P D]) of ≥5 0 % of u p t o 6 meas ura ble lesi o ns i n t he first 1 2 wee ks of 
t hera p y, wit h o ut cli nical deteri orati o n; 
2.  I R 2: A p peara nce of ne w lesi o ns, or gr owt h of 1 or m ore e xisti n g lesi o n(s) ≥5 0 % at a n y 
ti me d uri n g tr eat me nt, occ urri n g i n t h e c o nte xt of lac k of o v erall pr o gressi o n ( < 5 0 % 
i ncreas e) of o v erall t u m or b ur de n, as m eas ure d b y S P D of u p t o 6 lesi o ns at a n y ti me d uri n g 
treat me nt; a n d 
3.  I R 3: A n i ncreas e i n F D G u pta ke usi n g t he 5-P oi nt Scale per t he Dea u ville Criteria of 1 or 
m ore lesi o n(s) wit h o ut a c o nc o mita nt i ncrease i n lesi o n size or n u m ber.  
See A p pe n di x F of st u d y pr ot oc ol f or f urt h er details a n d criteria f or f oll o w -u p of a 
deter mi nati o n of I R.  
F or s u bjects wit h a n I R, i n vesti gat ors s h o ul d use cli nical j u d ge me nt t o deter mi ne t he 
a p pr o priate c o urse of acti o n f or f urt her e v al uati o n. Re peat i ma gi n g s h o ul d be perf or me d 
acc or di n g t o t he Sc he d ule of E ve nts ( or s o o ner if cli nicall y i n dicate d), a n d P D m ust b e 
c o nfir me d or ref ut e d base d o n L Y RI C f oll o w -u p criteria f or I R (C hes o n 2 0 1 6 ). I n a d diti o n, 
bi o ps y of sites of dise ase i n v ol ve me nt s h o ul d be str o n gl y c o nsi dere d . 
If a s u bject has a sec o n d deter mi nati o n of I R, t he n s u bse q ue nt re p eat i ma gi n g s h o ul d be 
perf or me d b et wee n 4 a n d 8  wee ks ( or earlier if cli nicall y i n dicate d). F oll o w -u p ra di o gra p hic 
assess me nt f or s u bjects wit h I R is n ot re q uir e d if a f oll o w -u p bi o ps y has bee n perf or me d t h at 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 3  of 2 7  
c o nfir ms t he s u bject's res p o nse. If t he s u bject c o n ti n ues i n f oll o w u p after c o nfir mati o n, 
s u bse q ue nt f oll o w-u p visits s h o ul d be per t he sc he d ule of e ve nts.  
6. 5  H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a  
Wit h t he e x ce pti o n of t he sce nari os c o v ere d i n t his secti o n, missi n g data will n ot be i m p ute d . 
A E dates will be i m p ute d f or t he p ur p ose of cal c ulati n g d urati o n of e ve nts a n d treat me nt -
e mer ge nt st at us (see 0  f or i m p utati o n d etails a n d 0  f or treat me nt-e mer ge nt defi niti o n).   
Ce ns ori n g will be des cri be d i n Secti o n 7  wit h eac h pla n ne d a nal ysis, as a p plica ble.  
U nless ot her wise s pecifie d, if t he n u meric val ue of a la b orat or y test is n ot a vaila ble beca us e it 
is bel o w t he l o w er li mit of q ua ntificati o n ( L L O Q), t he res ult will be a nal yze d as e q u al t o the 
L L O Q w he n a n u meric v al ue is re q uire d (e. g., calc ulati n g t he mea n) a n d be liste d as “ < L L O Q” 
i n t he listi n gs. 
6. 6  M ulti c e nt er St u di e s  
T here are m ulti ple ce nters i n t his st u d y, h o we v er it is n ot a ntici pate d t hat a n y ce nter will accr ue 
e n o u g h p atie nts t o warra nt a n a nal ysis b y ce nter.  
6. 7  M ulti pl e C o m p ari s o n/ M ulti pli cit y  
N o m ulti ple c o m paris o ns are pla n n e d a n d n o al p ha a dj ust me nt is nee de d i n t his p hase 2  st u d y. 
6. 8  E x a mi n ati o n of S u b gr o u p s  
As e x pl orat or y a n al ys es, s u b gr o u p a n al yses ma y be c o n d ucte d f or selecte d e n d p oi nts , w here 
t he siz es of s u b gr o u ps are n ot t o o s mall (e g. at least 1 0 s u bjects i n eac h s u b gr o u p).  S u b gr o u ps 
ma y i ncl u d e b ut are n ot li mite d t o t he f oll o wi n g:  
● 
A ge ( 1 2 – 1 7 years, 1 8 – 6 4 years, ≥6 5 years ol d)  
● 
A ge ( 1 2 -4 0 years, > 4 0 years ol d)  
● 
Ge n der ( Male, Fe male)  
● 
Cate g orize d wei g ht at baseli ne ( ≤1 0 0 , > 1 0 0 k g)  
● 
E C O G perf or ma nce stat us at baseli ne ( 0 ,  > 0 ) 
● 
Baseli ne B s y m pt o ms ( prese nt, a bse nt)  
● 
N u m ber of pri or treat me nts, i ncl u di n g a ut ol o g o us ste m cell tra ns pla nt ( A S C T) ( = 1, 
> 1)  
6. 9  C o v ari at e s  
C o variates are n ot c o nsi d ere d f or a dj ust me nt i n t he a nal yses.  
6. 1 0  Ti mi n g of A n al y s e s  
F or Part A, t he pri mar y a nal ysis will b e perf or m e d w he n all s u bjects i n t he f ull a nal ysis set f or 
Part A ha ve c o m plete d t he safet y re p orti n g peri o d.  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 4  of 2 7  
F or Part B a n d C, the pri mar y a nal ysis f or eac h p art will be perf or me d w he n all s u bjects i n t he 
f ull a nal ysis set f or t hat part ha v e h a d t heir stat us deter mi ne d f or t he pri mar y e n d p oi nt of C R 
rate at E O T. 
7  
P L A N N E D A N A L Y S E S  
7. 1  Di s p o siti o n  
T he n u m ber of s u bjects e nr olle d, treate d wit h A + A V D or A N + A D, a n d c o m pleti n g t he st u d y 
will be s u m marize d. A n acc o u nti n g of st u d y s u bj ects b y dis p ositi o n will be ta b ulate d a n d t he 
n u m ber of s u bjects i n eac h a nal ysis set will be s u m marize d. S u bjects w h o disc o nti n ue st u d y 
treat me nt will be s u m marize d b y reas o n f or disc o nti n uati o n a n d will be liste d wit h t he ti mi n g 
a n d reas o n f or disc o nti n u ati o n. S u bjects w h o wit h dra w fr o m t he st u d y will be s u m mariz e d b y 
reas o n f or wit h dra wal a n d will be liste d wit h t he ti mi n g a n d reas o n f or wit h dra wal or 
ter mi nati o n. 
7. 2  D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  
De m o gra p hics a n d baseli ne c haracteristics, i ncl u di n g a ge, ge n der, et h nicit y, race, h ei g ht, 
wei g ht, b o d y mass i n de x, E C G  ( n or mal, a b n or mal), A n n Ar b or Sta ge, I P S sc ore, b ul k y dis ease 
stat us, E C O G perf or ma n ce stat us , b o ne marr o w disease i n v ol ve me nt, a n d B s y m pt o ms  will be 
s u m marize d wit h descri pti ve statistics f or t he F A S a nal ysis s et. 
Listi n gs of de m o gra p hi cs  a n d disease c haracteristics will be pr o vi de d . 
7. 3  Pr ot o c ol D e vi ati o n s  
I m p ort a nt pr ot oc ol de viati o ns ( defi ne d as pr ot oc ol vi olati o ns b y Sea ge n, I nc ) are t h ose t hat 
re pres e nt a di ver ge nce fr o m t he pr ot oc ol t hat c o ul d ha ve a si g nifica nt effect o n t he i nte grit y of 
t he st u d y d ata, or o n t he s u bject’s ri g hts, safet y, or welfare.  I m p orta nt pr ot o c ol de viati o ns als o 
i ncl u de e x e m pti o ns t o t he st u d y i ncl usi o n/e xcl usi o n criteria a n d will be s u m marize d b y 
cate g or y.  A list of patie nts wit h i m p orta nt pr ot oc ol de viati o ns will be prese nte d.  
7. 4  Tr e at m e nt A d mi ni str ati o n  
Treat me nt a d mi nistrati o n will be s u m marize d b y Part  usi n g t he  F A S .  S u m mar y statistics f or 
d urati o n of  eac h treat me nt  per c ycle, t h e n u m ber of c ycles a n d t otal d ose will be prese nte d . 
T he n u m ber a n d perce nt a ge of patie nts w h o were treate d at eac h c ycl e a n d c o m plete d eac h 
c ycle, a nd patie nts wit h d ose m o dificati o n will be s u m marize d. C u m ulati ve d ose, a bs ol ute d os e 
i nte nsit y ( A DI) a n d relati ve d ose i nte nsit y ( R DI) will be s u m marize d.  L isti n gs ma y b e 
prese nte d as well.  F or Part A, t he n u m ber of s u bjects w h o recei ve d p e g ylat e d as well  as n o n-
pe g yl ate d G -C S F will be s u m marize d b y c ycle as well as t he d urati o n of eac h. A brea k d o w n 
of t he t y p es of G -C S F m e dicati o ns will als o be pr o vi de d.  
D urati o n of treat me nt (e x ce pt w he n calc ulati n g e x p os ure) is defi ne d as t he ti me fr o m first d ose 
date t o t he earliest of eit h er:  
● 
last d ose date + 1 4  d a ys or;  
● 
date of deat h  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 5  of 2 7  
● 
Start of s u bse q ue nt a nti -ca ncer t h era p y 
● 
A nal ysis d ata c ut off dat e if t he s u bject is still o n treat me nt at t he ti me of t he a nal ysis  
I nte n d e d D ose I nte nsit y (I DI) is defi n e d as t he i nte n de d d ose of dr u g per u nit of ti me acc or di n g 
t o st u d y pr ot oc ol.  A DI is defi ne d as t he act u al d ose per u nit of ti me t hat t h e s u bject recei ve d 
o ver t he e ntire tr eat me nt peri o d. F or t he p ur p ose of calc ulati n g A DI, tr eat me nt peri o d is 
defi ne d as ti me fr o m t he first d ose of st u d y dr u g t o Da y 2 8  of t he last treat me nt c ycl e, 
re gar dl ess of if deat h occ urs bef ore t he e n d of t h e c ycle. R DI is defi n e d as t he A DI o v er t he 
I DI. 
R DI = A DI/I DI * 1 0 0 %  
7. 5  Effi c a c y A n al y s e s  
All e fficac y a n al ys es will be prese nte d usi n g t he F A S , u nless ot her wise s pecifie d.  T h e P P S 
will be use d f or t he a nal ysis f or pri mar y e n d p oi nt a n d ma y b e use d f or a n al yses f or select e d 
sec o n dar y e n d p oi nts f or Part A. T he E E S ma y b e use d f or s electe d e n d p oi nts f or Part B a n d 
Part C. A nal ys es ma y als o be perf or me d usi n g t he s u b gr o u ps liste d i n Secti o n  6. 7 .  
7. 5. 1  Pri m ar y E n d p oi nt s  
7. 5. 1. 1  P art A  
F or Part A, t he rate of F N  is t he pri mar y e n d p oi nt. T he F N rat e is defi n e d as t he pr o p orti o n of 
s u bjects w h o e x perie nce treat me nt e mer ge nt F N. F N rat e a n d t he e x act t w o-si de d 9 5 % Cis 
usi n g t he Cl o p per -Pears o n met h o d ( C ollett 1 9 9 1 ) will be calc ulate d.  
7. 5. 1. 2  P art B a n d C  
F or Part B a n d C, t he pri mar y e n d p oi nt is t he C R rate at E O T. C R rate at E O T is defi ne d as 
t he pr o p orti o n of s u bjects wit h C R at E O T, acc or di n g t o t h e L y m p h o ma Res p o nse t o 
I m m u n o m o d ulat or y T h era p y Criteria ( L Y RI C) (C hes o n 2 0 1 6 ). S u bjects w h o d o n ot ha ve an 
E O T  assess me nt will be sc ore d as n o n -res p o n d ers f or cal c ulati n g t h e C R rate at E O T. 
C R rate at E O T a n d t he e x act 2 -si de d 9 5 % CIs usi n g t he Cl o p per-Pears o n met h o d (C ollett 
1 9 9 1 ) will be calc ulat e d . 
F or Part C a h y p ot hesis t est will be perf or m e d. T h e n ull a n d alter nati ve h y p ot heses are:  
•  N ull h y p ot hesis: C R rate at E O T ≤ 9 0 %  
•  Alter nati ve h y p ot hesis: C R rate at E O T > 9 0 %  
T he n ull h y p ot hesis will be teste d at a 1 -si de d al p ha of 0. 0 5. T he ass ociate d p-val ue will be 
calc ulate d bas e d o n t he n or mal a p pr o xi mati o n wit h a n e m pirical esti mate of t he varia nce. If p 
< 0. 0 5 is o bser ve d, t he n ull h y p ot h esis will be rej ecte d i n fa v or of t he alter nati ve h y p ot h esis.  
If e nr oll me nt i n Part C is st o p pe d pri or t o c o m pleti o n, n o h y p ot hesis testi n g will be perf or me d. 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 6  of 2 7  
7. 5. 2  S e c o n d ar y  E n d p oi nt s  
7. 5. 2. 1  P art A  
Pri m ar y R efr act or y Dise ase R ate  
T he pri mar y refract or y disease rate is  defi ne d as t he pr o p orti o n of patie nts wit h less t ha n C R 
or rela pse wit hi n 3 m o nt hs of E O T acc or di n g t o t he L u ga n o Classificati o n Re vise d Sta gi n g 
S yste m f or n o d al n o n -H o d g ki n a n d H o d g ki n l y m p h o mas.  
T he pri mar y refract or y disease rat e  a n d its e x act t w o-si ded 9 5 % c o nfi de n ce i nter val usi n g t he 
Cl o p per -Pears o n met h o d (C ollett 1 9 9 1 ) will be calc ulate d . 
C o m plete R es p o nse  R ate at E O T  
C o m plete res p o nse ( C R) rate is defi ne d as t he pr o p orti o n of patie nts wit h C R acc or di n g t o t he 
L u ga n o Classificati o n Re vise d Sta gi n g S yste m f or n o dal n o n -H o d g ki n a n d 
H o d g ki n 
l y m p h o mas.  
T he C R rate a n d its e x act t w o-si de d 9 5 % c o nfi de nce i nter val usi n g t h e Cl o p per-Pears o n 
met h o d (C ollett 1 9 9 1 ) will be calc ulate d . 
P h ysici a n Re p orte d Pr o gressi o n -Free S ur vi v al ( P F S)  
Pr o gressi o n -free s ur vi val ( P F S) is defi ne d as t he ti me fr o m start of st u d y treat me nt t o first 
d oc u me ntati o n of o bjecti ve t u m or pr o gressi o n or t o deat h d ue t o a n y ca use, w hic he ver c o mes 
first. S u bjects wit h o ut pr o gressi o n or deat h will be ce ns ore d o n  t he d ate of t he last ra di ol o gi cal 
assess me nt of meas ur e d lesi o ns . S u bjects  lac ki n g a n e val uati o n of t u m or res p o nse after t heir 
first d ose will be ce ns or e d o n  t heir first d ose date.  
T he p h ysi cia n -re p orte d P F S will be a nal yze d usi n g t he Ka pla n -Meier m et h o d a n d Ka pla n -
Meier pl ots will be pr o vi de d. P F S rat es a n d t he ass ociat e d 9 5 % CI will be calc ulate d b ase d o n 
t he c o m ple me ntar y l o g-l o g tra nsf or mati o n (C ollett 1 9 9 4 ). 
7. 5. 2. 2  P art B a n d C  
C o m plete R es p o nse R ate  
C R rate is defi ne d as t he pr o p orti o n of s u bjects wit h C R at E O T, acc or di n g t o t he L y m p h o ma 
Res p o nse t o I m m u n o m o d ulat or y T hera p y Cr iteria ( L Y RI C). S u bjects w h o d o n ot ha ve a n E O T  
assess me nt will be sc ore d as n o n -res p o n d ers f or calc ulati n g t he C R rate at E O T.  
T he C R rate  a n d its e x act t w o-si de d 9 5 % c o nfi de nce i nter val usi n g t h e Cl o p per-Pears o n 
met h o d (C ollett 1 9 9 1 ) will be calc ulate d . 
O bjecti ve R es p o nse R ate  
O R R is defi ne d as t he pr o p orti o n of s u bjects wit h C R or partial res p o nse ( P R) at E O T 
acc or di n g t o t he  L y m p h o ma Res p o nse t o I m m u n o m o d ulat or y T h era p y Criteria ( L Y RI C) 
(C hes o n 2 0 1 6 ) i n s u bjects. 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 7  of 2 7  
T he C R rate  at E O T a n d its e x act t w o-si de d 9 5 % c o nfi d e nce i nter val usi n g t he Cl o p per-
Pears o n met h o d (C ollett 1 9 9 1 ) will be calc ulat e d . 
D ur ati o n of Res p o nse  
D urati o n of res p o ns e ( D O R) is defi ne d as t he ti me fr o m t h e first d oc u m e ntati o n of o bj ecti ve 
t u m or res p o nse ( C R or P R) t o t he first d o c ume ntati o n of t u m or pr o gressi o n ( per t h e  L y m p h o ma 
Res p o nse t o I m m u n o m o d ulat or y T h era p y Crit eria ( L Y RI C) 
(C h es o n 2 0 1 6 ) or deat h, 
w hic he ver c o m es first. S u bjects wit h o ut pr o gressi o n or d eat h will be ce ns ore d usi n g t h e sa m e 
ce ns ori n g r ule as P F S. D urati o n of res p o ns e will o nl y b e calc ulate d f or t he s u b gr o u p of s u bjects 
ac hie vi n g a C R or P R.  
D urati o n of c o m plete res p o nse ( D O C R) is defi ne d as t he ti me fr o m start of t he first 
d oc u me ntati o n of c o m plete t u m or res p o nse ( C R) t o t he first d oc u me ntati o n of t u m or 
pr o gressi o n ( per t he  L y m p h o ma Res p o nse t o I m m u n o m o d ulat or y T hera p y Criteria ( L Y RI C) 
(C hes o n 2 0 1 6 ) or deat h, w hic he ver c o mes first. D O C R will o nl y be calc ulate d f or t he s u b gr o u p 
of s u bjects ac hie vi n g C R. Ce ns ori n g will be i n a ma n ner si milar t o D O R.  
D urati o n of res p o nse will be a nal yz e d usi n g Ka pla n -Meier met h o d ol o g y a n d Ka pla n -Mei er 
pl ots will be pr o vi de d.  T he me dia n d urati o n of res p o nse a n d its t w o -si de d 9 5 % CI usi n g t h e 
c o m ple me ntar y l o g-l o g tr a nsf or mati o n met h o d (C ollett 1 9 9 4 ) will be calc ulate d.  
Pr o g ressi o n -free S ur vi v al 
P F S is defi ne d as t he ti me fr o m start of st u d y tr eat me nt t o first d oc u me ntati o n of o bjecti ve 
t u m or pr o gressi o n or d eat h. S u bjects wit h o ut pr o gressi o n or d eat h will be ce ns ore d o n t he d ate 
of t he last ra di ol o gical ass es s me nt of meas ure d lesi o ns. S u bjects lac ki n g a n e val uati o n of t u m or 
res p o nse after t heir first d ose will be ce ns ore d o n t heir first d ose date. 
P F S will be a nal yze d usi n g t he Ka pla n -M eier m et h o d a n d Ka pla n -Meier pl ots will be pr o vi de d. 
P F S rates a n d t he ass oci ate d 9 5 % CI will be calc ulate d base d o n t he c o m ple me ntar y l o g -l o g 
tra nsf or mati o n (C ollett 1 9 9 4 ). 
E ve nt -Free S ur vi v al  
E ve nt -free s ur vi val ( E F S) is defi ne d as t he ti me fr o m t he start of st u d y treat me nt t o t he first 
d oc u me ntati o n of o bje cti v e t u m or pr o gressi o n, deat h d ue t o a n y ca us e, or recei pt of s u bse q ue nt 
a ntica ncer t hera p y t o treat resi d ual or pr o gressi v e disease, w hi c he ver occ urs first.  S u bjects 
wit h o ut pr o gressi o n, deat h, or recei pt of s u bse q ue nt a ntica ncer t hera p y t o treat resi d ual or  
pr o gressi ve disease will be ce ns ore d  o n t he date of t he last ra di ol o gical assess me nt of meas ure d 
lesi o ns. S u bjects lac ki n g a n e v al uati o n of t u m or res p o nse aft er t h eir first d ose will be ce ns ore d 
o n t heir first d ose date.  
E F S will be a nal yze d usi n g t he Ka p l a n-Meier met h o d a n d Ka pla n -M eier pl ots will be 
pr o vi de d. E F S rates a n d t he ass ociate d 9 5 % CI will be calc ulate d b ase d o n t he c o m ple me ntar y 
l o g-l o g tra nsf or mati o n (C ollett 1 9 9 4 ). 
O ver all S ur vi v al  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 8  of 2 7  
O verall s ur vi val is defi ne d as t he ti me fr o m start of st u d y tr eat me nt t o date of deat h d ue t o a n y 
ca use. I n t he a bse nce of c o nfir mati o n of d eat h, s ur vi val ti me will be ce ns ore d at t he last date 
t he s u bject is k n o w n t o be ali ve. 
O S will be a nal yze d usi n g t he Ka pla n -M eier m et h o d a n d Ka pla n -Meier pl ots will be pr o vi de d. 
O S rates a n d t he ass ociate d 9 5 % CI will be calc ulate d base d o n t he c o m ple me ntar y l o g -l o g 
tra nsf or mati o n (C ollett 1 9 9 4 ). 
7. 6  S af et y A n al y s e s  
T he F A S  will be use d t o s u m marize all safet y e n d p oi nts.  A d verse e ve nts will be c o de d usi n g 
Me dical Dicti o nar y f or R e g ul at or y A cti vities ( Me d D R A , versi o n 2 4. 0 or hi g her ). La b orat or y 
val ues will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E versi o n 4. 0 3 ). C o nc o mita nt me dicati o ns will be c o d e d 
usi n g W H O Dr u g.  
7. 6. 1  A d v er s e  E v e nt s  
A d verse e v e nts will be s u m marize d b y Me d D R A preferre d ter m i n desce n di n g fre q u e nc y of 
occ urre nce u nless ot her wise s pecifie d.  F or i nci de nce re p orti n g, if a patie nt re p orts m or e t ha n 
o ne A E t hat was c o de d t o t he sa me s yst e m or ga n class or preferre d ter m, t he patie nt will be 
c o u nte d o nl y o n ce f or t hat s pecific s yste m or ga n class or preferre d ter m.  
A treat me nt -e m er ge nt A E is defi ne d as a ne wl y o cc urri n g or w orse ni n g A E after t he first d ose 
of st u d y dr u g.  See A p p e n di x B  f or details re gar di n g tr eat me nt-e mer ge nt classificati o n . F or 
Part A, A Es will be assess e d d uri n g t he st u d y fr o m Da y 1 d osi n g a n d t hr o u g h 3 0 da ys f oll o wi n g 
last d ose of st u d y dr u g. F or Parts B a n d C, A Es will be assesse d d uri n g t he st u d y fr o m Da y 1 
d osi n g a n d t hr o u g h 3 0 d a ys f oll o wi n g t he  last d ose of bre nt u xi ma b ve d oti n, d o x or u bici n, or 
dacar bazi ne , or 1 0 0 da ys f oll o wi n g t he last d ose of ni v ol u ma b, w hic he v er is later. Certai n 
n o n -seri o us A Es of i nterest ma y be f oll o we d u ntil res ol uti o n, ret ur n t o baseli ne, or st u d y 
cl os ure.  
A n o verall s u m mar y of A Es will be pr o vi d e d f or eac h Part.  S u m maries of A Es will als o b e 
pr o vi de d f or t he f oll o wi n g: 
● 
All treat me nt -e mer ge nt A Es  
● 
T E A Es relate d t o bre nt u xi ma b  ve d oti n  
● 
T E A Es relate d t o A N + A D  
● 
Seri o us A d verse E v e nts ( S A Es)  
● 
S A Es relate d t o bre nt u xi ma b  ve d oti n  
● 
T E A Es lea di n g t o d ose m o dificati o n  ( disc o nti n uati o n, dela y, re d ucti o n, eli mi nati o n) of 
a n y c o m p o ne nt of  A + A V D  ( Part A) 
● 
T E A Es lea di n g t o d ose m o dificati o n  ( disc o nti n uati o n, dela y, re d ucti o n, eli mi nati o n) of 
a n y c o m p o ne nt of  A N + A D  ( Part B & C) 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 1 9  of 2 7  
● 
A Es lea di n g t o  deat h  
● 
Treat me nt -e mer ge nt A Es b y s yste m or ga n class a n d preferre d t er m  
● 
Treat me nt -e mer ge nt A Es b y S O C , P T  a n d ma xi m u m se verit y  
● 
Gra de 3  or hi g h er T E A Es  
● 
Treat me nt -e mer ge nt I m m u ne -Me diate d A d verse E ve nts  ( Part B & C o nl y ) 
● 
S u m mar y of T E A Es of p eri p heral ne ur o pa t h y (sta n dar dize d Me d D R A q uer y [ S M Q])  
● 
S u m mar y of o ns et of treat me nt e mer ge nt peri p heral ne ur o pat h y ( S M Q)  
● 
S u m mar y of i m pr o ve m e nt a n d res ol uti o n of treat me nt -e mer ge nt peri p heral ne ur o pat h y 
( S M Q)  
All a d verse e ve nts, seri o us a d verse e ve nts, a d verse e ve nts l ea di n g t o treat me nt disc o nti n uati o n, 
a n d a d vers e e v e nts lea di n g t o de at h will be liste d.  
7. 6. 2  A d v er s e E v e nt s of Cli ni c al I nt er e st  
Peri p her al Ne ur o p at h y  
Peri p heral Ne ur o pat h y ( P N) is defi ne d b y t he peri p heral ne ur o pat h y S M Q br oa d searc h.  T he 
i nci de nce of P N at bas eli ne will be s u m marize d.  T he i nci de nce of tr eat m e nt -e mer ge nt a n d 
treat me nt-relate d P N will eac h be s u m marize d b y preferre d ter m a n d s e verit y.  T he i nci de nce 
of P N lea di n g t o treat me nt disc o nti n uati o n or re q uiri n g d ose m o dificati o n will be s u m marize d.  
Ti me t o o nset, res ol uti o n, a n d i m pr o ve me nt of P N e ve nts will be s u m marize d.  
S u bjects wit h a n y e ve nt of treat me nt -e m er ge nt P N will be cate g orize d i nt o gr o u ps acc or di n g 
t o t he f oll o wi n g criteria: 
● 
Res ol uti o n of all e ve nts  
● 
At least 1 e ve nt r es ol ve d, b ut ot her  peri p heral ne ur o pat h y e ve nts di d n ot i m pr o ve  
● 
I m pr o v e me nt of at least o ne e ve nt  
○ 
All e ve nts eit her i m pr o ve d or res ol ve d 
○ 
S o me e ve nts i m pr o ve d, s o me e ve nts res ol ve d a n d s o me e ve nts neit her i m pr o ve d 
n or res ol ve d  
○ 
S o me e ve nts i m pr o ve d b ut n o e ve nts res ol ve d  
● 
N o i m pr o ve me nt or res ol uti o n of a n y e ve nts 
 
T he n u m ber of s u bjects will be s u m marize d f or t he cate g ories defi n e d as a b o ve.  
A d diti o nall y, s u bjects wit h a n y e ve nt of tr eat me nt -e mer ge nt P N will b e cat e g orize d i nt o 
4  gr o u ps acc or di n g t o t he w orst o utc o me of all e v e nts as f oll o ws:  
● 
Res ol ve d (  all e ve nts r es ol ve d)  
● 
I m pr o v e d (at least o ne e v e nt i m pr o ve d, all ot her e ve nts i m pr o ve d or res ol v e d) 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 0  of 2 7  
● 
Sa me (at least o ne e ve nt t he sa me, all ot her e ve nts t he sa me, i m pr o ve d or res ol ve d)  
● 
W orse ne d (at least o n e e ve nt w orse ne d)  
 
T he n u m ber of s u bjects will be s u m marize d f or eac h of t he 4 cate g ories.  F or e v e nts t hat are 
n ot res ol ve d n or i m pr o ve d, ‘t he sa me’ is d efi ne d as t he last rec or de d p ost-baseli ne gra d e f or 
t he e ve nt is t he sa me as t he gra d e at t he ti me t he e ve nt beca m e treat me nt -e mer ge nt ; w orse ni n g 
is defi ne d as i ncrease b y at le ast o ne gra d e fr o m t he gra de at t he ti me t he e ve nt beca me 
treat me nt-e mer ge nt t o t h e gra de at t he ti me of latest assess me nt. 
I n a d diti o n, treat me nt-e mer ge nt P N e ve nts will be s u m marize d i n a s hift ta ble c om pari n g t he 
baseli ne gra des t o t h e w orst p ost-baseli ne gra des f or pre -e xisti n g P N e ve nts, a n d c o m pari n g 
t he gra d es of t h e first o ns et P N e ve nts t o t h e w orst-p ost -baseli ne gra des f or n e wl y o nset e v e nts 
after first d ose of treat me nt dr u g.  Treat me nt -e m er ge nt  P N e v e nts will als o be s u m marize d i n 
a s hift ta ble c o m pari n g t h e w orst gra d es t o t he last gra des pri or t o a n d at E O T ( or t he last gra d es 
o n st u d y, or s u bse q u e nt l o west gra de o n st u d y).  If t he o utc o me of e ve nt is Rec o vere d/ Res ol ve d  
or Rec o vere d/ Res ol ve d w it h S e q uelae, t he n t h e gra de of s uc h e ve nt is d efi ne d as 0.  If t he 
s u bject has m ulti ple e ve nts wit h t he sa me preferre d ter m o n g oi n g at t he ti me p oi nt of i nterest, 
t he n t he gra de is t he w orst gra d e of t hes e e ve nts. 
M ot or ne ur o pat h y will b e defi ne d as peri p h eral n e ur o pat h y e v e nts meeti n g a n y of t he criteria 
bel o w:  
● 
C o de d t o a 
Me d D R A  preferre d ter m  of eit her ‘ peri p heral m ot or ne ur o pat h y’ or 
‘ peri p heral se ns ori m ot or ne ur o pat h y’, ‘per o neal n er ve pals y ’ 
● 
Ver bati m A E ter m c o ntai ns “ m ot or”, “ wea k ness ”, or “ pals y”  
T h e i nci de n ce of tr eat me nt -e mer ge nt m ot or ne ur o pat h y will be s u m marize d b y preferre d ter m 
a n d se verit y.  Ti me t o res ol uti o n a n d i m pr o ve me nt of m ot or ne ur o pat h y e v e nts will be 
s u m marize d. 
7. 6. 3  Cli ni c al L a b or at or y P ar a m et er s  
All la b orat or y res ults will be prese nte d  i n sta n d ar di ze d u nits. B ot h o bser ve d val ue a n d c ha n ges 
fr o m bas eli ne will be s u m marize d wit h descri pti ve statistics f or eac h s c h e d ule d visit. S hift 
fr o m baseli ne t o ma xi m u m p ost-baseli ne N CI C T C A E gra d e will be s u m marize d f or eac h la b 
test. Treat me nt-e mer ge nt la b orat or y a b n or malities will als o be s u m marize d. Treat me nt -
e mer ge nt la b orat or y a b n or malities i ncl u de t he a b n or malities, re p orte d d uri n g st u d y, t hat were 
ne w or w orse ni n g i n gra de or a n y a b n or malit y w he n baseli ne gra d e was u n k n o w n . If baseli ne 
gra de a n d p ost -b aseli ne gra de were i n differe nt directi o ns f or a bi -directi o nal la b test (e. g., 
fr o m baseli ne hi g h t o p ost-baseli ne l o w), it is als o c o nsi dere d treat me nt -e m er ge nt  a b n or m alit y. 
La b orat or y res ults a n d N CI C T C A E gra des f or he mat ol o g y a n d ser u m c he mistr y will be 
prese nte d i n data listi n gs. N or mal ra n ges will be d oc u me nte d, a n d o ut -of -ra n ge val ues will be 
fla g ge d. A se parate listi n g of la b orat or y res ults wit h C T C A E gra de 3 or hi g her will be 
prese nte d.  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 1  of 2 7  
7. 6. 4  E C O G P erf or m a n c e St at u s  
S hifts fr o m baseli ne t o t he best a n d w orst p ost -b aseli ne sc ore will be ta b ulate d f or eac h Part. 
7. 6. 5  Vit al Si g n s  
Vital si g n 
me as ure me nts (s yst olic a n d diast olic bl o o d press ur e, heart rate, a n d b o d y 
te m perat ur e) will be liste d b y patie nt f or eac h ti m e p oi nt a n d pres e nte d gra p hicall y f or eac h 
vital si g n b y s c he d ule d visit. 
7. 6. 6  C o n c o mit a nt M e di c ati o n s  
C o nc o mita nt me dicati o ns will be s u m marize d b y t h e W H O Dr u g A T C class a n d preferre d 
na me. T he n u m ber a n d perce nta ge of s u bjects ta ki n g c o n c o mita nt me dicati o ns will be 
ta b ulate d. C o nc o mita nt me dicati o ns will be liste d b y s u bject. 
8  
I N T E RI M A N A L Y SE S  
A n S M C will be res p o nsi ble f or m o nit ori n g p atie nt safet y i n Parts B a n d C of t he st u d y . 
O ne i nteri m f utilit y a nal ysis will be perf or me d f or Part C after a p pr o xi matel y 5 0  s u bjects have 
c o m plete d res p o ns e assess me nt at E O T. At t his i nteri m f utilit y a n al ysis, if t he C R rate at E O T 
is ≤8 0 %, t he s p o ns or i n c o ns ultati o n wit h t he S M C ma y deci de t o st o p f urt her e nr oll me nt of 
Part C of t he trial.  
I nteri m data fr o m t h e st u d y m a y be pres e nte d at sci e ntific meeti n gs s uc h as t he a n n u al meeti n gs 
of t he A merica n S ociet y of Cli nical O nc ol o g y a n d t he A merica n S oci et y of He mat ol o g y.  
9  
C H A N G E S F R O M P L A N N E D  A N A L Y S E S  
9. 1  C h a n g e s fr o m t h e Ori gi n al Pr ot o c ol  
Ke y c ha n ges are s u m mariz e d bel o w. F or m ore d et ails, plea se refer t o pr ot oc ol A p pe ndi x J.  
C h a n ges i n A me n d me nt 1  
•  C ha n ge d S eri o us A d vers e E ve nt re p orti n g i nf or mati o n  
•  Re vise d l o n g -ter m f oll o w-u p ( L T F U) i nf or mati o n t o i n dicate t hat partici p a nts will 
re mai n i n L T F U f or u p t o 2 years fr o m t he E n d of Treat me nt visit 
•  R e place d t he I nter nati o n al Pr o g n ostic I n d e x (I PI) sc ore s heet wit h I nter nati o nal 
Pr o g n ostic Sc ore (I P S) i nf or mati o n.  
C h a n ges i n A me n d me nt 2  
•  A d de d Part B: Treat me nt of c H L s u bjects wit h bre nt u xi ma b ve d oti n, ni v ol u ma b, 
d o x or u bici n, a n d dacar bazi ne ( A N + A D)  
•  Re visi o n of t he st u d y p o p ulati o n t o a t otal of 9 0 s u bjects  
•  Re vise d i ncl usi o n /e x cl usi o n criteria  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 2  of 2 7  
•  Re vise d t he E O T visit pr oce d ures  
C h a n ges i n A me n d me nt 3  
•  A d de d Part C: Treat me nt of earl y sta ge c H L s u bjects wit h bre nt u xi ma b ve d oti n, 
ni v ol u ma b, d o x or u bici n, a n d dacar bazi ne ( A N + A D)  
•  M o difie d i ncl usi o n criteri o n  
C h a n ges i n A me n d me nt 4  
•  Part B: A d de d s u bjects wit h A n n Ar b or Sta ge I c H L wit h b ul k y me diasti nal disease  
•  Part C: C ha n ge d “ n o n -b ul k y” t o “ wit h o ut b ul k y” f or s u bjects wit h A n n Ar b or Sta ge I 
or II c H L e nr olle d  i n Part C 
•  A dj uste d e x cl usi o n/i ncl usi o n criteria.  
C h a n ges i n A me n d me nt 5  
•  A d de d i nteri m a nal ysis f or Part C . 
•  S u bjects wit h Sta ge I or II c H L wit h o ut b ul k y dise ase will be assi g ne d t o Part C.  
•  A d de d a h y p ot hesis test f or Part C C R rate.  
C h a n ges i n A me n d me nt 6  
9. 2  A d mi ni str ati v e c h a n g e s  a n d cl arifi c ati o n s .C h a n g e s fr o m t h e Ori gi n al S A P  
C h a n ges i n Versi o n 2  
•  A d de d a nal ys es f or Part B a n d Part C . 
•  A d de d c ha n ge l o gs f or pr ot oc ol a me n d me nt a n d S A P.  
•  C ha n ge d d urati o n of tr eat me nt t o last d ose date + 1 4 da ys.  
•  U p date d T E A E al g orit h m  i n A p pe n di x B. 
C h a n ges i n Versi o n 2. 1  
•  A d de d t he defi niti o n of efficac y e val u a ble a nal ysis set .  
•  U p date d  t he calc ulati o n of C R rate at E O T. S u bjects w h o d o n ot ha ve a n E O T 
assess me nt will be sc ore d as n o n -res p o n d ers f or calc ulati n g t he C R rate at E O T.  
•  A d de d pr ot oc ol A me n d m e nt 6  t o c ha n ge l o gs. 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 3  of 2 7  
1 0  R E F E R E N C E S  
 
Barri n gt o n S F, Qia n W, S o mer EJ, et al. C o nc or da nce b et wee n f o ur E ur o p ea n ce ntres of P E T 
re p orti n g criteria desi g ne d f or use i n m ultice ntre trials i n H o d g ki n l y m p h o ma. E ur J 
N ucl Me d M ol I ma gi n g.  2 0 1 0; 3 7( 1 0): 1 8 2 4 -3 3.  
Bi g gi A, Galla mi ni A, C ha u vie S, et al. I nter n ati o nal Vali dati o n St u d y f or I nteri m P E T i n 
A B V D -Treate d, A d v a nce d -Sta ge H o d g ki n L y m p h o ma: I nter pret ati o n Criteria a n d 
C o nc or da nce Rate A m o n g Re vie wers. J N ucl Me d. 2 0 1 3; 5 4( 5): 6 8 3 -9 0.  
C hes o n B D, A nsell S, Sc h wartz L, et al. Refi ne me nt of t he L u ga n o Classificati o n l y m p h o ma 
res p o nse criteria i n t he era of i m m u n o m o d ulat or y t hera p y. Bl o o d. 
2 0 1 6; 1 2 8( 2 1): 2 4 8 9 -9 6.  
 
C hes o n B D, Fis her RI, Barri n gt o n S F, et al. Re c o m me n dati o ns f or i nitial e val uat i o n, sta gi n g, 
a n d res p o nse assess me nt of H o d g ki n a n d n o n -H o d g ki n l y m p h o m a: t he L u ga n o 
classificati o n. J Cli n O nc ol. 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 8.  
 
C ollett, D. M o delli n g Bi nar y Data, L o n d o n: C ha p ma n a n d Hall. 1 9 9 1.  
 
C ollett D. I nter v al -ce ns ore d s ur vi val data. M o d elli n g s ur vi val dat a i n me dical res earc h. 
L o n d o n, C ha p ma n & H all. 1 9 9 4: 2 3 7 -5 1.  
 
C o n n ors J M, J urcza k W, Stra us DJ, et al. Bre nt u xi ma b ve d oti n wit h c he m ot hera p y f or sta ge 
III or I V H o d g ki n's l y m p h o ma. N E n gl J Me d. 2 0 1 8; 3 7 8( 4): 3 3 1-4 4.  
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 4  of 2 7  
1 1  A P P E N DI C E S  
A P P E N DI X A: Im p ut ati o n  of  P arti all y U n k n o w n  A d v er s e  E v e nt  D at e s  
F or a n a d vers e e v e nt  ( A E) wit h a partial start or e n d date, if it ca n be d eter mi ne d t hat t he 
e ve nt occ urre d pri or t o t he date of first d ose of st u d y treat me nt, t he partial date will n ot be 
i m p ute d; Ot her wise, t he partial date will be i m p ute d usi n g t he r ules descri be d bel o w. A E 
start dates s h o ul d be i m p ute d bef ore i m p utati o n of A E c o n diti o n e n d date i n all cases.  
I nc o m plete A E St art D ate: 
A E d a y o nl y is missi n g  
If t he m o nt h/ year is t he s a me as t he m o nt h/ year of first d ose of a n y st u d y tr eat me nt : 
A E start date will be i m p ute d as t he first d ose dat e of a n y st u d y treat me nt  
If t he m o nt h/ year is after t he m o nt h/ year of first d ose of a n y st u d y treat me nt : 
A E start date will be i m p ute d as t he first da y of t h e m o nt h  
A E d a y a n d m o nt h are missi n g,  or m o nt h o nl y is missi n g  
If t he year is t he sa me as t he year of first d ose of a n y st u d y treat me nt:  
A E start date will be i m p ute d as t he first d ose dat e of a n y st u d y t reat me nt 
If t he year is after t he year of first d ose of a n y st u d y treat me nt : 
A E start date will be i m p ute d as J a n uar y 1st  
A E d a y, m o nt h a n d ye ar  are  missi n g , or ye a r o nl y is missi n g 
A E start date will be i m p ute d as t he first d ose dat e of a n y st u d y treat me n t 
 
If A E c o n diti o n e n d dat e * is n ot missi n g, a n d t he i m p ute d start date is after t he e n d date, t he 
start date will be set t o t he A E c o n diti o n e n d date.  
* o nl y use c o n diti o n e n d date if k n o w n a n d f ull e n d date is a vaila ble.  
I nc o m plete A E E n d D ate: 
If A E o utc o me is “ n ot r ec o vere d/res ol ve d”, “ u n k n o w n”, or bla n k:  A E c o n diti o n e n d date will 
n ot be i m p ute d.  
If A E o utc o me is “rec o v eri n g/r es ol vi n g”, “rec o vere d/res ol ve d”, “rec o vere d/res ol ve d wit h 
se q uelae”, or “fatal” a p pl y t he f oll o wi n g:  
A E d a y o nl y is missi n g  
A E c o n diti o n e n d date will be i m p ute d as t he mi ni m u m of ( deat h date, d ata e xtracti o n 
date, last da y of t he e n d date m o nt h/ year , E O S date) 
A E d a y a n d m o nt h are missi n g,  or m o nt h o nl y is missi n g  
If t he year is e q ual t o t he year of t h e last d ose date: 
A E c o n diti o n e n d date will be i m p ute d as t he mi ni m u m of (last d ose date + 3 0, deat h 
date, data e xtracti o n date, Dece m b er 3 1st of t he e n d date year , E O S date) 
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 5  of 2 7  
 
If t he year is n ot e q ual t o t he year of t he last d ose date: 
A E c o n diti o n e n d date will be i m p ute d a s t he mi ni m u m of ( deat h date, d ata e xtracti o n 
date, Dece m ber 3 1st of t he e n d date year , E O S date) 
A E d a y, m o nt h a n d ye ar  are  missi n g , or ye a r o nl y is missi n g 
A E c o n diti o n e n d date will n ot be i m p ute d  
Wit hi n a  si n gle rec or d, if t he i m p ute d st o p date is bef ore t h e start date, t h e n t he i m p ute d st o p 
date will be e q ual t o t he start date.  


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 6  of 2 7  
A P P E N DI X B: D E FI NI TI O N  O F T H E T E R M “ T R E A T M E N T -E M E R G E N T ” WI T H 
R E S P E C T T O A E  C L A S SI FI C A TI O N  
T he al g orit h m bel o w s h o ul d be use d t o deter mi ne w het her a n a d verse e v e nt ( A E) is classifie d 
as a treat me nt -e mer ge nt a d verse e ve nt ( T E A E).  A T E A E is defi ne d as a n y A E w hic h is 
ne wl y o cc urri n g or w ors e ni n g i n se v erit y, w here ne wl y o cc urri n g mea ns t hat t he A E was n ot 
prese nt at bas eli ne.  F or ease of rea di n g, b ot h pre -e xisti n g c o n diti o ns a n d A Es will be 
referre d t o as A Es f or t h e re mai n der of t his d oc u me nt.  A E dates s h o ul d be i m p ute d i n 
acc or da nce wit h t he al g orit h m detaile d i n A p pe n di x A  p ri or t o deter mi nati o n of T E A E 
classificati o n.   Details of t he T E A E classificati o n are as f oll o ws:  
1. F or eac h patie nt, d eter mi ne t he first d ose date, w hic h is t he earliest dat e t he patie nt 
recei v es a n y a m o u nt of st u d y dr u g. 
2.  Baseli ne A Es:  classif y a n A E rec or d as b aseli ne  A E if it satisfies b ot h  criteria a a n d b 
bel o w:  
a A E o nset satisfies eit her of i, ii or iii bel o w:  
i. 
O nset date is pri or t o t he first d ose date  
ii. 
O nset date is t he sa me as t he first d ose date, a n d O nset Peri o d is “starte d after 
c o nse nt b ut bef ore t he first d ose of a n y st u d y treat me nt”  or O nset Ti me R el ati ve 
t o St u d y Treat me nt is “s t arte d bef ore first i nf usi o n or bef ore i nf usi o n o n a n y 
d osi n g da y ”  
iii. 
O nset Peri o d is “starte d b ef ore t h e si g ni n g of c o ns e nt” or “starte d after c o nse nt 
b ut bef ore t he first d ose of a n y stu d y treat me nt”  
b  A E  e n d date s atisfies eit her of i or ii bel o w:  
i. 
E n d date is t he sa me as or after t h e first d ose dat e  
ii. 
E n d date is missi n g wit h o utc o me e q ual t o  
● 
rec o veri n g/res ol vi n g, or 
● 
n ot rec o vere d/ n ot res ol ve d, or  
● 
u n k n o w n or missi n g  
3.  P ost -baseli ne A Es:  classif y a n A E rec or d as p ost -baseli ne A E if it meets eit her of criteria 
a, b or c bel o w:  
a O nset date is after t he first d ose date  
b  O nset date is t he sa me as t he first d ose date, a n d O nset Peri o d is “starte d after t he first 
d ose of a n y st u d y treat me nt” or O nset Ti me R el ati ve t o St u d y Treat me nt is n ot 
“starte d bef ore first i nf usi o n or bef ore i nf usi o n o n a n y d osi n g d a y” 
c O nset Peri o d is “starte d after t he first d ose of a n y st u d y treat me nt”  
 
N ote: at i nteri m ti me p oi nt, if a n A E is cl assifie d as b ot h ‘ b aseli ne A E’ a n d ‘ p ost -
b aseli ne A E’ d ue t o d at a iss ues, t he A E is t o be c o nsi dere d ‘ p ost -b aseli ne A E’ i n t he 
deri v ati o n of T E A E fl a g.  
 


St u d y S G N 3 5 -0 2 7  
Statistical A nal ysis Pla n  
Versi o n 2 . 1 
Bre nt u xi ma b ve d oti n  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2 7  of 2 7  
4.  T E A E fla g will  be deri ve d as f oll o ws:  
a. F or all A E rec or ds  t hat ha ve a n e n d date pri or t o t he first d ose date, assi g n T E A E fla g 
t o ‘N’  
b.  F or all bas eli ne A Es, assi g n T E A E fla g t o ‘ N’  
c. F or p ost -bas eli ne A Es : 
•  If t he p ost-bas eli ne A E is a c o nti n ui n g e ve nt of a b aseli ne A E (i.e., e ve nts wit h 
t he sa me A E i de ntifier, w here A E i de ntifier is t h e n u m ber bef ore t he c ol o n i n 
S D T M A E. A E S PI D), t he n c o m pare t he C T C A E gra de of t h e p ost -baseli ne A E t o 
t he C T C A E gra de of t h e m ost rece nt baseli ne A E wit h t he sa me A E i de ntifier: 
o  If t he p ost-bas eli ne A E h as a hi g h er C T C A E gra d e, t he n assi g n T E A E fl a g 
t o ‘ Y’.  All s u bse q ue nt e pis o des of t he sa me A E s h o ul d ha ve T E A E fl a g = 
‘ Y’ re gar dless of t he C T C A E gra de. 
o  Ot her wise, assi g n T E A E fla g t o ‘ N’  
•  If t he p ost-bas eli ne A E is n ot a c o nti n ui n g e v e nt of a baseli ne A E, t he n assi g n 
T E A E fla g t o ’ Y’  
N O T E:  
1.  F or s u m m aries w hic h i ncl u de o nl y tre at me nt e mer ge nt A Es i ncl u de all A Es w hic h 
are cl assifie d as T E A Es as w ell as t h ose A Es f or w hic h T E A E st at us c o ul d n ot be 
deter mi ne d (e. g., t he v al ue of t he T E A E v ari a ble m a y be missi n g if t he e ve nt c a n n ot 
be i de ntifie d a s b aseli ne or p ost-b aseli ne - missi n g i nf or m ati o n o n t he A E C R F 
s h o ul d be q uerie d).  O nl y e xcl u de t h ose A Es w hic h were deter mi ne d t o n ot be 
tre at me nt e mer g e nt. 
2.  E ve nts t h at h a ve a n e n d d ate pri or t o t he first d ose d ate (e. g. pr ot oc ol pr oce d ure 
rel ate d e v e nt s) s h o ul d be cl assifie d as n ot tre at me nt e mer ge nt ( n ot T E A Es).